Clinical Neurology

Graeme J. Hankey
MBBS, MD, FRCP (Lond), FRCP (Edin), FRACP
Consultant Neurologist and Head of Stroke Unit
Department of Neurology, Royal Perth Hospital
and Clinical Professor
Department of Medicine, University of Western Australia
Perth, Australia

Joanna M. Wardlaw
MBChB, MD, FRCP, FRCR
Professor and Honorary Consultant Neuroradiologist
Department of Clinical Neurosciences, University of Edinburgh
Western General Hospital
Edinburgh, UK

MANSON
PUBLISHING
Copyright © 2002 Manson Publishing Ltd

ISBN 1–84076–010–9

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 Contents
Foreword 6 5 Vertigo 107
Vertigo 107
Preface 7 Benign Paroxysmal Positional Vertigo 110
Vestibular Neuronitis 111
Abbreviations 8 Ménière’s Disease 111
Further Reading 112
1 Neurologic Diagnosis 11
The Neurologic History 11 6 Movement Disorders 113
Neurologic Examination 13 Dystonia 113
Imaging the Brain 23 Essential Tremor 119
Imaging the Cerebral Circulation 26 Chorea 122
Imaging the Spine 29 Myoclonus 124
Lumbar Puncture (LP) and Cerebrospinal Fluid Dyskinesias 129
(CSF) Examination 31 Tourette Syndrome 130
Electroencephalography (EEG) 33 Neuroleptic Malignant Syndrome 133
Nerve Conduction Studies 35 Further Reading 135
Electromyography (EMG) 38
Evoked Potentials 40 7 Developmental Diseases of the
Further Reading 43 Nervous System 136
Arnold–Chiari Malformation 136
2 Disorders of Consciousness 44 Rachischisis (Dysraphism) 139
Coma 44 Tuberous Sclerosis 143
Brain Death 51 Neurofibromatosis 147
Permanent Vegetative State (PVS) 52 Sturge–Weber Disease (Encephalotrigeminal
Locked-in Syndrome 55 Vascular Syndrome) 151
Narcolepsy 56 Hereditary Hemorrhagic Telangiectasia (HHT)
Syncope 59 (Osler–Rendu–Weber Syndrome) 153
Further Reading 64 Further Reading 156

3 Epilepsy 65 8 Inherited Metabolic Diseases of the

Epilepsy 65 Nervous System of Adult Onset 157
Status Epilepticus (SE) 82 Wilson’s Disease (WD) (Hepatolenticular
Juvenile Myoclonic Epilepsy (JME) (Janz Syndrome) 86 Degeneration) 157
Progressive Myoclonic Epilepsies (PME) 87 Hallervorden–Spatz Disease 162
Further Reading 90 Mitochondrial (Oxidative Phosphorylation) Diseases 162
Adrenoleukodystrophy (ALD) 166
4 Headache 91 Metachromatic Leukodystrophy (MLD) 169
Headache 91 Adult-onset Globoid Cell Leukodystrophy (Krabbe
Migraine 95 Disease) 171
Muscle Contraction/Tension-type Headache 101 Late-onset GM2 Gangliosidosis 172
Cluster Headache (Migrainous Neuralgia) 103 Niemann–Pick Disease Type C (NP-C) 174
Further Reading 106 Further Reading 176

9 Traumatic Diseases of the Nervous System 177

Subdural Hematoma 177
Further Reading 180
10 Vascular Diseases of the Nervous System 181 12 Inflammatory Disorders of the
Neurovascular Syndromes 181 Nervous System 337
Transient Ischemic Attacks (TIAs) of the Acute Disseminated Encephalomyelitis (Post
Brain and Eye 186 Infectious Encephalomyelitis) (ADEM) 337
Stroke 192 Multiple Sclerosis (MS) 340
Atherosclerotic Ischemic Stroke 202 Neurosarcoidosis 350
Cardioembolic Stroke 209 Cavernous Sinus Syndrome 354
Infective Endocarditis 215 Further Reading 356
Antiphospholipid Syndrome and other
Prothrombotic States (Thrombophilias) 218 13 Tumors of the Central Nervous System 357
Dissection of the Carotid and Vertebral Arteries 224 Brain Tumors 357
Central Nervous System Vasculitis 227 Gliomas 364
Giant Cell Arteritis (GCA) 234 Optic Nerve Glioma 372
Primary Intracerebral Hemorrhage (PICH) 238 Meningioma 374
Arteriovenous Malformation (AVM) 245 Craniopharyngioma 377
Subarachnoid Hemorrhage (SAH) 249 Pituitary Tumors 379
Cerebral Venous Thrombosis 257 Acoustic Neuroma 383
Vascular Dementia 261 Primary CNS Lymphoma 385
Hypertensive Encephalopathy 265 Germ Cell Tumors of the CNS 388
Pituitary Apoplexy 268 von Hippel–Lindau Disease (VHL) 392
Further Reading 269 Metastases to the CNS 396
Paraneoplastic Syndromes 401
11 Infections of the Nervous System 273 Further Reading 406
Bacterial Infections
Acute Pyogenic (Bacterial) Meningitis 273 14 Degenerative Diseases of the
Subacute and Chronic Meningitis and/or Nervous System 407
Encephalitis 279 Alzheimer’s Disease (AD) 407
Tuberculous Meningo-encephalitis 281 Frontotemporal Dementia Associated with
Intracranial Abscess (Brain Abscess and Subdural Mutation in Tau (Pick’s Disease, Lobar Atrophy) 414
Empyema) 284 Huntington’s Disease (HD) 417
Tetanus 287 Parkinson’s Disease (PD) 420
Whipple’s Disease 289 Diffuse Lewy Body Disease (DLBD) 430
Progressive Supranuclear Palsy (PSP) 432
Viral Infections Multiple Systems Atrophy 435
Acute Aseptic Meningitis 291 Autosomal Dominant Cerebellar Ataxias 437
Viral Encephalitis 292 Friedreich’s Ataxia 441
Herpes Simplex Virus Encephalitis (HSE) 295 Ataxia Telangiectasia (Louis–Bar Syndrome) 444
Varicella-Zoster Virus Encephalomyelitis 299 Further Reading 447
Human Immunodeficiency Virus (HIV)-Associated
Cognitive Motor Complex (HIV-CMC) 301 15 Acquired Metabolic Diseases of the
Subacute Sclerosing Panencephalitis (SSPE) 304 Nervous System 449
Progressive Multifocal Leukoencephalopathy (PML) 307 Hypoxic Encephalopathy 449
Poliomyelitis (Infantile Paralysis) 309 Hepatic Encephalopathy (HE) 452
Central Pontine Myelinolysis 457
Other Infections Further Reading 459
Neurosyphilis 312
Lyme Disease (Neuroborreliosis) 316 16 Nutritional Deficiency and the
Cryptococcal Meningitis 318 Nervous System 460
Mucormycosis of the Nervous System 321 Wernicke–Korsakoff Syndrome 460
Toxoplasmic Encephalitis 323 Vitamin B12 Deficiency 463
Cysticercosis 326 Further Reading 467
Creutzfeldt–Jakob Disease (CJD) 330
Further Reading 335 17 Disorders of the CSF Circulation 468
Hydrocephalus 468
Normal Pressure Hydrocephalus 473
Idiopathic Intracranial Hypertension (IIH)
(Benign Intracranial Hypertension,
Pseudotumor Cerebri) 477
Further Reading 480
18 Cranial Neuropathies 481 Vasculitic Neuropathy 597
Olfactory (Ist Cranial Nerve) Neuropathy 481 Herpes Zoster Infection 599
Optic (IInd Cranial Nerve) Neuropathy 483 Human Immunodeficiency Virus (HIV) Neuropathy 601
Anterior Ischemic Optic Neuropathy (AION) 487 Leprosy 604
Optic Neuritis 489 Paraproteinemic Polyneuropathies 606
Leber’s Hereditary Optic Neuropathy (LHON) 491 Diabetic Neuropathy 610
Papilledema 492 Further Reading 613
Horner’s Syndrome 494
Holmes–Adie Syndrome 497 22 Mononeuropathies 615
IIIrd, IVth, and VIth Cranial Nerve (Ocular Motor) Dorsal Scapular Nerve (to Rhomboids) Neuropathy 615
Neuropathies 499 Long Thoracic Neuropathy 616
Trigeminal (Vth Cranial Nerve) Neuropathy 505 Suprascapular Neuropathy 618
Trigeminal Neuralgia (Tic Douloureux, Paroxysmal Axillary Neuropathy 620
Facial Pain) 509 Musculocutaneous Neuropathy 621
Facial (VIIth Cranial Nerve) Neuropathy 511 Radial Neuropathy 623
Acute Idiopathic Facial Paralysis (Bell’s Palsy) 515 Median Neuropathy 627
Vestibular-cochlear (VIIIth Cranial Nerve) Carpal Tunnel Syndrome (CTS) 630
Neuropathy 517 Ulnar Neuropathy 632
IXth Cranial Nerve (Glossopharyngeal) Neuropathy 520 Lateral Cutaneous Nerve of the Thigh Neuropathy 637
Vagus (Xth Cranial Nerve) Neuropathy 523 Posterior Cutaneous Nerve of the Thigh Neuropathy 639
Spinal Accessory (XIth Cranial Nerve) Neuropathy 525 Femoral Neuropathy 640
Hypoglossal (XIIth Cranial Nerve) Neuropathy 526 Obturator Neuropathy 642
Further Reading 528 Gluteal Neuropathy 643
Sciatic Neuropathy 644
19 Spinal Cord Diseases 529 Tibial Neuropathy 647
Hereditary Spastic Paraparesis 529 Peroneal Neuropathy 650
Spinal Muscular Atrophy (SMA) 532 Sural Neuropathy 654
Motor Neuron Diseases (MND) 534 Pudendal Neuropathy 655
Syringomyelia 541 Further Reading 656
Cervical Spondylotic Myelopathy and
Radiculopathy 545 23 Neuromuscular Junction Disorders 657
Acute ‘Slipped Disc’ 550 Myasthenia Gravis (MG) 657
Spinal Epidural Hematoma 554 Lambert–Eaton Myasthenic Syndrome (LEMS) 664
Spinal Epidural Abscess 555 Further Reading 667
Spinal Arachnoiditis 557
Spinal Cord Infarction 558 24 Muscle Disorders 668
Acute Transverse Myelitis 561 X-lined Dystrophinopathies 668
Human Immunodeficiency Virus (HIV) Myelopathy 564 Facio-scapulo-humeral Muscular Dystrophy (FSHD) 672
Radiation-induced Encephalo-myelo-radiculopathy 565 Limb-girdle Muscular Dystrophies (LGMD) 674
Spinal Cord Tumors 567 Myotonic Dystrophy 678
Further Reading 572 Polymyositis 681
Dermatomyositis 684
20 Autonomic Nervous System Disorders 573 Inclusion Body Myositis (IBM) 687
Autonomic Neuropathy 573 Metabolic and Endocrine Myopathies 688
Further Reading 578 Hypokalemic Paralysis 693
Further Reading 695
21 Diseases of the Peripheral Nerve 579
Peripheral Neuropathy 579 Index 696
Hereditary Neuropathies 584
Hereditary Motor and Sensory Neuropathy
(Charcot–Marie–Tooth Disease) 585
Hereditary Neuropathy with Liability to
Pressure Palsies (HNPP) 587
Guillain–Barré Syndrome (GBS) (Acute
Inflammatory Demyelinating
Polyradiculoneuropathy [AIDP]) 588
Chronic Inflammatory Demyelinating
Polyneuropathy (CIDP) 593
Neuralgic Amyotrophy 595
6
Foreword
Education and learning in clinical neurology involve a
process of integration. The student or trainee in the clinical
neurosciences must learn detailed information concerning
the clinical presentation, pathology, radiology, electro-
diagnosis, and, finally, treatment of neurologic diseases.
There are many excellent texts where these components are
separately reviewed. Clinical Neurology is a work where each
area has been integrated into a practical approach to the
patient. There is a high level of integration that brings
together clinical presentation, appropriate diagnostic studies
and treatment. The text is concise and, where appropriate,
a bulleted topic format is used. This makes information easy
to retrieve. High-quality illustrations present anatomic
drawings, radiographs and pathologic specimens. This
approach logically leads the reader through different clinical
scenarios from presentation to diagnosis and treatment.
The reader will be introduced to the principles of
neurologic diagnosis at the beginning of the book. This
detailed but concise initiation will be particularly useful to
the senior student or trainee in neurology. This is followed
by an introduction to all of the major types of study used to
aid in the diagnosis of patients with neurologic disease. The
book is organized to be practically useful. Drs Hankey and
Wardlaw present material which is organized according to
the presenting complaint of the patient or according to a
logical pathophysiologic and anatomic classification scheme.
For each disorder there is a clear definition, discussion of
etiology, clinical features, and investigations.
The authors have extensive experience as clinical
educators. This leads to a clarity of presentation that is ideal
for the advanced student or trainee in neurology. Program
or course directors responsible for clinical education in
neurology will find this text extremely useful. It can be used
directly as the major source work for a course in advanced
clinical neuroscience.
This is an important addition to the textbooks that are
available in clinical neurology. The overall quality of
production ensures that this will be a durable educational
text in neurology.
Anthony J Windebank, MD
Dean, Mayo Medical School
Neuroscience Research – Guggenheim 1501
Mayo Clinic and Mayo Foundation
Rochester
Minnesota
USA

Preface
Neurology is an exciting and evolving clinical science. Since
we began our training in neurology (GJH) and neuro-
radiology (JMW) in the 1980s, the understanding and
practice of clinical neurology and neuroradiology have been
transformed. Traditionally, the essence of neurology was the
rigorous application of meticulous clinical skills to localize the
presence (or absence) and precise location of neurological
lesions. Clinical findings were correlated with pathological
findings at autopsy, but understanding of disease mechanisms
was poor and therapeutic options were limited. Indeed, most
neurological disorders like stroke, epilepsy, Alzheimer’s
disease, multiple sclerosis, and motor neuron disease were
considered untreatable. Neurology was thus regarded by
many outside the specialty as rather erudite and nihilistic.
However, in the past 15 years, advances in neuroimaging,
basic neuroscience, molecular genetics, and the consequent
development and evaluation of therapies have brought new
meaning and life to the clinical features elicited at the
bedside. Furthermore, new diseases with potentially
devastating consequences have emerged, and traditional rigid
boundaries between neurology and psychiatry have blurred
with increased recognition of the interaction between mind
and body. Thus, clinical neurology has emerged as one of the
most exciting frontiers in medicine. The array of new and
emerging diagnostic and therapeutic options include:
• Superb, safe, and noninvasive diagnostic imaging of the
vasculature and the structure, metabolism and function
of the brain and spinal cord by magnetic resonance. This
has added a new dimension to clinico-pathologic
correlation, optimized diagnosis, exposed new insights
into pathophysiology, and facilitated new treatments.
• Advances in catheter technology and interventional
neuroradiology. The better availability of these less invasive
techniques is changing the focus of neurosurgery,
neurology and neuroimaging.
• The introduction of DNA analysis as a diagnostic and
prognostic tool. The enormous advances in molecular
biology have revolutionized our understanding of the
pathogenesis of many inherited and degenerative
neurologic conditions and facilitated accurate diagnosis,
predictive testing, and genetic counselling.
• Effective treatments have been recognized in large,
randomized controlled clinical trials for many neurologic
disorders, such as acute migraine, stroke, limb spasticity
and other movement disorders, partial epilepsy, multiple
sclerosis, Parkinson’s disease, Alzheimer’s disease, Guillain-
–Barré syndrome and other immune-mediate peripheral
neuropathies, myopathies, and myasthenia gravis.
However, many treatments are still not very effective and
there is enormous opportunity for improvement.
7
The fact that many previously untreatable diseases are
now known to be not only treatable but preventable, has
raised new optimism for the probability that treatments will
emerge for other currently incurable neurologic disorders.
To take full advantage of the breadth of techniques, know-
ledge and skills now available requires increased collabor-
ation between neurologists, neuroradiologists and other
clinical neuro disciplines.
These developments have been one of the prompts to
writing this book. Where appropriate and possible, we have
incorporated them, but only if their clinical effectiveness is
supported by high quality evidence. For therapies, the level
of evidence required is a systematic review of all (published
and unpublished) randomized trials, as published and
regularly updated in the Cochrane Library and Clinical
Evidence. Where such evidence is not available, we have
indicated so, and offered empirical recommendations based
on the best available evidence and our own experience.
Another prompt has been our impression of a void in
middle-sized clinical neurology texts which have some flesh
added to the raw, skeletal content of many handbooks, yet
which are not as bulky as comprehensive texts which we find
difficult to carry, read and use. We have therefore taken this
rapidly changing field and focused on the essentials. The
book is written and illustrated for students of clinical
neurology, particularly neurologists-in-training and
practicing neurologists, who wish to have ready access to a
comprehensive, up-to-date, and evidence-based guide to the
understanding, diagnosis and management of common and
important neurologic disorders.
We have included more than 800 illustrations in the text.
Many are images taken from our own patients, whom we
would like to thank for allowing us to photograph them or
the outcome of their investigations. Furthermore, we would
also like to thank Professor John Best, Dr Andrew
Chancellor, Professor Byron Kakulas, Dr Robin Sellar,
Mr Matthew Wade, and the Department of Medical
Illustrations, Royal Perth Hospital, for all providing
illustrations, as indicated throughout the book, and Dr
Peter Silbert for helpful comments on sections of the text.
Finally, we would like to thank our families and colleagues
for supporting us in this endeavour. We hope you enjoy the
book and welcome any comments and criticisms.
Graeme J Hankey
Joanna M Wardlaw
8

Abbreviations
α-TTP α-tocopherol-transfer protein CHOP cyclophosphamide, doxorubicin, vincristine and
AAG allergic angiitis and granulomatosis of Churg–Strauss prednisone-based therapy
ACA anticardiolipin antibody CIDP chronic inflammatory demyelinating polyneuropathy
ACE angiotensin-converting enzyme CJD Creutzfeldt–Jakob disease
ACh acetylcholine CK creatine kinase
AChR acetylcholine receptor CLAM cholesterol-lowering agentmyopathy
ACTH adrenocorticotropic hormone CMAP compound muscle action potential
AD Alzheimer’s disease CMT Charcot–Marie–Tooth disease
ADCA autosomal dominant cerebellar ataxia CMV cytomegalovirus
ADD attention deficit disorder CNS central nervous system
ADEM acute disseminated encephalomyelitis CO2 carbon dioxide
ADH antidiuretic hormone CoA coenzyme A
ADL activities of daily living COMT catechol-O-methyltransferase
ADP adenosine diphosphate COX cyclo-oxygenase
AF atrial fibrillation CPAP continuous positive airway pressure
AF-MSA autonomic failure with multiple system atrophy CPEO chronic progressive external ophthalmoplegia
AF-PD autonomic failure with Parkinson’s disease CPH chronic paroxysmal hemicrania
AGE advanced glycation end product CPT carnitine palmitoyl transferase
AHC anterior horn cells CREST calcinosis, Raynaud’s phenomenon, esophageal
AIDP acute inflammatory demyelinating dysmotility, sclerodactyly and telangiectasis
polyradiculoneuropathy CSDH chronic subdural hematoma
AIDS acquired immunodeficiency syndrome CSF cerebrospinal fluid
AION anterior ischemic optic neuropathy CT computerized tomography
ALD adrenoleukodystrophy CTS carpal tunnel syndrome
ALS amyotrophic lateral sclerosis CVST cerbral venous sinus thrombosis
AMAN acute motor-sensory axonal neuropathy CXR chest x-ray
AMN adrenomyeloneuropathy DBS deep brain stimulation
AMSAN acute motor-sensory axonal neuropathy DDAVP desmopressin
ANCA antineutrophil cytoplasmic antibody DGC dentate granule cell
ANNA anti-neuronal nuclear antibody DLBD diffuse Lewy body disease
AP antero-posterior DMD Duchenne’s muscular dystrophy
APA antiphospholipid antibodies DML
APCA-1 anti-Yo antibody DNA deoxyribonucleic acid
APLAb antiphospholipid antibody syndrome Dpt dilute prothrombin time
ApoE apolipoprotein E DRG dorsal root ganglia
APP amyloid precursor protein DRPLA dentato-rubro-pallido-luysian atrophy
APTT activated partial thromboplastin time dRVVT dilute Russell’s viper venom time
AR Argyll Robertson DSA digital subtraction angiography
ARR absolute risk reduction DSM IIIr Diagnostic and statistical manual of mental disorders
ASA arylsulfatase A – revised
ATP adenosine triphosphate DVT deep vein thrombosis
AVM arteriovenous malformation DWI diffusion-weighted imaging
anti-AChRAb anti-acetylcholine receptor antibody DZ dizygotic
ßA4 beta amyloid EBV Epstein–Barr virus
BAEP brainstem auditory evoked potential ECA external carotid artery
BAL British anti-lewisite EKG (ECG) electrocardiograph
BBB blood–brain barrier ECOG electrocorticography
BCG bacille Calmette–Guerin ECST
bd twice daily ECT electroconvulsive therapy
BMD Becker’s muscular dystrophy EEG electroencephalogram/electroencephalograph
BP blood pressure EGFR epidermal growth factor receptor
BSE bovine spongiform encephalopathy EITB enzyme-linked immunoelectrotransfer blot
BTX-A/F botulinum toxin A/F ELISA enzyme-linked immunosorbent assay
CADASIL cerebral autosomal dominant arteriopathy with EM electronmicroscopy
subcortical infarction and leukoencephalopathy EMG electromyography/electroencephalogram
CAM computer assisted myelography EPH episodic paroxysmal hemicrania
CANOMAD chronic ataxic neuropathy, ophthalmoplegia, M EPP end-plate potential
protein, agglutination, anti-disialosyl antibodies EPT enhanced physiological tremor
CAVATAS Carotid And Vertebral Artery Transluminal ERG electroretinogram
Angioplasty Study ESR erythrocyte sedimentation rate
CBF cerebral blood flow ET essential tremor
CCA common carotid artery FAME familial adult myoclonic epilepsy
cDNA complementary deoxyribonucleic acid FAST functional assessment staging test
CEA carcino-embryonic antigen FBP full blood picture
CGRP calcitonin gene-related peptide FDG fluorodeoxyglucose
 Abbreviations 9

FFI fatal familial insomnia JME juvenile myoclonic epilepsy

FHM familial hemiplegic migraine KCT kaolin clotting time
FPP familial (primary) periodic paralysis K–F Kayser–Fleischer
FSH follicle stimulating hormone KSS Kearns–Sayre syndrome
FSHD facio-scapulo-humeral muscular dystrophy
FTA fluorescent treponemal antibody test LA lupus anticoagulant
FTA-ABS fluorescent treponemal antibody absorption LACI lacunar infarct
LCM lymphocytic choriomeningitis
GABA gamma amino butyric acid LDL low-density lipoprotein
GAP guanosine triphosphatase-activating protein LEMS Lambert–Eaton myasthenic syndrome
GBS Guillain–Barré syndrome LG lymphomatoid granulomatosis
GCA giant cell arteritis LGMD limb-girdle muscular dystrophies
GCI glial cytoplasmic inclusions LH luteinizing hormone
GI gastrointestinal LHON Leber’s hereditary optic neuropathy
GLT glutamate transporter gene LP lumbar puncture
GP general practitioner
GPI glycoprotein I MAG myelin associated glycoprotein
GPl lateral globus pallidus MAO monoamine oxidase
GPm medial/internal globus pallidus MAOI monoamine oxidase inhibitor
GSS Gerstmann Straussler Scheinker syndrome MAP microtubule-associated protein
GTCS generalized tonic-clonic seizures MBP myelin basic protein
GTE glycerol trierucate MCA middle cerebral artery
GTO glycerol trioleate oil MCTD mixed connective tissue disease
GTP guanine triphosphate MELAS mitochondrial encephalomyopathy, lactic acidosis, and
stroke-like episodes syndrome
5-HT 5-hydroxytryptamine MEPP miniature end-plate potential
5-HT3 5-hydroxytryptophan-3 MERRF myoclonic epilepsy with ragged-red fibers
HAART highly active antiretroviral therapy Met methionine
HACEK Haemophilus spp., Actinobacillus MFS Miller Fisher syndrome
actinmycetemcomitans, Cardiobacterium hominis, Eikenella MG myasthenia gravis
corrodens, Kingella spp. MGUS monoclonal gammopathy of uncertain significance
HCG human chorionic gonadotrophin MI myocardial infarction
HCl hydrochloric acid MJD Machado Joseph disease
HD Huntington’s disease MLD metachromatic leukodystrophy
HDL high-density lipoprotein MLF medial longitudinal fasciculus
H&E hematoxylin and eosin MMSE Mini-Mental State exam
HE hepatic encephalopathy MNCV motor nerve conduction velocities
HexA hexosaminidase A MND motor neuron disease
HexB hexosaminidase B MPTP N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine
hGH human growth hormone MR magnetic resonance
HHT hereditary hemorrhagic telangiectasia MRA magnetic resonance angiography
Hib Haemophilus influenzae type b MRC Medical Research Council
HIV human immunodeficiency virus MRI magnetic resonance imaging
HIV-CMC human immunodeficiency virus-associated mRNA messenger ribonucleic acid
cognitive/motor complex MS multiple sclerosis
HLA human leukocyte antigen MSA multiple system atrophy
HMPAO hexamethylpropylenamine oxime MSU mid-stream urine
HMSN hereditary motor and sensory neuropathy MT metallothionein
HNA hereditary neuralgic amyotrophy mtDNA mitochondrial deoxyribonucleic acid
HNPP hereditary neuropathy with liability to pressure palsies MTS mesial temporal sclerosis
HR heart rate MUP motor unit potentials
HSAN hereditary sensory and autonomic neuropathy MZ monozygotic
HSE herpes simplex virus encephalitis
HSP hereditary spastic paraparesis NAIP neuronal apoptosis inhibitory protein
HS-tk herpes simplex thymidine kinase NASCET North American symptomatic carotid
HSV herpes simplex virus endarterectomy trial
HTI hemorrhagic transformation of the infarct NCV nerve conduction velocities
HTLV human T lymphocyte virus NF neurofibromatosis
NGF nerve growth factor
IA-DSA intra-arterial digital subtraction angiography NMDA N-methyl-D-aspartate
IBM inclusion body myositis NMS neuroleptic malignant syndrome
iC interstitial nucleus of Cajal NNT number needed to treat
ICA internal carotid artery NO nitric oxide
ICH intracerebral hemorrhage NP Niemann–Pick
ICP intracranial pressure NP-C Niemann–Pick disease type C
ICU intensive care unit NPH normal pressure hydrocephalus
IF intrinsic factor NRT nucleus reticularis thalami
IFN interferon NSE neuron-specific enolase
Ig immunoglobulin NTD neural tube defect
IIH idiopathic intracranial hypertension nvCJD new variant Creutzfeldt–Jakob disease
i.m. intramuscular
INR internal normalized ratio OCP oral contraceptive pill
IOH idiopathic orthostatic hypotension OFSM oculo-facial-skeletal myorhythmia
IQ intelligence quotient OMM oculomasticatory myorhythmia
i.v. intravenous OPCA olivopontocerebellar atrophy
IV DSA intravenous digital subtraction angiography OR odds ratio
IVIG intravenous immunoglobulin P100 positive wave at 100 ms
JCV JC virus PA pernicious anemia
10 Abbreviations

PACI partial anterior circulation infarct SLE systemic lupus erythematosus

PaCO2 partial pressure of carbon dioxide SMA spinal muscular atrophy
PAF pure autonomic failure SMN survival motor neuron protein
PAN polyarteritis nodosa SMNT survival motor neuron gene
PAS periodic acid-Schiff SNAP sensory nerve action potential
PCA posterior communicating artery SNc substantia nigra pars compacta
PCA-1 type 1 anti-Purkinje cell antibody SND striatonigral degeneration
PCR polymerase chain reaction SNr substantia nigra reticulata
PCV procarbazine, lomustine, and vincristine SOD Cu/Zn superoxide dismutase
PD proton density SPECT single photon emission computed tomography
PD Parkinson’s disease SS Sjögren’s syndrome
PDE phosphodiesterase SSCP single strand conformation polymorphism
PDW proton density weighted SSEP somatosensory evoked potentials
PDWI proton density weighted image SSPE subacute sclerosing panencephalitis
PE pulmonary embolism SSRI selective serotonin reuptake inhibitor
PED paroxysmal exertion-induced dyskinesia SSS sick sinus syndrome
PEG percutaneous endoscopic gastrostomy STIR short time inversion recovery
PET positron emission tomography STN subthalamic nucleus
PGI2 prostacyclin SUDEP sudden unexplained death in epilepsy
PGL phenolic glycolipid SUNCT short-lasting unilateral neuralgiform headache with
PHD paroxysmal hypnogenic dyskinesia conjunctival injection and tearing
PI protease inhibitor T1W T1 weighted
PICH primary intracerebral hemorrhage T2W T2 weighted
PKD paroxysmal kinesogenic dyskinesia TA Takayasu’s arteritis
PL phospholipid TACI total anterior circulation infarct
PLED periodic lateralized epileptiform discharge TACS total anterior circulation syndrome
PME progressive myoclonic epilepsies TB tuberculosis
PML progressive multifocal leukoencephalopathy TCD transcranial doppler ultrasound
PMR polymyalgia rheumatica TD Tourette disorder
PNKD paroxysmal non-kinesogenic dyskinesia tds three times daily
PNS peripheral nervous system TENS transcutaneous electrical nerve stimulation.
p.o. by mouth (per os) TETA triethylene tetramine dihydrochloride
POCI posterior circulation infarct TF tissue factor
POEMS polyneuropathy, organomegaly, endocrinopathy, TFPI tissue factor pathway inhibitor
monoclonal paraproteinemia, and skin hyperpigmentation TG therapeutic gain
PPRF paramedian pontine reticular formation TIA transient ischemic attacks
PrP prion protein TNF tumor necrosis factor
PROMM proximal myotonic myopathy TOE transesophageal echocardiography
PS-1/2 presenilin-1/2 tPA tissue plasminogen activator
PSA prostatic specific antigen TPHA Treponema pallidum hemagglutination test
PSD periodic synchronous discharge TPI Treponema pallidum immobilization test
PSP progressive supranuclear palsy TPP thyrotoxic periodic paralysis
PSS progressive systemic sclerosis tRNA transfer ribonucleic acid
PTHRP parathyroid hormone-related protein TS Tourette syndrome
PVC procarbazine, lomustine, and vincristine TSH thyroid stimulating hormone
PVS permanent vegetative state TSC tuberous sclerosis complex
PWI perfusion-weighted image TST thermoregulatory sweat test
Q-SART quantitative sudomotor axon reflex test TT thrombin time
TTE transthoracic echocardiography
RA rheumatoid arthritis
TTP thrombotic thrombocytopenic purpura
RBC red blood cells
RCT randomized controlled trial UCH ubiquitin carboxy-terminal hydrolase
REM rapid-eye movement UL upper limb
RFLP restriction fragment length polymorphism UMN upper motor neuron
RIA radioimmunoassay VC vital capacity
riMLF rostral interstitial nucleus of the medial longitudinal VDRL Venereal Disease Research Laboratory slide flocculation
fasciculus test
RNA ribonucleic acid VEP visual evoked potential
ROM rifampicin, ofloxacin and minocycline VGCC voltage-gated calcium channels
RPR rapid plasma reagin VHL von Hippel–Lindau disease
rRNA ribosomal ribonucleic acid Vim ventrointermediate nucleus
RRR relative risk reduction VL ventrolateral thalamus
RT reverse transcriptase VLCFA very long chain saturated fatty acids
rt-PA or r-tPA recombinant tissue plasminogen activator VMA vanillylmandelic acid
SAE subcortical arteriosclerotic encephalopathy VSD ventricular septal defect
SAF scrapie-associated fibrils vWF von Willebrand factor
SAH subarachnoid hemorrhage VZV varicella-zoster virus
SBMA androgen receptor WADA intracarotid amytal test
SC sickle cell WBC white blood cells
SCA spinocerebellar atrophy subtype WD Wilson’s disease
SCLC small cell lung cancer WFNS World Federation of Neurological Surgeons
SDH succinate dehydrogenase WG Wegener’s granulomatosis
SDS Shy–Drager syndrome WH Werdnig–Hoffman
SE status epilepticus WHO World Health Organization
SFEMG single fiber electromyography
SIADH syndrome of inappropriate antidiuretic hormone
 Chapter One 11

Neurologic
Diagnosis
THE NEUROLOGIC HISTORY
The purpose of the assessment of a patient with a suspected
neurologic disorder is to answer the following questions:
• Is there a neurologic lesion?/Is this a neurologic
disorder? Syndromic diagnosis.
• What is the level of the neurologic lesion in the neuraxis?
Anatomic diagnosis.
• Where is (are) the neurologic lesion(s)? Anatomic
diagnosis.
• What is the nature/cause of the neurologic lesion(s)?
Pathologic diagnosis.
• What are the patient's impairments, disabilities and
handicaps? Functional diagnosis.
• What is the likely outcome? Prognosis.
• What can be done about it? Treatment.
The history must be taken; a relevant, succinct history is
rarely given by the patient. The narrative history should be
emphasized, not a long list of complaints and detailed
systemic enquiry. Brief notes should be recorded as the
history unfolds, recording what the patient actually said
rather than your interpretation, to ensure greater reliability.
While taking the history, the clinician must indirectly assess
the patient’s mental status, and consider the circumstances
under which the symptoms occurred (e.g. seizure).
Concurrently, observe the patient for signs of underlying
disease that may be relevant to the presenting complaint
(1–3). If an adequate history is not available from the
patient, or needs verification, other useful sources include
family members, friends, employers, observers of any events,
and previous medical records.

The clinical history is the most 1 2

important and productive part of the
neurologic assessment. Although the
physical examination is often used to
localize the lesion accurately and elicit
physical signs suggestive of the cause,
the history provides most of the
information about the presence or
absence and nature/cause of the
lesion. Therefore, if time is at a
premium it is preferable to be selective
with the examination rather than with
the history, using the history to select
or target the appropriate examination.

1 This patient, who complained of altered

sensation in the feet and hands, is also
noticeably pale.The cause of her sensory
neuropathy and pallor was pernicious anemia.

3
2 Capillary hemangioma (port wine stain) on the left side
of the face in the distribution of the ophthalmic and
maxillary divisions of the left trigeminal nerve in a patient
with Sturge–Weber syndrome who presented following his
first epileptic seizure.

3 Right Horner’s syndrome (ptosis of the right eyelid and

miosis of the right pupil, arrow) due to right lateral
medullary infarction.
12 Neurologic Diagnosis
TAKING THE HISTORY
Record the patient’s name, age, address, occupation and
handedness.
Presenting symptoms and their duration
‘What is the problem?’
‘Why have you come to see me today?’
History of the presenting complaint
The mode of onset, evolution and course of the illness
should be recorded as it unfolds in chronologic sequence
from the patient’s own account. It can be prompted by
asking the patient:
‘When did this problem begin and what were you doing
at the time?’ or
‘Begin from when you were last perfectly well’.
Sometimes, asking the same question twice in different
ways may elicit further information: ‘Have you ever had
anything like this before?’.
The clinician’s role is to keep the patient focused on their
symptoms and signs, rather than the doctors who were
consulted, the tests ordered, and the opinions of casual
observers, unless they are relevant. The onset and evolution
of the symptoms, whether abrupt and gradually improving
thereafter, steadily progressive, fluctuating, or recurrent
often reflects the pathologic nature of the disease process.
If the patient or family cannot supply this information, it
may be possible to ascertain it by what the patient was able
to do at different times (e.g. still walk and work, or not).
The nature of the symptoms and part of the body that is
affected (e.g. loss of power and feeling in the legs together with
urgency of micturition) often reflects the anatomic location of
the lesion (e.g. spinal cord). It is important to ask questions to
assist in determining the level and location of the lesion(s),
thinking diagnostically while taking the history. Any
precipitating or relieving factors, or associated symptoms should
be recorded, particularly if the patient complains of pain:
Pain history (acronym: LOTTRADIO)
Location (site) of pain: precise part of the body.
Onset: when did the pain start and what was the patient
doing at the time? Was the onset sudden, slowly
progressive or preceded by other symptoms (e.g. visual
disturbance). Were there any precipitating and exacer-
bating factors (e.g. physical activity, bright light, noise)?
Type (quality): steady, throbbing, sharp, stabbing,
burning, tight or dull?
Timing: continuous or intermittent, any habitual pattern:
on awakening from sleep or at the end of the day?
Radiation: spread of pain to other sites.
Associated features (e.g. nausea, vomiting, photophobia,
phonophobia, neurologic symptoms of aura, fever,
palpitations, dyspnea).
Duration of pain: seconds, minutes, hours, days.
Intensity: severity.
Offset (relieving factors): bed-rest, cold, heat, particular
postures or medications.
Systems review (acronym: SANDWICH)
Since diseases which affect the nervous system may also
affect other systems, it is important to enquire about other
systems, phrasing each question to suggest normality so that
the patient has to contradict this assumption, which is less
likely to produce spurious information.
Sleep.
Appetite.
Nausea and vomiting.
Diarrhea.
Weight.
Indigestion.
Cough.
Headache.
Other systemic symptoms that may be relevant include
fever, sweats, chest pain, shortness of breath, intermittent
claudication, joint aches, and disturbances of sphincter
function, sexual function and menses.
Smoking and alcohol intake
Record the patient’s smoking, alcohol and other drug habits.
Medications
Current and recent past medications should be recorded.
Many patients with a long history of uncontrolled epilepsy or
migraine state that they have ‘tried everything’ without
success but it is important to ask them to name each drug,
the dose they took, the length of time it was taken for, and
the effect, because commonly an adequate trial of a
prophylactic drug has not been tried in an adequate dose for
sufficient duration. Patients often need to be asked specifically
if they are taking the oral contraceptive pill, vitamins,
alternative homeopathic and herbal remedies, or illicit drugs.
Past history
Any past history which could be relevant to the presenting
complaint is very important. For example, in a patient
presenting with a first seizure the antenatal, perinatal and
childhood history is particularly important, as is a history of
head injury with loss of consciousness.
Family history
An ever-increasing number of neurologic disorders are being
recognized as being of genetic origin. Some are caused by a
mutation in a single gene and show classical Mendelian
inheritance of a characteristic phenotype. All known autosomal
dominant, autosomal recessive, and X-linked disorders belong
to this category (e.g. Huntington’s disease). Others are ‘poly-
genic’ and tend to ‘run in families’, although the inheritance
pattern is complex and environmental influences can play a
major role in the final phenotype (e.g. premature vascular
disease, migraine). Determination of the inheritance pattern
is important because the risk to relatives diminishes more
rapidly as the relationship becomes more distant in polygenic
conditions compared with autosomal dominant inheritance.
In addition, when polygenic inheritance is involved, the risk
to siblings is increased with increasing number of affected
siblings, whereas in autosomal recessive conditions the number
of affected siblings does not modify the risk.
The differing versions of the same gene are called alleles.
The term genotype usually refers to the collection of alleles
inherited and carried by an individual. Phenotype refers to
the appearance of an individual in context (e.g. disease
status, hair color, height, blood group). For twins,
monozygous (MZ) twin pairs are genetically identical, while
dizygous (DZ) pairs have no more genetic similarity that
 Neurologic Examination
other siblings. If both twins in a pair have the same disease
or trait they are said to be ‘concordant’, while a single
affected twin is one of a ‘discordant’ pair.
Personal history
Details of the domestic, social, and business background
(e.g. the patient’s personality, relationship with family,
friends, employer and peer groups; sexual preference,
attitude to work and life, living arrangements, financial
state) may be relevant to both the genesis of the symptoms
and the management of the patient. Many neurologic
disorders impose some form of handicap on the patient
which may compromise their ability to negotiate the
bathroom, other rooms, or stairs in the house, ability to
drive a car, ability to go back to work or hobbies, self-
esteem, and the health and well-being of the partner or
carer. It is crucial not to ignore the social and emotional
impact of the illness on the patient and family.
Concluding history
Failure to take a good history is a common cause of failure to
make the correct diagnosis and optimally manage the patient.
Before proceeding with the examination, ask: ‘Is there
anything else you would like to tell me?’ and consider asking
at this stage: ‘What do you think the problem is due to?’
4 5
4, 5 Clubbing of the hands and feet in a young patient with cyanotic
congenital heart disease and brain abscess.
6 Dry skin (ichthyosis) of a patient with peripheral neuropathy due to
Refsum’s disease.
7 Purpuric skin rash of meningococcal septicemia.
13
NEUROLOGIC EXAMINATION
The aim of the neurologic examination is usually to confirm
a diagnostic hypothesis generated from the history.
Sometimes, the diagnosis is not at all clear from the history,
in which case it is important to be able to conduct the
neurologic examination in a uniform, sequential order so as
to avoid omission and perhaps also to facilitate record
keeping. However, in most patients not every neurologic
function needs to be assessed. The thoroughness of the
neurologic examination should be governed by the nature
of the clinical problem and the physical condition of the
patient (and also the experience of the examiner). For
example, a patient presenting with symptoms and signs of a
median neuropathy at the wrist does not require the same
intensity of assessment of cognitive and cerebellar function
as a patient presenting with forgetfulness and clumsiness.
GENERAL ASSESSMENT
Watch the patient enter the consulting room, noting the
appearance and behavior of the patient and the gait or form
of mobilization (e.g. wheelchair).
Whilst taking the history, listen to the speech and look
closely at the patient’s face, hands (4) and skin (5–7). Also
6
7
14 Neurologic Diagnosis
look at the eyes (8–11). Is there evidence of:
• Abnormal facial appearance.
• Ptosis or facial asymmetry.
• Reduced blink frequency, facial expression and voice
volume of Parkinsonism.
• Abnormal posture.
• Wasting or fasciculation.
• Tremor or other involuntary movements.
Also determine whether the patient is right or left
handed (i.e. which is likely to be the dominant hemisphere
for language).
MENTAL STATE (HIGHER MENTAL FUNCTION)
The patient’s alertness, speech, and intelligence can be
assessed during history-taking; taking the clinical history and
evaluating the competence of the patient to give an accurate
history involves an assessment of higher mental functioning.
So, a formal assessment of higher mental function is not
necessary in every patient. However, if suspicions are
aroused or the presenting complaint demands it, a
8 9
8 The patient’s right eye is affected by ischemic oculopathy (arrow).
Note the congested sclera, cloudy cornea, new vessel formation
(neovascularization) around the limbus of the iris (rubeosis iridis) and
mid-dilated pupil, which indicate chronic anterior segment ocular
ischemia due to carotid occlusive disease. (Reproduced with
permission from Hankey GJ and Warlow CP [1994] Transient
Ischaemic Attacks of the Brain and Eye.WB Saunders.)
10
10 Fundus of the severely ischemic right eye of the patient in 8
showing attenuated vessels and pallor of the retina due to retinal
edema caused by severe ischemia.
standardized test of higher mental function should be
undertaken. One of the many available is the Mini Mental
State examination (Table 1).
The Mini Mental State examination is only a screening
test however, and fails to assess other higher mental
functions, particularly non-verbal functions. Other aspects
to consider include:
Consciousness (see p.44)
Orientation in time, place and person
Attention
• Concentration: digit span (normal: 6±1 forwards [i.e.
abnormal <5 digits forward], 4±1 backwards [i.e.
abnormal <3 digits backwards]).
• Persistence: serial recitation (months of year backwards,
serial 7s); word list generation (words beginning with a
letter; normal >12/minute).
• Resistance to interference: alternating sequences:
+o+o+o.
9 Close-up view of the right eye in 8 showing rubeosis iridis more
clearly.
11
11 Fundus of the normal left eye of the patient in 8.
 Neurologic Examination 15

Table 1 Mini-mental state examination

Maximum score Maximum score
Orientation Language
What is the Time? Day? Month? Year? Season? 5 points Name two objects (e.g. a pencil and a watch). 2 points
What is the name of this Ward? Hospital? Town? Repeat a short phrase (e.g.‘No ifs, ands or buts’). 1 point
State? Country? 5 points Execute a three-stage command, scoring 1 point for
each stage (e.g.‘With the index finger of your left hand 3 points
Registration touch the tip of your nose and then your left ear.’).
Name three objects (e.g. car, dog, book) 3 points Read and obey the following ‘Close your eyes’. 1 point
and then ask patient to repeat these. Write a sentence of your own choice 1 point
The number of objects repeated correctly is the score. (the sentence must make sense and contain a subject
Endeavor, by further attempts and prompting, to have all and verb).
three repeated, so as to test recall later. Copy a diagram showing two intersecting pentagons. 1 point

Attention and calculation Total score 30 points

Subtract 7 from 100, and then 7 from the result. 5 points
Repeat this five times, scoring 1 point for each correct Scoring 23 or less denotes cognitive impairment (76% detection
subtraction. If the patient cannot/will not do this: spell rate, 4% false positive). (Adapted from Dick et al., J. Neurol. Neurosurg.
‘world’ backwards. Psychiatry, 1984; 47: 496.)

Recall
Name the three objects repeated in the registration test. 3 points
Score 1 point for each correct answer.

Memory • Dysphasia is a disturbance of language function, causing

• Retrograde: information (e.g. ‘who is the Prime difficulty understanding or expressing spoken or written
Minister/President, how many weeks in a year, dates of language.
World War 1 and II, define an island’). • Dysarthria is a disturbance of articulation of speech.
• Anterograde: verbal: register and recall three objects after
3 minutes; non-verbal: Rey Osterrieth complex figure test. Affect: mood and motivation, response to questions,
attitude to others
Other functions of intellect
• Calculation: serial 7s, or more simple calculations. Perception
• Abstraction: similarities (e.g. orange and banana, dog and • Illusions: misinterpretation of sensory stimuli (e.g.
horse), proverbs (e.g. ‘hunger is the best gravy’). confusional state).
• Praxis: • Delusions: incorrect beliefs that are held with conviction.
– Constructional: draw a clock, cube, flower; block design. • Hallucinations: sensory perceptions unrelated to sensory
– Ideomotor: buccofacial, limbs, body: ‘show how you stimuli.
would blow out a match, use a comb to comb your hair,
use a toothbrush to brush your teeth’. SKULL
• Visual–spatial perception: line bisection, star cancellation. Size and shape.
• Right–left orientation.
SPINE
Communication • Deformity.
• Verbal: • Tuft of hair in lumbosacral region (underlying spina
– Spontaneous speech: ‘describe what you can see in this bifida).
picture’. • Tenderness: spinal, paraspinal.
– Oral comprehension: one, two and three stage • Range of motion.
commands.
– Repetition: ‘If I were here then she could be there’. CRANIAL NERVES
– Naming: objects, body parts, lists of animals, words Nerve I (olfactory nerve)
beginning with a letter (e.g. ‘A’). • Olfactory sensation is seldom impaired in isolation.
– Reading: ‘point to the word ‘X’ on the card’. • As testing is time consuming, it need not be done unless
– Writing: write ‘ocean’, ‘groceries’, ‘some water is not there is a history of head trauma or possible dementia.
good to drink’.
– Articulation: labial sounds (‘pa’), lingual sounds (‘ta’), Nerve II (optic nerve)
palatal sounds (‘ka’). Visual acuity
• Non-verbal: prosody: use of intonation, gesture, • Only relevant if the patient has a history of ocular
appropriate turn-taking. problems or visual symptoms.
• Handedness: language is a function of the dominant • Record visual acuity in right and left eyes at 6 m (20 ft)
hemisphere (the left hemisphere in 96% of right-handers from a Snellen’s chart, with the patient wearing
and more than 50% of left-handers). spectacles if necessary.
16 Neurologic Diagnosis
Color vision
Color vision can be assessed at the bedside, ideally by testing
each eye with pseudoisochromatic plates. A more simple
convention is to take the bright-red top from a bottle of the
mydriatic solutions, place it over a small flashlight, and
present it to each eye. To a patient with optic nerve disease,
the color red will appear pale or brownish. The degree of
color desaturation can be roughly quantified by asking the
patient to express the value of the color as a percentage of
the value of the color perceived by the normal eye.
Visual fields
Test first; patients may be dazzled for minutes after pupil
tests and ophthalmoscopy.
Screen by confrontation, in which the patient is asked to
look at the examiner’s eyes. Check the upper temporal
quadrants by simultaneously wiggling your right and left
index fingers in the upper temporal visual fields of the
patient and yourself, ensuring that your moving fingers are
an equal distance between you and the patient so that you
both have the same visual field. Ask the patient to point (if
they can) to which fingers are moving: the right, left, or
both. If any doubt, repeat the test, wiggling one finger at a
time and then both fingers. Repeat in the lower temporal
quadrants. This technique detects conventional hemianopic
and quadrantanopic field defect as well as visual inattention.
If there is a visual field defect, the nasal and temporal
fields should be tested individually and the margins of any
defect discerned with the use of a 5 mm (0.2 in) white and
red pin head.
Central vision and the size of the blind spot should also
be tested by confrontation and using a pin head.
Confrontation testing is however only a screening
technique. Quantitative perimetry (colloquially known as
‘formal’ fields) is more accurate and precise.
Pupillary responses
Note the size and shape of each pupil, and the direct and
consensual response of each pupil to stimulation by light
and accommodation.
Argyll Robertson pupils are ‘Accomodation Retaining’
(pneumonic to remember that the accomodation reflex is
preserved in Argyll Robertson pupils, i.e. they both have the
initials ‘AR’); i.e. accommodation reflex present but light
reflex absent.
Horner’s syndrome consists of miosis, ptosis and
anhidrosis.
Ask the patient if the light appears equally bright when
shone in both eyes. If there is a difference, look for a relative
afferent pupillary defect. With the patient’s gaze fixed in the
distance, shine the light in one eye and note both pupils
constrict. Move the light to the other eye. During the light
beam’s transit across the nose, both pupils dilate slightly. In
normal eyes, both pupils constrict again when the beam of
light falls onto the other eye. If the patient has a relative
afferent pupillary defect, the pupil (and also the contralateral
pupil) continues to dilate when the light beam falls on it. This
usually indicates retinal or optic nerve dysfunction, but may
be observed with lesions as posterior as the optic tract. The
extreme example of an afferent pupillary defect is the
amaurotic pupil of the completely blind eye. The term Marcus
Gunn pupil is often used but what we now call a relative
afferent pupillary defect is not what Marcus Gunn described.
While the iris is illuminated, look for inflammation, arcus
senilis and a Kayser–Fleischer ring; the latter may require closer
examination with the ophthalmoscope or slit lamp, but can
even be seen by looking at the limbus through an auroscope
from which the attached ear piece has been removed.
Fundoscopy
Perform fundoscopy in all patients. Ask the patient to fix on
an external object with one eye while the other eye is being
examined. The examiner’s head must remain vertical so as
not to obscure the line of vision of the patient’s fixating eye.
Note any abnormalities on the surface of the eye and the
lens (e.g. cataract). Then focus on the:
• Optic disc: note its color – pale in optic atrophy, pink and
congested in papilledema (12). N.B. Temporal pallor of
the optic disk is a normal finding in many discs, but it
indicates optic atrophy when it is associated with
decreased visual acuity, a field defect, and an abnormality
of color vision.
• Optic cup: diminished in papilledema (12), enlarged in
glaucoma.
• Venous pulsation in the optic cup: absent if intracranial
pressure exceeds retinal venous pressure.
• Disc margins: blurred in papilledema (12). If the disc
cannot be seen, look even harder and change focus
because a swollen, red disc of papilledema may not be
obvious among the background red retina. In addition,
its surface will not be in focus when focusing on the
retina, because it is heaped up, as if looking from above
at a large mountain coming out of the sea.
• Retinal vessels: narrow and tortuous with arteriovenous
nipping in hypertension; microaneurysms with diabetes;
cholesterol, platelet or calcific emboli in arterioles
(13–16), distension or collapse of veins.
• Retinal surface: exudates, hemorrhages (17), retinitis
pigmentosa, choroiditis.
12
12 Ocular fundus showing papilledema in a patient with headache due
to idiopathic intracranial hypertension. Note the congested swollen
optic disc, loss of the physiological cup, blurred disc margins and
congested retinal veins. (Courtesy of Mr M Wade, Department of
Medical Illustrations, Royal Perth Hospital, Australia.)
 Neurologic Examination
13
13 Fundus examination showing cholesterol emboli (arrows) as bright,
orange-yellow, refractile, crystalline, glinting lipid emboli, so-called
Hollenhorst cholesterol plaques.They are usually unilateral, multiple
and found at the bifurcation of retinal arterioles.They frequently arise
from ulcerated atherosclerotic plaque in the ipsilateral carotid system.
(Reproduced with permission from Hankey GJ and Warlow CP [1994]
Transient Ischaemic Attacks of the Brain and Eye.WB Saunders.)
15
15 Ocular fundus showing narrow arterioles and veins, pallor of the
retina, and a cherry-red spot over the fovea (arrow) due to
accentuation of the normal fovea, which is devoid of ganglion cells, by
the opalescent halo, in a patient with central retinal artery occlusion.
(Courtesy of Mr M Wade, Department of Medical Illustrations, Royal
Perth Hospital, Australia.)
17 Ocular fundus showing a retinal hemorrhage (arrow) due to
thrombocytopenia in a patient who presented with a symptomatic
intracerebral hemorrhage.
17
14
14 Ocular fundus of a patient with inferior temporal branch retinal
artery occlusion showing pallor of the inferior half of the retina
(arrows) due to cloudy swelling of the retinal ganglion cells caused by
retinal infarction. (Courtesy of Mr M Wade, Department of Medical
Illustrations, Royal Perth Hospital, Australia.)
16
16 Ocular fundus showing multiple small retinal infarcts due to fat
emboli (arrows). (Courtesy of Mr M Wade, Department of Medical
Illustrations, Royal Perth Hospital, Australia.)
17
18 Neurologic Diagnosis

Nerves III, IV, and VI (oculomotor, trochlear, and Facial sensation

abducens nerves) Not necessary to test rigorously unless the patient complains
Ask the patient to look straight ahead at a target (e.g. the tip of facial sensory disturbance; patients usually know when
of a hat pin or pen; the use of a finger may miss subtle they have a disturbance of spinothalamic or trige-
diplopia) and examine the eyes in the primary position of minothalamic sensation because, for example, when they
gaze, noting the position of each eye (whether the eyes are have a shave or shower they may note the temperature of
conjugate or not), whether there are any involuntary the water feels different. Patients have much greater
movements of the eyes (e.g. nystagmus [vertical, rotational, difficulty in discerning a loss of other sensory modalities.
horizontal], opsoclonus, ocular bobbing, fixational instability:
square wave jerks), the size of the palpebral fissures (whether
there is ptosis or lid retraction on one or both sides) and
whether there is any fatiguability with prolonged gaze. 18
Ask if the patient sees one or two targets. If they have
double vision, assess this with a simple ‘cover-uncover’ test
that is accurate if one extraocular muscle is weak but can be
misleading if two or more muscles are weak:
• Find the position of the target that causes maximum
separation of the images.
• Holding the target steady in your right hand, cover one
of the patient’s eyes with your left thumb (pronating
your wrist and resting the dorsum of your distal left
fingers [flexed at the metacarpophalangeal joints] against
the patient’s lower central forehead), and ask which (if
any) object disappears – the outer (more peripheral)
object is seen by the defective eye and the inner (more
central) object is seen by the ‘good’ eye.
• Swing your left thumb to cover the patient’s other eye
and the other object should disappear. If the same object 18 Eye movements in each of the nine cardinal positions of gaze
disappears, the patient has not understood the test or the showing a left esotropia and left gaze palsy (in each eye, but
diplopia is monocular (i.e. intraocular pathology such as dysconjugate) due to an ischemic stroke involving the abducens nuclear
vitreous hemorrhage; or functional). complex in the left low pons.The patient had non-insulin dependent
diabetes mellitus. (Courtesy of Mr M Wade, Department of Medical
Ask the patient to follow a slowly moving target (no Illustrations, Royal Perth Hospital, Australia.)
faster than 30° per second, otherwise smooth pursuit will
be normally interrupted by saccadic intrusions) to examine
ocular pursuit in each of the nine cardinal positions of gaze 19
(straight ahead, left, right, up, down, up and to the right,
up and to the left, down and to the right and left) and
during convergence and accommodation. Ocular pursuit
should be smooth, maintaining the target fixed on the
macular, but may be interrupted by saccadic intrusions
(jerky, cogwheel or saccadic pursuit) in various disease states
such as extrapyramidal or cerebellar dysfunction. If double
vision occurs in any position of gaze carry out the
‘cover–uncover’ test described above. Nystagmus unrelated
to vestibular disease seldom produces symptoms and should
be closely looked for (see pp.107, 110, 138).
Look voluntarily in each of the cardinal positions of gaze
to test voluntary/saccadic eye movements that are generated
from frontal eyefields in Brodmann’s area 8 of the
contralateral frontal cortex (18, 19). A frontal lobe lesion may
result in a conjugate horizontal gaze palsy to the opposite side
and so the eyes will be deviated to the side of the lesion due
to unopposed action of the contralateral frontal lobe.

Nerve V (trigeminal nerve)

Corneal response
• Need not be tested routinely because it can be
unpleasant to the patient, carry a risk of corneal damage,
and be unreliable.
• Perform only if you really want to assess the integrity of
the trigeminal nerve (e.g. other cranial nerve damage or
suspected acoustic neuroma or syringobulbia).
• Use cotton wool.
19 Eye movements in each of the nine cardinal positions of gaze
showing bilateral ptosis, skew deviation due to hypotropia of the right
eye, and a supranuclear upward gaze palsy due to an ischemic stroke in
the left midbrain (causing a nuclear oculomotor palsy) and left
thalamus caused by an embolus to the top of the basilar artery,
occluding the P1 segment of the left posterior cerebral artery.
(Courtesy of Mr M Wade, Department of Medical Illustrations, Royal
Perth Hospital, Australia.)
 Neurologic Examination
Masticatory muscles
• The bulk of the temporalis and masseter should be
examined by inspection and palpation; ask the patient to
clench their jaw and feel the muscle bulk.
• To test pterygoid muscle power, ask the patient to open
the mouth fully. A unilateral trigeminal motor neuropathy
will manifest with deviation of the lower jaw (chin) to the
paretic side. Bilateral weakness, which may be suspected
if the patient needs to support the jaw with their hand
during conversation, may be seen in myasthenia gravis
and myopathies such as dystrophia myotonica.
• Less severe weakness may be detected by trying to close
the opened jaw with the heel of your palm.
Jaw jerk
Unreliable and unhelpful as a screening test but it has a role
in determining the level of bilateral corticospinal tract
lesions; if brisk it suggests bilateral lesions above the mid-
pons (a trigeminal nerve reflex: stretching and contraction
of the masticatory muscles).
Nerve VII (facial nerve)
Facial muscle power will have been assessed informally during
history-taking: facial asymmetry, dysarthria. Ask the patient to:
• Raise their eyebrows (or look up to the ceiling): the
frontalis muscle is spared in contralateral upper motor
neuron (supranuclear) lesions due to bilateral
hemispheric representation.
• Smile and show their teeth: weak in lower and upper
motor neuron lesions of VII, and note any asymmetry.
• Grimace by making a maximal effort to draw the lower
lip and angle of the mouth downward and outward, at
the same time tensing the skin over the anterior surface
of the neck, to test the platysma. The examiner generally
needs to demonstrate the test and instruct the patient to
mimic him or her.
Altered, and even unpleasant taste, may be a symptom of
facial palsy.
Nerve VIII (auditory and vestibular nerve)
Rub your thumb and middle finger together repetitively in
both hands, about 2–3 cm (0.8–1.2 in) away from both of the
patient’s ears. Ask the patient if they hear the sound and if there
is any asymmetry. Alternatively, rub your thumb and middle
finger together repetitively next to one ear (to produce a
masking sound) and whisper quietly in, or hold a ticking clock
adjacent to, the other ear (the testing ear) at varying distances.
If there is any difficulty hearing, conduct the Rinne and
Weber tuning fork tests and inspect the external auditory
meatus and tympanic membrane. The Rinne test involves
striking the 256 Hz tuning fork and holding the vibrating
tuning fork about 2–3 cm (0.8–1.2 in) from the ear. Ask the
patient if they can hear it. Then place the base of a vibrating
tuning fork behind the ear, over the mastoid process and
ask the patient if they can hear it and whether the sound is
louder ‘in the front’ (outside the ear) or ‘at the back’ (over
the mastoid process). It is normally louder in the front
(positive Rinne test), but if not (negative Rinne test), this
suggests conductive hearing loss, due to blocked ears or a
middle ear defect, for example. For the Weber test, the
vibrating tuning fork is placed over the vertex of the head
in the midline and the patient is asked where they hear the
buzzing sound. Normally, it is heard in the middle of the
19
head. If it lateralizes to one side this suggests either
conductive hearing loss on that side (diminished masking of
external sounds) or sensorineural hearing loss on the other
side (poor bone conduction to that side). The Rinne and
Weber tests are not always reliable. Vestibular nerve function
is tested by eye movement and balance tests.
Nerves IX and X (glossopharyngeal and
vagus nerves)
Inspect the palate and ask the patient to say ‘Ah’. If the
palate moves to one side this indicates a lesion of the vagus
nerve (motor to the palate) on the contralateral side; the
contracting palatal muscles pull the palate up and
ipsilaterally. If the palate does not move this may be due to
bilateral supranuclear, nuclear or infranuclear vagus nerve
lesions, depressed consciousness, or even a disturbance of
neuromuscular junction or muscle function.
It is not necessary to test the gag reflex because it is
unpleasant to the patient and is rarely abnormal in the
presence of normal palatal movement (i.e. it is very unusual
to have a palatal sensory deficit due to a IXth nerve palsy
without a palatal motor deficit due to a Xth nerve palsy).
Nerve XI (accessory nerve)
• Ask the patient if they have neck pain; cervical
spondylosis is common and neck pain may not only be
uncomfortable but cause spurious weakness.
• Place the palm of your right hand over the patient’s left
mandible and ask the patient to turn their head to the
left against your resistance to test the power of the right
sternocleidomastoid. Repeat on the other side.
• Place your hand on the patient’s forehead and ask them
to push forward. This should usually be performed with
the patient lying supine because it may evoke neck pain.
Painless weakness is suggestive of motor neuron disease,
myasthenia gravis, or a myopathy such as dystrophia
myotonica and polymyositis.
• Ask the patient to elevate (shrug) the shoulders,
observing and palpating any asymmetry of contraction
of the upper trapezius muscles, and test muscle strength
by attempting to depress the shoulders by pushing down
on both shoulders against the patient’s resistance. The
lower portion of the trapezius can be tested by having
the patient brace the shoulders backward and down.
Unilateral paralysis of the trapezius is evidenced by
inability to elevate and retract the shoulder and by
difficulty in elevating the arm above the horizontal. The
trapezial ridge is depressed, exposing the levator scapulae;
the scapula appears rotated, the upper end laterally and
down, the lower end up and in.
Nerve XII (hypoglossal nerve)
Ask the patient to:
• Open the mouth: inspect the tongue while it is at rest in
the floor of the mouth, noting any wasting or fasciculation.
• Protrude the tongue: observe any deviation (toward the
side of a nuclear/infranuclear lesion, away from the side
of a supranuclear lesion).
• Move the tongue quickly from side to side: this is slow
with pyramidal or extrapyramidal disease.
Tongue power can be tested by asking the patient to
push the tongue into the cheek on each side but there is no
reliable test for tongue power.
20 Neurologic Diagnosis
UPPER LIMBS
Inspection
Ask the patient to hold the arms outstretched, palms down,
with fingers abducted and eyes open. Note any deformity,
skin lesions, muscle wasting and fasciculations, and
involuntary movements.
• Slight wrist flexion with hyperextension at the meta-
carpophalangeal joints, particularly if unilateral, is a sign
of hypotonia, most commonly seen in cerebellar disease.
If bilateral it can be normal, particularly in Asian people.
• Slow, unintended movements of the fingers (‘pseudo-
athetosis’) suggest a loss of proprioception (‘sensory
ataxia’). This can be confirmed by asking the patient to
close their eyes and then touch the tip of their nose with
each outstretched index finger, in turn. The patient can
then open their eyes, and carry out the finger-nose test
of coordination (see below).
• Tap on each forearm in turn, displacing it down by about
10 cm (4 in) and observe the limb rebound to its former
position; in cerebellar disorders, the rebounding move-
ment is slow to stop so that the affected limb shoots past
the initial position (rebound phenomenon).
• Ask the patient then to make rapid piano playing move-
ments, repetitively tap the thumb and index finger, or
perhaps best of all for testing patterned movement, to alter-
nately tap two fingers (e.g. the index and middle fingers,
or ring and little fingers) whilst keeping the palm steady (if
normal, an abnormality of motor function is unlikely).
• Ask the patient to keep the arms outstretched but to
supinate the forearms and face the palms up. Observe
over the next 10–15 seconds.
• Mild flexion of the elbow and gradual pronation and
downward drift of the forearm (‘pronator drift’) on one
side reflects a slight increase in tone of the pronator
muscles compared with supinator muscles that occurs
with mild pyramidal dysfunction.
Tone
Muscle tone refers to the activity of the stretch reflexes,
which is usually assessed by the resistance encountered on
stretching the muscle at increasing velocities.
Passively pronate and supinate the patient’s forearms, and
flex and extend the wrists and elbows, noting a steady
resistance that is insensitive to the velocity of stretch (‘lead
pipe’ rigidity) and may be interrupted by tremor (‘cog-
wheel rigidity’), or an increased resistance in proportion to
the velocity at which the muscle is stretched (‘spasticity’).
Power
Test in an orderly sequence, proceeding from proximal to
distal muscles, testing abductor groups before adductors,
and flexors before extensors.
Muscle power may be graded according to the Medical
Research Council (MRC) scale:
0 No movement.
1 A flicker of movement in the muscle.
2 The muscle can move the limb if the force of gravity is
eliminated (e.g. support the joint so that it can be
rotated around its vertical axis).
3 The muscle can maintain the limb against the force of
gravity.
4 The muscle can move the limb against resistance supplied
by the examiner.
5 Normal power.
As the MRC scale lacks sensitivity in discriminating the
most common degrees of muscular weakness between 4 and
5, the scale is often subdivided into: 3+, 4–, 4, 4+, 5–, 5 out
of 5; or alternatively 4, 4.25, 4.5, 4.75, 5 out of 5.
Reflexes
• A brisk tap over the muscle tendon or a vibration wave
induced by percussion of bone to which the tendon
attaches, stretches the muscle spindle and Golgi tendon
organs, and excites a monosynaptic phasic stretch reflex.
• Stretching of the primary spindle endings activates group
Ia afferent fibers which synapse directly with alpha motor
neurons in the anterior horn of the spinal cord. This
results in contraction of the extrafusal muscle fibers
innervated by these neurons.
• Stretching of secondary spindle endings activates group
II afferent fibers which are mainly inhibitory on extensor
motor neurons and facilitatory of flexor motor neurons.
• Stretching of Golgi tendon organs activates group Ib
afferent fibers.
• Descending motor pathways (corticospinal, reticulo-
spinal, vestibulospinal) regulate alpha and gamma motor
neuron excitability.
Deep tendon reflexes Main segment
Jaw jerk Cranial nerve V (motor)
Biceps C5,6
Brachioradialis/supinator C5,6
Triceps C6,7,8
Finger-flexion C8
Reflexes may be depressed or absent if the reflex arc is
disturbed (e.g. anterior horn cell disease, peripheral
neuropathy, muscle disease) or if antagonists contract (e.g.
extrapyramidal rigidity, poor relaxation). However, in many
muscle diseases (excluding inclusion body myositis) the
reflexes are relatively preserved (i.e. only mildly depressed)
compared with the degree of weakness. Depressed reflexes
may be enhanced by reinforcement (e.g. clenching the teeth
tightly at the time of striking the tendon with the reflex
hammer).
Reflexes may be augmented by an upper motor neuron
(supranuclear) lesion, anxiety, exercise, and thyrotoxicosis.
The reflex may ‘spread’ (e.g. a tap over the distal radius may
evoke contraction of the biceps, triceps or finger flexors) if
alpha motor neurons are hyperexcitable or if a wave of
vibration spreads to excite muscle spindles in distant
muscles, causing them to contract reflexly.
Coordination
• Finger–nose test: ask the patient to touch the tip of their
nose, then the examiner’s finger which is held at arm’s
length in front of the patient, then their nose again. This
may elicit a tremor (an action tremor accompanies the
movement throughout its course whereas an intention
tremor increases in amplitude as the target is approached)
or dysmetria: the finger falls short of the target or exceeds
it (past-pointing) or deviates to one side or the other.
• Rapid alternating movements: dysdiadochokinesia.
• Rebound phenomenon.
 Neurologic Examination 21

Sensation Power
Ask the patient if they have noted altered sensation on any When testing the power of hip flexors, keep one hand under
part of the body, such as altered temperature sensation when the heel of the opposite foot if you suspect the patient is not
having a bath/shower. If so, the area in question can be trying hard to flex the hip (because of pain, malingering or
examined with a pin and a cold object, such as a part of the hysteria) because normal counter pressure will not be felt
metal tuning fork. The pin is advanced from the area of on the opposite side (Hoover’s sign).
apparent sensory impairment toward the normal area until a If lower limb weakness extends up to the trunk, ask the
line of demarcation is reached where sensation becomes patient to try to sit up from the lying position without the
normal. If not, and if there is no ‘pseudoathetosis’ of the out- use of the arms. If this is not possible, the trunk is weak.
stretched fingers (see above), a sensory disturbance is unlikely. The upper limit (the ‘motor level’) can sometimes be
Proprioception can be tested formally by taking hold of ascertained by noting the position of the umbilicus with the
the sides of one of the patient’s distal interphalangeal joints patient supine and then asking the patient to lift their head
between your left thumb and index finger and the sides of off the bed (to contract the rectus abdominis). If the
the distal phalanx between your right thumb and index umbilicus deviates upwards, this indicates that the lower
finger and passively move the patient’s distal phalanx up or abdominal muscles are weaker than the upper abdominal
down, asking the patient (with eyes closed) to state the muscles (Beevor’s sign of a lesion around T10 level).
direction of movement. Only small movements are required
as they should normally be detected. If not, try larger Reflexes
movements and, failing that, proceed proximally to check Deep tendon reflexes
movement at the proximal interphalangeal joints, wrist, and Hip adductors L2,3
elbow if necessary. Knee L3,4
Other sensory modalities that may be tested with the Hamstrings L5
eyes closed include: Ankle S1
• Two-point discrimination (normally >3 mm [>0.1 in] on
the pulps of the fingers). Polysynaptic reflexes that are often relayed through
• Stereognosis (ability to distinguish the nature, size and more than one segment
texture of small objects such as coins placed in the hand). Reflex Segment
• Graphesthesia (figure/number writing).
Corneal Cranial nerve V (sensory) and
The method of testing sensation depends on the VII (motor)
question or hypothesis being explored. If a central lesion is Abdominal
suspected (e.g. the patient also has a hemiparesis) then Upper T9,10
sensation should be tested ‘side to side’, comparing one part Lower T11,12
of the body with the corresponding contralateral side. Cremasteric L1,2
However, if a peripheral lesion is suspected (e.g. the patient Plantar S1,2
has a wrist drop) then the sensation in each of the relevant Bulbocavernosus S2,3,4
dermatomes (e.g. C6,7,8) and peripheral nerve regions (e.g. Anal S3,4,5
radial nerve) should be examined closely.
The plantar reflex
LOWER LIMBS The outer border of the sole of the foot (S1 dermatome) is
Inspection stimulated by a light stroke with a mildly noxious pressure
As for upper limbs, and also check for pes cavus deformity. stimulus such as a key or a spatula (bisected in the longitudinal
plane), after warning the patient of the impending stimulus.
Tone The great toe normally plantar-flexes. Until the age of
With the patient lying on the bed or couch, and the legs 18 months or subsequently, after damage to upper motor
relaxed, grasp the knee with one hand and rotate the leg neuron corticoreticulospinal pathways that inhibit flexor
briskly to and from about the hip. Normally, the foot inverts reflexes, the great toe extends (dorsiflexes) with or without
and everts passively. If tone is decreased, as in cerebellar and abduction (fanning) of the toes (Babinski sign). This is part
lower motor neuron disorders, the passive movement is of a greater uncontrolled protective flexor response which
increased. If tone is increased (as in spasticity and involves all the flexors of the lower limb and which is
extrapyramidal rigidity), the foot excursions are decreased normally inhibited from the brainstem by a reticulospinal
so that the foot moves rigidly with the leg. Because pathway so that flexor pathways may be used for volitional
disorders affecting tone usually have more impact distally, it movement such as walking.
is seldom necessary to test tone at the hip or knee.
Clonus is a rhythmic series of muscle contractions in Bulbocavernosus reflex
response to maintained stretch, that may be elicited at the The examiner flicks or pinches the foreskin of the penis or
ankle by supporting the patient’s knee, flexed about 15°, pricks the foreskin or glans with a pin to evoke a reflex
and then suddenly and forcefully dorsiflexing the patient’s contraction in the bulbocavernosus muscle at the base of the
foot with the palm of the examiner’s right hand. Up to penis. The contraction may be observed, but it is, as a rule,
three beats of clonus is normal. more easily palpated.
22 Neurologic Diagnosis

Anal reflex
The tip of the finger, covered with a glove, is inserted into
the anal ring, and contraction of the anal ring is felt as the
skin around the anus and the perineum is scratched or
pricked with a pin; or the contraction simply may be
observed without being palpated. This is a test specifically
of the external or voluntary anal sphincter. In the presence
of a flaccid paralysis of the external anal sphincter, the
normal tonus of the internal sphincter is felt to give way on
insertion of the finger. As the finger is withdrawn, the anus
remains open or patulous. This does not indicate a loss of
internal anal sphincter function.
• Squat down and arise from a squat (to detect proximal
hip girdle muscle weakness).
• Stand still with feet together, first with eyes open and
then shut, and notice any change in stability that may
reflect impaired joint position sense (Romberg’s sign). If
uncertain about the result, challenge the patient by
standing behind them and, when the patient is stable
with eyes open, tell the patient you are going to pull back
on the shoulders and ask them to try to remain upright
(if they cannot, they will fall back into your arms). If they
manage to remain upright, repeat this with the patient’s
eyes closed.

Coordination N.B. If the patient can walk, and if the history suggests
• Heel–knee–shin test: the patient lifts one leg, places it on a disturbance of gait or lower limb function, it is often
the opposite knee and runs it down the shin. preferable to begin the lower limb examination by asking
• Rapid tapping movement of the feet against the the patient to stand and walk.
examiner’s hand.
• Toe–finger test Functional consequences
It is important to observe the functional consequences of any
N.B. Tests of coordination require reasonable muscle neurologic impairment on the patient’s activities of daily
power. living, such as dressing, feeding, grooming, and walking.

Sensation CONCLUDING THE CONSULTATION

As for the upper limbs. Frequently patients have certain ideas about what their
symptoms are due to (and they may well be right) or they may
Stance and gait be fearful that they have a certain diagnosis (such as one that
• Ask the patient to walk 10 m (33 ft), turn around, and afflicted a friend or family member, such as a brain tumor). By
walk back. asking the patient ‘What do you think the problem is?’ can
sometimes be helpful in management (e.g. if the patient says
Note the speed of initiation of gait, the posture, stride they think it is due to stress and you agree with them), and
length, heel strike, and extent and symmetry of arm swing. sometimes it allows the clinician to be able to reassure the
As the patient turns, pay particular attention to the number
of steps taken to turn and any evidence of slight
overbalancing that may occur with extrapyramidal or
cerebellar lesions. Dystonic movements and tremor are also 20
often enhanced by walking. Pyramidal tract lesions cause the
foot to drag and the toes to scuff (spastic foot drop) because
of involuntary plantar flexion and inversion of the foot to
varying degrees. The knee flexes less than normal (or not at
all) and with unilateral lesions in particular, the pelvis rocks
to the normal side to help raise the dragged foot from the
floor and overcome weakness of the hip abductors (a
Trendelenburg-type gait).
Flaccid foot drop is manifest by the feet having to be
lifted high to avoid catching the toes on the floor. If the
foot is also stamped on the floor, joint position sense is likely
to be impaired. Foot drop may be bilateral (e.g. distal
[sensori-]motor, sciatic or peroneal neuropathies) or
unilateral. A high-stepping gait and stamping is a classical
sign of tabes dorsalis.
Ask the patient to:
• Walk heel-to-toe to test tandem gait; patients with a
lesion of the cerebellar vermis may only manifest truncal
ataxia and have no evidence of limb ataxia on finger–nose
and heel-knee-shin testing.
• Walk on the toes (to detect weakness of the gastrocnemii
due to a sciatic nerve or S1 nerve root lesion, for
example, that may be difficult to elicit otherwise).
• Walk on the heels (to detect weakness of tibialis anterior
due to a peroneal nerve or L4/L5 root, or pyramidal 20 ‘Scout’ view for a CT brain scan.This consists of a lateral view of
tract lesion for example). the skull (usually) with lines representing the axial image positions
superimposed. Note the number at the left-hand end of each line
corresponds with the axial image of that number.
 Imaging the Brain 23

patient that they have not got what they a fearing. Alterna-
tively, the patient may be asked: ‘Do you have any concerns
about what the problem/diagnosis might be?’, or ‘Has anyone
suggested what the problem/diagnosis might be?’.
One of the most frequent complaints patients and
families make about doctors is that the doctor did not
explain (or they could not understand) what had happened
and what was likely to happen. So conclude the consultation
by asking the patient: ‘Do you have any questions or would
you like to discuss anything else?’.
IMAGING THE BRAIN
COMPUTERIZED TOMOGRAPHY (CT) SCANNING
Advantages
CT (20–24) is a great technique, particularly for acutely ill
patients, due to its rapidity, ease of access to the patient, and
relatively wide availability. It is useful in acute neurology in
patients with headache, focal neurologic deficit, loss of
consciousness, and suspected subarachnoid hemorrhage,
hydrocephalus, brain tumor, stroke, brain abscess, prior to
lumbar puncture and for demonstrating cerebrospinal fluid
(CSF) leaks, and for paranasal sinus and mastoid diseases. It
is vital following head and spine trauma, facial fractures,
skull base bone lesions and for post-operative neurosurgical
complications. In the spine it is most useful in trauma, for
lumbar discs, and combined with myelography for thoracic
and cervical lesions.

21–23 Axial views from a 21 22

normal CT brain scan
taken on soft tissue
window settings, at the
level of the fourth ventricle
21), the third ventricle
(2
22) and the bodies of the
(2
23).
lateral ventricles (2

24 Axial view of the skull 23 24

base from a normal CT
brain scan imaged on bone
window settings to display
bone detail optimally (but
at the expense of soft
tissue detail).
24 Neurologic Diagnosis
Disadvantages
CT uses ionizing radiation (an average brain CT scan
exposes the patient to the equivalent of a year of
background radiation!). It is not so good for demonstrating
white matter diseases (such as multiple sclerosis [MS]),
encephalitides, small lesions in the temporal lobes and
posterior fossa (because of streak artefact from the adjacent
bones) and spinal cord lesions.
Technique
A standard CT brain scan consists of 10 to 15 axial slices
from the foramen magnum to the vertex at about 1.0 cm
intervals (0.5 cm slice intervals through the posterior fossa).
Modern scanners will produce many more thinner slices
very quickly, but there is the danger of increasing radiation
without necessarily increasing diagnostic yield.
The basic scan can be modified to include thinner slices at
narrower intervals to show greater detail (e.g. in the pituitary
fossa or orbits), or at different scan angles (e.g. coronal), or
after an injection of intravenous iodinated x-ray contrast (e.g.
iopamidol), or using different scan parameters to demonstrate
bone optimally. A standard scan takes less then 2 minutes to
perform with modern technology (not including the time
taken to get the patient into and out of the scanner).
Precautions
Patients who are, or might be pregnant should not undergo
CT unless absolutely essential. If CT is essential, the
abdomen and pelvis should be shielded with lead aprons.
Patients with previous allergic reaction to iodinated
contrast should not be given contrast again (although it is
worth checking out the patient’s story in some detail as
often so-called ‘allergic reactions’ are in fact something else).
Patients with atopic history are more likely to have a de
novo contrast reaction than those without an atopic history.
Scan techniques these days are complicated with lots of
different possible ways of conducting the investigation. In
order to get the answer to the patient’s problem with imag-
ing, it is essential to give the radiologist ALL the relevant
information or you may end up having to repeat the scan
because it was not done in the correct way (to demonstrate
whatever disease condition) the first time, thus exposing the
patient to the inconvenience of an additional scan plus an
extra year’s worth of background radiation! The same applies
to all radiologic investigations. There is no such thing as a
simple and hazard-free radiologic test. So use them wisely!
Appearance of various tissues on CT
The appearance of a tissue on CT depends on how much
radiation it absorbed as the x-ray beam passed through it,
which in turn is dependent on the atomic number of its
main components. The higher the atomic number, the
greater the absorption. Densely calcified structures like bone
absorb most radiation so look white; fresh blood is less
white; gray matter is gray but whiter than white matter;
white matter is gray but a bit darker; CSF (basically water)
looks black; fat looks even blacker; and air (which absorbs
virtually no radiation) looks very black.
HOW TO REVIEW A CT SCAN
Most scans, be they CT or MR, are displayed in more or less
the same way on the hard copy. The hard copy is printed onto
radiographic film and transilluminated to view. There are
usually about 12 images on each film. Usually the scan starts
at the posterior fossa and works up to the vertex. A ‘scout’
view (like a lateral skull x-ray) showing where in the patient
the image slices have been taken, is usually displayed at the
start or the end of the sequence of images (20).
Usually the right side of the patient is on the left side of
the film, but check! – some scanners display the other way
round. A large ‘R’ or ‘L’ should indicate which is which.
Each image shows the patients name, and often a date of
birth, and the date of the scan – all useful information:
50 year old females have a different range of disease from
20 year old males.
To read the images, follow a system much as you would
do to examine the patient, that way you will not miss things.
Start at the bottom of the head and work up: look at the
orbits, skull base including neural foramina, and petrous
bones. Then look at the intracranial structures: the IVth
ventricle should lie slightly closer to the front of the posterior
fossa than the back (21). It should also be in the shape of a
‘frown’. If it is nearer the back or starts to ‘smile’, there may
be a mass distorting it.
The brain stem and midbrain and surrounding CSF spaces
should be symmetrical. The pituitary fossa, IIIrd ventricle,
basal ganglia, lateral ventricles, cerebral white matter and
cortex should all be symmetrical with similar appearance of
the frontal, parietal, temporal and occipital lobes. It is worth
‘eyeballing’ these lobes and the basal ganglia in turn, this
helps to highlight subtle abnormalities (and make obvious
ones more visible for the learner). If you do all this each time,
you will not miss anything.
Finally, if you cannot see anything wrong, double check
the orbits, pituitary fossa, posterior fossa and basal ganglia
(review areas where people tend to miss things), and possibly
suggest that the patient be given contrast.
The review of spine images is on similar principles but the
scout view is very useful as it helps you keep your bearings.
There is nothing worse than getting the disc level wrong.
Count carefully and use the slice number to line up with the
numbering on the scout view. Really helpful scanners display
a mini scout view in the corner of each scan image.
MAGNETIC RESONANCE (MR) IMAGING (MRI)
The principles behind how you produce a picture of the brain
by putting the patient into a strong magnetic field are
completely beyond the scope of this book and will not be
discussed further. It is more important for the neurology
student to know about the advantages and disadvantages of
MR and a few basics about what tissues look bright or dark.
The principles of reading an MR scan (25–28) are the same
as for a CT scan, except that there are usually far more images
to go through (so rather more daunting) including a midline
sagittal set (which are useful for impressing your tutors by
looking for herniation of the cerebellar tonsils). Thus apply
the principles outlined above and you will not go far wrong.
Advantages
The principal advantages of MR are its great ability to
demonstrate soft tissue detail especially in the brain and
spinal cord, muscles, ligaments and cartilages.
In neurology it is very useful for demonstrating
suspected white matter diseases (such as MS, encephalitis,
metabolic disease), cervical and thoracic cord disease,
metastatic involvement of the spine, lumbar discs (though
CT is good for that too), precise delineation of tumors,
posterior and pituitary fossa diseases.
 Imaging the Brain 25

It can be used to show blood vessels (arteries and veins)
inside the head and in the neck (MR angiography [MRA]),
perfusion and diffusion of fluids in the brain and metabolites
in the brain (using advanced techniques such as MR
spectroscopy).
Images can be obtained in any plane, at millimeter
intervals, with paramagnetic contrast for demonstration of
areas of blood–brain barrier breakdown, and using all sorts
of fancy sequences to highlight different features.
Disadvantages
Having a cardiac pacemaker or intracranial aneurysm clip or
metallic intraocular foreign body are all absolute contra-
indications to MR (the pacemaker will stop working, the
aneurysm clip may move and tear the artery and the ocular
foreign body may move causing an intraocular hemorrhage).
Relative contraindications include other metallic
prostheses or foreign bodies, or tattooed-in eyeliner
(contains metallic particles which can cause burns). All
patients are carefully screened for these factors and x-rayed
if necessary to exclude intraocular foreign bodies. Welders
particularly are prime suspects for intraocular foreign bodies.
Deodorants and talcs and eye makeup must be removed as
they may contain metallic bits.
Claustrophobic patients may have difficulty going into
the very enclosed space of the scanner (though modern
scanners are becoming more open access).

25 T1W midline sagittal 25 26

view of the brain. Note
the brain appears as a
rather bland gray texture
and CSF is black.
Subcutaneous fat is
white.

26 T2W axial view of

the brain. Note the CSF
appears white, the gray
matter appears whitish
and white matter dark.
The gray matter is easily
differentiated from the
white.

27 Proton density (PD) 27 28

weighted axial view of the
brain. Note the CSF is
grayish and difficult to
distinguish from brain, gray
matter is whiter than white
matter.

28 Magnified T1W
coronal image of the
pituitary gland (long
arrow), optic chiasm
(arrow head), pituitary
stalk (short arrow), and
internal carotid arteries * *
(asterisks).
26 Neurologic Diagnosis
Appearance of various tissues on MR
The two basic sequences which are most commonly used
are called ‘T1’ and ‘T2’ weighted.
On T1 weighted (T1W) images CSF looks black, gray
matter looks dark gray, white matter looks pale gray, fat
looks white, blood varies with the age of the hematoma,
flowing blood, bone and air look black.
On T2 weighted (T2W) images CSF looks white, gray
matter looks pale gray, white matter looks dark gray, fat
looks white (depending on where it is), blood varies with
the age of the hematoma, and flowing blood, bone and air
look black.
How to review an MR scan
The method of reviewing an MR scan is the same as for CT
(it’s a brain or spine after all!) but there are more images in
different planes to look at. The trick is to work through
them systematically. Do not expect the answer to leap out
at you and do not feel conscious of how long you are taking
to review the film, just take your time and be thorough.
POSITRON EMISSION TOMOGRAPHY (PET) AND
SINGLE PHOTON EMISSION COMPUTED
TOMOGRAPHY (SPECT) SCANNING
PET and SPECT are isotope techniques whose use is mainly
confined to research work. Some centers may use either or
both for cerebrovascular disease, diagnosis of dementias,
diagnosis of post-radiation necrosis, investigation of
temporal lobe epilepsy, but as neither is widely available,
both are expensive and require a source of isotopes, their
use is likely to remain mainly experimental for the foresee-
able future.
OTHER MISCELLANEOUS TECHNIQUES
CT cisternography
This technique is used when a CSF leak from the skull base
is suspected, to identify the site of the leak prior to surgical
repair. About 5–10 ml of x-ray contrast (iopamidol 300 or
equivalent) is introduced into the spinal subarachnoid space
through a lumbar puncture and run up into the head by
putting the patient in the prone head-down position for a
few seconds.
The patient will experience a sudden, severe headache as
soon as the contrast enters the head due to the meningeal
irritation. The patient is then transferred to the CT scanner
in the prone position and scanned in the coronal plane
through the paranasal sinuses from the front of the frontal
to the back of the sphenoid sinuses. Leakage of contrast is
shown by the high density contrast passing into the sinus
from the cranial cavity and possibly by an associated break
point in the bone of the skull base.
This is an invasive procedure and should not be
undertaken unless a direct therapeutic maneuver is planned
and CSF has been demonstrated in the nasal cavity by litmus
paper test. Occasionally it may be justified in patients with
no definite leak but who have recurrent meningitis which is
likely to be due to a dural tear allowing a direct connection
from the nasal to the cranial cavity.
Isotope cisternography
This technique is used in some centers to diagnose normal
pressure hydrocephalus by demonstrating a slow rate of
clearance of an isotope from the ventricles.
IMAGING THE CEREBRAL
CIRCULATION
CONTRAST ANGIOGRAPHY
This is an invasive technique which is used to obtain images
of the cerebral blood vessels. It can be done by inserting a
catheter into the femoral artery under local anesthetic,
wriggling it until the tip lies in one of the arteries to the
brain, then injecting about 5 ml (a teaspoon) of x-ray
contrast through it and taking x-ray pictures rapidly as the
contrast passes through the blood vessels (29–33). In the
old days the images were taken directly onto x-ray film and
then the bones had to be subtracted away by hand (very
tedious). Nowadays most modern angiography machines
take the images via a computer so that the bones can be
subtracted instantaneously, leaving the picture of the
contrast outlining the artery and nothing else (digital
subtraction angiography).
A variation of this process is to inject a larger amount of
x-ray dye (up to 100 ml) through a large bore catheter
inserted into a peripheral arm vein, waiting until the bolus
of contrast passes through the heart, round the lungs, back
to the heart and up into the head arteries and then taking a
rapid set of pictures of the blood vessels in the head or neck.
The bones are then subtracted off instantaneously as for the
intra-arterial version to leave just the blood vessels outlined
with x-ray contrast. This is called intravenous digital
subtraction angiography (IV DSA), but results in poorer
quality images (than the intra-arterial version) and at some
risk (due to the greater risk of allergic reactions, cardiac
failure and arrhythmias due to irritation from the large
volume of contrast). The contrast gets diluted as it passes
29
3
2
2
3
4
4
1
29 Normal arch aortogram done by injecting contrast into the aortic
arch and then digitally subtracting the bones to leave the image of the
contrast in the aortic arch (1), common carotid (2), vertebral (3) and
subclavian arteries (4).The origins of all the major head and neck
arteries are visible, though note there is some overlap.
 Imaging the Cerebral Circulation
through the heart resulting in poorer opacification of the
blood vessels plus there is overlap making individual blood
vessels difficult to see. IV DSA is not a good way of
investigating the cranial circulation for all these reasons and
it is much better to use intra-arterial angiography.
Intra-arterial angiography with selective injection of the
carotid or vertebral arteries is the gold standard for the
delineation of the cranial vasculature. It is risky and invasive
and often requires an overnight stay in hospital. In the
general population it has a 1% risk of stroke and 0.1% risk
of death. In the subsection of older patients with
symptomatic ischemic cerebrovascular disease who have
been screened with doppler ultrasound and are known to
have a carotid stenosis, the risk of intra-arterial angiography
is greater: 4% risk of stroke and 1% risk of death as a direct
result of the procedure even in experienced hands. Thus it
should not be undertaken lightly.
30
3
2 1
30 Anteroposterior intra-arterial digital subtraction angiogram (DSA)
showing the internal carotid (1), middle cerebral (2) and anterior
cerebral (3) arteries (arterial phase).
32 Lateral view of
same arteries as in
30 but in the
capillary phase.
33 Anteroposterior
view (DSA) of the
venous phase of the
intracranial
circulation following
intra-arterial
injection.The sagittal
(1), both transverse
(2) and sigmoid (3)
sinuses are clearly
seen.
27
Interpretation of cerebral angiograms
The detailed identification of intracranial arteries and veins
is a job for the neuroradiologist. The neurologist should
know that the carotid arteries supply the front 2/3 of the
cerebral hemispheres, the vertebral arteries the back 1/3,
brainstem and cerebellum, there are about 90 possible
variations of the anastomotic pathways around the circle of
Willis, and there are lots of potential collateral pathways
between the intra- and extracranial arteries which can open
up if an internal carotid or vertebral artery gets blocked.
The main abnormalities which one might see on an
angiogram include carotid stenosis (focal narrowing of the
artery), an aneurysm (focal little balloon-like outpouching),
an occlusion (abrupt end to the artery), vasculitis (focal
dilatation and narrowing of the fine branches of the
intracranial arteries), and arteriovenous malformations
(irregular networks of wriggly arteries and veins which fill
31
3 2
31 Lateral view of the same arteries as in 30.
32 33
1
2
2
3
3
28 Neurologic Diagnosis
quickly before the normal cerebral veins and can occur in
any part of the head) and tumor blood supply (usually a
‘blush’ or contrast with displacement or enlargement of
arteries and veins).
MAGNETIC RESONANCE ANGIOGRAPHY (MRA)
MRA is a recent technique in which the patient lies in the
MR scanner (so all the above contraindications and
precautions apply) and the scanner uses the fact that the
moving blood will have different magnetization from the
static brain to produce an image of the blood vessels (34,
35). This can be used to look at arteries or veins but there
are a number of pitfalls for the unwary:
• The patient must keep very still (i.e. not swallow if the
examination is on the neck).
• A tight stenosis in the internal carotid artery may result
in a ‘flow void’ or area where the artery apparently
disappears due to the very fast flowing blood.
• Although there have been numerous studies comparing
MRA with conventional angiography and ultrasound and
CT angiography, MRA is still undergoing development,
has problems with observer reliability and should not be
regarded as an alternative to conventional angiography
just yet.
CT ANGIOGRAPHY
The development of very fast CT scanners which can scan
through a long distance in the body (around 10 cm [4 in])
34
2 3
1 systole (arrow) which is a
35 1 carotid bulb.
2 3
5
4
34, 35 Anteroposterior (3 34) and axial (3
35) views of an MRA (3D) of
the circle of Willis. Note the internal carotid (1), middle (2), anterior
(3) and posterior (4) cerebral arteries and the basilar tip (5). On the
left there is a dominant posterior communicating artery feeding the
posterior cerebral artery (arrow).
in one go has led to the development of CT angiography.
In this technique a large intravenous injection of x-ray
contrast is given into an arm vein (around 100 ml) and a
very rapid scan performed through the length of artery
which is to be imaged. The cross-sectional images thus
obtained are processed through the scan computer to
produce 2D or 3D reconstructions of the arteries with the
bones and soft tissues subtracted away.
This technique, like MRA, is very promising for the
visualization of carotid stenoses, intracranial aneurysms and
arteriovenous malformations, but is still under evaluation and
is not yet an alternative to conventional selective intra-arterial
angiography. All the contraindications to CT and x-ray
contrast described above apply including the real risk of
precipitating cardiac failure or renal failure in elderly patients.
ULTRASOUND
Color doppler ultrasound is the method of choice for
screening patients for significant disease of the neck arteries,
but only in experienced hands (36–39). There is no place
for dabbling in it. It looks easy but is notoriously littered
with pitfalls for the unwary inexperienced operator. It is
however totally safe and pleasant for the patient and quick
– an average neck examination takes about 15 minutes.
Ultrasound of the brain in adults is of use in research but
is not yet appropriate for use in clinical practice with the
exception of intraoperative ultrasound which is increasingly
used in neurosurgery.
36 36 Color Doppler
ultrasound. Normal internal
and external carotid arteries
in systole (top) and diastole
(bottom). Note the blue
flash in the carotid bulb in
normal finding due to eddy
currents swirling in the
 Imaging the Spine
37
37 Color doppler ultrasound. Origin of the vertebral artery (arrow)
from the subclavian artery (arrowhead).This is usually visible unless the
chest is hyperinflated or the patient is very obese.
38
38 Color doppler ultrasound.Vertebral artery in the vertebral canal.
Note the regular shadows (arrows) cast by the vertebrae which
intermittently obscure the view of the artery.
39
29
IMAGING THE SPINE
MYELOGRAPHY
Myelograms were widely used in the past to investigate spinal
disease at all levels (called a radiculogram when confined to
the lumbar region). MRI has largely replaced myelography
although there is still occasionally the need for it in patients
who cannot tolerate MRI or who have pacemakers or other
internal devices which are contraindications to MRI.
About 10–12 ml of x-ray contrast are introduced
through a lumbar puncture (LP) into the spinal subarach-
noid space. The patient’s position is altered to make the
contrast, which is heavier than CSF, roll into the areas of the
spine to be examined. The contrast outlines the nerve roots
and spinal cord and a standard series of x-ray pictures are
taken (see 700, 709–711). The procedure is invasive, so all
standard sterile precautions must be taken. The smallest
possible LP needle is used (this reduces post-LP headache).
Myelography is contraindicated in patients with epilepsy
(the contrast agent is epileptogenic) though this is relative,
and pregnant patients (though can be done with lead
shielding if absolutely necessary). Caution is required in
patients with asthma, atopic history or history of previous
contrast reaction.
After the myelogram, patients should be encouraged (1)
to drink extra fluid to keep well hydrated and (2) not to lie
flat as that helps stop the contrast entering the head and
causing a bad headache. Note this is contrary to standard
post-neurologic LP instructions. If the patient gets a
headache after the first 24 hours they can lie flat (at that stage
it is usually a low pressure headache due to continuous CSF
leakage through the LP site) and keep drinking extra fluid.
CT MYELOGRAPHY
After the x-ray contrast is put into the spinal CSF, CT scans
can be obtained through an area of interest to help delineate
discs or osteophytes, or whatever.
In the lumbar region, CT without contrast is useful for
examination of patients with suspected disc prolapse, but
above the upper lumbar region it is no good for spinal cord
or root abnormalities because there is not enough natural
contrast between the CSF and cord. Thus x-ray contrast must
be put into the CSF to examine the thoracic or cervical
regions. However, for purely bony problems such as deline-
ation of fracture fragments, plain CT is satisfactory (see 62).
39 Color doppler ultrasound. Color ‘power’ doppler ultrasound of the
circle of Willis looking axially across the cranium through the temporal
bone window.The patient’s face is to the left of the image and the back
of the head to the right.The tips of the internal carotid arteries
(arrows), the anterior (arrowhead) and posterior (short arrow)
cerebral arteries are visible.
30 Neurologic Diagnosis

MRI OF THE SPINE
MR is an excellent tool for delineating all sorts of spinal or
nerve root disease or disease of the surrounding bones (not
fractures) (40–43).
Midline sagittal images can be obtained of the whole
spine using a body coil (not so much detail but good
coverage), or of localized bits of spine using a spine coil
(more detail but less coverage). Thus if you are not sure
where a lesion might be you are better to say that on the
request form because then the radiologist will try to cover
a larger area of the spine.

40 41

40, 41 MRI cervical spine of a 35 year old woman who presented

with a subacute Brown–Sequard syndrome of left hemisensory
disturbance below C5 and right leg weakness in a pyramidal
distribution. 40 Sagittal plane,T2W MR image, shows an ovoid shaped
white area of increased signal (arrow), representing demyelination, in
the upper cervical spinal cord at the level of C3, measuring about
1 cm (0.4 in) in cranio-caudal dimensions, and about 5 mm (0.2 in)
in maximum diameter. 41 Axial plane,T2W MR image at C3 showing
the lesion in the right hemi-cord (arrow).

42 43

42, 43 MRI cervical spine, fast spin echo T2W images, sagittal (4 42)
and axial (443) sections, showing a heterogeneous hypointense and
hyperintense mass in the left side of the upper cervical spinal cord (C1
to C3), and hyperintense edema extending superiorly to the obex and
inferiorly to the lower border of C5, with swelling of the cord.The
lesion is a cavernous hemangioma.
 Lumbar Puncture (LP) and Cerebrospinal Fluid (CSF) Examination
LUMBAR PUNCTURE (LP) AND
CEREBROSPINAL FLUID (CSF)
EXAMINATION
TECHNIQUE
• Ensure the patient is not drowsy and does not have
papilledema or focal neurologic signs that are
unexplained (i.e. that the patient is not at risk of coning
with lumbar puncture, see Complications below).
• Explain the procedure to the patient and why it is being
carried out.
• Lay the patient on their side on the near edge of a firm
bed, with the back and legs flexed as much as possible.
Place a pillow between the knees and ensure the
shoulders and pelvis are perpendicular to the floor.
• Ensure the patient is comfortable.
• Identify and mark the L4 and L5 vertebral spinous
processes, the former of which lies between the anterior
superior iliac spines; the caudal part of the spinal cord
ends about the level of the interspace between the first
and second lumbar vertebrae.
• Wash your hands and put on a sterile gown and gloves.
• Sterilize a large area of skin over the lumbosacral spine
and drape the area.
• Draw up 7 ml of 2% lignocaine and inject the skin and
subcutaneous tissue down to the supraspinous ligament,
and even the epidural space, between the L4 and L5
vertebral bodies.
• Wait a few minutes for the local anesthetic to work,
during which time check that the stylet tip is smooth and
flush with the outer hollow needle, and assemble the
three-way tap to the manometer.
• Insert the lumbar puncture needle (20 gauge atraumatic
needle) in the midline of the L4/5 interspace, and advance
it in the sagittal plane, parallel to the floor and at a slight
angle towards the patient’s umbilicus (44). Resistance is
felt as the needle penetrates the supraspinous ligament and
again at the dura. After penetrating the dura, remove the
stylet and, if the needle is in the spinal subarachnoid space,
CSF will flow out of the needle. Attach the three-way tap
and manometer and wait a minute or so for the CSF to
rise up the manometer and stabilize before recording the
CSF pressure (in millimeters of CSF; normal less than
about 200 mm CSF). Check that the CSF moves up and
down a little in the manometer with respiration or with
relaxing the legs (i.e. extending the hips a little).
• Empty the CSF from the manometer into one sterile
bottle for biochemical examination (protein, glucose,
IgG/albumin ratio, oligoclonal bands) and then allow
another 3–5 ml of CSF to run from the needle into a
sterile bottle for microbiologic examination (cells,
culture) and another bottle for DNA analysis (e.g.
polymerase chain reaction), spectrophotometry, or
cytology. Label the sterile bottles first, second and third.
• Remove the needle, place a band-aid/plaster over the
skin puncture and advise the patient to lie down in any
comfortable position for an hour or so before getting up.
Warn the patient that if they get a headache when sitting
or standing up, to lie down and drink plenty of fluids.
• Take a simultaneous blood glucose test.
• Send the CSF and blood specimens to the appropriate
laboratories immediately. Otherwise refrigerate them at
4°C (39.2°F).
31
• If a lumbar puncture needs to be repeated within 1 or
2 weeks, do not use the same interspace because the
needle may not go into the subarachnoid space but
rather an epidural or subdural collection of CSF that has
formed via a dural leak.
Problems
If the needle hits bone or a nerve root, evoking root pain
down the leg, withdraw the needle to the subcutaneous
tissue, check the alignment of the needle in the sagittal,
coronal and axial planes, and re-insert it.
If CSF does not flow, despite the needle seeming to be
in the subarachnoid space, do not attempt to aspirate CSF
but try rotating the open needle slightly. Rarely, a ‘dry tap’
is due to a compressive lesion of the cauda equina or chronic
adhesive arachnoiditis.
If fresh blood emerges from the needle, the needle may
be in the epidural venous plexus or occasionally a small
blood vessel on one of the nerve roots, causing a ‘traumatic
tap’, or it may be from a subarachnoid hemorrhage. Try
again through another disc space (e.g. L3/4).
If the lumbar puncture fails, try again through the L4/5
interspace, and then if necessary the L3/4 interspace. Do not
go any higher than this because the caudal part of the spinal
cord, which ends about the level of the interspace between
the first and second lumbar vertebrae, may be injured by the
needle. Attempts lower than the L4/5 interspace may not
be fruitful because the dural sac containing CSF may have
ended. Alternatively, try again with the patient sitting up
rather than lying on their side, and consider using a standard
needle in patients with a high body mass index; atraumatic
needles have a higher failure rate than standard needles in
patients with a high body mass index.
If lumbar puncture is impossible, a lateral cervical
approach under x-ray control is an alternative. Cisternal
puncture should not be required.
44
Dura mater
Subarachnoid
L4 space
Interspinous containing CSF
ligament
Vertebral body
L5
Supraspinous Intevertebral
ligament disc
S1
Skin
44 Midline sagittal section through the mid-lumbar spine to show the
course of a lumbar puncture needle.
32 Neurologic Diagnosis
COMPLICATIONS
• Herniation of the medial temporal lobe through the
tentorial opening (transtentorial herniation) or of the
medulla through the foramen magnum (coning), leading
to medullary compression and death (45). This is the most
serious complication but can be avoided by never doing a
LP if there is clinical evidence of raised intracranial pressure
(see p.477), or focal cerebral or posterior fossa signs. If
there is raised intracranial pressure with shift of the
intracranial contents, or obstruction to CSF flow, then
removing CSF by LP, or continuing leakage of CSF after
the LP, may create a lower pressure in the vertebral canal
than in the intracranial compartments, leading to mass
movements and herniation of the brain. On the other
hand, if there is diffusely raised intracranial pressure with
free flow of CSF through all parts of the intracranial and
spinal CSF compartments, which can only be discerned
with CT or MRI scan, then LP should be safe.
• Spinal nerve root damage, usually caused by inserting the
needle lateral to the midline.
• Low-pressure headache (30% [1–70%] of LPs) due to
continuing CSF leakage through the hole in the dura. It is
present only after sitting or standing for minutes to hours
and is relieved by lying down. If the headache comes on
suddenly or is accompanied by drowsiness, then perform a
CT scan to see if an intracranial subdural or subarachnoid
hemorrhage is present. Treatment otherwise involves the
patient lying flat in bed with the foot of the bed elevated
and drinking plenty of fluids. If the headache persists then
it can be stopped in some patients by an autologous blood
‘patch’ in the epidural space over the site of the presumed
dural hole or, as a last resort, by open surgery to seal the
dural leak. Strategies to minimize the incidence of post-LP
syndrome are to use a needle of small diameter and
atraumatic shape, and to reinsert the stylet before removing
the needle. Otherwise a strand of arachnoid that may have
entered the needle with the outflowing CSF may be
threaded back through the dural defect and facilitate
prolonged CSF leakage along the arachnoid.
• Infection of the CSF, or an epidural abscess, if sterile
precautions are not taken or if the needle is inserted
through inflamed or infected skin.
• Transient back stiffness. If persistent, consider a spinal
hemorrhage.
• Spinal hemorrhage (epidural, subdural, or subarachnoid).
This may manifest as severe back and/or nerve root pain,
nerve root compression or spinal cord compression, but
is very rare unless the patient has a bleeding diathesis
(e.g. platelet or coagulation defect).
• Intracranial subdural and subarachnoid hemorrhages are
very rare.
INDICATIONS
• Diagnosis: suspected subarachnoid hemorrhage, menin-
gitis, encephalitis, MS, dementia and idiopathic intra-
cranial hypertension.
• Investigation: previously to introduce contrast media
such as metrizamide for myelography and CT scanning,
radioisotopes for ventriculo-cisternography, and air for
pneumoencephalography; MRI has superseded these.
• Treatment: to introduce local spinal anesthetics and occa-
sionally antibiotic or antitumor agents into the subarach-
noid space, and to remove regularly CSF to lower the CSF
pressure in idiopathic intracranial hypertension.
CONTRAINDICATIONS
• Intracranial space-occupying lesion (e.g. abscess, hema-
toma, tumor), particularly in the posterior fossa.
• Obstructive hydrocephalus.
• Generalized brain edema with obliteration of the CSF
cisterns around the upper brainstem.
• If a CT scan is not available, then LP is contraindicated
in patients with clinical features suggestive of the above
three conditions (e.g. papilledema and/or focal neuro-
logic signs and/or coma). If bacterial meningitis is
suspected, it is essential to treat the patient immediately
and empirically with broad spectrum antibiotics (after
collecting blood cultures) rather than risk brain
herniation by performing a lumbar puncture in order to
obtain CSF and isolate the organism (see p.273).
• Infection of the skin in the lumbar region.
• Bleeding diathesis.
NORMAL VALUES
• Pressure. Less than 250 mm of CSF/water, and usually
less than 200 mm, if the patient is relaxed and there is
free flow of CSF (the CSF fluctuates in the manometer
with respiration and coughing). Falsely low CSF pressure
may be due to removing too much CSF before
measuring the CSF pressure, a CSF leak around the
needle, transtentorial herniation and brainstem coning.
• Red blood cells: normally the CSF is clear with no red
blood cells (RBC). If the CSF is bloody it should be
centrifuged immediately and the supernatant examined
by spectrophotometry (or, if not available, the naked
eye). Yellow (xanthochromic) pigmentation is due to the
breakdown of products of hemoglobin (e.g. oxyhemo-
globin and bilirubin), and is seen in patients with
subarachnoid hemorrhage (at least 12 hours before),
jaundice or a very high CSF protein. Pinkish pigmen-
tation is due to hemoglobin from disintegrated RBCs.
45
45 A potential complication of lumbar puncture if the patient has an
intracranial mass lesion. Photograph of the under-surface of the
cerebellum showing swelling and grooving of the inferior mesial parts
of both cerebellar hemispheres (mainly the ventral paraflocculi or
tonsillae) (arrows) which have herniated, with the medulla, through the
foramen magnum, and compressed the medulla. (Courtesy of
Professor BA Kakulas, Royal Perth Hospital, Australia.)
 Electroencephalography (EEG) 33

• White blood cells: <5 lymphocytes per mm3 and no
polymorphs. If the CSF is contaminated by blood from
a traumatic tap, one alternative is to repeat the CSF after
a few hours (through a different lumbar interspace) or
to calculate the number of white blood cells (WBC) that
have been introduced into the CSF from the traumatic
bleed by using the following formula: (WBC in
peripheral blood/RBC in peripheral blood) × RBC CSF.
As there are about 1000 times more RBC in the
peripheral blood than WBC, this formula is usually about
0.001 × RBC CSF. An estimate of the true CSF WBC
count can then be made by subtracting the number of
WBC introduced from the number observed but, as this
tends to be an over-estimate, it is best to consider a definite
excess CSF WBC count as the ratio of observed CSF WBC
to calculated number of WBC introduced exceeding 10.
• Glucose: normally more than 50% of the simultaneous
blood glucose.
• Protein: 0.15–0.45 g/l (15–45 mg/dl), depending on
the laboratory. A very high CSF protein concentration
causes the CSF to clot (Froin’s syndrome).
• Immunoglobulin G (IgG) is a component of the CSF
protein, normally making up less than 15% of the total
protein.
• IgG/albumin ratio in the CSF is normally less than
about 0.25.
• IgG index ([CSF IgG/serum IgG]/[CSF albumin/serum
albumin]) is a better measure of CSF IgG because it takes
into account the serum level of IgG and albumin; if the
IgG level in the blood is abnormal, it is otherwise difficult
to interpret the level of IgG in the CSF.
• Oligoclonal bands: perhaps a more sensitive measure of
locally synthesized immunoglobulin in the CSF. Polyacry-
lamide gel electrophoresis separates two or more gamma
globulins (IgG) in the CSF on the basis of their charge
and size, which appear as two or more bands. Need to
check that no similar bands are present in the serum.
ELECTROENCEPHALOGRAPHY (EEG)
DEFINITION
The EEG is a recording, by means of electrodes attached to
the scalp, of the electric field generated by the spontaneous
neuronal activity of the underlying brain. The recording
reflects the electric currents that flow in the extracellular space
and these in turn reflect the summated effects of innumerable
excitatory and inhibitory synaptic potentials that occur in
cortical neurons. The spontaneous activity of cortical neurons
is influenced by subcortical structures, especially the thalamus
and rostral brainstem reticular formation.
TECHNIQUE
Electrodes (usually 21), which are solder or silver–silver
chloride discs 0.5 cm (0.2 in) in diameter, are placed
equidistantly over the surface of the scalp according to an
international convention (10–20 System) (46). They are
attached to the scalp by means of adhesive material such as
collodion or bentonite (bentoquatam, quaternium-18
bentonite), using EKG paste under the electrode to make
contact with the scalp. They are wired up to separate
amplifying units, or ‘channels’. Potential electric differences
between pairs of electrodes or combinations of electrodes
can be recorded, amplified, and displayed on an oscilloscope
or digital screen or a paper trace moving at a standard speed
of 3 cm/s. The resulting EEG or voltage-versus-time graph
appears as a number of parallel wavy lines, each representing
one channel.

Causes of an increase in CSF IgG and

oligoclonal bands
• Increased IgG in the blood and breakdown of the blood-
brain barrier. 46
• Contamination of the CSF by red cells.
• Multiple sclerosis.
• Meningitis.
• Encephalitis.
• Acute post-infectious encephalomyelitis. Fp1 Fp2
• Subacute sclerosing panencephalitis.
• Cerebral infarction.
• Brain tumors. F7 F3 Fz F4 F8
• Neurosyphilis.
• Sarcoidosis.
• Cerebral systemic lupus erythematosus.
• Acute inflammatory demyelinating polyradiculo-
neuropathy (Guillain–Barré syndrome). T3 C3 Cz C4 T4

CSF taken from the cervical spinal canal and the

ventricles contains fewer cells and has a lower protein
T5 P3 Pz P4 76
concentration (up to 0.15 g/l [15 mg/dl]) than lumbar
canal CSF, but the glucose concentrations are similar in the
different compartments. O1 O2

46 The international 10–20 electrode system.

34 Neurologic Diagnosis
Patients are usually examined in the awake state, lying or
sitting down in a quiet room with their eyes closed. The
resting electrocerebral activity is recorded for about
30 minutes, during which time a number of ‘activating’
procedures are usually carried out:
• Sleep: the patient is allowed to fall asleep, because sleep may
enhance potentially epileptogenic or epileptiform activity.
• Hyperventilation: the patient is asked to breathe deeply
20 times a minute for 3 minutes, evoking hypocapnia,
alkalosis and cerebral vasoconstriction. The rhythm slows
and a paroxysm of spike wave activity or another
abnormality may be induced.
• Photic stimulation: a powerful flashing light (strobo-
scope) is placed about 40 cm (16 in) from the patient’s
eyes and flashed at varying frequencies of 1–20 per
second with the patient’s eyes open and closed. The EEG
over the occipital region may show waves corresponding
to each flash of light (evoked response or photic driving)
or to abnormal discharges (e.g. a photoparoxysmal
response).
Other techniques that can be used to identify epileptic
foci include:
• Sleep recordings, which may reveal abnormalities not
evident when the subject is awake or in light sleep.
• Prolonged (6–8 hours) telemetric recordings.
• Video EEG.
RECORDINGS
Normal EEG recordings
Awake
Amplitude: 50–200 μV.
Waveforms/rhythms:
• Alpha waves: 8–13 per second (Hz), 50 μV sinusoidal
waves, recorded over the occipital region when the eyes
are closed and are attenuated or suppressed completely
by eye opening or mental activity. The occipital alpha
rhythm depends on synchronous discharge of cells in the
visual cortex.
• Beta waves: 14–22 Hz, low amplitude (10–20 μV) is
recorded maximally and symmetrically from the frontal
regions.
• Theta waves: 4–7 Hz, is prominent in children, gradually
diminishing during adolescence. A small amount of theta
activity may be normal over the temporal regions,
somewhat more so in older people (over 60 years of age).
• Delta waves: 1–3 Hz, 50–350 μV is a normal finding
only in early childhood; it is not present in the normal
waking adult.
• Mu rhythm: of alpha frequency but has a characteristic
appearance like the Greek letter μ or the top of a picket
fence, and is distributed asymmetrically in the central
regions of the head.
• Lambda waves: generated in the occipital region by
saccadic eye movements when the eyes are open.
Sleep
The alpha rhythm slows symmetrically and characteristic
waveforms (vertex sharp waves and sleep spindles) appear.
If sleep is induced by benzodiazepine or barbiturate drugs,
an increase in fast frequencies occurs normally.
Abnormal EEG recordings
• Absent brain waves – generalized ‘electrocerebral silence’:
the electric activity of the cortical mantle measured at the
scalp is absent or less than 2 μV. This may be due to
artefacts (which can be identified as the gains are
increased), hypothermia or acute intoxication with
anesthetic levels of drugs, such as barbiturates, and severe
diffuse cerebral ischemia and hypoxia.
• Absent brain waves – localized: indicates a large area of
brain softening, tumor or extra- or subdural hematoma.
This is rare because most lesions are not large enough to
abolish brain waves or prevent recording of abnormal
waves arising from the borders of the lesion.
• Slow waves (delta or theta) – generalized: encountered
in coma and any diffuse brain disorder such as a
metabolic/toxic disturbance.
• Slow waves – localized: recorded over the site of any focal
brain lesion such as a hemorrhage, infarct, herpes simplex
encephalitis, tumor.
• Spikes or sharp waves: transient high-voltage waveforms
that have a pointed peak at conventional paper speeds and
a duration of 20–70 ms. Spikes or sharp waves that occur
interictally are referred to as epileptiform discharges.
• Spike discharges or sharp waves – localized: indicate a
potentially epileptogenic focus.
• Combined spike and slow wave (spike wave) discharges
– generalized: ‘typical’ if well formed at 3 Hz; ‘atypical’
if of higher or lower frequency than 3 Hz and if their
pattern includes multiple spikes (polyspike wave
complexes) (47). Such patterns are commonly associated
with epilepsy.
• Periodic discharges: may occur regularly in certain
pancortical diseases such as Creutzfeldt–Jakob disease
(CJD), subacute sclerosing panencephalitis (SSPE) and
metabolic encephalopathies.
47
47 16 channel electroencephalograph of a patient who was confused
but able to answer simple questions, showing epileptiform features in a
patient with non-convulsive status epilepticus (arrowheads).
 Nerve Conduction Studies 35

ROLE NERVE CONDUCTION STUDIES

• Accurate diagnosis of epilepsy (see p.71).
• Determine the nature of some pancortical disturbances:
SSPE, CJD.
• Confirm the clinical localization of some brain lesions
(imaging techniques do this better).
• Monitor progress (e.g. HSE).
An EEG should only be requested if there is a clear
question to be answered and the question is answerable by
means of EEG. A succinct and relevant clinical history is
crucial to accurate interpretation of the recording.
INTERPRETATION
Considerable training, skill and caution is required to
interpret accurately the EEG. There is considerable variation
in the normal EEG and all too often minor deviations can
be erroneously diagnosed as abnormal or, even worse, as
indicative of epilepsy or other brain disorders.
These involve percutaneous stimulation of peripheral nerve
fibers and recording of the compound muscle and sensory
nerve action potentials.
MOTOR NERVE CONDUCTION STUDIES
An accessible motor or mixed sensori-motor nerve (e.g. the
median nerve at the wrist) is stimulated electrically through
surface electrodes applied to the skin and the resulting
compound muscle action potential (CMAP) is recorded by
surface electrodes on the skin over the motor end point of
the muscle (e.g. abductor pollicis brevis) (48). The CMAP
is filtered, amplified and displayed graphically on a digital
screen. The amplitude of the CMAP is measured in
millivolts and reflects the number of depolarized muscle
fibers. A reduced CMAP amplitude may indicate:
• Fewer motor fibers in the motor nerve (axonal
neuropathy).
• Fewer muscle fibers in a motor unit (denervated muscle).
• Temporal dispersion of conduction velocities
(demyelinating neuropathy).

The delay (latency) between the time that the stimulus

48 was delivered to the time of onset of the CMAP is measured
in milliseconds (e.g. the distal motor latency for median
A nerve stimulation at the wrist may be 3.6 ms in a patient).
If the same nerve is stimulated again, but at a more
B proximal point (e.g. the cubital fossa), the distance
measured between the two stimulus sites (e.g. 200 mm) can
C be divided by the difference in latency for the two responses
(7.6 ms–3.6 ms = 4 ms) to produce a conduction velocity
D in m/s (e.g. 50 m/s).
In newborn infants the motor conduction velocity is
E about one-half that of adults and increases with age to reach
‘adult values’ at about 3–5 years. The conduction velocity
F is a measure of the conduction in the fastest conducting
fibers in the nerve; the large diameter, well myelinated
nerves. Small myelinated and unmyelinated nerve fibers are
not assessed. Nerve conduction velocity is also influenced
A by temperature, decreasing by about 1.9 m/s per °C below
normal temperature. Because proximal nerve fibers have a
B
larger diameter and are a little warmer than distally,
conduction velocities are a little faster in proximal nerve
segments. Limb temperature must be known and controlled
C
before nerve conduction studies can be carried out and
interpreted reliably.
D
Normal distal motor latency to onset of CMAP ms
E Median nerve (wrist to abductor pollicis brevis, 6–8 cm) <4.2
Ulnar nerve (wrist to abductor digiti minimi, 6–8 cm) <3.5
F
Normal motor conduction velocities m/s
Median nerve in forearm >49
48 Upper diagram illustrates the CMAP recorded from the Ulnar nerve in forearm >51
hypothenar eminence after electrically stimulating the ulnar nerve at Common peroneal nerve (extensor digitorum brevis) >41
various points in the upper limb: the supraclavicular fossa (A), axilla (B), Tibial nerve >40
above and below the elbow (C, D, E) and wrist (F).
Lower diagram illustrates the SNAP recorded from various points in SENSORY NERVE CONDUCTION STUDIES
the upper limb after electrically stimulating the ulnar nerve in the little Antidromic conduction in accessible sensory or mixed
finger (orthodromic conduction). Note the different time and voltage sensori-motor nerves can be assessed by electrically
scale compared with motor nerve conduction studies above. stimulating the sensory nerve proximally (e.g. the median or
36 Neurologic Diagnosis
ulnar nerve at the wrist) and recording the resulting sensory
nerve action potential (SNAP) distally (e.g. from ring
electrodes around the index or little fingers respectively)
(48). Alternatively, orthodromic sensory conduction can be
assessed by electrically stimulating the distal sensory fibers
(e.g. of the median nerve in the index finger) through
surface (ring) electrodes applied to the skin and recording
the SNAP by surface electrodes on the skin over the nerve
more proximally (e.g. the median nerve at the wrist).
The SNAP reflects the number of nerve fibers that have
responded to the stimulus and conducted to the recording
point. Lesions of the sensory nerves distal to the dorsal root
ganglia lead to a reduction or loss of the amplitude of the
SNAP. Sensory nerve action potentials are of very small
amplitude (10–20 μV) compared with CMAPs (2–20 mV),
and consequently sensory nerve conduction velocities are
more technically demanding and less reliable than motor
nerve conduction studies. Sensory nerve conduction
velocity can be calculated by recording the SNAP at two
separate points over a nerve.
Normal sensory action potentials
Latency to peak (ms) Amplitude (μV)
Median nerve <3.5 >15
(wrist to index finger, 12–14 cm)
Ulnar nerve <3.1 >10
(wrist to little finger, 10–12 cm)
Sural nerve <4.0 >6
(point B, 14 cm)
These values depend on the age of the patient. The
temperature of the limb and the distance between the electric
stimulus and the recording site need to be controlled.
PATHOLOGIES
Four pathologic processes may affect peripheral nerves.
Wallerian degeneration
This follows mechanical injury (e.g. transection or crush) or
ischemia (e.g. vasculitis) of nerve fibers (49).
Neuropathology
• Within 4–5 days, both the axon and myelin distal to the
site of injury degenerate.
• The degenerating myelin forms linear arrays of ovoids
and globules along the degenerating axon.
• The axon of the proximal segment regenerates forming
sprouts which grow distally, and some re-innervate the
surviving distal neurilemmal tubes of the Schwann cell
basement membrane, inside which the Schwann cells
have divided and arranged themselves in line. The
regenerating axons are then myelinated by the Schwann
cells but the nerve fibers are smaller in diameter and have
shorter internodal lengths than originally.
Neurophysiology
• Following nerve transection, the fibers continue to
conduct impulses at normal or near normal conduction
velocities until about 1–4 days later when the fibers
become totally inexcitable and conduction ceases
altogether.
• Conduction may be restored following nerve fiber
regeneration but conduction velocities are rarely as fast
as previously.
Axonal degeneration
Follows most metabolic, toxic and nutritional diseases of
peripheral nerves, which result in a disturbance of the
metabolism of the cell body, or perikaryon, that impedes fast
axonal transport and other functions so that the most distal
parts of the axon (which may be up to 1 m (3.3 ft) from the
cell body) are affected first and die back from the periphery
(‘dying-back neuropathy’).
Neuropathology
Axonal degeneration of the distal portion of the nerve fiber,
similar to the Wallerian degeneration.
Neurophysiology
The intact proximal segments conduct normally but
conduction fails over the distal degenerating part of the
axon in the same way that it does in Wallerian degeneration.
Segmental demyelination
Follows primary damage of the myelin sheath by a
disturbance of Schwann cell metabolism (e.g. some
hereditary neuropathies), a direct immune-mediated attack
on the myelin or the Schwann cell (e.g. Guillain–Barré
syndrome), or toxic damage to the myelin sheath (e.g.
diphtheria toxin).
Neuropathology
• Demyelination usually begins paranodally and tends to
affect peripheral nerves proximally (e.g. the roots) and
very distally at the nerve terminal more than (or, as much
as) intervening regions.
• The axon remains intact unless demyelination is severe,
causing secondary axonal degeneration.
• Remyelination occurs when Schwann cells divide and
form new internodes of irregular length with thin myelin
sheaths.
• Repeated episodes of demyelination and remyelination
results in the formation of concentric layers of Schwann
cell cytoplasm around the axon (‘onion-bulb’ formations).
49
49 Autopsy specimen of the thoracic spinal cord in cross section
showing evidence of Wallerian degeneration of the contralateral and
ipsilateral corticospinal tracts (arrows) secondary to a more proximal
corticospinal tract lesion (i.e. internal capsule lacunar infarct).
 Nerve Conduction Studies
Neurophysiology
• Demyelination may result in slowing of conduction,
conduction block, inconsistent and incomplete trans-
mission of rapid trains of impulses, and increased
susceptibility to changes in temperature.
• In normal myelinated fibers, impulses conduct rapidly from
one node of Ranvier to the next by saltatory conduction.
• In demyelinated nerve fibers conduction between nodes
is delayed or, as with unmyelinated nerve fibers,
conduction becomes continuous across the demyelinated
segments. The delay in conduction results in slowing of
conduction velocity, temporal dispersion, and therefore
a slightly lower amplitude of the action potential.
• Conduction block is present when a proportion of nerve
fibers fail to transmit any electric impulses across a
demyelinated segment. When the stimulating electrodes
are moved proximally along the nerve segment, the
CMAP attenuates by more than 50% in area and
amplitude between a distal and proximal site of
stimulation, indicating failure of conduction in at least
some nerve fibers. Conduction block may be caused by
focal nerve compression and inflammatory neuropathies.
Neuronopathy or primary nerve cell degeneration
• Primary destruction of nerve cell bodies in the anterior
horn cells (e.g. spinal muscular atrophy, poliomyelitis,
amyotrophic lateral sclerosis) or dorsal root ganglia (e.g.
hereditary, Friedreich’s ataxia, paraneoplastic).
• The peripheral sensory axons degenerate distally and the
ascending sensory tracts in the posterior columns and
other spinal tracts degenerate proximally. As the cell
bodies are destroyed, there is no recovery.
LATE WAVES
F-waves
F-waves are late, small motor responses that are evoked by
a supramaximal stimulus of a motor nerve. The stimulus to
the nerve (e.g. the median nerve at the wrist) not only
activates motor fibers that travel orthodromically to produce
the initial direct muscle action potential but also activates
motor fibers that travel antidromically to the anterior horn
cells. Here, some anterior horn cells may be activated to
produce a later orthodromic response. So, after a latency
longer than that for the direct motor response, a second
small muscle action potential is recorded (F-wave).
The latency of the F-wave is a measure of the time of
conduction in motor fibers from the site of stimulation to
the motor neuron and then back again to the recording site,
and can be a measure of conduction in the proximal
segments of nerves and spinal roots. The consistency of the
response to serial stimuli (e.g. 10 electric shocks) is also
recorded as a measure of conduction but the validity of this
measure remains controversial.
H-reflex
H-reflex is a monosynaptic reflex evoked by low intensity,
submaximal electric stimulation of a motor nerve (e.g.
posterior tibial nerve), insufficient to produce a direct motor
response, which selectively activates the largest fibers in the
nerve, the afferent Ia fibers originating from the muscle
spindles. This produces impulses that ascend the Ia sensory
fibers to the spinal cord, where they synapse with the
anterior horn cells, and are then transmitted down the
motor fibers to the muscle, producing a muscle contraction
37
(H-wave) after a latency that is much longer than that of the
direct motor response (M-wave).
Thus, the H-reflex is the electric representation of the
tendon reflex circuit and provides a means of quantitating
reflex changes; it is decreased or absent in most peripheral
neuropathies and increased in upper motor neuron
disorders. It is rarely assessed nowadays in routine neuro-
physiologic practice.
REPETITIVE STIMULATION STUDIES
Normally, if repeated supramaximal electric stimuli are
delivered to a nerve (e.g. the ulnar nerve at the wrist) at
rates of up to 25 per second (which most patients would not
be able to tolerate), each motor response (CMAP) will have
the same form and amplitude. If the stimulus continues at
this rate for more than 60 seconds or so, fatigue will occur
and a decrement in successive CMAPs appears.
In myasthenia gravis, the initial CMAP produced by
electric stimulation is normal (or reduced) but supramaximal
stimulation at 2 Hz results in a decrement in amplitude of
the first four responses (50). In the Lambert–Eaton
myasthenic syndrome, post-exercise facilitation is seen with
a marked increase from initial very low amplitude potentials
toward normal amplitude motor unit potentials after
10 seconds of exercising the relevant muscle. This is also a
feature of botulism.
CENTRAL MOTOR CONDUCTION
Central motor conduction down the corticospinal tract can
be measured by electromagnetic stimulation of the motor
cortex and recording the CMAPs and latencies in distal limb
muscles.
50
Normal
Myasthenia gravis
50 Repetitive nerve stimulation studies. Compound muscle action
potentials evoked by repetitive electrical stimulation of the ulnar nerve
at the wrist at 4 Hz in a normal person (top) and a patient with
myasthenia gravis (bottom). Myasthenia gravis is characterized by a
decrement in amplitude of the first four responses.
38 Neurologic Diagnosis
ELECTROMYOGRAPHY (EMG)
The recording through a needle or surface electrode of
electric activity from muscles. The signals are amplified and
displayed visually on a screen and broadcast audibly through
a loudspeaker.
NORMAL MUSCLE ACTIVITY
Insertional activity
When the needle is moved gently within the muscle, a brief
burst of electric activity occurs (51).
At rest
No electric activity from muscle fibers at rest (52).
Muscle activation
• With slight voluntary activation of muscle the smallest
motor neuron in the motor neuron pool will begin to
fire slowly, producing a stereotyped recurrent individual
motor unit action potential discharge on the screen and
over the loudspeaker.
• With increasing voluntary effort, more and larger motor
units are activated. Initially these are identifiable as
individual potentials on the screen and over the loud-
speaker but as more and more units are recruited they
begin to overlap and produce a ‘recruitment pattern’.
• With maximum effort, a full recruitment pattern is seen.
ABNORMAL MUSCLE ACTIVITY
Insertional activity:
• Increased in denervation and many forms of muscle
disease.
• Decreased in advanced denervation or myopathy where
muscle fibers have been largely replaced by fat and
connective tissue.
At rest (spontaneous)
Fibrillation potentials are characterized by an initial positive
(downward) deflection followed by a largely negative
deflection of 100–300 µV in amplitude and 1–2 ms in
duration (52, 53). They represent the spontaneous
contraction of a single muscle fiber that has lost its nerve
supply. If a motor neuron or nerve fiber is destroyed by
disease or when its axon is interrupted, the distal part of the
axon degenerates over several days. Within 10–14 days from
the time of denervation, all of the muscle fibers connected
to the branches of the dead axon (the motor unit) begin to
generate random spontaneous biphasic or triphasic action
potentials (fibrillation potentials) and positive sharp waves
(see below).
Fibrillation potentials may also be recorded in some
primary muscle diseases with muscle fiber splitting,
inflammation or vacuolation (e.g. Duchenne muscular
dystrophy, polymyositis, inclusion-body myositis), because
the terminal innervation of some muscle fibers is damaged
by the disease process. Fibrillation potentials continue until
the muscle fiber is re-innervated by progressive
proximal–distal regeneration of the interrupted nerve fiber,
by the outgrowth of new axons from nearly healthy nerve
fibers (collateral sprouting), or until the atrophied muscle
fibers degenerate and are replaced over many years by
connective tissue. Fibrillation potentials may take the form
of positive sharp waves (51, 53), which are spontaneous,
initially positive diphasic potentials of longer duration and
slightly greater amplitude than the biphasic or triphasic
spikes of fibrillation potentials.
Fasciculation potentials are single motor unit action
potentials produced by spontaneous discharges in
degenerating nerve fibers (52). Such contractions of a
motor unit or part of a motor unit may be large enough to
cause a brief visible twitching or dimpling under the skin.
Commonly they are several millivolts in amplitude, last from
5 to >15 ms and usually fire irregularly. They are evidence
of motor nerve fiber irritability and not necessarily nerve
fiber destruction or motor unit denervation. They may
occur in normal people in the calves and hands, and may be
induced by low temperature and low serum calcium levels.
However, their occurrence in isolation in a relaxed muscle
is characteristic of motor nerve fiber degeneration, and this
can be confirmed by the presence of associated fibrillation
Normal 51
End-plate noise
Positive waves
Myotonic discharge
Bizarre repetitive potential
51 Insertional activity. Diagram illustrating the electric activity that may
be evoked by insertion of a needle electrode into muscle.
The top tracing shows the normal brief discharge of electric activity
(insertion potentials) that last little longer than the movement of the
needle. Insertional activity may be prolonged in denervated muscle,
myotonic disorders, and as a normal variant; and may be reduced in
periodic paralysis during paralysis and if muscle is replaced by
connective tissue or fat (e.g. chronic, end-stage myopathy).
‘End-plate noise’ and associated muscle fiber action potentials is
electric activity evoked when the needle is in contact with motor end
plates and irritates small intramuscular nerves.‘Positive waves’ are
evoked in denervated muscle.
‘Myotonic discharges’ are the action potentials of muscle fibers firing
in a prolonged fashion after external excitation.The potentials take two
forms (positive waves and brief spikes) depending on the relationship of
the recording electrode to the muscle fiber, and wax and wane in
amplitude and frequency (40–100 per second) due to an abnormality in
the muscle fiber membrane, caused by cholesterol-lowering agents
(CLAM), myotonic dystrophy, myotonia congenita, paramyotonia,
hyperkalemic periodic paralysis, polymyositis and acid maltase deficiency.
‘Bizarre repetitive potentials’, now referred to as ‘complex repetitive
discharges’ are action potentials of groups of muscle fibers discharging in
near synchrony at high rates (3–40 per second).They occur in a wide
range of chronic neuropathies (e.g. poliomyelitis, motor neuron disease,
spinal muscular atrophy, radiculoneuropathies) and chronic myopathies
(chronic polymyositis, Duchenne dystrophy, limb-girdle dystrophy).
 Electromyography (EMG) 39

potentials and certain changes in the motor unit potentials
(see below).
Myokymia: persistent spontaneous rippling and quivering
of muscles at rest, due to groups of repetitive firing
potentials, each group firing at its own rate. Often associated
with radiation nerve damage.
Myotonia: high frequency repetitive discharges which
generally have a positive sharp waveform and wax and wane
in frequency and amplitude, producing a ‘dive-bomber’
sound over the loudspeaker (51). Elicited during voluntary
muscle contraction and mechanically by movement of the
needle electrode. After muscle contraction, a prolonged
afterdischarge occurs for up to several minutes, consisting
of long trains of fibrillation-like potentials, corresponding
to the clinical feature of failure of voluntary relaxation of
muscle following forceful contraction.
Complex repetitive discharges: spontaneous repetitive
potentials with a bizarre configuration that start and stop
abruptly. A sign of chronicity (>6 months) in chronic
neurogenic processes and some neuromyopathies.
Continuous muscle fiber activity (neuromyotonia): high
frequency (up to 300 Hz) repetitive discharges of varying
wave forms. Successive discharges show decrements in
amplitude. These discharges probably originate in the distal
peripheral nerve, where activity of afferent nerve fibers
excites distal motor terminals.
Voluntary muscle activation
Upper motor neuron lesion: poor drive from the upper motor
neuron results in few motor units being activated and hence
poor recruitment of motor unit potentials. This pattern of
recruitment may also be seen in patients who do not (e.g.
hysteria), or cannot (e.g. due to joint pain), make an
adequate voluntary effort.
Lower motor neuron lesion: after denervation of certain
muscle fibers and motor units within a muscle, the surviving
nerve fibers that innervate other motor units within the
muscle begin to sprout new nerve twigs from nodal points
and terminals of undamaged axons, and re-innervate some
or all of the denervated fibers. This process results in the
addition of more muscle fibers to the surviving motor units,
which appear on the EMG and large amplitude, long
duration, complex (polyphasic) potentials, which are
characteristic of partial denervation and subsequent

52 Spontaneous electric activity in Normal 52

voluntarily relaxed muscle.
Normal: no electric activity. Fibrillations:
action potentials of single muscle fibers that
are twitching spontaneously and usually Fibrillation
regularly at rates of 0.5–15 per second in
the absence of innervation.They take two
forms (positive waves and brief triphasic or
biphasic spikes).
Fasciculation: action potential of a group
of muscle fibers innervated by an anterior Fasciculation: single discharge
horn cell that discharges in a random,
irregular fashion.They may arise from any
portion of the lower motor neuron, from
the cell body to the nerve terminal.

53 Needle electromyographic recording of a resting muscle showing 53

abnormal spontaneous fibrillation potentials (upward spikes) and
positive sharp waves (downward spikes).
40 Neurologic Diagnosis
re-innervation. With increasing voluntary effort, only one
or a few, large motor units are activated, and they fire
repetitively, resulting in a reduced recruitment pattern (54).
Neuromuscular junction disease: during sustained weak
muscle contraction, a single motor unit may vary in
amplitude. EMG recordings of single muscle fibers
belonging to the same motor unit may show varying
intervals between successive discharge of two single muscle
fiber action potentials belonging to the same motor unit
(‘jitter’), due to variability in synaptic delay at the
neuromuscular junction. This may increase to the point of
actual block in conduction.
Muscle disease (myopathy): muscle fibers are destroyed
resulting in fewer functional muscle fibers in each motor
unit. Activation of these smaller motor units is seen on the
EMG as low amplitude, short duration potentials which are
also commonly polyphasic because the compound motor
unit potential is fragmented into its constituent single fiber
potentials and because of slowing of the propagated action
potentials of affected muscle fibers (54, 55). With voluntary
muscle activation, a higher proportion of these small motor
units need to be recruited to generate the force required,
resulting in rapid recruitment.
Normal 54
Myopathy
Lower motor neuron disease
54 Motor unit action potentials during weak voluntary contraction of
the biceps brachii in a normal person (top); a patient with muscular
dystrophy (middle): low amplitude, short-duration motor unit
potentials; and a patient with motor neuron disease (bottom): high
amplitude, long-duration motor unit potentials.The time base for the
action potentials recorded on the left is slower (100 cycles per second)
than those on the right (1000 cycles per second).
55
EVOKED POTENTIALS
Stimulation of sensory organs or peripheral nerves evokes a
small time-locked, event-related response (or potential) in
the appropriate primary sensory cortex of the brain and a
number of subcortical relay stations as well. The larger
random background activity in the EEG or EMG is filtered
out by averaging methods. Three types of sensory evoked
potential are commonly performed.
VISUAL EVOKED POTENTIALS (VEPs)
With recording electrodes placed over the occipital region,
the patient looks at a black and white checker board pattern,
which alternates each second, while the overall luminance
of the entire retina remains constant. In a normal person
with synchronous conduction in the optic pathways, this
repetitive visual stimulus evokes a characteristic electric
potential over the occipital region of the head: the pattern-
reversal visual evoked potential. By continuously stimulating
the retina and recording the signals with electrodes over the
occipital region, it is possible to average the signals recorded
after a series of stimuli. Averaging ultimately cancels out
random background EEG activity and clearly defines a
characteristic positive wave at about 100 ms (P100) (56).
Demyelinating lesions along the optic pathway delay
conduction and lead to an increase in the latency (56).
Neurophysiologic evidence of delayed conduction in the
visual pathways is found in about 90% of patients with
clinically definite MS, whether or not they have a past
history of optic neuritis. About one-third of patients with
MS who have no history or clinical evidence of optic nerve
involvement have abnormalities of the VEP.
Abnormalities of the P100 may be produced by other
diseases of the optic pathway such as glaucoma, retinal
diseases, compressive lesions of the optic nerve, toxic and
nutritional optic neuropathies, ischemic optic neuropathy,
and Leber’s hereditary optic neuropathy. Impaired visual
acuity has little effect on the latency but it correlates well
with the amplitude of the evoked response.
BRAINSTEM AUDITORY EVOKED
POTENTIALS (BAEPs)
The patient wears a set of headphones though which a series
of between 1000 and 2000 pure tones (clicks) are delivered
first to one ear and then to the other. Each tone evokes an
auditory potential. The auditory evoked potential has a
characteristic waveform with seven peaks: the first peak
(wave I) is produced in the cochlea and auditory nerve, the
second in the cochlear nuclei (pons), the third in the
superior olive, the fourth in the lateral lemniscus, and the
fifth in the inferior colliculus (midbrain). The generators of
waves VI and VII are uncertain but possibly the sixth is in
the medial geniculate and seventh in the auditory radiation
to the auditory cortex (57).
The BAEPs can be used to assess cochlea and auditory nerve
function and detect lesions of the VIIIth cranial nerve (e.g.
acoustic neuromas) and the auditory pathways of the
brainstem. A lesion that affects one of the relay stations or its
55 Needle electromyographic recording of a contracting muscle
showing a normal motor unit (left), and a small, polyphasic (myopathic)
motor unit (right).
 Evoked Potentials 41

56 immediate connections causes a lower amplitude of the wave

or a delay in its latency and an absence or reduction in
amplitude of subsequent waves. These effects are more
pronounced on the side of the stimulated ear than
contralaterally, despite the fact that the majority of the cochlear-
superior olivary-lateral lemniscal-medial geniculate fibers cross
to the opposite side at the level of the superior olivary nuclei.
Almost one half of patients with clinically definite MS
and a lesser number with possible or probable MS have
abnormal BAEPs, even in the absence of clinical symptoms
or signs of brainstem dysfunction (58). However, BAEPs
examine only a relatively short segment of the central
pathways and are less sensitive in detecting demyelination
A than VEPs and MRI imaging of the brain. The latter has
greatly diminished the need for BAEPs.

56 Abnormal pattern-shift visual evoked potentials (VEPs).

A.The upper channel represents a VEP with a vertex reference
derivation and the bottom channel a VEP with an ear reference
derivation.The vertical line represents the upper limit of the latency of
the major positive peak (P100 or P2) for 99% of the normal
population.The positive peak is broad in contour, and its center is
slightly to the right, and therefore exceeds, the upper limit of normal.
B.The upper channel shows a markedly prolonged latency of the
VEP with a latency of the major positive peak being about 150 ms; the
lower channel (ear reference) is contaminated by noise artefact.This
patient has symptomatic visual loss secondary to demyelinating optic
nerve disease. Refractive errors, ocular opacities and visual inattention,
B and lesions posterior to the optic chiasm do not usually prolong the
latency of the VEP but tend to affect the amplitude of the VEP.

2 4 6 ms 57 58 Abnormal brainstem 2 4 6 58
V auditory evoked potentials
I II III IV (BAEP).The upper two
channels (top: A1–CZ, and
below: A2–CZ) recorded
VI after left ear stimulation in
A1–Cz
VII
a patient with MS show
that waves IV and V are
absent, indicating a lesion
in the upper pons,
probably contralateral to
the stimulated left ear.The
solid straight vertical lines
A1–Cz
indicate 2, 4 and 6 ms
respectively.The lower two
channels (top: A1–CZ, and
below: A2–CZ) show a
prolonged III-V interpeak 2 4 6
latency, indicating a lesion
57 Normal far-field brainstem auditory evoked potentials probably in the lateral
(BAEPs). Normally, in response to serial high frequency clicks at lemniscus causing slower
the ear, electrodes at the ear (left: A1, right: A2) and the vertex conduction between the
(CZ) record a total of 7 short-latency waves from within 10 ms of superior olivary complex
the click. By convention, vertex positivity is displayed as an upward (wave III) and inferior
deflection and the individual waves are labelled by their positive colliculus (wave V). As with
peaks.The upper two channels (top: A1–CZ, and below: A2–CZ) other evoked potentials, an
recorded after left ear stimulation in a normal person show abnormality indicates an
duplication of waves I through VII.The solid straight vertical lines anatomic lesion and not a
indicate 2, 4 and 6 ms respectively.The sweep duration is 10.2 ms. specific disease process.
42 Neurologic Diagnosis

SOMATOSENSORY EVOKED POTENTIALS (SSEPs)
Consecutive electric stimuli are applied, at frequencies of
1.8 Hz, 2.1 Hz or a little faster (but not a multiple of 60,
to avoid 60 Hz artefact), to sensory or mixed peripheral
nerves (e.g. the posterior tibial, median and ulnar nerves)
while recording the evoked potentials from electrodes (for
the upper limb) over Erb’s point above the clavicle, the
dorsal root entry zone, the spinal cord at C2, and the scalp
overlying the contralateral parietal cortex, and (for the lower
limb) over the lumbar and cervical spine and the contra-
lateral sensory cortex. Characteristic waveforms, designated
by the symbol P (positive) or N (negative) and a number
indicating the interval of time from stimulus to recording
(e.g. N9), are produced in each of these locations, and
averaged by computer (59, 60).
The integrity of the large sensory nerve fibers and their
central pathways though the posterior columns, medial
lemniscus, and thalamus to the parietal cortex are tested.
Delay between the stimulus site and Erb’s point or lumbar
spine indicates peripheral nerve disease; delay from Erb’s
point (or lumbar spine) to C2 implies an abnormality in the
appropriate nerve roots or in the posterior columns; delay
of subsequent waves recorded from the parietal cortex infer
lesions in the medial lemniscus or thalamoparietal
connections.
SSEPs are used in cases of suspected MS and cervical
spondylitic myelopathy and in monitoring the integrity of
the spinal cord during spinal cord operations such as
scoliosis surgery. They are abnormal in up to 70% of patients
with clinically definite MS (61), but are not as sensitive as
VEPs and MRI brain and spinal cord in detecting central
demyelination.

59 60 Fpz’ Cz’

10 20 ms +1.0 μV STIM
N19
C31–Fz

T12S
P22
C31–FII L3S

N12
CII–Fz

N10

Erb2 0 10 20 30 40 50 ms

STIM
59, 60 Normal short-latency somatosensory evoked potentials. 59 Stimulation of the median nerve at the wrist initially evokes a sharp,
predominantly negative potential over Erb’s point at about 10 ms (bottom channel) as the sensory and retrograde motor compound action
potentials pass beneath it in the brachial plexus at midclavicle, behind the sternomastoid.The next response is a surface negative bifid peak (N12)
over the second cervical vertebra (C2) with instrumental phase reversal (channels 2 and 3). Finally a potential is recorded over the contralateral
parietal lobe somatosensory cortex (C3’: 2 cm [0.8 in] behind C3), with a negative peak at about 19 ms (N19) and a positive wave at about 22 ms
(P22). 60 Stimulation of the posterior tibial nerve at the ankle and recording somatosensory evoked potentials at the popliteal fossa, spine and
scalp.

61 10 20 40 61 Abnormal short-latency somatosensory evoked potentials.

Stimulation of the median nerve at the wrist in a patient with multiple
sclerosis and loss of proprioception in the hands evokes potentials
initially over Erb’s point at about 10 ms (bottom channel), but then the
potentials over the second cervical vertebral (N12) and cortex (N19)
are not clearly seen.

N10

FURTHER READING
NEUROLOGIC EXAMINATION
Acierno MD (2001) Ophthalmoscopy for the
neurologist. The Neurologist 7: 234–251.
Blessing WW (2000) Alternating two finger tap-
ping as part of the neurological motor exami-
nation. Aust. NZ. J. Med., 30: 506–507.
Mayo Clinic and Mayo Foundation (1981) Clin-
ical Examinations in Neurology 5th edn. W.B.
Saunders, Philadelphia.
Pandit RJ, Gales K, Griffiths PG (2001) Effec-
tiveness of testing visual fields by confronta-
tion. Lancet, 358: 1339–1340.
Weaver DF (2000) A clinical examination tech-
nique for mild upper motor neuron paresis of
the arm. Neurology, 54: 531–532.
Further Reading
IMAGING THE BRAIN
Rudkin TM, Arnold DL (1999) Proton magnetic
spectroscopy for the diagnosis and manage-
ment of cerebral disorders. Arch. Neurol., 56:
919–926.
Costa DC, Pilowsky LS, Ell PJ (1999) Nuclear
medicine in neurology and psychiatry. Lancet,
354: 1107–1111.
IMAGING THE CEREBRAL CIRCULATION
Bendszus M, Koltzenburg M, Burger R, et al.,
(1999) Silent embolism in diagnostic cerebral
angiography and neurointerventional proce-
dures: a prospective study. Lancet, 354:
1594–1597.
Keir SL, Wardlaw JM (2000) Systematic review of
diffusion and perfusion imaging in acute is-
chemic stroke. Stroke, 31: 2723–2731.
Markus HS (1999) Transcranial Doppler ultra-
sound. J. Neurol. Neurosurg. Psychiatry, 67:
135–137.
43
LUMBAR PUNCTURE AND CSF
EXAMINATION
Serpell MG, Rawal N (2000) Headaches after di-
agnostic dural punctures. BMJ, 321: 973–974.
Steigbigel NH (2001) Computed tomography of
the head before a lumbar puncture in suspect-
ed meningitis – is it helpful? N. Engl. J. Med.,
345: 1768–1770.
Thomas SR, Jamieson DRS, Muir KW (2000)
Randomised controlled trial of atraumatic ver-
sus standard needles for diagnostic lumbar
puncture. BMJ, 321: 986–990.
ELECTROENCEPHALOGRAPHY
Blume WT (2001) Current trends in electro-
encephalography. Curr. Opin. Neurol. 14:
193–197.
Fish D (2001) Anticipation of epileptic seizures
from standard electro-encephalographic
recordings. Lancet 357: 160–161.
44 Chapter Two
Disorders of
Consciousness
COMA
DEFINITION
0 • Occasional eye opening, flexion or extension of muscles
A state of unresponsiveness in which a person is unaware of
themself and the environment and cannot be aroused into
a state of awareness or respond to the environment.
CLASSIFICATION OF LEVELS OF CONSCIOUSNESS
Various stages of clouded or impaired consciousness are
recognized and are loosely defined below. However, it is
more important to describe in detail the clinical state of the
patient, and postures and responses to various stimuli than
to apply only one of these labels that may be interpreted
differently by different people.
Normal consciousness
• Alert wakefulness.
• Orientated in time and place.
• Responsive immediately and appropriately to stimuli.
Confusion
• Clouding of consciousness.
• Impaired capacity to think with customary clarity,
coherence and speed; understand; respond to and
remember stimuli.
• Disorientated in time and place to some degree.
• Poor attention and concentration; distractible and
forgetful.
Delirium
• A more profound confusional state.
• Anxiety, excitement, agitation, motor restlessness,
hallucinations, disorientation and sometimes delusions
(e.g. delirium tremens).
Obtundation
Drowsy and indifferent to the surroundings but responds
to verbal stimuli.
Stupor
• Somnolent: patient may appear asleep.
• Little or no spontaneous activity, with some kind of
voluntary response only to vigorous stimulation or pain,
and then lapsing back into somnolence.
Coma
• Unrousable.
• Absence of any understandable response to external
stimuli or inner need.
in the limbs, grunting or groaning in response to painful
stimuli, and primitive reflexes are all that may be present.
PHYSIOLOGY OF CONSCIOUSNESS
Consciousness depends on intact and interacting brainstem
reticular formation and cerebral hemipheres. The reticular
formation (from the Latin reticulum, meaning ‘a net’)
consists of a net of small and large cells and their connec-
tions throughout the brainstem from the medulla to the
thalamus. All major sensory pathways project to the reticular
formation where they interact before proceeding to the
sensory cortex. The part of the reticular formation which is
most concerned with arousal and maintaining wakefulness
is the ascending reticular formation (reticular activating
system) in the midbrain and thalamus, which projects
diffusely to the cerebral cortex.
PATHOGENESIS
Coma is caused by:
• Dysfunction of the ascending reticular formation in the
thalamus or brainstem, and/or
• Dysfunction of both cerebral hemispheres.
N.B. Small focal lesions in the brainstem and even larger
lesions of one cerebral hemisphere do not cause coma unless
they encroach on the reticular formation.
Supratentorial lesions may cause coma by displacing the
brain laterally or caudally, as a result of their mass effect, and
compromising the function of the reticular formation in the
region of the thalamus and midbrain (62, 63). Lateral
expansion may also compress and disturb the function of
the contralateral cerebral hemisphere.
Infratentorial space-occupying lesions initially compress
adjacent structures, increasing the pressure in this tight,
inexpandable compartment. Further expansion leads to
upward herniation of the brainstem through the tentorial
notch and downward herniation of the cerebellar tonsils and
medulla through the foramen magnum.
Patterns of supratentorial brain shift
Cingulate herniation
The expanding hemisphere shifts across the intracranial
cavity, forcing the cingulate gyrus under the falx cerebri,
compressing and displacing the internal cerebral vein and
the ipsilateral anterior cerebral artery (62, 63). Infarction
in the territory of the anterior cerebral artery may occur.
 Coma 45

Central or transtentorial herniation of the diencephalon
Caudal displacement of the hemispheres, basal nuclei, and
eventually diencephalon and adjoining midbrain through
the tentorial notch (62, 64). The great cerebral vein is
compressed, raising the hydrostatic pressure of the deep
territory it drains, causing venous congestion, edema and
even infarction. The resultant cerebral edema further
compromises venous flow, leading to more mass effect,
brain shift and herniation. The aqueduct and subarachnoid
spaces are also compressed, compromising cerebrospinal
fluid (CSF) circulation, and leading to hydrocephalus and
further elevation of supratentorial CSF pressure. The medial
perforating branches of the basilar artery are stretched (the
basilar artery cannot shift downward because it is tethered
to the circle of Willis), leading to paramedian brainstem
ischemia (and hemorrhage if perfusion continues) (65).

62

62 Herniation of the brain. Left: Uncal and transtentorial herniation. A mass such as a cerebral hemorrhage, cerebral infarct or hemorrhagic infarct in one
cerebral hemisphere displaces the diencephalon and mesencephalon horizontally and caudally.The cingulate gyrus on the side of the lesion herniates
under the falx cerebri (top arrow).The uncus of the ipsilateral temporal lobe herniates under the tentorium cerebelli (lower arrows) and becomes
grooved and swollen and may compress the ipsilateral oculomotor (IIIrd cranial) nerve causing pupillary dilatation (Hutchinson's sign).The cerebral
peduncle opposite the supratentorial mass becomes compressed against the edge of the tentorium, leading to grooving (Kernohan's notch) and a
paresis homolateral to the cerebral mass lesion. Central downward displacement also occurs but is less marked than in the adjacent figure on the right.
Right: Central transtentorial herniation. Diffuse or multifocal swelling of the cerebral hemispheres (or bilateral subdural or epidural hematomas)
compress and elongate the diencephalon from above.The mamillary bodies are displaced
63 caudally.The cingulate gyrus is not herniated. (Adapted from Plum F, Posner JB [1985] The
Diagnosis of Stupor and Coma, 3rd edn. FA Davis, Philadelphia, Chapter 2, p92.)

63 Herniation of the brain. Coronal section of the brain of a patient with a massive
right temporal lobe glioblastoma multiforme who died after developing the syndrome of
uncal herniation.

64 Coronal section of the brain of a patient with multiple cerebral metastases causing
brain swelling, raised intracranial pressure, and compression, elongation, and caudal
displacement of the diencephalon and medial temporal lobes.

64 65 65 Axial section through the

mid pons showing Duret
hemorrhages in the central
core of the brainstem of a
patient who died after rapid
expansion of an acute lobar
intracerebral hemorrhage
causing transtentorial
herniation, downward
displacement of the midbrain
and pons, and stretching of the
medial perforating arteries of
the basilar artery (which is
tethered to the circle of Willis
and cannot shift downward).
46 Disorders of Consciousness

Uncal herniation: expanding lesions in the temporal fossa Vascular

shift the inner, basal edge of the uncus and hippocampal Subarachnoid hemorrhage.
gyrus toward the midline so that they bulge over the
incisural edge of the tentorium, and push the adjacent Non-neurologic (psychiatric)
midbrain against the opposite incisural edge (66). The IIIrd Malingering or hysteria.
cranial nerve and the posterior cerebral artery on the side of
the expanding temporal lobe are often caught between the CLINICAL FEATURES
overhanging swollen uncus and the free edge of the Before, or while, undertaking a clinical assessment, the
tentorium or the petroclinoid ligament, leading to a IIIrd patient’s vital functions should be attended to, paying
nerve palsy and occipital and medial temporal lobe particular attention to the airway (with adequate
infarction and swelling due to posterior cerebral artery
territory ischemia, which further compounds the problem.
66
ETIOLOGY
Supratentorial (15%) and infratentorial (15%) lesions
• Brain hemorrhage: intraparenchymal, subdural, subarach-
noid (67).
• Brain infarction.
• Venous-sinus thrombosis.
• Meningo-encephalitis.
• Brain abscess.
• Brain tumor.
• Head injury.

Diffuse brain disturbances (70%)

Metabolic
• Hypoxia (see Hypoxic encephalopathy, p.449): cardiores-
piratory arrest, status asthmaticus, chronic obstructive
airways disease, pneumonia, and prolonged hypotension.
• Hyponatremia: excess water ingestion, decreased water
excretion (e.g. nephrotic syndrome), inappropriate
antidiuretic hormone (ADH) secretion (e.g. central brain
lesions, carbamazepine), or carcinoma (a paraendocrine
phenomenon).
• Hypoglycemia: insulin or oral hypoglycemic agent excess 66 The under-surface of the forebrain at autopsy in a patient who
(pancreatic islet cell tumor, diabetes), prolonged fasting, died after transtentorial herniation showing swelling and grooving of
alcoholism, hypopituitarism and hypothyroidism. the uncus of the left medial temporal lobe (arrows) which has
• Hyperglycemia, hyperosmolality and acidosis: diabetes herniated through the tentorium cerebelli, and compressed the
(N.B. hyperglycemia may not be the cause but may be a midbrain. (Courtesy of Professor BA Kakulas, Royal Perth Hospital,
consequence of other causes of coma such as stroke, head Australia.)
injury and meningitis).
• Renal failure (uremia): predisposes to dehydration, hypoten-
sion, electrolyte disturbances, uremia, metabolic acidosis, 67
infection and impaired excretion of drugs and other toxins.
• Liver failure: predisposes to ammonia and drug toxicity,
and hypoglycemia.
• Hypocalcemia: renal failure, hypoparathyroidism.
• Hypercalcemia: primary hyperparathyroidism, malig-
nancy and prolonged immobilization.
• Hypothermia: hypothyroidism, immersion.
• Hypothyroid.
• Thiamine deficiency: chronic alcoholism.

Toxic
Drugs: overdose of sedative/hypnotic drugs (alcohol,
benzodiazepines, barbiturates, opiates, phenothiazines, and
tricyclic antidepressants alone or in combination).

Inflammatory
Meningo-encephalitis.
67 Section through the pons and cerebellar hemispheres, axial plane,
Epilepsy showing massive fatal pontine hemorrhage extending into the fourth
Generalized seizures (primary or secondary). ventricle. (Courtesy of Professor BA Kakulas, Royal Perth Hospital,
Australia.)
 Coma 47

oxygenation), blood pressure and circulation (with fluid and Odor of breath: alcohol, ketones (diabetes), hepatic or renal
electrolyte balance). failure.

HISTORY Clubbing of fingernails: respiratory or gastrointestinal

Contact family and friends to obtain an eyewitness account
of the preceding events, and when the patient was last seen,
how the patient was behaving, whether the patient is a known
epileptic, alcoholic or drug abuser, and any known psychiatric
and medical conditions, medications or drug habits.
PHYSICAL EXAMINATION
General examination
This often yields important clues.
Skin and mucous membranes
• Color: blue (cyanosis); pink (carbon monoxide
poisoning); pale (anemia); yellow (jaundice).
• Purpura: bleeding diathesis (?intracranial hemorrhage).
• Rash: infection (e.g. meningococcemia) or inflammatory
disease.
• Pigmentation: Addison’s disease.
• Puncture wounds: diabetic, recreational drug abuse.
disease.
Heart rate: tachy- or bradyarrhythmia, or atrial fibrillation:
embolism from the heart to the brain.
Blood pressure
• Hypotension: shock, myocardial infarction, septicemia,
Addison’s disease.
• Hypertension: may be secondary or the primary cause
(hypertensive encephalopathy).
Neck or cardiac bruits: ischemic stroke.
Tracheal deviation, chest dullness to percussion, bronchial or
soft breath sounds: respiratory disease.
Abdominal organomegaly: liver disease (bleeding diathesis),
polycystic kidneys (subarachnoid hemorrhage).

Temperature Neurologic
• Fever: meningitis, encephalitis, brain abscess, systemic Position, posture and spontaneous movements.
infection, recent seizure.
• Hypothermia: exposure to low environmental Level of consciousness: record serially:
temperatures, intoxication with alcohol or other • Glasgow coma scale (Table 2): the most widely used
sedatives, peripheral circulatory failure, or hierarchic grading scale.
hypothyroidism. • Supra-orbital pressure and nail bed pressure to test
response to pain: note nature and (a)symmetry of
Respiration response.
• Deep and rapid: metabolic acidosis, pneumonia,
brainstem lesion. Skull and spine: neck stiffness, Kernig’s sign.
• Shallow and slow: drug intoxication.
• Periodic: brainstem lesion. Brainstem function
• Pupillary reaction:
– Dilatation of one pupil with no response to light: IIIrd
nerve compression by uncal herniation (or other causes:
Table 2 The Glasgow coma scale posterior communicating artery aneurysm).
Score – Non-reactive (fixed) mid-position pupils: mid-brain
Eyes open lesion, anesthesia.
Nil 1 – Small reactive pupils: metabolic/toxic encephalopathy.
To pain 2 – Small (pin-point) pupils: pontine lesion, opiates,
To verbal stimuli 3 pilocarpine eye drops.
Spontaneously 4 – Non-reactive (fixed) dilated pupils: significant brain stem
damage or effect of atropine-like drugs.
Best verbal response – Horner’s syndrome: hypothalamic, brainstem or carotid
No response 1 lesion.
Incomprehensible sounds 2 • Resting position of the eyes and spontaneous eye
Inappropriate words 3 movements:
Disorientated and converses 4 – Minor degrees of divergence of the eyes: normal in
Orientated and converses 5 unconscious patients.
– Roving conjugate or dysconjugate eye movements,
Best motor response similar to those of sleep: common among patients in
No response 1 light coma; indicate an active brainstem.
Extension (decerebrate rigidity) 2 – Conjugate deviation of the eyes to one side: focal
Abnormal flexion of upper limbs (decorticate rigidity) 3 ipsilateral hemispheric or contralateral low pontine lesion,
Flexion – withdrawal to pain 4 or status epilepticus.
Localizes pain 5 – Conjugate depression of the eyes: midbrain tectum
Obeys commands 6 (posterior commissure) lesion or compression (e.g.
hydrocephalus).
Total 15 – Skew deviation: brainstem (pontomedullary junction)
lesion.
48 Disorders of Consciousness
• Resting position of the eyes and spontaneous eye
movements (continued):
– Dysconjugate eyes: nuclear or infranuclear oculomotor
or abducens nerve lesion, or internuclear ophthalmo-
plegia (medial longitudinal fasciculus).
– Regular conjugate horizontal eye movements (‘ping-
pong gaze’): brainstem lesion.
– Eyes jerk backwards into orbits (retractory nystagmus):
midbrain lesion.
– Intermittent downward jerking of the eyes (ocular
bobbing): low pons lesion.
– Spontaneous nystagmus: rare in comatose patients because
the fast phase is a corrective saccade generated by the
frontal cortex and requires intact and interactive vestibular
pathways, cerebral cortex and oculomotor system.
• Oculocephalic reflex: rotating the patient’s head from
side to side in a comatose patient with an intact
brainstem evokes conjugate eye movements in the
opposite direction to the head movement, so that the
eyes move in the orbit but remain ‘focused’, looking
straight ahead (‘doll’s eye movements’). If the
oculovestibular reflex is interrupted, due to brainstem
dysfunction, the eyes move dysconjugately, or do not
move in the orbits, remaining in the mid-position of the
head, ‘looking’ in the direction of the head movement.
• Oculovestibular responses: after examining the intact
tympanic membranes, 50–200 ml of ice cold water is
instilled into one of the external auditory meati. If the
oculovestibular reflex is intact, the eyes deviate tonically
toward the irrigated ear. In a conscious patient (or
psychogenic coma) with intact corticopontine fibers, the
frontal cortex tries to drive the eyes back to mid-position
thus generating the fast phase of nystagmus away from
the side of stimulation. Tonic and conjugate deviation of
the eyes toward the irrigated ear, without corrective
ocular saccades (the fast phase), indicates an intact
brainstem and a supratentorial cause for the coma. If the
response is dysconjugate, or absent, brainstem
dysfunction is the likely cause of the coma. Both external
auditory meati should be irrigated independently;
simultaneous irrigation will evoke vertical conjugate eye
movement and corrective saccades (nystagmus).
• Corneal response: may be absent in light coma due to
drug intoxication but otherwise is usually retained until
deep coma and then its absence is a poor prognostic factor.
• Respiration:
– Post-hyperventilation apnea: bilateral hemispheric
disturbance.
– Long-cycle Cheyne–Stokes respiration: diencephalic
dysfunction.
– Central neurogenic hyperventilation: low midbrain and
upper pons lesions.
– Short-cycle Cheyne–Stokes respiration: medullary
dysfunction.
– Yawning, vomiting, hiccough: brainstem dysfunction.
Ophthalmoscopy: look for papilledema, sub-hyaloid hemorr-
hages, retinal emboli, diabetic or hypertensive retinopathy.
The absence of papilledema or venous pulsation does not
exclude raised intracranial pressure.
Motor function
• Glasgow coma scale.
• Lateralizing features are important (facial grimace; limbs).
• Seizures: focal or generalized.
• Multifocal myoclonus: diffuse cortical irritation due to
anoxia or metabolic disturbance.
• Muscle tone, deep tendon reflexes, and plantar responses:
abnormal with corticospinal tract lesions and also some-
times with hepatic and hypoglycemic encephalopathy.
DIFFERENTIAL DIAGNOSIS
Coma or not?
Confusion
Confusion is often caused by acute metabolic or toxic
disturbances, particularly in the elderly (e.g. hypoxia,
hypercapnia, fluid and electrolyte disturbance, hypogly-
cemia, drug intoxication, and drug withdrawal), or sleep
deprivation, pain and as a transient phenomenon after
seizures. It needs to be differentiated from dysphasia,
amnesia, acute psychosis, the retardation of severe
depression and dementia.
Delirium
Delirium is commonly caused by metabolic and toxic
disorders but can be mimicked by degenerative brain
disease, acute psychosis and hypermania.
Stupor
Stupor needs to be differentiated from catatonic
schizophrenia or severe retarded depression. The EEG is
always abnormal in stupor due to organic disease.
Persistent vegetative state (see p.52)
Locked-in syndrome (see p.55)
Brain death (see p.51)
Etiology of the coma
Coma with focal neurologic signs or evidence of head injury
• Supratentorial or infratentorial mass lesion (vascular,
inflammatory, neoplastic).
• Hypoglycemic encephalopathy.
• Hepatic coma.
Coma with meningism but no focal/lateralizing
neurologic signs
• Subarachnoid hemorrhage.
• Meningo-encephalitis.
Coma without focal/lateralizing neurologic signs or
meningismus
Metabolic/toxic encephalopathy:
• Hypoxic encephalopathy.
• Hyponatremia. Altered consciousness and seizures,
without focal neurologic signs.
• Hypoglycemic encephalopathy:
– Altered consciousness.
– Focal neurologic signs, such as hemiparesis, may be
present.
– Excess sympathetic adrenergic activity (pallor, sweating,
dilated pupils, tremor, tachycardia).
– Underlying diabetes, alcoholism, hypopituitarism,
hypothyroidism or pancreatic islet cell tumor.
 Coma
• Hyperglycemia, hyperosmolality and acidosis:
– Diabetic ketoacidosis: dehydration, hyperosmolality, aci-
dosis, and deep sighing respirations (Kussmaul breathing).
– Hyperosmolar coma, with dehydration but no
ketoacidosis: older patients taking oral hypoglycemic
drugs or small doses of insulin
– Non-ketotic lactic acidosis in diabetic patients taking
hypoglycemic agents such as metformin. The blood
sugar may or may not be elevated.
– Hyperglycemia may not be the cause of the coma; it may
be a consequence of other causes of coma such as stroke,
head injury and meningitis.
• Renal failure (uremia).
• Liver failure (hepatic encephalopathy, see p.452):
– Confusion or delirium.
– Asterixis: an inability to maintain the arms outstretched
with the hands and fingers held dorsiflexed because of
periodic inhibition of contraction of the wrist and finger
extensors causing recurrent lapses in posture of the hands
at the wrists, giving rise to the appearance of a ‘liver flap’.
• Hypocalcemia:
– Tetany and seizures: underlying renal failure and
hypoparathyroidism.
• Hypercalcemia:
– Dehydration, weakness, nausea, anorexia, and vomiting:
Underlying primary hyperparathyroidism or malignancy,
or prolonged immobilization.
• Hypothermia and hypothyroidism:
– History of prolonged immersion in water or exposure to
the cold.
– Hypothyroidism: coma can be precipitated by cold, infec-
tion or withdrawal of thyroid medication. Clinical features
include obesity, coarse myxedema facies, low body
temperature and delayed relaxation of the ankle jerks.
• Thiamine deficiency (Wernicke’s encephalopathy [see
p.460]):
Malnourished chronic alcoholics, recent increased
glucose intake.
– Confusion, ophthalmoplegia (bilateral abducens nerve
palsies), nystagmus and ataxia, but some present in coma.
Peripheral neuropathy may present.
Drug overdose:
• History and circumstances of discovery.
• A discrepancy between marked depression of brainstem
responses and relatively light coma is present in some
patients.
• Pin-point pupils suggest opiate poisoning.
Subarachnoid hemorrhage (see p.249): neck stiffness is
usually, but not always, present.
Meningo-encephalitis (see p.273): fever, neck stiffness may
be absent in a deeply comatose patient.
Generalized epilepsy (nonconvulsive status or post ictal state):
• History of epilepsy.
• Evidence of tongue biting and incontinence.
Non-neurologic (malingering or hysteria):
• Normal rate and depth of respiration, pupillary reactions,
muscle tone, deep tendon and abdominal reflexes, and
plantar responses.
• Attempts to open the patient’s eyes may be resisted.
49
• Slow, roving eye movements are not evident.
• Irrigation of the ears with ice-cold water is noxious and
usually evokes nausea, sometimes with vomiting, and
nystagmus with the fast phase beating away from the side
of the irrigated ear (which is a cortical response to the
tonic deviation of the eyes toward the irrigated ear, that
is mediated by the brainstem reflex).
INVESTIGATIONS
Coma with focal neurologic signs or evidence of
head injury
• CT or MRI brain scan: supratentorial or infratentorial
mass lesion.
• Blood glucose.
• Liver function tests.
N.B. Lumbar puncture (LP) is contraindicated in the
presence of space-occupying lesions that increase the
pressure in one brain compartment, particularly the
infratentorial compartment, because it may lower pressure
in the spinal canal and increase the pressure differential
across different brain compartments and precipitate
herniation of brain, particularly through the foramen
magnum (‘coning’) (see p.31).
Coma with meningism but no focal/lateralizing
neurologic signs
• CT brain scan: subarachnoid blood, or focal collections
of blood or pus.
• LP, depending on results of CT scan, to examine CSF for
blood, inflammatory cells, and micro-organisms.
Coma without focal or lateralizing neurologic signs
or meningismus:
• Full blood count and ESR.
• Urea and electrolytes.
• Plasma and urine osmolality.
• Blood glucose.
• Red blood cell transketolase.
• Thiamine.
• Liver function tests.
• Calcium and phosphate.
• Thyroid function tests.
• Arterial blood gases.
• Drug and toxin screen in blood and urine.
• EEG: triphasic waves of hepatic and uremic
encephalopathy, non-convulsive status epilepticus or a
post ictal recording.
• CT or MRI brain may be necessary but the chance of
finding a focal abnormality is low.
• LP may occasionally be indicated to exclude an
inflammatory or infectious cause.
50 Disorders of Consciousness

TREATMENT Clinical signs

Resuscitation
• Establish an adequate airway: consider if endotracheal
intubation, assisted respiration and oxygen are required.
• Establish intravenous access:
– Withdraw blood to measure blood glucose, electrolytes,
metabolites, and drug levels.
– Stabilize the circulation: blood volume expansion or
vasodepressor agent may be required.
Clinical, radiologic and laboratory assessment
(see above)
Specific treatment of the underlying cause
For example:
• Naloxone (opiate intoxication).
• Glucose (hypoglycemia).
• Thiamine (Wernicke’s encephalopathy): 100 mg
intravenously daily for 7 days and then regular oral
vitamin supplements.
The constellation of brainstem reflexes are the most
important prognostic clinical signs; there is no single
prognostic sign.
After 24 hours of coma
• Absent pupillary or corneal reflexes, or oculovestibular
responses, in the absence of sedative drugs: almost
incompatible with recovery of independence, irrespective
of the cause of coma.
• Absent corneal reflexes and oculovestibular responses,
together with extension of the limbs in response to pain:
<3% chance of any useful recovery.
• Intact pupillary and corneal reflexes, and movements of
localization: 40% chance of achieving independence.
After 48 hours of coma
• Nystagmus induced by oculovestibular testing, and
vocalization of any recognizable word: 50% chance of
good recovery.

Continuing care
• Intensive care unit: protect, monitor and maintain
respiration, circulation, skin, and bladder and bowel
function; correct medical or surgical abnormalities, and
control epileptic seizures.
• Corticosteroids and hyperventilation may be indicated
for cerebral edema but are not of any value in the routine
management of the comatose patient.

PROGNOSIS
Determined by the etiology, depth and duration of coma
and the constellation of clinical signs of brainstem function.

Etiology
A continuing vegetative state is most likely to occur after
head injury or hypoxic ischemic damage. The chances of 68
making a good recovery for patients in coma due to the
following are:

• Stroke, including subarachnoid hemorrhage: <5%.

• Hypoxic-ischemic encephalopathy: 10%.
• Metabolic or infective encephalopathy: nearly 30%.
• Head injury: worse prognosis if intracranial hematoma,
increasing age of patient, and severe systemic injury.

Depth of coma
Poor prognostic factors:
• No response to eye opening (compared with eye opening).
• No vocal response to pain (compared with grunting).
• Poor motor response to pain (compared with flexion of
the limbs).

Duration of coma
• 6 hours: about 12% make a good recovery.
• 24 hours: 10% make a good recovery.
• 1 week: 3% good recovery.
• >1–2 weeks: almost all die or enter a continuing
vegetative state.

68 Ventral surface of the brain of a patient who died from acute

meningo-encephalitis.
 Brain Death
BRAIN DEATH
DEFINITION
Death
• Irreversible cessation of all function of the brain or
irreversible cessation of circulation of blood in the body.
• Irreversible loss of the capacity for consciousness, com-
bined with the irreversible loss of the capacity to breathe.
Brain death
• Irreversible loss of function of the brain or brainstem.
• The state in which brain tissue is damaged to such an
extent that vital brain functions are irreversibly impaired,
regardless of whether or not the heart is beating.
ETIOLOGY AND PATHOPHYSIOLOGY
• Hypoxic-ischemic insults: cardiac arrest, carbon
monoxide poisoning, status asthmaticus.
• Head trauma.
• Stroke: ischemic, hemorrhagic.
• Brain infections: encephalitis, meningitis (68).
• Metabolic/endocrine failure.
• Drug toxicity.
CLINICAL FEATURES
The clinical assessment should be carried out by two physi-
cians on at least two separate occasions 12–24 hours apart.
• Unconscious.
• Apnea.
• Absent brainstem function:
– Pupils: mid position or fully dilated, fixed in diameter
and non-reactive to sharp changes in the intensity of
instant light.
– Corneal reflexes: absent.
– Vestibulo-ocular reflexes (oculocephalic [‘doll’s eye’] and
caloric-induced eye movement): absent.
– Stimulation of any somatic area within the cranial nerve
distribution fails to elicit a motor response: noxious
stimulation of the face fails to provoke a facial reflex
response.
– Cough, suck and root reflexes: absent.
– Gag reflex: absent and there is no response to tugging
an intratracheal tube or bronchial stimulation by a
suction catheter passed down the trachea.
– Ventilatory reflexes: absent; there is no spontaneous
respiration when the patient’s ventilator is disconnected
for a time sufficient to ensure that arterial carbon dioxide
tension has risen above the threshold for stimulation of
respiration (arterial PaCO2 >8 kPa [60 mmHg] with
pH <7.30).
• Patient not hypothermic or hypotensive.
• Flaccid tone and absent spontaneous or induced
movement.
• Consistent examination findings throughout a pre-
determined period of observation.
DIFFERENTIAL DIAGNOSIS
• Coma (see p.44):
– Metabolic: hepatic and renal failure; hypo/hyper-
glycemia, hypo/hypernatremia.
– Endocrine failure: hypothyroidism.
– Toxicity: depressant drugs (e.g. sedatives, analgesics,
muscle relaxants, illicit drugs).
51
– Hypothermia.
– Hypotension.
• Permanent vegetative state (see p.52).
• Locked-in syndrome (see p.55).
• Psychogenic unresponsiveness.
INVESTIGATIONS
Eliminate remediable or reversible conditions
• CT or MRI brain scan: remediable brainstem
compression.
• Full blood count and ESR.
• Urea and electrolytes.
• Blood glucose.
• Liver function tests.
• Thyroid function tests.
• Urine drug samples: convenient but provide retrospective
data on substances eliminated by renal mechanisms and
are poor indicators of the amount ingested.
• Plasma drug samples: more informative but do not
measure tissue concentrations at the site of concern, such
as the brain. There can be wide variability in the rate and
extent of drug absorption, with up to fourfold dif-
ferences in cerebral effects for a given blood concentra-
tion. The rate of transport of drugs between blood and
brain tissue is a function of several factors: the protein
binding and physicochemical properties of the drug, and
physiologic factors, such as cerebral blood flow, drug
diffusion, and active transport processes over the
specialized endothelium of the cerebral capillaries.
• EEG: may be useful in the differential diagnosis of coma
(e.g. triphasic waves of hepatic encephalopathy) and for
determining prognosis.
Brain death
• EEG: electrocerebral silence, but not necessary for the
diagnosis of brain death if all the clinical criteria are
fulfilled (see below).
• Cerebral angiography: absent cerebral blood flow.
• Radionuclide brain scan: absent cerebral blood flow.
DIAGNOSIS
Lack of clinically observable brain function:
• The patient must be deeply comatose.
• All brainstem reflexes must be absent and remain absent
during repeated testing at intervals up to 24 hours.
• The patient has to be maintained on a ventilator because
spontaneous respiration has ceased or is inadequate.
• The cause of brain death has been fully established,
having absolutely excluded the effects of hypothermia,
depressant drugs, and potentially reversible metabolic,
toxic and endocrine causes of coma.
• There is no doubt that the patient’s condition (loss of
consciousness and loss of brainstem reflex responses and
respiratory center function, or cessation of intracranial
blood flow) results from irremediable brain damage of
known etiology and is irreversible.
• Some activity may be detectable (e.g. endocrine function
or low voltage EEG activity).
52 Disorders of Consciousness
MANAGEMENT
Establish brain death with certainty using
recognized criteria
• Diagnosis (Wijdicks, 2001).
• Exclusion of potential confounding factors: metabolic,
endocrine and toxic causes. Wait at least four half-lives of
elimination of the relevant drug in the absence of factors
known to delay excretion. This is usually 3 or 4 days.
Evidence of delayed excretion may necessitate confirma-
tory cerebral vessel radiocontrast or radionuclide
angiography.
• Observation (6–48 hours depending on the age of the
patient).
• Examination:
– Proof of extensive brain damage.
– Exclusion of reversible causes of coma.
– Clinical examination of brainstem reflexes: pupillary,
corneal, oculocephalic, oculovestibular, gag, cough.
– Assessment of somatic responses.
– Demonstration of apnea despite arterial PaCO2 >8 kPa
(60 mmHg) with pH <7.30.
• Repeat examination (more than 2 hours after first
examination).
• Certification by two practitioners.
Prepare and discuss with the family or family
spokesperson
• The underlying condition.
• What constitutes brain death.
• Why and how it has occurred.
• Differences between brain death and permanent
vegetative state.
Provide emotional and practical support
Continual contact between the family and:
• A responsible decision maker.
• The intensive care/ward staff providing hour-by-hour
care.
When counselling
• Sit close enough to be easily seen and heard in an area
where you will not be disturbed.
• Avoid physical barriers such as tables or desks.
• Achieve and sustain eye contact.
• Extend a comforting touch to the relative’s shoulder or
hand, if appropriate.
Allow time for acceptance of the situation
• Do not rush or pressurize a decision.
• Do not become impatient with requests to cover the
same ground many times.
• Do not withhold information.
• Do not peripheralize the family in the decision processes.
• Do not over-promote the issue of organ donation.
Involve the family centrally in final decision making
and participation in the ‘switch off’ process if
requested
After brain death is determined, life support
is removed
• Do not withdraw contact after the ‘switch off’.
PERMANENT VEGETATIVE
STATE (PVS)
DEFINITION:
• A condition of ‘wakefulness without awareness’.
• The absence of any adaptive response to the external
environment and any evidence of a functioning mind
which is either receiving or projecting information, in a
patient who has long periods of wakefulness.
The vegetative state
• A clinical condition of unawareness of self and environ-
ment in which the patient breathes spontaneously, has a
stable circulation, and shows cycles of eye closure and eye
opening which may simulate sleep and waking.
• May be a transient stage in the recovery from coma or it
may persist until death.
The continuing or persistent vegetative state
• The vegetative state has continued for more than 4 weeks
and it has become increasingly unlikely that the condition
is part of a recovery phase from coma.
The permanent vegetative state
• A diagnosis based on a high degree of clinical certainty
that the continuing vegetative state is irreversible; usually
a continuing vegetative state for more than 12 months
after head injury and more than 6 months following
other causes of brain damage.
• Avoiding this state is one of the most important aspects
of attempting to assess prognosis early in coma.
EPIDEMIOLOGY
Prevalence: 10 000 to 25 000 adults and 400–1000 children
in the USA.
PATHOPHYSIOLOGY
• Severe damage to part or all of the cerebral hemispheres,
with an intact brainstem.
• Can occur with damage to the more rostral part of the
brainstem.
PATHOLOGY
Three main patterns:
• Diffuse axonal injury, typically as a sequel to severe closed
head trauma, giving rise to degeneration of the white
matter throughout the cerebral hemispheres.
• Extensive laminar necrosis of the cerebral cortex,
following global cerebral hypoxia or ischemia (69).
• Thalamic necrosis, occasionally.
ETIOLOGY
• Head injury.
• Hypoxic-ischemic encephalopathy: cardiac arrest, carbon
monoxide poisoning.
• Stroke: ischemic or hemorrhagic.
• Hypoglycemia.
• Intracranial infection.
• Brain tumor.
• End stage of degenerative brain disorders: Alzheimer’s
disease.
 Permanent Vegetative State (PVS)
CLINICAL FEATURES
• Inattentive and unaware of the surroundings but
breathes spontaneously, without mechanical support, and
has a stable circulation.
• At times the eyes are closed and the patient appears
asleep, at other times the eyes are open and they seem to
be awake.
• May be aroused by painful or prominent stimuli, opening
the eyes if they are closed, increasing the respiratory rate,
or occasionally grimacing or moving the limbs.
• When the eyes are open the eyelids may blink in response
to any threat to the eye.
• A range of spontaneous movements may occur such as
roving eye movements, chewing, teeth-grinding,
groaning, grunting and even swallowing is possible.
More distressingly, patients may smile, shed tears, moan
or scream, without any discernible reason. Sometimes,
the head and eyes turn fleetingly to follow a moving
object or sound.
• Body posture may be decorticate or decerebrate.
• Brainstem reflexes (pupillary, oculocephalic [doll’s eye],
corneal and gag) are usually preserved.
• Primitive reflexes such as pouting and sucking reflexes,
grasp reflex, and withdrawal reflexes to pain may be
present.
• Painful stimuli may provoke an extensor or a flexor
response.
• Plantar responses are commonly extensor.
N.B. Any unambiguous sign of conscious perception or
deliberate action (e.g. any evidence of communication,
including a consistent response to command, or any
purposeful movement) is incompatible with the diagnosis
of vegetative state. Careful prolonged observation is
required before concluding that a patient’s wakefulness is
unaccompanied by awareness.
69
69 Microscopic section of a part of a cerebral hemisphere showing
laminar necrosis and demyelination in the white matter due to carbon
monoxide poisoning. (Courtesy of Professor BA Kakulas, Royal Perth
Hospital,Western Australia.)
53
DIAGNOSIS
Two medical practitioners experienced in assessing
disturbances of consciousness and awareness should
separately assess the patient (this includes discussion with
other medical and nursing staff, relatives and carers about
the reactions and responses of the patient, and to ensure that
the patient is not sentient) and document their findings and
conclusions in the medical record. If there is any uncertainty
about the diagnosis of the permanent vegetative state, then
a re-assessment should be undertaken at a later date.
DIAGNOSTIC CRITERIA
Preconditions
• A cause for the syndrome has been established.
• Persisting effects of sedative, anesthetic and neuro-
muscular blocking drugs have been excluded by the
passage or time or by appropriate analysis of body fluids.
• Reversible metabolic causes have been corrected or
excluded as the cause.
Clinical criteria
All three of:
• No evidence of awareness of self or environment at any
time. No volitional response to visual, auditory, tactile or
noxious stimuli, and no evidence of language
comprehension or expression.
• Cycles of eye closure and eye opening which may
simulate sleep and waking shall be present.
• Hypothalamic and brainstem function is sufficiently
preserved to ensure the maintenance of respiration and
circulation.
Other clinical features include:
• Spontaneous blinking.
• Inconsistent, non-purposeful reflex movements in
response to external stimuli:
– Apparent smiling.
– Facial ‘grimacing’ to painful stimuli.
– Watering of the eyes.
– Startle myoclonus.
– Occasional movements of the head and eyes towards a
peripheral sound or movement.
– Purposeless movement of the limbs and trunk.
• Retained pupillary and corneal responses (usually).
• Absence of visual fixation and ability to track moving
objects with the eyes or show a ‘menace’ response.
• Roving eye movements may be present.
• Conjugate or dysconjugate tonic eye movement, without
corrective saccades (nystagmus) in response to ice water
caloric testing.
• Variable deep tendon reflexes (reduced, normal or brisk)
and plantar responses.
• Clonus and other signs of spasticity may be present.
• Incontinence of bladder and bowel.
54 Disorders of Consciousness

DIFFERENTIAL DIAGNOSIS • Single photon emission computed tomography (SPECT)

• Locked-in syndrome (see p.55): a brainstem lesion dis-
rupts the voluntary control of movement but arousal and
the content of awareness are not abolished. Patients are
able to communicate by movement of the eyes or eyelids.
• Coma (see p.44): most patients who are in ‘coma’ for
weeks, months or years are in a continuing vegetative
state.
• Brain death (see p.51): implies the irreversible loss of all
brainstem functions. It is, in a sense, the converse of
PVS, in which brainstem function survives while the
function of the cerebral hemispheres is lost or gravely
impaired. Brain death is followed, within hours or days,
despite intensive care, by cardiac arrest.
• Akinetic mutism: a state of profound apathy with
evidence of preserved awareness and attentive visual
pursuit, giving an unfulfilled ‘promise of speech’. The
responsible lesions often involve the medial frontal lobes.
• Psychogenic unresponsiveness.
The differentiation of these conditions from the
vegetative state is based on clinical findings (Table 3).
INVESTIGATIONS
• CT or MRI head scan: may show non-specific focal or
diffuse abnormalities, brain atrophy, and hydrocephalus.
and positron emission tomography (PET): show a
reduction in cerebral metabolism.
• Neurophysiology studies: EEG, somatosensory evoked
potentials (SSEPs), and electrodermal techniques; very
variable results. Often these studies provide evidence of
some cortical activity, reminding us that an accurate
clinical diagnosis of vegetative state does not imply
cortical silence. They are of little value in predicting
outcome, other than early EEG evidence of burst suppres-
sion and SSEP evidence of an absent N20 potential.
No findings are diagnostic of the permanent vegetative
state.
PROGNOSIS
• Determined by the age of the patient, underlying cause
and the duration of the vegetative state.
• The outlook is better in children, and after traumatic (as
opposed to non-traumatic) brain injury. If the cause is
not head injury, there is very little hope of recovery of
sentience after 3 months and none after 6 months.
• If the cause is head injury, a longer time should elapse
(e.g. 6 months) before being confident that the chances
of recovery are extremely low (and almost non-existent
after 12 months).

Table 3 Differentiation of vegetative state from other conditions

Condition Locked-in syndrome Vegetative state Coma Brain death

Self-awareness Present Absent Absent Absent

Cyclical eye Present Present Absent Absent

opening

Glasgow coma scale

Eye opening 4 4 1–2 1
Motor response 1 1–4 1–4 1–2
Verbal response 1 1 1–2 1

Motor function Eye movement preserved in No purposeful movement No purposeful None or only
the vertical plane and able movement reflex spinal
to blink volitionally movement

Pain sensation Yes No No No

Respiratory Normal Normal Depressed Absent

function or varied

EEG activity Normal or minimally Polymorphic delta or theta Polymorphic Electrocerebral

abnormal –sometimes slow alpha delta or theta silence or theta

Brain Minimal/moderate ≥50% reduction ≥50% reduction Absent or

metabolism reduction great reduction

Prognosis Depends on cause Depends on cause Recovery, No recovery

Recovery unlikely and duration vegetative state,
or death within
2–4 weeks
 Locked-in Syndrome
MANAGEMENT
Establish the diagnosis of a permanent vegetative state by
(1) identifying the clinical state of the patient, (2) the cause
for the syndrome, and (3) the lapse of time. Because many
patients entering a vegetative state emerge from it within a
few weeks or months, supportive early management is
usually appropriate. The diagnosis of a permanent vegetative
state implies that recovery cannot be achieved and further
therapy is futile. It merely prolongs an insentient life for the
patient and a hopeless vigil for relatives and carers.
Medical care
• Appropriate nursing or home care.
• Maintain oxygenation, circulation and nutrition.
• Correct complicating factors such as infection and
hypoglycemia.
• Sensitive discussion with, and education of, relatives and
carers about the cause, clinical state, ‘hopeless’ prognosis,
and implications, including the possibility of withdrawing
artificial means of administering food and fluid.
• Decisions to withdraw nutrition, hydration and other
life-sustaining medication such as insulin for diabetes,
should currently be referred to the court before any
action is taken.
• Decisions not to intervene with cardio-pulmonary
resuscitation or prescribe antibiotics are clinical decisions,
but they should take account of, and respect, the views
of the relatives, carers and patient, if known, whether
formally recorded in a written document (or advance
directive) or not.
• The role of sensory stimulation remains uncertain,
despite the writings of Hippocrates: ‘the patient in a state
of coma should be spoken to in a loud voice, splashed
with cold water and exposed to bright light’.
70
55
LOCKED-IN SYNDROME
DEFINITION
A de-efferented state whereby patients are aware of
themselves and their environment but are unable to respond
due to loss of motor and speech function.
PATHOGENESIS
• A supranuclear (upper motor neuon) lesion of the
descending corticospinal tracts, usually in the ventral
portion of the brainstem (commonly the pons), below
the level of the IIIrd cranial nerve nuclei, causes paralysis
of the muscles innervated by the lower cranial nerves and
peripheral nerves.
• A widespread nuclear or infranuclear (lower motor
neuon) disease of motor nerves.
ETIOLOGY
Ventral brainstem lesion
• Infarction or hemorrhage (commonly hypertensive
patients) (70, 71).
• Tumor.
• Demyelination (multiple sclerosis).
• Central pontine myelinolysis, following profound
hyponatremia (see p.457).
• Head injury.
Polyneuropathy
• Critical illness polyneuropathy.
• Acute onset post-infectious polyradiculoneuropathy
(Guillain–Barré syndrome).
71
71 Autopsy specimen of a cross section of the midpons and
cerebellum in the axial plane of a patient who was ‘locked-in’
showing hemorrhagic infarction in the ventral pons bilaterally.
70 Proton density weighted axial MR scan showing high signal in
the basilar artery (due to thrombus, arrow) and increased signal in
the pons due to pontine infarction (arrowhead) in a patient who
presented ‘locked-in’.
56 Disorders of Consciousness
CLINICAL FEATURES
• Unable to speak.
• Unable to move the limbs.
• Awareness and consciousness are preserved because the
brainstem tegmentum, including the reticular formation
and oculomotor nerves and pathways are spared.
• Able to open the eyes and move them, (particularly in
the vertical plane) and blink, in order to try and
communicate.
INVESTIGATIONS:
• CT or MRI brain scan: ventral pontine or midbrain lesion.
• Other investigations, as appropriate, to ascertain the
cause (e.g. serum sodium, EEG, EMG).
DIAGNOSIS
Diagnosis is clinical, based on the presence of total paralysis
of the limbs and muscles innervated by the lower cranial
nerves, but with the ability of the patient to open and close
the eyes voluntarily and in response to commands, and to
respond to verbal and sensory stimuli by blinking.
TREATMENT
General (see Coma, p.44)
Patients can see, hear and feel everything (including pain
and itch) so are sensitive to what staff are saying. They are
also very frustrated that they cannot move.
• Prevention of complications of immobility: pneumonia,
deep vein thrombosis, contractures, urinary tract infection.
• Rehabilitation: physiotherapy, swallowing and speech
therapy, occupational therapy, psychologic support and
therapy.
Specific
Correct the underlying cause (e.g. hyponatremia; see
Central pontine myelinolysis, p.457).
PROGNOSIS
Prognosis is poor. Some patients recover, usually with
residual limb spasticity.
NARCOLEPSY
DEFINITION
A syndrome of excessive sleepiness and abnormally regulated
rapid-eye-movement (REM) sleep.
EPIDEMIOLOGY
• Prevalence: 1 in 500 000 (Israel), 1 in 5000 (USA,
Europe), 1 in 600 (Japan).
• Age: 5–50 years, usually 15–35 years.
• Gender: M=F.
PATHOLOGY
Unknown.
ETIOLOGY AND PATHOPHYSIOLOGY
• Inherited susceptibility: probably dominant with variable
penetrance.
• Linked strongly to certain Class II HLA antigens: HLA-
DR2 and HLA-DQw1 antigens in 98–100% of patients.
Classic narcolepsy (narcolepsy associated with cataplexy)
has almost a 100% association with the DRw15 subtype
of the HLA-DR2 antigen, the DQw6 subtype of the
HLA-DQw1 antigen, and the HLA-Dw2 subtype of the
HLA-D antigen.
• The ‘narcolepsy-susceptibility’ gene has not been located
exactly but is likely to be just outside the HLA-DQ and
HLA-DR subregions on the short arm of chromosome 6.
• The occurrence of normal periods of REM sleep at the
onset of sleep or within 10 minutes thereafter is the most
characteristic and striking physiologic abnormality, and
probably indicates impaired sleep–wake regulation rather
than an excessive need for REM sleep.
• The mechanism may be abnormalities of monoaminergic
and cholinergic functioning in the brain (e.g. impaired
release of norepinephric neurotransmitters).
• Abnormalities in the orexin (hypocretin) neurotrans-
mitter system are directly involved in the pathogenesis of
narcolepsy in two animal models. Decreased levels of
orexin A in the CSF are found in narcoleptic patients,
and an association of a rare polymorphism in the prepro-
orexin gene with narcolepsy in a cohort of 178 patients
has been reported recently.
• Hypnagogic hallucinations, sleep paralysis and cataplexy
appear to be associated manifestations of REM sleep that
intrude into wakefulness.
CLINICAL FEATURES
Excessive sleepiness (rather than increased sleep)
• Brief (a few to 30 minutes), irresistible episodes of
daytime sleep, sometimes associated with dreaming, and
preceded by increasing drowsiness.
• Most apparent in boring, sedentary situations.
• Partially alleviated by mental stimulation and motor
activity.
• Cannot be fully relieved by any amount of sleep.
• Patients usually feel refreshed after a sleep attack.
• Chronic excessive daytime sleepiness between attacks of
sleep.
• The degree of sleepiness usually remains stable after the
first few months.
• Increased sleepiness after several years suggests the
presence of an additional disorder, such as sleep apnea.
 Narcolepsy
Cataplexy
• Attacks, lasting from a few seconds to several minutes, of
sudden reduction or loss of muscle tone, usually precipi-
tated by excitement, emotion (such as surprise, anger,
laughter) and athletic activities. Severe attacks cause
complete paralysis except for the respiratory muscles.
More common partial episodes cause patients to drop
objects, sit down, stop walking, and even lose sphincter
control (e.g. fecal incontinence).
• Consciousness is almost always maintained.
• Most attacks last less than 1 minute.
• Prolonged episodes may be associated with hallucinations.
• Rarely, cataplexy that is almost continuous (‘status
cataplecticus’) may occur.
• Sleep paralysis (60% of patients).
• Brief episodes of inability to move during the onset of
sleep or on awakening.
• Patient may feel as if he or she is struggling to move.
• Lasts up to 10 minutes.
Hypnagogic hallucinations (60% of patients)
• Hallucinatory experiences, usually visual but can be
auditory or tactile, that accompany the onset of sleep or
awakening.
• May have a dream-like quality but awareness of sur-
roundings is preserved.
• May accompany sleep paralysis or occur independently.
Other symptoms
• Automatic behavior (up to 80% of cases): episodes of
semi-purposeful activity, such as writing off the edge of
the page, putting clothes in the refrigerator, usually
during monotonous or repetitive behavior, and for which
the patient is amnesic.
• Brief lapses in speech and concentration.
• Disrupted nocturnal sleep.
• Memory disturbances, due to impaired attention and
fluctuating levels of alertness.
• Blurred or double vision (10–14%).
• Depression (?due to altered central monoamine function).
72
72 Macroscopic appearance of the brain, coronal section through the
thalami and upper midbrain showing a pineal germinoma occupying the
third ventricle (arrows) and compressing the rostral midbrain in a
patient who presented with recurrent episodes of daytime sleepiness
and was initially considered to have narcolepsy.
57
DIFFERENTIAL DIAGNOSIS
Epilepsy
Although a single episode may be clinically indistinguishable
from a complex partial or absence seizure, the ‘sleep-like’
appearance of the patient and the association of the episodes
with drowsiness and passive situations helps to distinguish
automatic behavior from the repetitive stereotyped behavior
that accompanies epileptic seizures.
Schizophrenia
Patients with narcolepsy and prominent hallucinations may
be misdiagnosed as schizophrenic.
Daytime sleepiness
• Sleep apnea: obstructive sleep apnea is characterized by
recurrent episodes of partial or complete upper airway
obstruction during sleep (causing habitual snoring and
witnessed apneas) which are terminated by arousal. The
recurrent arousals have a destructive effect on sleep and
so the common symptoms are excessive daytime sleepi-
ness, and impairment of mood, memory and concen-
tration. Consequently, the patients’ work, family and
social lives are disrupted and the risk of accidents is
increased. Obstructive sleep apnea affects about 4% of
middle-aged men and half as many women. Predisposing
factors include male gender, increasing age, obesity,
alcohol and sedative abuse, family history, specific upper
airway abnormalities (nasal obstruction, tonsil-
lar/adenoidal hypertrophy, micrognathia, retrognathia,
Marfan’s syndrome), endocrine diseases (hypothyroid-
ism, acromegaly) and neuromuscular diseases (decreased
ventilatory drive, decreased upper airway muscle tone).
Treatment strategies include modification of predisposing
factors; reduction of weight, smoking, alcohol and
sedatives; modification of sleeping posture; nasal con-
tinuous positive airway pressure (CPAP); dental splints;
and surgery (nasal [if obstructed], palatal, mandibu-
lar/maxillary).
• Insufficient sleep.
• Medication effects.
• Diencephalic lesions: tumors in the region of the third
ventricle (72).
Excessive sleepiness without REM-sleep
abnormalities or cataplexy
• Narcolepsy which progresses with time to include
abnormalities of REM sleep and cataplexy.
• Atypical depression.
• Irregular sleep schedules.
• Idiopathic hypersomnia (a diagnosis of exclusion, having
excluded depression, insufficient sleep, and abnormalities
of REM sleep).
REM sleep at onset of sleep
• Endogenous depression.
• Sleep deprivation: sleep apnea, disturbances of the sleep-
wake schedule.
• Drug and alcohol withdrawal.
• Some structural brain lesions.
58 Disorders of Consciousness

INVESTIGATIONS CLINICAL COURSE AND PROGNOSIS

• Multiple sleep latency test (73): monitors the time to the
onset of sleep and the type of sleep that occurs during
attempts to sleep at 2 hourly intervals throughout the
day. More than 80% of patients with narcolepsy have a
mean sleep latency of less than 5 minutes and at least two
REM periods at the onset of sleep during the procedure.
• MRI brain scan is sometimes indicated to exclude the
most unlikely possibility of a diencephalic structural
lesion.
DIAGNOSIS
• Excessive sleepiness and frequent REM periods at the
onset of sleep.
• Confirmation with a formal multiple sleep latency test is
essential in view of the long term implications of the
diagnosis.
• Sleepiness usually precedes cataplexy by several months
but 6–10% of patients experience cataplexy initially, and
10–15% do not develop cataplexy until 10 years or more
after the onset of sleepiness.
• The degree of sleepiness usually remains stable after the
first few months and rarely lessens. Increased sleepiness
after several years suggests the presence of an additional
disorder, such as sleep apnea.
• Cataplexy, hypnagogic hallucinations, and sleep paralysis
improve or disappear with age in about one-third of
patients.

TREATMENT
Narcolepsy
• Avoid occupations and situations where nodding off to
sleep is a danger to the patient or to others, such as
driving.
• Take regular 15–20 minute naps.

Stimulants:
• Enhance the synaptic availability of noradrenaline.
• Methylphenidate 10–60 mg/day, or
• Dextroamphetamine 5–50 mg/day. FP1-F3 73
• Higher doses offer little additional benefit and increase
F3-C3
the risk of adverse effects.
• Pemoline or protriptyline may be tried if methyl- C3-P3
phenidate and dextroamphetamine are not successful or P3-O1
not tolerated.
• Modafinil (an alpha1-adrenergic agent) 100 mg bd, FP2-F4
mazindol (an imidazole derivative), and selegiline (a F4-C4
monoamine oxidase-type B inhibitor) improve daytime
C4-P4
alertness and may have fewer adverse effects than
amphetamine. P4-O2
• Narcoleptics are not immune to the problems associated
with the chronic use of stimulants.
LOC
Cataplexy and sleep paralysis ROC
• Tricyclic antidepressants (e.g. imipramine, clomipramine, LUE
protriptyline) in low doses (10–50 mg): act by inhibiting
reuptake of noradrenaline and serotonin rather than LAE
cholinergic blockade.
• Specific serotonin reuptake inhibitors (e.g. fluoxetine):
EMG
may be as effective with fewer anticholinergic adverse
effects.
• Noradrenaline reuptake inhibitors (e.g. viloxazine).
• Gamma-hydroxybutyrate (sodium oxybate): increases 73 Electroencephalography (EEG) of a middle-aged male with
slow-wave sleep and REM sleep; effective in some. episodes of loss of consciousness (sleep attacks) and automatic
• Abrupt discontinuation of tricyclic agents can lead to a behavior (mini-sleeps). Multiple sleep latency test gave evidence of
rebound increase in cataplexy. narcolepsy with short sleep latency (2 minutes) and sleep-onset REM
• Gradual withdrawal of tricyclic antidepressants followed periods (REM latency 1 minute).Typical features during REM sleep
by a drug holiday sometimes helps restore efficacy. include rapid eye movements, absent muscle artefact, and drowsy
EEG pattern.
Disturbed nocturnal sleep LOC: left outer canthus; ROC: right outer canthus; LUE: left under
• Short acting hypnotic (e.g. temazepam) one or twice a eye; LAE: left above eye. Ocular electrodes were referential to A1A2.
week; regular nightly use is rarely beneficial. (Reproduced with permission from the editor (Elaine Wyllie, MD)
and publisher (Williams & Wilkins) of Wylie E (ed) (1997) The
Treatment of Epilepsy: Principles and Practice, 2nd edn.Williams &
Wilkins, Baltimore.)
 Syncope 59

SYNCOPE Reduced stroke volume

Acute reduction
Low blood volume:
DEFINITION • Acute fluid loss: burns, vomiting, diarrhea, dehydration.
A transient loss of postural tone and consciousness resulting • Hemorrhage.
from an acute reduction in blood flow to the brain. • Addison’s disease.
• Diuretics.
EPIDEMIOLOGY • Very low salt diet.
• Incidence: The most common non-epileptic cause of loss
of consciousness. Obstruction to venous return to the heart:
• Age and gender: any age and either sex. • Cough/micturition/defecation.
• Cardiac tamponade.
PATHOPHYSIOLOGY
Basic neurophysiology Impaired outflow from the heart: acute myocardial
The conscious state depends on the integrity of the infarction.
brainstem reticular activating system interacting (through
its ascending pathways) with both cerebral hemispheres. Obstruction to outflow from the heart:
Therefore, to disturb consciousness, the function of the • Pulmonary embolus.
brainstem or both cerebral hemispheres needs to be • Aortic dissection.
disturbed (see Coma, p.44).
Chronic reduction
Basic vascular physiology: Impaired outflow from the heart:
• Blood flow to the brain depends on the mean arterial • Cardiomyopathy: dilated.
blood pressure and the intracranial pressure. • Congenital heart disease.
• Blood pressure is the product of the cardiac output
(heart rate × stroke volume) and total peripheral Obstruction to outflow from the heart:
resistance. • Atrial myxoma or ball valve thrombus (impaired
• Blood flow in the brain is maintained by autoregulation ventricular filling).
in response to minor changes in systemic blood pressure. • Hypertrophic obstructive cardiomyopathy.
However, sudden, dramatic reductions in blood pressure • Aortic stenosis (syncope on exertion).
below a mean arterial BP of about 8 kPa (60 mmHg)
result in a parallel fall in brain perfusion, resulting in a Reduced peripheral resistance
gradual loss of consciousness. Central autonomic neuropathy
• Multiple systems atrophy (see p.435).
Altered heart rate • Parkinson’s disease.
Bradyarrhythmia • Primary autonomic failure.
Primary: • Spinal cord injury.
• Complete heart block (Stokes–Adams attack).
• Atrial fibrillation. Peripheral neuropathy
• Sinus arrest. • Diabetic neuropathy.
• Guillain–Barré syndrome.
Secondary: • Tabes dorsalis.
• Carotid sinus hypersensitivity (head turning, neck • Amyloid neuropathy.
massage). • Acute porphyria.
• Swallow syncope: swallowing can activate a vagal reflex. • Autonomic ganglionitis and neuritis.
It may indicate an underlying structural abnormality of
the esophagus, glossopharyngeal neuralgia, digoxin Other
toxicity, or ischemic heart disease. • Vaso-vagal (the most common cause of syncope).
• Stretch syncope. • Drugs: vasodilators (e.g. glyceryl trinitrate, prazosin,
• Ice-cream syncope: cold food held in the mouth can hydralazine, calcium channel blockers) and other anti-
activate a vagal reflex. hypertensives (e.g. diuretics, ganglion blockers), levodopa,
• Prostatic syncope: rectal examination may activate a vagal bromocriptine, antidepressants, phenothiazines, sedatives.
reflex. • Large meal (dilatation of splanchnic vessels).
• Vaso-vagal attack: often precipitated by emotion. • Heat (dilatation of cutaneous vessel).
• Baroreceptor dysfunction (age, hypertension, prolonged • Anemia.
bed rest, autonomic neuropathy). • Hyponatremia.
• Old age and prolonged recumbency.
Tachyarrhythmia
Supraventricular tachycardia:
• Wolff–Parkinson–White syndrome.
• Prolonged QT syndrome.
• Complex partial seizures (very rare).

Ventricular tachycardia.
60 Disorders of Consciousness

ETIOLOGY (see Table 4) • Generalized weakness.

CLINICAL FEATURES
History
The history should be directed firstly toward confirming
that the patient has syncope, and secondly towards finding
the cause. Interview the patient and a witness if available.
Precipitating/contributory factors
• Venesection, acute pain or emotional shock, prolonged
standing, overcrowding, heat (vaso-vagal syncope).
• Valsalva maneuver: deliberate or during weight lifting,
playing a wind or brass musical instrument, or straining
at stool.
• Coughing.
• Micturition.
• Changes in posture (e.g. standing after sitting or lying in
bed for a prolonged period) and head position.
• Drugs (nitrates, α-adrenoreceptor blockers [veno-
dilators]; diuretics [low blood volume]).
• Hot environment (vasodilatation of cutaneous vessels).
• Large meal (vasodilatation of splanchnic vessels).
Pre-syncopal symptoms
• Light headedness.
• Faintness.
• ‘Dizziness’ (not vertigo).
• Dimming or loss of vision in both eyes (not to be
confused with lone bilateral blindness), sounds seem to
be distant/muffled.
• Symptoms of adrenergic activity such as nausea, hot and
cold feelings and sweating.
• Palpitations and chest pain may indicated a cardiac cause,
but palpitations are also common in panic attacks and
overbreathing.
Associated features during the attack:
• Pale (rather than cyanosed).
• Sweaty/clammy.
• Floppy (rather than rigid).
• Pulse: absent or difficult to feel (but this cannot be relied
upon).
• Incontinence of urine may occur.
• Motor symptoms, such as a brief tonic contraction of the
trunk, tonic-clonic movements, and multifocal,
arrhythmic, myoclonic jerks may occur, particularly if an
upright or semi-upright posture is maintained.
Duration
Syncope lasts seconds to 1 or 2 minutes, provided the
patient assumes the recumbent position, and isn't held
upright (by someone or an obstacle).
Sequelae
As consciousness is regained quickly there is very little
mental confusion or difficulty recalling the warning
symptoms (unless there has been head trauma), in contrast
to the prolonged confusion, drowsiness and myalgia that
may be seen after a generalized seizure. Convulsive syncope

Table 4 Etiology of syncope

Type or cause of syncope Characteristics Severity Population prevalence %

(range)
Reflex-mediated
• Vaso-vagal Warmth, nausea Benign 18 (8–37)
• Situational After daily activity Benign 5 (1–8)
• Other After neck pressure Benign 1 (0–4)
or head turning

Orthostatic hypotension After standing Benign 8 (4–10)

Medications After drug use Benign to severe• 3 (1–7)

Psychiatric Frequent events Benign 2 (1–7)

Neurologic Headache, diplopia Moderate 10 (3–32)

hemiparesis, seizures
Cardiac
• Organic heart disease Chest pain, dyspnea Severe 4 (1–8)
exertional, post operative
• Arrhythmias Sudden syncope, injury 14 (4–38)
– Bradyarrhythmias Moderate
– Tachyarrhythmias Palpitations Severe

Unknown Negative workup Benign to 34 (13–41)

moderate

* Severity ranges from benign (e.g. prazosin-induced syncope) to severe (e.g. quinidine-induced torsades de pointes).
 Syncope 61

may occur following prolonged vagal stimulation (causing Cardiovascular

pronounced bradycardia or asystole) with or without a
prolonged upright posture. The patient becomes pale and
falls limply, followed by a stiffening of the body or
opisthtonous, clonic movements, upward deviation of the
eyes, and urinary incontinence. It is common, particularly
in children and young adults, affects girls more commonly
than boys, and is benign.
Systemic enquiry
• Autonomic symptoms: bladder, bowel, sexual, and
thermoregulatory dysfunction.
• Extrapyramidal symptoms: slowness, stiffness, tremor.
• Polyneuropathy: altered sensation, weakness.
• Medications/drugs: hypotensive.
Physical examination
Commonly normal. Skin and mucous membranes are dry
with reduced tissue turgor if dehydrated, pigmented buccal
mucosa if Addison’s disease.
• Pulse: rate, rhythm, character.
• Blood pressure: supine and standing. A fall in diastolic
BP of 1.3 kPa (10 mmHg) and systolic BP of 2.7 kPa
(20 mmHg) or more in the standing position is defined
as postural hypotension.
• Jugular venous pressure: low if hypovolemic, raised if
pulmonary embolism or cardiac failure.
• Heart: auscultation for features of aortic stenosis and
other causes of outflow obstruction (e.g. hypertrophic
obstructive cardiomyopathy).
• Serial pulse and standing BP over 30 minutes. Normally,
the pulse increases to a maximum at the 15th beat after
standing but with autonomic failure, loss of
consciousness may occur without a recordable increase
in the peripheral pulse rate or the presence of skin
vasoconstriction.
Neurologic
• Extrapyramidal dysfunction: rigidity, bradykinesia, tremor.
• Brainstem dysfunction.
• Peripheral neuropathy: muscle wasting, weakness,
areflexia, sensory loss.

DIFFERENTIAL DIAGNOSIS
Epilepsy (see Table 5 and p.65)

Vertebrobasilar artery territory ischemia

Table 5 Differential diagnosis: syncope vs Seldom causes isolated loss of consciousness; other
epileptic seizure symptoms of focal brainstem ischemia coexist: vertigo,
Syncope (faints) Seizures (fits)
diplopia, ataxia. Carotid territory ischemia does not cause
loss of consciousness unless bilateral and severe.
Onset Often gradual Sudden
Circumstances Special Non-specific Causes
Relation to upright Common No • Atherothromboembolism.
posture • Embolism from the heart.
Symptoms Light headed/faint Amnesic • Migraine (often children, with a history of severe
Blurred/dimmed vision occipital headache).
Sounds seem distant • Arnold–Chiari malformation (vertebral artery and
Tinnitus brainstem compression).
Weakness • Cervical spondylosis: osteophytes may compress the
Nausea vertebral artery as they traverse the transverse foramen
Hot and cold of the cervical vertebrae and compromise blood flow in
Sweating the posterior circulation but this is a far less common
Skin color Pale Blue or normal cause of ‘dizziness’ and syncope than is commonly
Respiration Shallow Stertorous believed. More frequently, the diagnosis is a peripheral
Aura or premonitory Usually Sometimes labyrinthine disorder such as benign paroxysmal
symptoms positional vertigo (see p.110).
Tone Floppy* Rigid
Convulsion Rare Common
Urinary incontinence Rare** Common
Tongue biting Rare Common
Post ictal confusion Minimal Common and
prominent
Focal neurologic No Occasional
symptoms
Clues to underlying Cardiac arrhythmia
cause Aortic stenosis
Cardiomyopathy
Postural hypotension
* A tonic phase is common in convulsive syncope
** Traditionally not a feature but actually not uncommon.
62 Disorders of Consciousness
Drop attacks
• Spontaneous episodic raised intracranial pressure may
impair brain perfusion (e.g. colloid cyst of the third
ventricle [74, 75], posterior fossa tumor). Usually
associated headache and visual obscurations
• Cryptogenic drop attacks: abrupt episodes of falling to the
ground without any warning, precipitating factor, or loss
of awareness. Usually in middle-aged women and benign.
Metabolic disorders
• Hypoglycemia: usually diabetes but may be caused by
insulinoma, Addison’s disease, and post-gastrectomy.
Tends to occur after fasting. Associated symptoms may
include sweating and a sensation of hunger.
• Pheochromocytoma: episodic release of catecholamine
may lead to transient palpitations, headache, sweating,
and hypotension. Many patients have postural
hypotension due to chronic excess secretion of
catecholamines, but rarely causes syncope.
• Hyperventilation-induced alkalosis.
Sleep disorders
• Narcolepsy: excessive daytime sleepiness (see p.57).
• Cataplexy: sudden onset of focal or generalized loss of
muscle tone, often precipitated by emotion such as
laughter, and resulting in either episodic limb weakness
or sudden collapse from an upright position (see p.57).
• Obstructive sleep apnea.
Psychiatric
Pseudoseizures.
INVESTIGATIONS
The history, physical examination and EKG are the core of the
diagnostic workup. In most patients, there is an obvious
precipitant and no investigations are required, or at most an
EKG and hemoglobin. For example, syncope in the elderly
often results from polypharmacy and abnormal physiologic
responses to daily events. The need for further investigations are
74 75
determined by the certainty of the clinical diagnosis and nature
of the clinical findings.
Cardiologic
Indicated in patients with known or suspected heart disease
(e.g. history of congestive heart failure or ventricular
arrhythmia), exertional syncope, and recurrent syncope.
Non-invasive
• EKG: to exclude complete heart block, an aberrant
conduction pathway, and an acute cardiac event (76, 77).
• 24-hour ambulatory or patient activated EKG recording
(Holter monitoring): can be useful if the attacks are
frequent enough to be captured and the patient is known
to have, or is suspected of having, heart disease.
However, it may fail to detect arrhythmias if they do not
occur during the monitoring period, and increasing the
period of monitoring only slightly improves sensitivity.
If an arrhythmia is detected (e.g. frequent ventricular
ectopic beats) but it is associated with no symptoms, it
does not prove that the arrhythmia is the cause of the
syncope. Nevertheless, the arrhythmia may point to an
underlying structural heart disease.
• Echocardiography: if valvular heart disease, outflow
obstruction or cardiomyopathy is suspected.
• Carotid sinus stimulation under EKG control: aims to
detect carotid sinus hypersensitivity but is of limited use.
Should be performed with the patient lying supine. A
period of more than 3 seconds of asystole on EKG
monitoring is positive, although this response is non-
specific, being present in up to 20% of the asymptomatic
population.
• Upright tilt table testing: a method of diagnosing vaso-
vagal syncope in patients with frequent recurrent
undiagnosed syncopal events but no heart disease and
patients with recurrent syncope and heart disease but no
evidence of arrhythmias. The technique involves constant
EKG recording and blood pressure monitoring while the
patient is brought from a supine to an upright position
74 Contrast-
enhanced CT brain
scan, coronal plane,
showing a colloid
cyst of the third
ventricle as a round
hyperintense mass
lesion (arrow),
causing obstructive
hydrocephalus.
75 T2W MRI brain
scan, axial plane,
showing a colloid
cyst of the third
ventricle (arrow).
 Syncope
(e.g. 70° head-up tilt) in a series of stages, and
maintained in that position, in the absence of drugs for
up to 40 minutes. The test is positive if there is syncope
or presyncope in association with hypotension and/or
bradycardia. The sensitivity of this test is up to 70% but
the specificity is uncertain. If there is no abnormal
response, an isoprenaline (isoproterenol) infusion can be
given to improve sensitivity further (at the expense of
specificity). It is commenced at 1 µg per minute and the
rate progressively increased every 5 minutes by a further
microgram per minute at successive tilts. The
isoprenaline (isoproterenol) infusion initially increases
the heart rate and then the rhythm may change from
sinus to another rhythm (e.g. junctional rhythm),
resulting in a fall in blood pressure and symptoms of
syncope. The symptoms resolve with resumption of the
supine posture. The test is again positive if there is
syncope or presyncope in association with hypotension
and/or bradycardia.
Invasive
• Electrophysiologic studies: directly assess intracardiac
conduction and the presence of inducible supraventricular
and ventricular arrhythmias by intracardiac stimulation.
Although invasive, the morbidity is low (1–2%) and
mortality very low. May be indicated if recurrent and
disabling syncopal episodes, clinical suspicion of an
arrhythmia, abnormal resting EKG, arrhythmias on
Holter monitoring, and structural heart disease.
76
76 Electrocardiograph (EKG) showing slow atrial fibrillation with a
ventricular rate of about 45 per minute.
77
63
Blood
Basic laboratory tests are not usually helpful and should be
minimized:
• Hemoglobin level may reveal anemia.
• Serum urea and electrolytes and glucose may reveal the
most common metabolic causes.
• Prolonged fast to exclude hypoglycemia.
• Short tetracosactrin (cosyntropin) test, if abnormal urea
and electrolytes, to exclude Addison’s disease.
Urine
24-hour urine collection for vanillylmandelic acid to exclude
pheochromocytoma.
Neurologic
Neurologic investigation is rarely helpful unless additional
neurologic symptoms or signs are present.
• CT or MRI brain scan: if drop attacks or suspected
Arnold–Chiari malformation, hydrocephalus, colloid cyst
of the third ventricle, or subdural hematoma.
• EEG (combined with simultaneous EKG monitoring): if
suspected seizure disorder. A positive EEG may support
the diagnosis of epilepsy but a negative study does not
exclude it.
• Nerve conduction studies and EMG: if neuropathy
suspected.
• Autonomic function tests.
Biopsy
Rectal: if amyloidosis suspected (rare).
Psychiatric
Occasionally a psychiatric assessment may be useful in
patients with otherwise unexplained frequent syncopal
events and no injury, as patients with anxiety disorders,
panic reaction and somatization disorders may report
syncope as a symptom.
DIAGNOSIS
The key to the diagnosis of syncope is a sound clinical
history from the patient and an eyewitness.
TREATMENT
Aims to identify and correct the specific underlying cause:
• In most patients, whose syncope was due to the
simultaneous occurrence of several predisposing factors
(e.g. dehydrated, tired, hot and stuffy room), an
explanation and reassurance is all that is required.
• Attend to any heart disease: e.g. pacemaker insertion may
help patients with complete heart block and carotid sinus
hypersensitivity.
• Correct any metabolic and hormonal deficiencies.
77 Electrocardiograph (EKG) showing bifascicular block (a combination
of right bundle branch block and left anterior hemiblock) due to
coronary artery disease in a 70 year old male who presented with three
episodes of collapse due to cardiac syncope related to paroxysmal
bradycardia. Electrophysiologic studies failed to induce clinically significant
tachycardia and the patient responded well to permanent pacemaker
insertion. Bifascicular block can develop into complete conduction block
due to trifascicular block or complete AV block.
64 Disorders of Consciousness

Postural hypotension • Advise patients with recurrent syncope to avoid precipi-

• Stop any drugs that may cause postural hypotension (if tating factors (e.g. large meals) and circumstances that
possible), particularly in the elderly. These include may lead to injury if they do lose consciousness and to
diuretics (particularly in hot weather), α-adrenoreceptor stand slowly. Driving should be restricted until free of
blockers (e.g. prazosin), psychotropic drugs with α- recurrent syncopal episodes for up to 1 year if the cause
adrenoreceptor blocking activity (tricyclic antidepres- of the loss of consciousness has not been elucidated and
sants, antipsychotics, including prochlorperazine treated appropriately.
[Stemetil]); α-methyldopa, nitrovasodilators (e.g.
glyceryl trinitrate, including long-acting formulations), PROGNOSIS
and antiparkinsonian drugs (L-dopa, bromocriptine). Depends upon the underlying cause; benign in many cases,
• Avoid large meals, especially when accompanied by alcohol. a warning sign of sudden death in a minority of others.
• Change posture, from supine to standing, slowly (avoid Sudden death occurs within the next year in about 20% of
sudden changes). patients with syncope due to ischemic or structural heart
• Waist-high supportive garments (e.g. elasticated disease. The spontaneous remission rate is high and the rate
stockings) or antigravity suits may be helpful for venous of sudden death is low in patients with unexplained syncope
pooling but can be uncomfortable. after intensive investigation.
• Elevate the head of the bed at night.
• High salt diet.
• Prophylactic medication such as the mineralocorticoid
fludrocortisone in low dose; sympathomimetics such as
ephedrine; caffeine; non-steroidal anti-inflammatory drugs
such as indomethacin, if there is no contraindication; ergot
alkaloids, theophylline, β-adrenoreceptor antagonists with
intrinsic sympathomimetic activity; disopyramide and
octreotide (somatostatin analogue). Insertion of a
pacemaker may be indicated for cardiogenic syncope if
medical therapy fails.

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Review by a working group convened by the
Royal College of Physicians and endorsed by
the conference of Medical Royal Colleges and
their Faculties of the United Kingdom (1996)
The Permanent Vegetative State. J. R. Coll.
Physicians Lond., 30: 119–121.
Zeman A (1997) Persistent vegetative state.
Lancet, 350: 795–799.
NARCOLEPSY
Aldrich MS (1990) Narcolepsy. N. Engl. J. Med.,
323: 389–393.
Aldrich MS (1998) Diagnostic aspects of nar-
colepsy. Neurology, 50 (Suppl 1): S2–S7.
Broughton RJ, Fleming JAE, George CFP, et al.
(1997) Randomized, double-blind, placebo-
controlled crossover trial of modafinil in the
treatment of excessive daytime sleepiness in
narcolepsy. Neurology, 49: 444–451.
Douglas NJ (2001) The sleepy patient. J. Neurol.
Neurosurg. Psychiatry, 71 (suppl 1): i3–i6.
Fry JM (1998) Treatment modalities for nar-
colepsy. Neurology, 50 (Suppl 1): S43–S48.
Gencik M, Dahmen N, Wieczorek S, et al (2001)
A prepro-orexin gene polymorphism is associ-
ated with narcolepsy. Neurology, 56: 115–117.
Guilleminault C, Brooks SN (2001) Excessive day-
time sleepiness. A challenge for the practising
neurologist. Brain, 124: 1482–1491.
Krahn LE, Black JL, Silber MH (2001) Narcolep-
sy: new understanding of irresistible sleep.
Mayo Clin. Proc., 76: 185–194.
SYNCOPE
Arthur W, Kaye GC (2000) The pathophysiology
of common causes of syncope. Postgrad. Med.
J., 76: 750–753.
Kapoor WN (2000) Syncope. N. Engl. J. Med.,
343: 1856–1862.
Linzer M, Yang EH, Estes M III, Wang P, Vor-
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Med., 92: 623–629.
 Chapter Three 65

Epilepsy
EPILEPSY • Age: any age. Peak incidence in early childhood and a
second peak in the elderly (over-60 age group).
• Gender: slight excess among males.
DEFINITION
Epileptic seizure CLASSIFICATION
A paroxysmal, stereotyped disturbance of consciousness, Epileptic seizures are now classified as generalized and
behavior, emotion, motor function, perception or sensation partial, based on clinical and electroencephalograph (EEG)
(which may occur singly or in any combination), that results distinctions. This classification replaces such imprecise terms
from cortical neuronal discharge. as ‘grand mal’ and ‘petit mal’.
N.B. Epilepsy may manifest itself in the form of more
Epilepsy than one seizure type in the same patient. In addition,
A condition in which epileptic seizures recur, usually
spontaneously.

EPIDEMIOLOGY Table 7 International classification of epilepsies and

• Incidence: 20–70 per 100 000 per year. epileptic syndromes
• Prevalence: 0.5–1.0% of the population (active epilepsy). Localization-related (local, focal, or partial) epilepsies and syndromes
• Cumulative/lifetime (or total) prevalence: • Idiopathic epilepsy with age-related onset:
– Single seizure (including seizure with acute illness, but – Benign childhood epilepsy with centro-temporal spikes
not febrile seizure): 3%. – Childhood epilepsy with occipital paroxysms
– Active epilepsy and/or on treatment: 4–5 per 1000. • Symptomatic epilepsy
– N.B. These figures exclude febrile convulsions, which
occur in about 5% of children. Generalized epilepsies and syndromes
• Idiopathic epilepsy with age-related onset (listed in order of
age of onset):
Table 6 International classification of seizures – Benign neonatal familial convulsions
– Benign neonatal non-familial convulsions
Prevalence in adults
– Benign myoclonic epilepsy in infancy
Partial seizures (beginning focally) 55%
– Childhood absence epilepsy (formerly known as pyknolepsy)
• Simple partial seizures (without impaired
– Juvenile absence epilepsy
consciousness) 5%
– Juvenile myoclonic epilepsy (formerly known as impulsive
– With motor symptoms
petit mal)
– With somatosensory or special sensory symptoms
– Epilepsy with generalized tonic-clonic seizures (GTCS) on
(e.g. olfactory, auditory, visual hallucinations)
awakening
– With autonomic symptoms
• Other idiopathic epilepsies
– With psychological symptoms
• Idiopathic or symptomatic epilepsy (listed in order of age of
• Complex partial seizures (with impaired consciousness) 15%
onset):
– Simple partial onset followed by impaired consciousness
– West’s syndrome (infantile spasms)
– Impaired consciousness at onset
– Lennox–Gastaut syndrome (childhood epileptic
• Partial seizures evolving into secondary
encephalopathy)
generalized seizures 35%
– Epilepsy with myoclonic-astastic seizures
Generalized seizures (convulsive or non-convulsive) 35% – Epilepsy with myoclonic absence seizures
• Absence seizures • Symptomatic epilepsy
– Typical 1% • Non-specific syndromes:
– Atypical – Early myoclonic encephalopathy
• Myoclonic seizures 1% – Early infantile epileptic encephalopathy with suppression
• Clonic seizures burst.
• Tonic seizures • Specific syndromes:
• Tonic-clonic seizures 30% – Epileptic seizures complicating other disease states (such as
• Atonic seizures cerebral malformations, inborn errors of metabolism, and
• Status epilepticus disorders presenting as progressive myoclonic epilepsy)
Unclassifiable/undifferentiated epileptic seizures 10% Continued on page 66
66
Table 7 (continued)
Epilepsies and syndromes with both focal and generalized seizures
• Neonatal seizures
• Severe myoclonic epilepsy of infancy
• Epilepsy with continuous spike waves during slow-wave sleep
• Acquired epileptic aphasia (Landau–Kleffner syndrome)
Special syndromes
• Situation-related seizures:
– Febrile convulsions
– Seizures related to other identifiable acute metabolic or toxic
events (such as stress, hormonal changes, drugs, alcohol
withdrawal, or sleep deprivation)
• Isolated, apparently unprovoked, seizures or isolated status
epilepticus
• Epilepsies characterized by specific modes of seizure
precipitation
• Chronic progressive epilepsia partialis continua of childhood
seizures of one type may be easy to control in some patients
but difficult to treat in others.
Epileptic syndromes are determined by: seizure type(s),
age of onset, EEG findings (interictal and ictal) and
associated findings (e.g. family history, neurologic signs).
They provide information about the likelihood of
identifying an underlying cause, the prognosis, and the
appropriate investigations and management, including
medications, lifestyle modification and genetic counselling.
ETIOLOGY
Epilepsy (like stroke) is a symptom of an underlying
disorder(s) of the brain. The likely causes vary depending
on the type of epilepsy and the age of the patient (i.e. more
likely to be idiopathic in young people, whereas in the
elderly about half are idiopathic, a third due to vascular
diseases, and the majority of the remainder due to tumors
and other structural lesions).
Idiopathic
In about two-thirds of epilepsies no specific cause is found
(idiopathic epilepsies). Idiopathic generalized absence
epilepsies:
• Age-dependent onset between childhood and adolescence.
• Distinct phenotypic expression.
• Frequent familial clustering.
• Abnormal EEG in about 10% (but up to 30%) of
otherwise healthy family members.
Genetic factors
Inheritance of epilepsy is predominantly polygenic and
multifactorial.
Generalized epilepsy
Siblings or children of people with generalized epilepsy have
up to a 10% risk of developing epilepsy.
• Primary generalized epilepsies:
– 30–50% of cases may have a genetic basis.
– 5–10% of children whose parents or siblings have a
primary generalized epilepsy develop epilepsy.
– Usually inherited as an autosomal dominant trait,
probably polygenic.
Epilepsy
– Benign familial neonatal convulsions – chromosomes 8q
and 20q.
– Benign familial infantile convulsions – chromosome 19.
• Juvenile myoclonic epilepsy – possibly HLA region of
chromosome 6p (controversial: see p.86).
• The ‘spike wave trait’: an autosomal dominantly inherited
tendency to develop paroxysms of spike wave complexes,
usually at 3 Hz, but infrequently associated with clinical
seizures.
• Some progressive myoclonic epilepsies are inherited as a
recessive trait (see p.87).
Partial epilepsy
Siblings of people with focal epilepsy have a <5% risk of
epilepsy.
Simple (single gene) inheritance
• Uncommon single gene disorders: tuberous sclerosis,
familial cavernous angiomas (chromosome 7q), familial
periventricular heterotopia (chromosome Xq28).
• Autosomal dominant nocturnal frontal lobe epilepsy:
– One family was found to have a missense mutation in a
gene on chromosome 20 which is closely related to the
neuronal nicotinic acetylcholine receptor alpha 4 subunit,
which is important for modulating glutamate.
– Incomplete penetrance.
– Onset usually in childhood.
– Aura often present on awakening; tonic spasms or
hyperkinetic motor symptoms.
• Autosomal dominant partial epilepsy with variable foci.
• Familial temporal lobe epilepsy: dominantly inherited.
• Autosomal dominant rolandic epilepsy with speech
dyspraxia.
Complex (polygenic or multifactorial) inheritance:
• Idiopathic partial epilepsies: benign partial epilepsy of
childhood with centro-temporal spikes (benign rolandic
epilepsy).
• Cryptogenic/symptomatic partial epilepsies: temporal
lobe epilepsy.
• Situation-related seizures: siblings of people with febrile
seizures have an 8% risk of epilepsy.
Perinatal factors
The contribution of perinatal damage to the development
of partial epilepsy is difficult to assess but is probably less
important than previously thought. Perinatal causes include
birth trauma, intracranial hemorrhage, hypoxia and
hypoglycemia.
Structural cerebral cortex lesions
Interfere with function of the cortex or lead to cortical gliosis.
Congenital
• Hamartomas.
• Arteriovenous malformations (cavernous angiomas) (78).
• Tuberous sclerosis (79).
• Storage diseases: cerebral lipidosis.
• Neuronal migration disorders causing cortical malformations.
• Generalized (agyria, pachygyria/lissencephaly and band
heterotopias).
• Unilateral hemispheric (hemimegalencephaly).
• Focal (cortical dysplasia, polymicrogyria, schizencephaly,
focal heterotopias).
 Epilepsy
Trauma
• Birth injury (trauma or hypoxia).
• Head injury (cortical contusion more than laceration).
Vascular
• Ischemic or hemorrhagic stroke.
• Cerebral edema: hypertensive encephalopathy.
Infection
• Meningitis.
• Abscess.
• Encephalitis.
Tumor
Primary and secondary.
Degenerative
Alzheimer’s disease.
Metabolic/toxic factors
Epileptic seizures may be caused, or exacerbated by, many
disturbances to cellular metabolism, such as hyperthermia,
hypoxia, hypocapnia, hyponatremia, uremia, hypocalcemia,
hypoglycemia, liver failure, porphyria, pyridoxine deficiency,
drugs (e.g. solvents, cytotoxic drugs [e.g. nitrogen mustard
drugs and ifosfamide]), drug and alcohol withdrawal, fatigue,
pregnancy and toxins (e.g. insecticides and heavy metals).
PATHOPHYSIOLOGY
Focal epilepsy
• Gliosis or a local deficiency of inhibitory neuro-
transmitters (gamma aminobutyric acid [GABA], glycine
and taurine) lead to a failure of normal modulation of
dendrites of neurons from surrounding cells.
• Shortening of dendrites bring excitatory inputs closer to
the cell body.
78
78 Facial photograph of a young male with Sturge–Weber disease and
epilepsy due to a left fronto-parietal venous hemangioma of the
meninges over the left fronto-parietal lobes and atrophy of the
underlying subcortex. Note the deep red port wine nevus
(hemangiomatous malformation) not only within but also outside the
distribution of the left trigeminal nerve.
67
• Depolarization waves (paroxysmal depolarization shift)
affect dendrites of epileptic neurons.
• Electric current flows from neutral cell bodies in layers 5
and 6 of the cerebral cortex to depolarized dendrites in
the superficial layer of the cortex, which is recorded by
EEG scalp electrodes as a negative spike discharge.
• The epileptic discharge also activates inhibitory feedback
circuits which repolarize the cell bodies while the
dendrites are recovering from depolarization, resulting
sometimes in a surface-negative slow wave following the
spike discharge; current flows from the hyperpolarized
cell body to the neutral dendrites, causing a surface-
negative slow wave in the EEG.
• Spike wave complexes may remain localized, spread over
the cortex via association fibers, or spread to the opposite
cerebral hemisphere through the corpus callosum causing
a ‘mirror focus’ or a generalized epileptic seizure.
Generalized epilepsy
• Thalamo-reticular and thalamo-cortical projections
combine with inhibitory intra-thalamic projections to
generate a rhythmic discharge.
• Absence seizures result from synchronous burst-firing
generated in the thalamocortical circuit, which is made up
of three principal neuronal populations: neocortical
pyramidal cells, thalamic relay neurons, and the exclusively
GABAergic neurons which form nucleus reticularis thalami
(NRT). The frequency of burst-firing between reciprocally
interconnected thalamic relay neurons and neocortical
pyramidal neurons is synchronized by NRT neurons.
GABAergic neurotransmission is important in the
generation of synchronous burst-firing in the thalamo-
cortical circuit. PET scanning in patients with generalized
epilepsies shows thalamic activation.
79
79 Photograph of the face of a patient with epilepsy due to tuberous
sclerosis. Note the diffuse small adenoma sebaceum (pink, wart-like
angiofibromas) over the cheeks, resembling acne. (Courtesy of Dr AM
Chancellor,Tauranga, New Zealand.)
68 Epilepsy

PATHOLOGY lip smacking

There are many single, and in some patients dual, chewing
pathologies which may cause epilepsy. These are listed in the fiddling, fumbling with clothing
Etiology section (see Structural cerebral cortex lesions, slight jerking of limbs (myoclonus)
above). However, special mention is made below of mesial passing urine
temporal sclerosis because this is the most common falling to the ground (akinetic attack).
pathology in patients with temporal lobe epilepsy. – Suspect in children who:
appear inattentive in class
Mesial temporal sclerosis (MTS) ‘switch on and off’, day dream
• Neuronal loss/gliosis in hippocampus ± amygdala, fall for no obvious reason.
uncus, parahippocampal gyrus is found in 50–75% of – Attacks cease in 80% of children by the age of 20 years.
patients undergoing temporal lobe surgery for temporal • Cause: generated at the thalamic level, involving
lobe epilepsy (80–82). thalamo-cortical projections.
• Synaptic reorganization of dentate granule cell (DGC)
axons (mossy fibers) within the hippocampal formation. Myoclonic seizures
• Pathogenesis is unknown; a history of febrile seizures in • Age group: children and juveniles.
early childhood is more frequent, though not exclusive. • Symptoms: brief jerking of the face, trunk, arms or legs.
• Duration: 1–5 seconds.
CLINICAL AND EEG FEATURES • Ictal EEG: polyspike waves, spike waves, or sharp and
Generalized epileptic seizures slow waves.
Absences (petit mal) • Special features: often occur in series.
• Age group: children and juveniles.
• Symptoms: sudden brief loss of consciousness, staring Atonic or akinetic seizures (astatic)
and blinking; immediately regain consciousness. • Age group: infants and children.
• Duration: few–30 seconds. • Symptoms:
• Ictal EEG: paroxysmal generalized rhythmic regular – Sudden loss of muscle tone causing fall and head injury.
3 (2–4) Hz spike-and-wave discharges. – No loss of consciousness.
• Special features: – May occur together with absence attacks.
– Long absences may be accompanied by: • Duration: a few seconds.
simple actions (automatisms) • Ictal EEG: polyspike waves, flattening, or low-voltage
upward rolling of the eyes fast activity.

80 81

82 80 Microscopic examination of the normal Ammon’s horn showing

the lateral geniculate body in the upper left of the photograph,
Sommer’s sector in the upper right, and the dentate gyrus in the
center.

81 Microscopic examination of sclerosis of Ammon’s horn in a patient

with complex partial seizures.

82 Microscopic examination of infarction of Ammon’s horn in a

patient with complex partial seizures.
 Epilepsy
• Special features:
– Suspect in children who fall for no obvious reason.
– May occur together with absence attacks.
– Absence and akinetic attacks associated with tonic
seizures and mental retardation constitute the
Lennox–Gastaut syndrome in which the EEG usually
shows atypical spike-wave paroxysms of 2–2.5 Hz and
the prognosis for seizure control is poor.
• Effect of the seizure: temporary failure of the reticulo-
spinal pathways leading to inhibition of normal postural
mechanisms.
Infantile spasms (West’s syndrome)
• Age group: first year of life.
• Symptoms:
– Forward flexion with arms outstretched (salaam attacks)
– Commonly associated with tuberous sclerosis
• EEG: grossly abnormal (hypsarrhythmia)
• Special features:
– Mental retardation in most.
– Seizures may respond to vigabatrin, ACTH or
corticosteroids.
Generalized tonic-clonic seizures (grand mal)
• Age group: any age.
• Symptoms:
– Premonitory irritability, headache, elation, depression in
some; others have no warning.
– Focal onset (an aura) indicates initial partial seizure.
– Tonic phase (15–30 seconds):
contraction of facial, jaw, limb, chest, trunk muscles
initial cry sometimes as air is expelled
loss of muscle tone (fall)
cyanosis; tonic convulsions.
– Clonic phase: rhythmic jerking/convulsions of limbs.
– Post-ictal phase:
muscle relaxation
slow deep breathing through clenched jaws
deep sleep, stupor, confusion for minutes to hours
awareness of headache and muscle soreness later.
• Duration: 1–3 minutes.
• Ictal EEG: generalized epileptiform activity (focal or
generalized onset).
• Special features:
– Tongue biting and urinary incontinence sometimes.
– A succession of tonic-clonic seizures, without regaining
consciousness for more than 30 minutes, is known as
convulsive status epilepticus (see p.82).
Partial epileptic seizures (clinical types of seizures)
Simple partial seizures (focal)
• Age group: any age.
• Symptoms: depend on location of seizure focus (see
subtypes below); no loss of consciousness and no
postictal confusion.
• Duration: seconds to minutes.
• Ictal EEG: contralateral epileptiform discharges.
N.B. scalp recordings may reveal no ictal abnormalities.
• Special features: an ‘aura’ is a simple partial seizure.
69
• Subtypes:
– Focal motor seizures (Jacksonian epilepsy): described by
Hughlings Jackson, English neurologist 1835–1911,
usually start with twitching of face or thumb which
spreads over several seconds to the ipsilateral arm and leg
as epileptic activity ‘marches’ over the contralateral motor
cortex.
– Focal sensory seizures: arise from primary sensory cortex
and can take the form of contralateral paresthesia
(somatosensory cortex), unformed visual hallucinations,
e.g. light flashes (visual cortex), transient vertigo and
simple auditory hallucinations such as crackling, buzzing
(auditory cortex-superior temporal gyrus).
Complex partial seizures
• Age group: any age.
• Symptoms: depend on location of seizure focus (see sub-
types, below); impaired consciousness; postictal confusion.
• Duration: minutes.
• Ictal EEG: unilateral epileptiform discharges; may spread
bilaterally.
• Subtypes:
– Olfactory and gustatory hallucinations: usually
unpleasant smells and taste, and dreamy state, arise from
uncus of temporal lobe.
– Visual and auditory hallucinations: formed visual
hallucinations of objects, animals and people originate in
the visual association cortex; complex hallucinations of
music and conversation may arise in the auditory
association cortex.
– Emotional disturbances: rapid onset of unexplained
fear/terror or elation, may arise in the temporal lobe.
– Memory disturbances (transient):
amnesia
dèja vu (a false sensation of familiarity)
jamais vu (a false feeling of unfamiliarity and strangeness)
illusion of time passing more quickly or slowly.
– Automatisms:
episodes of movements and apparently confused
behaviors, with impaired awareness and consciousness
(e.g. lip smacking, chewing movements, picking at
clothes, fumbling with objects, and driving a car)
ictal or post-ictal
patient cannot remember them.
Secondarily generalized seizures
• Initial symptoms depend on:
– Seizure type (simple/complex partial).
– Location of seizure focus.
• Subsequent symptoms:
– Generalized tonic-clonic convulsions.
70 Epilepsy
Partial epileptic seizures (anatomic origin
of seizures)
Frontal lobe seizures
• Simple partial, complex partial, ± secondary generalization.
• Brief episodes, lasting seconds, of:
– Adversive head movements.
– Prominent motor manifestations (particularly in the
legs).
– Impaired consciousness.
• Recovery is rapid with very little post-ictal confusion.
• Recur in clusters several times daily or often overnight.
• EEG: focal epileptiform activity may be difficult to
identify among movement artefact.
Temporal lobe seizures
• Complex partial ± secondary generalization:
– Epigastric rising sensation.
– Olfactory and gustatory hallucinations.
– Dèja vu, jamais vu.
– Oral and other primitive automatisms.
– Visual hallucinations.
– Postictal confusion.
Parietal lobe seizures
• Simple partial ± secondary generalization:
– Sensory and/or motor symptoms (Jacksonian march).
– Painful sensations occasionally.
Occipital lobe seizures
• Simple partial ± secondary generalization:
– unformed visual phenomena (sparks, flashes, phosphenes).
SPECIAL FORMS OF EPILEPSY
Febrile convulsions
• 3 months to 6 years of age, usually (2–4% of children
<5 years of age).
• Boys > girls.
• >one-third have a relative who has had febrile convulsion(s).
• Fever.
• Respiratory infections, otitis media and tonsillitis are
frequently associated.
• No intracranial infection or metabolic derangement.
• Benign mostly and not requiring drug treatment.
• Diazepam or phenobarbitone (phenobarbital) at times
of high fever prevents seizures but adverse effects limit
its use.
• Rectal diazepam or intranasal midazolam can be used at
home to stop prolonged seizures.
• Explain to parents, reassure, and watch temperature: the
mainstay of treatment.
• Recurrence in 30–40% of children; 75% within the first
year, 92% by 2 years. Higher risk of recurrence if
<18 months of age, family history of febrile convulsions
and lower and less prolonged fever associated with febrile
convulsion.
• Long term treatment not necessary.
• Epilepsy develops in only 3% of children who have had
>1 febrile convulsions.
• Features that increase the risk of subsequent epilepsy:
– Focal seizure.
– Prolonged seizure (more than 15 minutes).
– Residual neurologic abnormality as a result of the seizure.
– More than one seizure in the same day, or frequent
febrile convulsions.
– Underlying neurologic or developmental abnormality.
– Family history of epilepsy in a parent or sibling.
– If none of these features, the risk of epilepsy is no greater
than for other children. If all of these features, the risk of
epilepsy is still only 10%.
DIAGNOSIS OF EPILEPSY
1. Is it epilepsy?
• Clinical, based on a detailed description of events
experienced by the patient before, during, and after a
seizure and, as importantly, on an eye-witness account.
• May be supported by EEG findings.
• Should be made only when certain, or as certain as one
can be, and communicated to the patient and family when
plenty of time is available to discuss the issues (see below).
• If there is any doubt about the diagnosis, wait for a
further description of another episode.
• The diagnosis is a shock to many people, particularly as
they have usually been previously well, and because it fre-
quently has major emotional, social, scholastic, vocational
and economic implications for the patient and family.
• There is more to be lost by prematurely misdiagnosing
a non-epileptic as epileptic than delaying the diagnosis of
epilepsy by a few days, weeks or even months, provided
safety precautions are attended to in the interim.
2. What type of epilepsy it is?
• See Classification, above.
• This can be a clue to the cause, treatment and prognosis.
3. What is the cause of the epilepsy?
See Etiology, above.
4. Should the epilepsy be treated?
This depends on the prognosis for recurrent seizures and
adverse sequelae, the risks and benefits of antiepileptic
treatment, and the patients wishes.
5. If so, how should it best be treated?
See Treatment, below.
DIFFERENTIAL DIAGNOSIS
Syncope (faints) (see p.59)
• Gradual onset over several seconds to minutes, and often
in special circumstances (e.g. upright posture).
• Light headedness and nausea followed by loss of
consciousness.
• Associated pallor and flaccid muscle tone. Incontinence
may occur.
• Rapid recovery of consciousness upon restoring the
blood flow to the brain, without prolonged postictal
confusion or drowsiness.
Transient ischemic attacks of the brain (TIA)
(see p.186)
• Abrupt onset of negative symptoms of loss of focal
neurologic or monocular function.
• Maximal deficit at onset, without intensifica-
tion/spread/‘march’ to other body parts.
N.B. Partial epileptic seizures usually cause sudden
positive sensory or motor phenomena which spread, albeit
quickly, to adjacent body parts over a minute or so.
 Epilepsy 71

Migraine aura (classical migraine) (see p.95) INVESTIGATIONS

• Past or family history of migraine. Blood tests
• Gradual onset of positive symptoms over 5–20 minutes. • Full blood count and ESR.
• Gradual ‘build-up’/migration/‘march’ from one body • Urea and electrolytes.
part to another, or one modality to another (e.g. from • Blood glucose.
visual symptoms to paresthesia to dysphasia). • Serum calcium and magnesium.
• Headache, nausea and/or photophobia usually follow • Serum prolactin, if doubt as to whether epileptic seizure
the neurologic aura symptoms. or not: serum prolactin is raised two to three times the
baseline level (above 18–23 μg/l [18–23 ng/ml]) at
Movement disorders 15–20 minutes after most generalized tonic-clonic
• Dystonias (see p.113). seizures, and some partial seizures, declining to baseline
• Paroxysmal choreoathetosis: transient unilateral muscle levels by 60 minutes. Prolactin may also be raised after
spasms or movements. syncope however.
• Tremors. • Serum lactate and pyruvate, muscle biopsy and DNA
• Tics. analysis if mitochondrial cytopathy suspected (see p.162).
• Other. • White blood cell (lysosomal) enzyme assay for suspected
storage disorders.
Drop attacks
• Sudden loss of postural tone, often when walking, Electroencephalography (EEG)
causing sudden fall without warning. Role
• Many causes (see p.62). • Aid to the clinical diagnosis of epilepsy:
– A single interictal EEG may show specific epileptiform
Breath-holding attacks discharges in about 35% of epileptics, and may rarely
• Infants or young children. ‘capture’ a seizure.
• Hold their breath, become cyanosed (but can be pale, if – The yield is higher if performed within 24 hours of the
due to head injury), lose consciousness, and may have suspected seizure.
minor clonic limb jerking. – Repeated recordings, often sleep-deprived or during
• Often a form of manipulative behavior when frustrated sleep, increase the yield to up to 85% but the EEG never
and angry. shows epileptiform activity in 15% of epileptics, either
because intermittent epileptic discharges are missed, or
Psychologic disturbances (pseudoseizures) small voltage, epileptic discharges from deep in the brain,
• Hyperventilation attacks. such as mesial temporal cortex, are not detected by scalp
• Panic attacks. electrodes.
• Anxiety attacks. – Abnormalities are more common with idiopathic
• Faints. generalized seizures than partial seizures.
• Tantrums. • Classification of epilepsy into one of the epilepsy
• Deliberate simulation. syndromes.
• Identification of an underlying structural brain lesion
Consider (e.g. focal slow wave, sharp wave or spike wave
• The circumstances and nature of the attack. abnormalities) or neurodegenerative condition (e.g.
• Weeping is common but need to distinguish it from ictal periodic high-amplitude sharp and slow wave complexes
crying. of Creutzfeldt–Jakob disease).
• The emotional context (anxiety, indifference or
ambivalence).
• The history: often vague and inconsistent.
• Evidence of social disruption, personality disturbance.
• History of other functional disorders or unexplained
somatic symptoms.
• Potential for gain.
• A ‘model’ with a real illness (e.g. friend or relative with
epilepsy).
• Ask the patient to hyperventilate and see if the symptoms
can be reproduced.
72 Epilepsy

Patterns – Localized: partial epilepsy, focal brain lesion may be

• Epileptiform activity: spike, sharp wave, or spike-and- present (83–85).
wave discharges (83–85). • Slow wave activity (asymmetric or bilateral), or
– Diffuse: generalized epilepsy (primary or secondary), asymmetric normal rhythms: non-specific.
focal lesion unlikely (86, 87).

83 84

83 EEG of a patient with complex partial seizures due to a right
medial temporal lobe tumor showing a normal background over the
left hemisphere (top four channels) and random focal polymorphous
delta slowing and epileptiform sharp wave activity over the right
hemisphere, phase reversing around the right midtemporal area (T4).
85
84 EEG of a 65 year old malewho presented with a large left
hemisphere cerebral infarct causing a right hemiparesis, dysphasia and a
right homonymous hemianopia that was complicated on day 3 by a
decline in conscious state due to cerebral edema, and concurrent
partial motor seizures involving the right face and limbs.The EEG
shows attenuation of the background rhythm, particularly over the left
hemisphere, and periodic lateralized epileptiform discharges (PLEDs)
over the posterior left hemisphere (channels 3 and 4).

85 EEG (16 channel) of a patient with complex partial seizures

showing epileptiform activity (sharp and slow wave) over the right
fronto-temporal region (F8–T8).

87

86

86, 87 Ictal EEGs (86, 8 channel; 87, 16 channel) showing typical 3 Hz spike and wave of absence seizures.
 Epilepsy 73

EEG: waking and sleep
• If the waking EEG is normal and epilepsy is suspected, a
sleep-deprived recording may unmask epileptiform
activity that is enhanced by sleep deprivation and
entering the sleep state.
• EEG prolonged recording + video monitoring over
12–24 hours or more: to try and capture an episode.
Electrocorticography (ECOG)
Subdural electrodes may be placed via burr holes to monitor
and localize more accurately a seizure focus, or at operation
to guide the extent of the surgical resection. For example,
after conventional temporal lobectomy, residual
intraoperative epileptiform activity recorded from subdural
electrodes over the posterior medial temporal lobe guides
the surgeon to extend the surgical resection postero-
medially. This practice reduces postoperative seizures.
CT brain scan (usually with intravenous contrast)
• Not necessary if a child or young adult with generalized
epilepsy (clinical and EEG).
• Indicated if a focal brain lesion is suspected:
– Partial seizure.
– Focal neurologic signs.
– Lateralized abnormality on EEG.
• May identify a tumor, stroke, AVM, congenital defect or
area of cerebromalacia which may be responsible for the
patient’s seizures, but fails to identify hippocampal
atrophy and mesial temporal sclerosis.
MRI brain scan
• Patients with temporal lobe epilepsy who are candidates
for surgery should have a high definition MRI of the
temporal lobes to look for mesial temporal sclerosis
(88–90).
(Continued overleaf)

88 89

88 T2W MRI in the coronal plane showing right mesial temporal 90

sclerosis. Note the medial part of the right temporal lobe (arrow) is
atrophied and of slightly brighter signal than the left.

89, 90 MRI brain scans, coronal plane,T2 (89) and T1 (90) weighted
images, in a patient with complex partial seizures, showing enlargement
of the temporal horn of the right lateral ventricle (arrow) due to a loss
of brain substance in the hippocampus and amygdaloid nucleus of the
medial temporal lobe as a result of mesial temporal sclerosis.
74 Epilepsy
MRI brain scan (continued)
• Patients with troublesome epilepsy and a normal CT scan
should have an MRI to exclude neuronal migration
disorders, small structural lesions (e.g. hamartomas,
tumors, or areas of gliosis) in the hippocampus, mesial
temporal sclerosis and hippocampal atrophy which are
missed on CT (88–96).
• The diagnosis of mesial temporal sclerosis on MRI can
be difficult and may require accurate measurement of the
temporal lobes to assess size, which with currently
available methods is very laborious. The MRI results
should be interpreted in conjunction with EEG and
clinical findings. Mesial temporal sclerosis appears as a
loss of brain substance in the hippocampus and
amygdaloid nucleus of the medial temporal lobe
combined in some cases with increased signal on T2W
imaging (88–90).
91
93
Single photon emission computed
tomography (SPECT)
• Useful for localizing seizure focus, particularly when
clinical features, EEG and anatomic neuroimaging
studies (CT and MRI) are not definitive (97).
• Localizes temporal lobe seizure foci more accurately than
extratemporal foci.
• Ictal SPECT (97% correct) is superior to postictal (71%)
and interictal (48%) SPECT in localizing seizure foci in
unilateral temporal lobe epilepsy. Interictal positron
emission tomography (PET) and functional MRI have a
role here, if available.
TREATMENT
Aim: to help the patient and family understand the
implications of their epilepsy and to restore normal life by
preventing seizures without affecting quality of life.
92
91–93 Dysembryoplastic neuroepithelial tumor (arrows).
91 T2W axial and 92 T1W coronal post contrast MRI.
The small size, peripheral site and lack of enhancement are
typical. 93 T1W axial post contrast MRI from a different
patient shows a slightly larger tumor with more mixed
signal and one area of enhancement.

General advice
• Avoid excessive alcohol, fatigue (late nights) and missing
meals.
• Contraceptive advice for epileptic women of reproductive
age.
School and work
• Avoid occupations that involve moving heavy machinery,
electric wiring, truck driving and working at heights (i.e.
roofing); the airlines and armed services do not accept
people who have epilepsy to be a pilot or to handle a gun
respectively.
94, 95 Hamartoma of the tuber cinerarium presenting with gelastic seizures. 94 T1W midline sagittal, and 95 T2W axial MRI
showing a non-enhancing mass (arrow) arising inferior to the hypothalamus. (Courtesy of Dr P Brennan, Consultant
Neuroradiologist, Beaumont Hospital, Dublin, Eire.)
96
96 MRI brain scan, coronal plane,T2W image, in a patient
with refractory complex partial seizures, showing an
overall reduction in volume (atrophy) of the entire right
temporal lobe (left side of the photograph) probably due
to a previous vascular insult or trauma.The hippocampi
appear normal.
Epilepsy 75
• Suggest to the patient that they consider informing their
close friends and school teacher or immediate work
colleagues of the diagnosis, typical manifestations of
seizures, first-aid principles and who to contact in the
event of a seizure.
Activities
Encourage patients to pursue their interests and participate
in all activities as long as they do not put them in a position
where they could be a danger to themselves or others if they
have a seizure (e.g. driving a car, climbing trees and
rooftops, swimming alone).
94 95
97
Ictal Interictal
97 Single photon emission computed tomography (SPECT) scan after
intravenous (i.v.) injection of the radioligand 99m Tc-hexamethylpro-
pylenamine oxime (HMPAO) at the time of a complex partial seizure
showing computer reconstructions of images of regional cerebral
perfusion obtained with rotating gamma cameras.The ictal scan (left)
shows a red area of increased regional blood flow in the temporal lobe
on the left (arrow) due to a left temporal lobe seizure focus, which
resolves on the interictal scan (right).
76 Epilepsy

• Most pregnant patients with epilepsy deliver perfectly

Table 8 Driving guidelines (in Australia) healthy babies.
Condition Recommended seizure-free
period before driving Eclampsia
Magnesium sulfate is at least 50% more effective than
Isolated seizure 3–6 months phenytoin or diazepam in preventing recurrent seizures, and
Recently diagnosed epilepsy 3–6 months causes less morbidity in mothers and children.
Chronic epilepsy Up to 2 years Anti-epileptic medication
(history of previously uncontrolled seizures) Indications for treatment
Recurrent seizures due to 3 months • Recurrent unprovoked epileptic seizures that are not
known provocation (e.g. illness) separated by years.
and previously seizure-free • Single seizure in patients with:
– A relevant underlying brain lesion or neurologic
Recurrent seizures on 1 month after resuming effective abnormality, or
withdrawal of medication medication – A specific epileptic syndrome and an unprovoked seizure
2 years if refusing to resume that will eventually need treatment, such as juvenile
medication myoclonic epilepsy.
Seizure causing accident 12 months (minimum) • The risks and benefits of both treatment and no treatment
have been discussed extensively with the patient.
Seizures only in sleep 12 months (if seizure free while • The patient understands that the drug must be taken
awake) regularly and continued for at least 3 years from the time
Temporal lobectomy 12 months of the last seizure, and that about 40% of patients will
need to take anti-epileptic medication lifelong,
Withdrawal of anti-epileptic During the withdrawal and for at depending on the seizure syndrome and other factors.
drug therapy least 3 months thereafter
Principles of anti-epileptic drug therapy
• Aim to control seizures with the lowest effective dose
Driving that causes no adverse effects.
Consider national guidelines: most countries prohibit driving • The goal is not to achieve the quoted ‘therapeutic drug
until the person has been seizure-free for between 6 months level’:
and 2 years, depending on the type of epilepsy, frequency of – A ‘therapeutic’ drug level may not be effective or
seizures, compliance with medication and other issues (Table 8). therapeutic for some patients; higher, so-called ‘toxic’
levels may be required.
Pregnancy – A so-called ‘therapeutic’ drug level may be toxic for
• Seizures increase in about one-third of epileptic women others, and seizures may be controlled with so-called
during pregnancy, often because anti-epileptic drug levels ‘sub-therapeutic’ levels.
have fallen. • Start with low dose and increase slowly until the desired
• Anti-epileptic drug therapy, if indicated, should comprise therapeutic effect (i.e. seizure control) is achieved or until
the most appropriate monotherapy. adverse effects of the drug occur, whichever comes first.
• Fetal malformations such as neural tube defects (e.g. spina • Judge the response primarily on clinical grounds.
bifida), cleft lip and palate, and ventricular septal defect
(VSD) are 25% more common among pregnant women Choice of anti-epileptic drug:
with untreated epilepsy (5–7%) than pregnant women • Select the single most appropriate drug for the seizure
without epilepsy (3.6–5%), and twice as common among type and patient (Tables 9, 10).
pregnant epileptic women taking anti-epileptic drugs • Carbamazepine and valproate are the first line treatments
(7–10%). The risk of a neural tube defect and other skeletal for focal epilepsies.
abnormalities is highest with sodium valproate (1–2%) and • Valproate is the first line treatment for generalized
carbamazepine (0.5–1%), and the risk of cleft lip and palate epilepsies.
and VSD is highest with phenytoin and barbiturates. • Lamotrigine is also very effective for generalized epilepsies.
Supplementing maternal intake of folic acid with 0.4–0.8 • Phenytoin and clonazepam still have a place, but
mg daily reduces the incidence of neural tube defects and barbiturates are now used less.
does not adversely affect epileptic control. The newer • Vigabatrin, lamotrigine, topiramate, tiagabine and
antiepileptic drugs are still under study. gabapentin are of proven benefit in 25–50% of patients
• It is generally best to err on the side of maintaining with refractory partial seizures. It is not clear which is the
seizure control with anti-epileptic drugs than risking most effective drug but vigabatrin is not recommended
seizure recurrence by withholding treatment. because it may cause constriction of the visual fields.
• Pregnant women taking anti-epileptic drugs which enter • Ethosuximide is only used for juvenile abscence epilepsy.
the fetal circulation, induce liver enzymes, and reduce • The cost of newer anti-epileptic drugs (e.g. lamotrigine,
the activity of vitamin K-dependent clotting factors in the topiramate, gabapentin, tiagabine, vigabatrin) is about
fetus, should take vitamin K 20 mg/day during the last 10 times greater than older drugs (phenobarb, phenytoin).
month of pregnancy and be given vitamin K intra-
muscularly during delivery to prevent neonatal hemorr-
hage. Vitamin K is also given to the baby.
 Epilepsy 77

Table 9 Drugs of first, second and third choice in the treatment of seizure types
Seizure type First Second Third
Partial Carbamazepine Lamotrigine Phenytoin Clobazam
(Simple/complex)* Sodium valproate Phenobarbitone (phenobarbital)
Topiramate Gabapentin
Tiagabine Vigabatrin
* With, or without, Oxcarbazepine Levetiracetam
secondary generalization Zonisamide
Generalized
Tonic-clonic Sodium valproate Topiramate Phenobarbitone (phenobarbital)
Lamotrigine Lamotrigine Benzodiazepines
Myoclonic Sodium valproate Phenobarbitone (phenobarbital) Clonazepam
Phenytoin Zonisamide

Absence Sodium valproate Lamotrigine Clobazam

Ethosuximide
Undifferentiated Sodium valproate Phenytoin
Lamotrigine

Sodium valproate (Epilim)

• Uncertain mechanism of action. Increases synthesis and Table 10 Adverse effect profiles of anti-epileptic drugs
slows the breakdown of GABA. • Cognitive impairment
• Effective for the primary generalized epilepsies, Marked: phenobarbitone (phenobarbital), clonazepam
particularly tonic-clonic seizures, absences and myoclonus. Mild: topiramate, phenytoin, carbamazepine, clobazam
• As effective as carbamazepine and phenytoin for partial Possible: sodium valproate, oxcarbazepine
seizures, especially if secondary generalization. • Behavioral disturbance
• Available as a 40 mg/ml syrup for pediatric or Marked: phenobarbitone (phenobarbital)
nasogastric tube use, crushable 100 mg tablets, and Mild: clonazepam, clobazam, vigabatrin
200 mg and 500 mg enteric-coated tablets. Possible: topiramate, zonisamide
• Plasma half-life: 6–9 hours, so may be administered as • Ataxia
two or three divided doses daily. Carbamazepine >> phenytoin > sodium valproate
• Starting dose in adults: 200 mg twice daily (bd), given • Tremor
after meals to minimize gastric irritation, and increasing Sodium valproate
to 400 mg bd after 2 days, if tolerated. The full • Visual field defects
pharmacologic action may not occur for some weeks. Vigabatrin
• Dose can be increased slowly to 1 g three times daily • Weight gain
(tds) if necessary and tolerated. Sodium valproate
• Monitoring of blood levels is often not necessary as there • Liver dysfunction
is a poor relation between serum concentrations and anti- Phenytoin, carbamazepine
epileptic efficacy or toxicity. • Osteoporosis
• Drug interactions: increases concentrations of other anti- Phenytoin, phenobarbitone (phenobarbital) > carbamazepine
epileptic drugs such as carbamazepine (and its • Cardiac disturbance
metabolities) and phenobarbitone (phenobarbital), by Phenytoin i.v., carbamazepine oral (bradycardia)
inhibiting their metabolism, and decreases plasma levels • Urinary retention
of phenytoin; it is a minor inhibitor of oxidative Carbamazepine
metabolism but is not a liver enzyme inducer. • Hyponatremia
• Adverse effects: tremor, weight gain due to appetite Carbamazepine
stimulation, and thinning or loss of hair. Cognitive • Hematologic (thrombocytopenia, neutropenia)
impairment is uncommon. Stupor and encephalopathy, Carbamazepine > sodium valproate
although potentially dangerous, are rare idiosyncratic • Skin rash
effects and may be due to accumulation of ammonia. Carbamazepine > lamotrigine
The prothrombin time can be prolonged but not
sufficient to cause bleeding. Liver toxicity, in the form of
a microvesicular steatosis, may occur idiosyncratically,
particularly in young children and when combined with Carbamazepine (Tegretol)
other (?anti-epileptic) drugs. Other adverse effects • First used in 1964.
include anorexia, dyspepsia, nausea, vomiting and rash • Effective for the prophylaxis of generalized tonic-clonic
(predictable), and acute pancreatitis, thrombocytopenia, and partial seizures but not for absence or myoclonic
hyperammonemia, teratogenicity (idiosyncratic). epilepsy (which it may aggravate).
78 Epilepsy
Carbamazepine (Tegretol) (continued)
• Available as 100 mg and 200 mg tablets, or 200 and
400 mg controlled-release tablets that are helpful for
avoiding peak-dose adverse effects.
• Plasma half-life: 24–45 hours initially but after continued
long term use it falls to about 9 (8–24) hours.
• The drug must be introduced in a low dose to offset mild
neurotoxicity (sedation, vertigo, ataxia, diplopia, nausea,
headache). The usual starting dose in adults is 100 mg
three times daily, or preferably, half a 200 mg or 400 mg
controlled-release tablet twice daily for 2 days, followed
by half a tablet in the morning and a whole tablet at night,
and further increases if necessary, aiming to maintain the
plasma level within the therapeutic range and control
seizures (rather than waiting for another seizure to occur).
Even with this cautious approach and the development of
tolerance some patients are unable to remain on carbama-
zepine because of neurotoxicity. In addition a morbilliform
skin rash limits its usefulness in 5–8% of patients.
• Adverse effects:
– Dose-related: neurotoxicity (dizziness, double vision,
unsteadiness), nausea, vomiting, cardiac arrhythmia and
orofacial dyskinesia.
– Idiosyncratic: skin rash (5–8% of patients), agranulocytosis,
aplastic anemia, syndrome of antidiuretic hormone secretion
(leading to fluid retention and hyponatremia) hepatotoxicity,
photosensitivity, Stevens–Johnson syndrome, lupus-like
syndrome, thrombocytopenia and pseudolymphoma.
• A major inducer of hepatic cytochrome P450 activity.
Variable autoinduction of metabolism accounts for the
wide range of doses and for the substantial interindividual
variation in concentration found with the same dose.
• Drug interactions: carbamazepine accelerates the clearance
of itself (i.e. it induces its own metabolism), ethosuximide,
clonazepam, clobazam, corticosteroids, theophylline, halo-
peridol, warfarin and hormones. So, most women taking
the oral contraceptive pill require daily estrogen in a dose of
50 µg. Mutual enzyme induction or inhibition with
phenobarbitone (phenobarbital), phenytoin, or primidone
can result in a small rise or fall in steady-state concentrations
of either of both drugs. The metabolism of carbamazepine
is inhibited, causing neurotoxicity, by sodium valproate,
cimetidine, danazol, dextropropoxyphene (propoxyphene),
diltiazem, erythromycin, isoniazid, and verapamil.
Phenytoin (Dilantin)
• First used as an antiepileptic drug in 1938.
• Effective for generalized tonic-clonic and partial seizures.
• No longer a drug of first choice, particularly in young
women, because it may cause cosmetic changes (gum
hyperplasia, acne, hirsutism, and facial coarsening), as
well as sedation and unfavorable effects on cognitive
function (e.g. attention, memory).
• Available as a 6 mg/ml suspension, as chewable 50 mg
tablets, and as capsules of 30 mg and 100 mg.
• Plasma half-life: about 24 (9–40) hours.
• One of only a few drugs with zero order kinetics at
therapeutic dosage – as the concentration rises, the
capacity of the hepatic cytochrome P-450 enzyme system
to metabolize the drug becomes saturated (usually at
around 300 mg/day), and so a small increment in dose
can produce a large rise in serum level. Conversely, the
circulating concentration may fall precipitously when the
dose is modestly reduced.
• Starting dose for children: 5 mg/kg daily, for adults
starting and maintenance dose: 300 mg daily, given as a
single dose or in divided doses. (Note, this is not the
loading dose that is required for status epilepticus.)
• If seizures continue, an increment of 30 mg is
appropriate, particularly if the serum concentration is
above 12 mg/l (60 µmol/l).
• Adverse effects: mental slowing, unsteadiness of gait,
slurred speech and tremor, and physical examination
reveals gaze-evoked nystagmus and tandem gait ataxia.
Other predictable adverse effects include nausea,
anorexia, vomiting, dyspepsia, cognitive impairment,
depression, aggression, drowsiness, headache, paradoxical
seizures, megaloblastic anemia, hyperglycemia,
hypocalcemia, osteomalacia and neonatal hemorrhage.
Prolonged use is associated with coarsening of facial
features, gum hyperplasia (98), acne and hirsutism.
• Idiosyncratic effects include blood dyscrasia, lupus-like
syndrome, reduced serum IgA, pseudolymphoma
(lymphadenopathy), rash, Stevens–Johnson syndrome,
Dupuytren’s contracture, hepatomegaly and hepato-
toxicity and teratogenicity. Long term use may cause
peripheral neuropathy, cerebellar degeneration due to
Purkinje cell loss and osteomalacia.
• Drug interactions: an enzyme inducer and may reduce
the efficacy of many lipid-soluble drugs such as other
anti-epileptic drugs, anticoagulants, corticosteroids,
cyclosporine, oral contraceptives, and theophylline. Its
metabolism may be inhibited, causing neurotoxicity by
enzyme inhibitors such as allopurinol, amiodarone,
chloramphenicol, cimetidine, imipramine, isoniazid,
metronidazole, phenothiazines and sulfonamides.
Barbiturates
Phenobarbitone (phenobarbital)
Has been used an anti-epileptic drug since 1912.
• Inexpensive, widely available and as good as
carbamazepine and phenytoin in controlling generalized
tonic-clonic and partial seizures.
• Main drawback: its effect on cognition and behavior:
fatigue, listlessness and tiredness in adults and insomnia,
hyperkinesia and aggression in children (and sometimes
in elderly patients). Subtle impairments of mood,
memory and learning can occur in all age groups.
• Usual dose varies from 90 to 300 mg/day.
98
98 Gum hypertrophy in a 20 year old female caused by many years’
ingestion of phenytoin for epilepsy.
 Epilepsy
• Long plasma half life of 3–4 days; can therefore be taken
as a single daily dose.
• In adults, it should be restricted to patients who cannot
tolerate first-line anti-epileptic drugs or as an adjunct to
first line therapy in refractory epilepsy.
• Withdrawal can lead to a temporary increase in seizure
frequency.
Methylphenobarbitone (Prominal) (mephobarbital)
Methylphenobarbitone (mephobarbital) is metabolized to
phenobarbitone (phenobarbital), and is given in twice the
dose of phenobarbitone but confers no special advantage.
Primidone (Mysoline)
Primidone is metabolized to phenobarbitone (phenobarbital)
and phenylethylmalonamide, both of which are pharma-
cologically active. Efficacy is similar to that of phenobarbitone.
Clonazepam (Rivotril)
• A 1,4 benzodiazepine (like diazepam).
• Effective for generalized tonic-clonic and myoclonic
seizures, and generalized absence (petit mal) epilepsy and
partial seizures.
• Has more sustained and effective anti-epileptic activity
than diazepam (Valium) but tolerance develops.
• Available as 0.5 mg and 2.0 mg tablets.
• Dose varies from 0.5–4.0 mg three times daily.
• Long plasma half life of 20–40 hours.
• Adverse effects include sedation, irritability, and
aggression.
• Few patients benefit from long term treatment and
nearly half have an exacerbation of seizures when the
drug is withdrawn, particularly if pre-existing brain
damage.
Clobazam (Frisium)
• A 1,5 benzodiazepine.
• Less sedative than clonazepam and diazepam but still
commonly cause tiredness as well as depression and
irritability.
• Has a limited role as a long term anti-epileptic drug (like
clonazepam) but can be effective as a short term
treatment to ‘cover’ for special events such as holidays,
weddings and surgery and for catamenial exacerbations.
• A single dose of 10–30 mg can also be helpful if taken
immediately after the first seizure in patients who have
regular clusters of generalized tonic-clonic and partial
seizures.
Vigabatrin (gamma-vinyl GABA) (Sabril)
• A specific, irreversible inhibitor of GABA transaminase,
leading to elevated GABA levels and enhanced inhibitory
GABAergic transmission.
• Available in 500 mg tablets for use in partial seizures.
• Dose: one 500 mg tablet twice daily, increasing weekly
as required to a dose of 2–3 g/day.
• Effective as a first line or add-on therapy in reducing
partial seizure frequency by more than half in 30–60% of
patients with drug-refractory complex partial seizures.
• Well tolerated; adverse effects mainly constitute
drowsiness, agitation, irritability, weight gain, depression
and psychotic behavior.
• Microvacuolation had been seen in the brains of dogs
(but not humans) after vigabatrin treatment.
79
• Visual field defects are the most common serious adverse
effect, which limits the use of this drug.
Lamotrigine (Lamictal)
• Inhibits voltage-gated sodium channels and reduces the
release of glutamate, an excitatory amino acid
neurotransmitter implicated in the pathophysiology of
epilepsy.
• Effective in both partial and generalized tonic-clonic and
absence seizures in adults and children.
• A weak inhibitor of dihydrofolate reductase, so long term
therapy may disturb folate metabolism.
• Does not significantly induce or inhibit hepatic oxidative
drug-metabolizing enzymes, nor affect the plasma
concentrations of concomitant anti-epileptic drugs.
• Metabolism induced by anti-epileptic drugs that induce
liver enzymes such as carbamazepine, phenytoin and
phenobarbitone (phenobarbital) (half-life about 15 hours).
• Metabolism inhibited by sodium valproate (half-life
about 60 hours).
• Plasma half-life: about 29 hours (mean).
• Eliminated largely as an N-glucuronide conjugate.
• Available as 5 mg dispersible, 25 mg, 50 mg, 100 mg
and 200 mg standard tablets.
• Starting dose in patients not taking sodium valproate is
25 mg once a day for 2 weeks, followed by 100 mg per
day given in two divided doses for 2 weeks. Thereafter,
the dose should be increased to achieve the optimal
response. The usual maintenance dose is 200–400 mg
per day in two divided doses.
• Starting dose in patients taking sodium valproate is
25 mg every alternate day for 2 weeks, followed by
25 mg once a day for 2 weeks. The usual maintenance
dose is 100–200 mg a day, given once a day or in two
divided doses.
• Adverse effects: a generalized maculopapular skin rash
appears within 4 weeks of gradually starting treatment in
about 2–5% of patients. The incidence of rash is propor-
tional to the rapidity with which the drug is commenced.
It usually resolves after immediate withdrawal of lamotri-
gine, after which the drug can be re-introduced slowly.
Rarely, serious skin rashes such as Stevens-Johnson syn-
drome and angioedema have been reported. Some patients
complain of insomnia which can be minimized by giving
the second dose in the afternoon. Dose-related adverse
effects include dizziness, headache, diplopia, ataxia,
somnolence, nausea, asthenia, blurred vision and vomiting.
Gabapentin (Neurontin)
• A GABA-related amino acid.
• Mechanism of action: uncertain; it may affect L-type
voltage-dependent calcium channels.
• Effective when used in doses of 1800 mg/day and as an
‘add-on’ treatment in reducing the frequency of seizures
by more than half in about 40% of patients with complex
partial seizures and 60% with secondarily generalized
tonic-clonic seizures.
• Not effective for absence seizures.
• Available as 300 mg and 400 mg capsules.
• Usual maintenance dose: 1200–2400 mg/day, but
higher doses may be more effective.
• Does not seem to interact with other anti-epileptic drugs.
• Adverse effects on cognitive function may arise with
higher doses.
80 Epilepsy
Ethosuximide
• Used only for absence seizures; not effective against
generalized tonic–clonic seizures.
• Infants require a dose of 20–40 mg/kg per day but
lower weight-related doses are used in adults. In children
over 6 years of age, it is started with a dose of 250 mg
capsules twice daily, increasing if necessary to three of
four capsules daily.
• Adverse effects include drowsiness and bone marrow
depression.
Topiramate (Topamax)
• A sulfamate derivative structurally unique among anti-
epileptic drugs.
• Reversibly decreases the number of action potentials in
spontaneous epileptiform bursts and reduces burst
duration in cultured hippocampal neurons, suppressing
intrinsic bursting of proximal subiculum neurons, and
reducing voltage-gated sodium currents in cultured
cerebellar granule cells.
• Reduces elevated levels of excitatory amino acids,
glutamate and aspartate.
• Reversibly enhances post-synaptic GABA receptor
currents.
• Effective as adjunctive therapy for partial seizures, in
Lennox–Gastaut syndrome and possibly some primary
generalized epilepsies such as drop attacks. It is not
helpful for, and may aggravate, absence seizures.
• Needs to be commenced gradually, with 25 mg alternate
days at night or daily at night, otherwise adverse cognitive
effects may be prohibitive. Cognitive disturbances may
manifest as slowed speech (and even mimic dysphasia and
dysnomia) and a vulnerability to behavioral disturbances
(i.e. cranky, not the same person). Other adverse effects
include weight loss, renal stones in 1% of patients and a
theoretical risk of teratogenicity.
Tiagabine
• A derivative of nipecotic acid that potently and selectively
inhibits neuronal and glial GABA uptake. It specifically
inhibits the GABA transporter GAT-1 and interacts only
weakly with GABA receptors.
• Effective against partial and generalized convulsive seizures.
• May be contraindicated in generalized absence epilepsy.
Failed monotherapy
A single agent (monotherapy) generally achieves satisfactory
seizure control without significant adverse effects in about
half of patients. Although another 15–20% attain better
control with the addition of a second anti-epileptic drug, it
is often better to strive for seizure control with monotherapy
by gradually introducing another agent and then gradually
withdrawing the initial agent. Overall, about 70% of patients
can be controlled with monotherapy.
Withdrawal of antiepileptic medication
• Anti-epileptic drug withdrawal should be considered in
patients who have been free of seizures for 2 years or
longer; taking anti-epileptic drugs long term is
inconvenient and costly, and associated with adverse
cognitive and behavioral effects, so it is essential to
ascertain whether they are still necessary or not.
• Drug withdrawal is not likely to be successful (i.e.
seizures recur) if:
– Late age at onset (>16 years of age).
– Mental retardation.
– Symptomatic epilepsy (i.e. underlying untreated cause).
– Certain epileptic syndromes, such as juvenile myoclonic
epilepsy, when unprovoked seizures have occurred.
– Family history of epilepsy.
– Slow wave activity or focal epileptiform activity on EEG
prior to medication withdrawal.
– History of atypical febrile seizures.
• There are no definite predictors of recurrence but EEG
findings of epileptiform activity prior to, or during, drug
withdrawal are highly predictive of a further seizure if
anti-epileptic medication is ceased. Relapses may also
occur in patients with normal EEGs however.
• Withdrawal of any anti-epileptic drug must always be
gradual in a step-wise fashion, over at least 6 weeks (and
probably months for barbiturates) because abrupt
withdrawal may provoke rebound seizures.
Status epilepticus (see p.82)
Surgical treatment of epilepsy
Practised for more than a century, but improved under-
standing of the pathogenesis of epilepsy and the recent
advent of high resolution MRI brain imaging and improved
surgical expertise have made it an effective treatment for
refractory seizures. Once undertaken, it is irreversible.
Pre-requisites
• The patient has epilepsy and it is resistant to anti-epileptic
drugs in maximally tolerated doses.
• No realistic hope of spontaneous remission of the
epilepsy.
• All diagnostic tests point to a single common epilepto-
genic focus (see below).
• The seizures are causing medical, social and educational
handicap and the patient’s quality of life is likely to
improve after successful surgery.
• The risk–benefit ratio for the proposed surgery is
acceptable.
• A nationally recognized epilepsy surgery programme
with comprehensive pre-and post-surgical evaluation and
support facilities is available.
Pre-surgical evaluation
• Clinical history and seizure pattern.
• Scalp EEG (background, interictal and ictal features).
• MRI brain.
• Neuropsychometry.
• Visual field examination.
• Intracarotid amytal or ‘WADA’ test: determines the
dominant hemisphere for speech and whether memory
can be sustained without the function of the temporal
lobe that is to be removed. In some centers, this is only
performed in left handed patients.
If the above tests are concordant and identify a single
focus and a visible structural lesion (e.g. focal cortical
dysplasia, mesial temporal sclerosis, Sturge–Weber syn-
drome), then no further investigation may be required.
However, most centers still perform video-EEG to capture
at least a couple of seizures to be absolutely sure that the
lesion that is to be resected is the lesion responsible for the
seizures.
 Epilepsy 81

If the scalp EEG is not clearly lateralizing or the MRI
shows no definite lesion, then further studies are required:
• Video-telemetry with scalp (and, in some centers,
foramen ovale-sphenoidal) EEG recording (video-EEG).
• Interictal and ictal SPECT (may be helpful in some but
not all cases), and interictal PET (if available) (99, 100).
• Intracranial/subdural electrode recording (usually to
differentiate between temporal and extratemporal foci,
but again not in all cases).
Surgical procedures
• Removal of a mass of epileptogenic tissue:
– Amygdalo-hippocampectomy: intractable partial epilepsy
and seizure onset in mesial temporal lobe.
N.B. Anterior temporal lobectomy used to be
undertaken in cases of intractable partial epilepsy with
seizure onset in temporal lobe and normal memory
function in remaining brain, but is no longer done because
the seizure focus is often the amygdala/hippocampus,
even in the presence of a temporal lobe structural lesion.
• Removal of structurally abnormal tissue:
– Lesionectomy (usually frontal lobe): refractory seizures
due to a focal pathology in resectable cortex.
– Hemispherectomy: intractable focal +/– generalized
seizures with unilateral hemispheric pathology and
contralateral non-functional hemiparesis.
• Disconnection procedures (separation of epileptogenic
cortex from rest of brain):
– Multiple subpial transections (usually in areas of eloquent
cortex): intractable partial seizures emanating from
unresectable foci in primary cortices.
– Corpus callosotomy (the anterior two-thirds is sectioned
initially, and the posterior one-third about 6–12 months
later): usually for drop attacks.
several factors such as the epilepsy syndrome and other factors
listed below.
As stated above (p.80), predictors of an increased risk of
recurrence are:
• Late age at onset.
• Mental retardation.
• Epilepsy syndrome (e.g. juvenile myoclonic epilepsy).
• Etiology (symptomatic epilepsies tend to recur whereas
idiopathic and cryptogenic epilepsies do not).
• A family history of epilepsy.
• Slow wave activity on EEG prior to medication
withdrawal.
• A history of atypical febrile seizures.
However, there are no definite predictors of recurrence.
For example, although EEG findings of paroxysmal
discharges certainly increase the risk of a relapse after anti-
epileptic drug withdrawal, they don’t indicate a 100% risk,
and relapses also occur in patients with normal EEGs. So,
the EEG findings alone are not a sufficient guide for anti-
epileptic drug withdrawal. Anti-epileptic drug withdrawal
should be considered in all patients, even those with risk
factors for recurrence, but other factors can be crucial in
coming to a decision (such as whether the patient is going
to drive a motor vehicle or not).
99 100

Outcome
• Seizure-freedom:
– Anterior temporal lobectomy and amygdalo-
hippocampectomy: >80% of patients. If concordant
video-EEG and MRI brain.
– Lesionectomy: 30–40% of patients (poorer localization
of a single focus, and obvious pathology is less common).
– Hemispherectomy: 75–85% of patients.
– Corpus callosotomy: 30–40% of patients; best response
with atonic and tonic seizures.
• Other favorable outcomes include improved physical
functioning, psychosocial behavior and learning.

PROGNOSIS

Risk of a second seizure after a first seizure

• 31–71%, depending on other risk factors:
– EEG: epileptiform discharges: 80% risk; non-specific
abnormalities: 40% risk; normal: 12% risk.
Risk of seizure recurrence after >2 years remission
About 30% of children with epilepsy who are free of seizures
for 2 years or longer will experience a recurrence of seizures
when their medications are withdrawn and about 70% will
remain free of seizures. As epilepsy is a heterogeneous entity
(like TIA and stroke, see pp.186, 192), the chance of
recurrence varies among individual patients and depends on
Interictal Ictal
99, 100 Positron emission tomography (PET) scan of metabolism
of 18-fluorodeoxyglucose (fludeoxyglucose F 18) (a physiologic
radionuclide) that is injected intravenously and its uptake and
distribution is measured and imaged.The kinetics of brain uptake of
18-FDG reflect the kinetics of glucose brain uptake and therefore
provide an index of brain metabolism. Interictally (99) there is
evidence of diminished glucose metabolism in the region of the
epileptic focus in the left fronto-temporal lobes (a blue or green or
yellow ‘cold spot’) but during the ictus (100) there is increased
metabolism (a white or red ‘hot spot’)
82 Epilepsy

Prediction equation for recurrence of seizures STATUS EPILEPTICUS (SE)

Increased risk
Age >16 years at onset of seizures add 45
Taking >1 anti-epileptic drug add 50 DEFINITION
Seizures occurred after starting anti-epileptic A continuous seizure lasting at least 30 minutes, or two or
drug treatment add 35 more discrete seizures without interictal recovery (i.e.
History of primary or secondarily generalized between which the patient does not recover consciousness)
tonic-clonic seizures add 35 and lasting more that 30 minutes. SE is a medical
History of myoclonic seizures add 50 emergency.
Abnormal EEG in past year add 20
CLASSIFICATION
Decreased risk Convulsive
Increasing time (number of years, t) without seizures add 200/t • Generalized tonic-clonic status epilepticus (SE).
• Partial SE (e.g. somatomotor [epilepsia partialis
subtract 175 continua], somatosensory, aphasic).

Total score T Non-convulsive

Divide total score (T) by 100 and exponentiate z = eT/100 • Generalized SE:
– Absence SE (other names: petit mal SE, epilepsia minor
Probability of recurrence of seizures: continua, spike wave stupor, prolonged petit mal
• Continued treatment automatisms).
By 1 year 1–0.89z – Atypical absence SE.
By 2 years 1–0.79z • Partial SE (confusional state, coma.)
• Slow withdrawal
By 1 year 1–0.69z EPIDEMIOLOGY
By 2 years 1–0.60z • Incidence: 15–30 per 100 000 per year.
• Age: any age.
(Medical Research Council Anti-epileptic Drug Withdrawal Study
Group [1993] Prognostic index for recurrence of seizures after ETIOLOGY
remission of epilepsy. BMJ, 306: 1374–1378.) Epilepsy (two-thirds of convulsive SE, the vast
majority of non-convulsive SE)
Mortality • Poor anti-epileptic drug compliance.
The standardized mortality ratio for epilepsy is high. About • Recent reduction in dose or discontinuation of anti-
25% of deaths may be related directly to seizures: status epileptic drug.
epilepticus, accidental injury and sudden unexplained death • Drug (alcohol, phenobarbitone [phenobarbital]) withdrawal.
in epilepsy (SUDEP).
Symptomatic (one-third of convulsive SE have no
Risk factors in children history of epilepsy)
• Onset of epilepsy in the first 12 months of life. • Traumatic brain injury.
• Severe developmental delay present at the onset of • Stroke: the most frequent cause of simple partial status.
epilepsy. • Hypoxic encephalopathy.
• Symptomatic epilepsy (e.g. brain malformation). • Fever/infection.
• Severe myoclonic epilepsies of infancy and early • Meningoencephalitis.
childhood. • Brain abscess.
• Infantile spasms (deaths mainly due to the treatment of • Brain tumor.
spasms – with steroids and ACTH). • Metabolic disturbance: hyponatremia, uremia, hypogly-
cemia, hepatic encephalopathy, hypocalcemia, hypomag-
Risk factors in adults nesemia, mitochondrial encephalopathy.
• Young age. • Toxins.
• Male sex. • Drug overdose: tricyclic antidepressant, phenothiazine,
• Generalized convulsive seizures. theophylline, cocaine, isoniazid, chemotherapy drugs.
• Underlying structural brain lesions.
• Sleep. PATHOPHYSIOLOGY
• Non-compliance with anti-epileptic medication. Delayed control of SE is associated with prolonged epileptic
activity which may outstrip metabolic capacity and glucose
delivery, and lead to metabolic and hypoxic-ischemic brain
and systemic injury. The seizures compromise cerebral
vascular autoregulation, which in turn compromises
hypothalamic autonomic regulation, and raised intracranial
pressure may supervene.
Complications such as cardiovascular collapse, arrhythmias,
aspiration pneumonia, acute lung injury, and pulmonary
hypertension may compromise cerebral oxygen delivery
further. Metabolic derangement and cerebral and systemic
 Status Epilepticus (SE) 83

acidosis with hyperpyrexia, rhabdomyolysis, and disseminated 101

intravascular coagulation may cause multiple organ failure.

CLINICAL FEATURES
The clinical presentation of SE can be categorized into:
• Prolonged seizures.
• Convulsive generalized status characterized by uncon-
sciousness, cyanosis and repeated generalized tonic-clonic
convulsive movements of the limbs with no interictal
recovery.
• Convulsive partial status characterized by repeated partial
seizures manifesting as focal motor convulsion or
neurologic deficits (e.g. somatosensory, visual, auditory)
not associated with altered consciousness or secondary
generalization. The most common forms are:
somatomotor simple partial SE (a succession of simple
partial seizures with Jacksonian march, without persistent
segmental myoclonus) and epilepsia partialis continua 102
(persistent myoclonus in a limited area of the body,
present for weeks or months and sometimes in
combination with somatomotor or tonic-clonic seizures).
• Non-convulsive SE presenting with continuous or
fluctuating clouding of consciousness, confusion,
automatisms, fluttering of the eyelids or other involuntary
orofacial dyskinetic movements and amnesia. Fluctuating
conscious level is more frequent in absence status whereas
focal neurologic signs point to complex partial SE.

History from a witness, examination of the patient, and

investigations must proceed concurrently with instituting
appropriate treatment.

DIFFERENTIAL DIAGNOSIS
Pseudostatus epilepticus should be suspected if there is aberrant
motor activity, an on/off pattern of seizure activity, poor
response to treatment and lack of metabolic consequences.

INVESTIGATIONS
• Electroencephalogram (EEG) (101–103).
• Full blood count and ESR.
• Urea and electrolytes.
• Plasma glucose.
• Liver function tests.
• Plasma calcium, phosphate and magnesium.
• Anti-epileptic drug levels.
• Toxicology screen.
• Arterial blood gases. 103
• EEG.
• CT brain scan: exclude structural intracranial lesion.
• Lumbar puncture: if CNS infection possible.
• Serum lactate: may be useful to help exclude pseudo-
seizures.

101, 102 EEGs (101, 8 channel; 102, 16 channel) of two young

adolescents each in a state of prolonged clouding of consciousness
due to non-convulsive generalized absence status epilepticus.

103 EEG (21 channel) showing generalized non-convulsive status

epilepticus on the left hand side of the recording which is terminated in
the middle of the recording by the i.v. injection of clonazepam 1 mg.
84 Epilepsy
DIAGNOSIS
• Repetitive epileptic seizures without interictal recovery
and epileptiform activity on the EEG.
• Diagnosis may require EEG monitoring because some
patients have seizure discharge without detectable motor
activity and may be difficult to diagnose.
• If the EEG is normal without evidence of even interictal
slowing of the background rhythm then the diagnosis
should be reconsidered.
• If the diagnosis is in doubt (e.g. ?pseudostatus epilepti-
cus), observe one tonic-clonic attack and assess the level
of consciousness post-ictally. If further doubt, attempt to
capture at least one episode whilst monitoring the patient
and the EEG.
TREATMENT
All forms of convulsive SE are neurologic emergencies that
must be treated promptly and aggressively to prevent
adverse sequelae. In non-convulsive status, other medical
factors such as the age and respiratory status may need to
be taken into consideration. The aims are to stop the
seizures as soon as possible and identify and treat the cause.
Immediate treatment for premonitory SE
• Ensure protected airway, remove false teeth if present.
• Oxygen 10 l/min via high-flow mask. Be prepared for a
rapid sequence induction and endotracheal intubation
because all anti-epileptic drugs except phenytoin can
cause neurologic depression and depress respiratory drive
even in the face of metabolic acidosis.
• Insert an i.v. line and take 30 ml venous blood for urea
and electrolytes, glucose, liver function tests, calcium,
magnesium, full blood count, anti-epileptic drug
concentrations and toxicology screen.
• Administer a benzodiazepine, either:
– i.v. diazepam 2 mg boluses per minute up to 20 mg
(10 mg if older than 60 years of age or hypotensive), or
– i.v. clonazepam 0.2 mg boluses per minute up to 1 mg, or
– i.v. midazolam up to 5mg, or
– i.v. lorazepam over 1–2 minutes (or rectal if no venous
access), or
– intramuscular midazolam if difficulties with venous access.
Lorazepam is often preferred as it has a long duration of
anti-epileptic effect and the best parenchymal distribution.
Any of these measures controls the status in about 80% of
cases but may take minutes to work. In the 20% of cases who
do not respond, this regime can be repeated in 5–10 minutes
time or another benzodiazepine can be given. Beware of
adverse events which include respiratory and CNS depression
causing respiratory arrest, hypotension and impaired
consciousness. N.B. Benzodiazepines are not a substitute for
a long term parenteral anti-epileptic drug (see below).
• Dextrostix (glucose test): if low dextrostix reading or
known diabetic, give glucose 50 ml of 50% i.v., and
thiamine 100 mg i.v.
• Arterial puncture (usually femoral artery) for arterial
blood gases.
• Correct metabolic abnormalities, such as hypoxia and
hypoglycemia, and treat the underlying cause if known:
i.e. dexamethasone 16 mg if a brain tumor, arteritis or
parasitic brain infection, and thiamine 100 mg if the
patient is alcoholic. It is not usually necessary, and may
be harmful, to give bicarbonate to correct acidosis.
Early SE
• Decide promptly whether to use a long term parenteral
anti-epileptic drug, the aim of which is to prevent seizure
recurrence. Most patients are treated with phenytoin,
and some are now treated with fosphenytoin.
• Intravenous phenytoin loading dose of 18 mg/kg in
100–150 ml of 0.9% normal saline given no faster than
50 mg/min by infusion pump, and while monitoring the
pulse, blood pressure, respirations and cardiac rhythm with
EKG.
– Brain concentrations of phenytoin peak at 10 minutes and
are three to four times those in plasma after injection.
– If the patient is currently prescribed phenytoin, blood
levels are usually low due to poor compliance.
– Never give phenytoin intramuscularly because phenytoin
has a pH of 12.
– Phenytoin, when coadministered with diazepam, will
abolish at least 80% of episodes of convulsive SE.
– Systemic and local reactions to i.v. phenytoin are
common. Respiratory and CNS depression, and cardiac
arrhythmias can be life threatening. Thrombophlebitis
necessitates frequent changes of cannulas and makes
central administration the preferred route.
• Fosphenytoin is a disodium phosphate ester of phenytoin,
which has been licensed recently because it offers several
advantages over phenytoin (which has to be given i.v. and
major adverse effects are common). Fosphenytoin is freely
soluble in aqueous solutions and can be administered i.v. or
intramuscularly. Intravenous fosphenytoin is tolerated at
infusion rates up to three times faster than those for
phenytoin, therapeutic levels are established within
10 minutes, it is rapidly metabolized (conversion half-life of
8–15 minutes) into phenytoin by endogenous phosphatases
in the body, and it is as effective as phenytoin in treating SE.
Intramuscular administration of fosphenytoin is characterized
by rapid and complete absorption, no requirement for
cardiac monitoring, and a low incidence of adverse effects
which are similar to those of parenteral phenytoin
(nystagmus, dizziness pruritus, paresthesias, headache,
somnolence, and ataxia). It has the promise to be suitable for
administration in the ambulance because it causes few local
adverse effects (e.g. pain, burning and itching at the injection
site) and does not cause respiratory and CNS depression.
N.B. Avoid neuromuscular blockade initially because it
masks ongoing ictal activity.
Absence status
• Clonazepam i.v. (see above).
• Valproic acid: via nasogastric or rectal route.
Resistant SE
• Reconsider the diagnosis (particularly if you are saying to
yourself ‘I have never seen anything like this before’: con-
sider pseudostatus and seek EEG confirmation, if possible).
• Review the patient’s ventilatory status and consider
intubation.
 Status Epilepticus (SE)
• Intravenous phenobarbitone (phenobarbital)
15–20 mg/kg, no faster than 100 mg/min (preferably
50 mg/min), or until seizures stop (e.g. additional
10 mg/kg doses even up to 100 mg/kg; pheno-
barbitone is a very effective drug and is generally better
to pursue than chopping and changing with the
alternatives below). Monitor for respiratory depression
and hypotension, or
• Benzodiazepine infusion (e.g. clonazepam 3 mg in
500 ml 5% dextrose at 20 ml/hour and titrate). Not a
substitute for phenytoin. Monitor for respiratory
depression,
Or
• Intravenous chlormethiazole 0.8% 40–100 ml over
10 minutes.
If seizures stop, continue the infusion at 0.5 to
1.0 ml/min and monitor respiration.
Or,
• Intramuscular paraldehyde 5–10 ml, or dilute 10 ml
paraldehyde in 100 ml 0.9% normal saline and infuse
over 10–15 minutes or until seizures stop.
• However, in Australia chlormethiazole is no longer used,
and paraldehyde is no longer available.
• For patients in partial status epilepticus, despite
phenytoin and clonazepam, consider administering
vigabatrin, which is very water-soluble, via nasogastric
tube in a dose of 1 g stat, which is repeated 8–12 hours
later and then continued 8–12 hourly.
Refractory SE
Seizure activity for about an hour in which the patient has
not responded to therapy.
• Reconsider the diagnosis.
• Transfer to an intensive care unit.
• Monitor vital signs closely and treat hyperthermia.
• Initiate therapy for the underlying etiology as soon as
possible.
• Further doses of phenobarbitone (phenobarbital) or a
continuous infusion of the older anesthetic agent
thiopentone (thiopental) or the newer agent propofol
will usually control the seizures. (N.B. it is unwise to
paralyse the patient, because clinical signs will be lost,
unless continuous EEG activity is being monitored.)
• Monitor EEG.
• If the EEG suggests ongoing seizures or if the patient
has overt convulsions, and the patient has received full
loading doses of phenytoin and phenobarbital (pheno-
barbital), an i.v. infusion of midazolam or clonazepam
may help. Midazolam has the advantage of a shorter half-
life and so the patient wakes up sooner after the infusion
has ceased. Midazolam is given i.v. with a loading dose
of 200 μg/kg as a slow i.v. bolus, followed by
0.75–10 μg/kg/min continuous infusion. Higher doses
may be necessary, especially with prolonged infusion, due
to possible tachyphylaxis. Adjust the maintenance dose
to stop electrographic seizures based on EEG
monitoring. EEG should be recorded continuously for
the first 1–2 hours during and after the initiation of
midazolam loading and infusion, and then monitored
either continuously or for 30–60 minute intervals every
2 hours during the maintenance phase. The primary aim
of therapy is suppression of electrographic seizures.
85
• Continue maintenance doses of phenytoin and
phenobarbital (phenobarbital), and follow levels to
determine optimal doses.
• Use i.v. fluids and dopamine (up to 10 μg/kg/min) to
treat hypotension. Decrease the dosage of thiopentone
(thiopental) or midazolam if any signs of cardiovascular
compromise.
• Discontinue the midazolam infusion at 12 hours while
monitoring the EEG and observe for further clinical or
electrographic seizure activity. If seizures recur, reinstate
the infusion and repeat this step at 12–24 hour intervals
or longer if the patient’s seizures remain refractory.
N.B. Although barbiturate coma is extremely effective in
terminating refractory generalized SE, it frequently causes
hemodynamic instability due to myocardial depression and
vasodilatation (and thus requires invasive hemodynamic
monitoring and the use of pressor agents) and patients may
take days to wake up after it has ceased and so they require
prolonged intubation. Continuous i.v. infusion of
midazolam can be as effective and less toxic. Midazolam is
a water-soluble benzodiazepine with rapid CNS penetration
and a short elimination half-life of 1.5–3.5 hours.
Maintenance treatment
When seizures have been abolished, an appropriate oral
regimen is required:
• Regular anti-epileptic medication should be recom-
menced.
• For previously untreated patients, continue with
phenytoin. An oral loading dose of 300 mg should be
given 6–12 hours after the initial i.v. injection. Thereafter
the dose can be altered according to clinical response,
adverse effects and serum concentrations.
• If the seizure type can be characterized, or if the patient
is a young woman, preference may be given to
commencing an oral regimen of carbamazepine or
sodium valproate. If the patient is unconscious or cannot
swallow, both can be given via a nasogastric tube.
PROGNOSIS
Convulsive SE
• High mortality (up to 10–12%): more often due to the
underlying cause than direct neurologic damage caused
by the status.
• Morbidity: determined by the underlying cause and
duration of SE. The longer the duration, the more
refractory it becomes to treatment and the higher the
morbidity and mortality.
Non-convulsive SE
• Generalized absence SE: good outcome if treated
appropriately.
• Complex partial SE: prognosis depends on the
underlying cause and the quality of treatment.
86 Epilepsy
JUVENILE MYOCLONIC EPILEPSY
(JME) (JANZ SYNDROME)
DEFINITION
A clinically distinct form of primary idiopathic generalized
epilepsy characterized by bilateral myoclonic jerks
experienced with full consciousness. In addition to the jerks,
most patients also have generalized tonic-clonic seizures,
and about one-third also have absence seizures.
EPIDEMIOLOGY
• Incidence: the most common epilepsy syndrome in
adolescence. Accounts for 5–10% of all patients with
epilepsy.
• Age of onset: 8–18 years (may be later).
• Gender: M=F.
ETIOLOGY AND PATHOPHYSIOLOGY
• Idiopathic, but almost exclusively genetic.
• Mode of inheritance is complex. Several modes of
inheritance have been proposed: autosomal recessive,
polygenic, two loci recessive dominant or recessive
recessive, and single locus dominant.
• Involvement of more than one gene is implicated by
segregation analysis. Linkage of JME to chromosome
15 q has been proposed, as has a locus near the human
leukocyte antigen (HLA) region of the short arm of
chromosome 6p. A recent study found no linkage to
chromosome 15 but positive linkage to chromosome 6,
but it may be that JME is linked to different genes in
different ethnic groups.
CLINICAL FEATURES
• Myoclonic jerks, typical absences and generalized tonic-
clonic seizures occur in a characteristic age-related
sequence.
• Myoclonic jerks, which follow a circadian pattern and
occur when drowsy or shortly after awakening, are
bilateral, single or multiple, and affect the arms
predominantly. They result in the patient dropping and
spilling things first thing in the morning (i.e. at the
breakfast table) and settle down over an hour or two.
Frequently, they are not recognized by the patient as
being of any significance and are not reported.
• Juvenile-type absences occur in 10–30% of cases.
• Generalized tonic-clonic seizures occur in about 90% of
patients, usually in the morning. They are almost
invariably preceded by a flurry of myoclonus, building
up to a crescendo.
• Seizures are commonly provoked by factors such as sleep
deprivation, alcohol ingestion, and, to a lesser extent,
menstruation and photic stimuli such as flickering lights.
• A family history of epilepsy in close relatives is not
uncommon. The clinical picture in affected family
members from the same pedigree is variable and includes
different syndromes, such as childhood absence epilepsy,
juvenile absence epilepsy, or epilepsy with generalized
tonic-clonic seizures on awakening. Asymptomatic family
members may have abnormal EEGs showing typical
diffuse polyspike wave or spike wave complexes similar
to the interictal discharges seen in affected members.
INVESTIGATIONS
EEG
Ictal
Rapid (3.5–6 Hz) irregular, generalized spike and polyspike
wave discharge
Interictal
Normal or brief discharges of generalized, symmetric or
multiple spikes and slow waves at frequencies from
3.5–6 Hz in about 95% of untreated patients and about 30%
of patients being treated with valproate, resembling ictal
trace (104, 105). Photosensitivity is common (70–80% of
cases); a photoconvulsive response is seen in about 33–40%
of patients and is not necessarily associated with
photosensitive seizures. Focal EEG abnormalities, either
independent or associated with the generalized paroxysms,
may be seen.
Brain imaging
CT and MRI brain scan are normal if performed, but are
not necessary in the presence of the above clinical and EEG
features.
DIFFERENTIAL DIAGNOSIS
• Familial adult myoclonic epilepsy (FAME): an autosomal
dominant primary generalized epilepsy, characterized by
adult-onset (mean 37 years) of myoclonic jerks in the
upper and lower extremities, tremulous finger move-
ments, and rare generalized tonic-clonic seizures. Myo-
clonic episodes can be precipitated by fatigue, insomnia
and photic stimuli. The EEG is similar to JME. The
FAME gene has been localized to chromosome 8q24.
FAME is similar to JME in that it is probably a primary
disorder of membrane excitability with a benign (non-
progressive) course, but is distinguished by an older age
of onset (in adulthood), whereas JME has onset in early
adolescence and myoclonic jerks predominantly on
awakening.
• Progressive myoclonic epilepsy: seizures are more likely
secondary to neurodegeneration rather than being a
primary disorder of neuronal excitability. Patients quickly
develop dementia and ataxia, and usually live only 10–20
years after diagnosis.
• ‘Epilepsy with generalized tonic-clonic seizures on
awakening’: usually commences in the second decade of
life. Commonly it may be precipitated by sleep depriva-
tion, photosensitivity, and is associated with a positive
family history, but there is no myoclonic component.
DIAGNOSIS
• History of myoclonus on awakening, usually early in the
morning; all older children, adolescents and young adults
who present with a tonic-clonic seizure should be asked
about early morning myoclonus because they may not
volunteer this information.
• Seizures that occur mainly in the morning.
• Typical EEG.
TREATMENT
The aims of treatment are to control absences and GTCS
and minimize myoclonus on awakening. Medical manage-
ment is often very successful in achieving these goals.
 Progressive Myoclonic Epilepsies (PME) 87

Anti-epileptic drugs PROGRESSIVE MYOCLONIC

• Sodium valproate is the drug of choice because it
achieves complete control in more than 80% of patients.
• Clonazepam is an effective alternative, but is less
accepted by patients because it may have adverse effects
on cognition, particularly with long term use.
• Lamotrigine seems to be effective, both as add-on
therapy and monotherapy. On occasions, the adverse
effects of valproate (weight gain, tremor and hair loss)
may be such that lamotrigine can be considered as a
suitable alternative.
• Other anti-epileptic drugs may control the GTCS but
not the myoclonus. Indeed, carbamazepine and
vigabatrin may make it worse.
Lifestyle
Lifestyle issues need to be discussed in detail with the
patient and the family, such as avoiding seizure-precipitating
factors like late nights (sleep deprivation), alcohol, and
flickering lights in nightclubs, particularly at the time of
menstruation.
EPILEPSIES (PME)
DEFINITION
A heterogeneous group of rare genetic disorders, most of
which are familial (autosomal recessive inheritance),
characterized by onset in childhood or adolescence of
generalized or fragmentary myoclonic seizures, often other
epileptic seizures, and progressive neurologic deterioration,
especially cerebellar ataxia and dementia.
EPIDEMIOLOGY
• Incidence: rare.
• Age of onset: childhood or adolescence.
• Gender: M=F.

Pregnancy
Due to the early age of onset and the lifelong nature of
JME, many female patients are likely to contemplate
pregnancy while taking the necessary anti-epileptic drug
therapy. If the patient is a sexually active female, the risks of
epilepsy and anti-epileptic drugs associated with pregnancy
need to be carefully discussed. Sodium valproate has a 1–2%
risk of severe spina bifida. The teratogenicity of lamotrigine
is unknown. If pregnancy is a possibility, sodium valproate 105
should be supplemented with prophylactic folic acid (0.5–5
mg daily) for at least 1 month before conception and for the
first 3 months of pregnancy. In some patients with provoked
seizures, it may be possible to cease anti-epileptic medication
before conception and for the first 3 or 4 months of preg-
nancy, if the risk of seizure recurrence and its complications
(including sudden death) are thought to be very low.

PROGNOSIS
A life-long condition for most patients but excellent response
to valproate. Withdrawal of anti-epileptic medication is
associated with a high relapse rate (in 80% of patients).

104

104, 105 Interictal EEGs showing the typical 4–6 Hz bilaterally

symmetric generalized polyspike and wave pattern in an adolescent
with juvenile myoclonic epilepsy.
88 Epilepsy
ETIOLOGY
Disorders in which the clinical presentation is
typically PME
• Unverricht–Lundborg disease (previously termed ‘Baltic
myoclonus’): caused by mutations in the human EPM1
gene, which encodes cystatin B, an intracellular protein
that competitively inhibits intralysosomal cystein
proteases known as cathepsins. The function of cystatin
B may be to prevent intracellular damage that could
otherwise occur after ‘leakage’ of cysteine proteases from
lysosomes into the cytoplasm.
• Lafora body disease (106): caused by a mutation in one
of the four exons of the EPM2A gene or non-coding
regions of EPM2A. The EPM2A gene codes for laforin,
which is a functional protein tyrosine phosphatase.
• Sialidosis.
Disorders in which the clinical presentation is
occasionally PME
• Neuronal ceroid lipofuscinosis.
• Mitochondrial cytopathies.
Uncommon causes of PME
• Huntington’s disease.
• Hallervorden–Spatz disease.
• Neuroaxonal dystrophy.
• Wilson’s disease.
• Gaucher’s disease (non-infantile neuronopathic form).
• GM2 gangliosidosis (late infantile, juvenile forms).
• Biotin-responsive encephalopathy.
CLINICAL FEATURES
• Myoclonic seizures (generalized or fragmentary): sudden,
brief, lightning-like jerks that may be generalized or
limited to one or more muscle groups. They are not
associated with loss of consciousness and are frequently
precipitated by stimuli such as movement, bright light,
or stress.
• Epileptic seizures of other types.
• Progressive neurologic decline: particularly cerebellar
ataxia and cognitive decline (dementia).
DIFFERENTIAL DIAGNOSIS
Non-epileptic myoclonus (see Myoclonus, p.124)
Myoclonic epilepsies
Epileptic seizures accompanied by myoclonus:
• Infantile spasms.
• Lennox–Gastaut syndrome.
• Juvenile myoclonic epilepsy (see p.86).
Other, more common, generalized epilepsies
Early in the course of PME the clinical triad of myoclonic
seizures, tonic-clonic seizures and progressive neurologic
decline may not be present and PME can be mistaken for
more benign forms of epilepsy before progressive neurologic
signs or intractable seizures develop:
• Typical absence epilepsy.
• Primary generalized epilepsy combined with anti-
epileptic drug toxicity.
Other static or progressive secondary generalized
epileptic encephalopathies
Brain disorders characterized by various forms of general-
ized (including myoclonic) seizures, and a fixed neurologic
deficit with or without slow deterioration.
• Inherited metabolic disorders (see p.157).
• Tuberous sclerosis (see p.143).
• Birth injury.
• Encephalitis (see p.273).
The PMEs can usually be distinguished from these
disorders by evidence of normal development until the onset
of the disease, and a relatively rapid decline thereafter.
Progressive myoclonic encephalopathies
Progressive brain disorders characterized by myoclonus with
or without generalized (including myoclonic) seizures:
• Inborn errors of metabolism:
– Gaucher’s disease.
– Hexosaminidase deficiency (see p.172).
• Infections:
– Subacute sclerosing panencephalitis (see p.304).
– Creutzfeldt–Jakob disease (see p.330).
– Post-encephalitic parkinsonism (see p.420).
Progressive myoclonic ataxias
A syndrome comprising myoclonus and progressive
cerebellar ataxia with infrequent or absent epileptic seizures
and little or no cognitive dysfunction. Causes include:
• Mitochondrial disease.
• Spinocerebellar degenerations.
• Celiac disease (possibly).
INVESTIGATIONS
• Full blood count:
– Lymphocyte vacuolation in sialidosis and certain cases of
neuronal ceroid lipofuscinosis.
– Pancytopenia is common in Gaucher’s disease.
• Blood and CSF lactate: raised in mitochondrial cytopathies.
106
106 Light microscopic examination of the brain of a 20 year old
patient with Lafora body disease, who died after a 6 year history of
focal occipital seizures and relentless decline in cognitive function,
showing the presence of a characteristic periodic acid–Schiff (PAS)-
positive inclusion (Lafora body).
 Progressive Myoclonic Epilepsies (PME)
• Blood mitochondrial DNA analysis: mutations in some
cases of mitochondrial cytopathy.
• Serum tartrate-resistant isoenzymes of acid phosphatase:
elevated in Gaucher’s disease.
• Serum and leukocyte β-hexosaminidase A and B: GM2
gangliosidosis.
• Urinary thin-layer chromatographic oligosaccharide
screen: sialidosis.
• Urinary sediment dolichol estimation: neuronal ceroid
lipofuscinosis.
• Urinary organic acid estimation: biotin-responsive
encephalopathy.
• Electroencephalograph:
– Typically shows a slowing of background rhythms with
generalized epileptiform discharges and photic sensitivity.
– More specific findings include occipital discharges in
Lafora–body disease and photosensitive spikes on low-
frequency stimulation in late infantile neuronal ceroid
lipofuscinosis and in certain adult cases.
• Visual evoked potentials (VEP): may be enlarged or
diminished in neuronal ceroid lipofuscinosis.
• Electroretinogram (ERG): absent B wave in neuronal
ceroid lipofuscinosis.
• Somatosensory evoked potentials: enlarged in many
forms of PME.
• Skin + muscle biopsy:
– Eccrine sweat gland duct cells stained for polysaccharide
(Lafora–body disease).
– Acid phosphatase stain and electronmicroscopy (EM)
(neuronal ceroid lipofuscinosis).
– Modified Gomori’s trichrome and oxidative enzyme
reactions for ragged-red fibers (mitochondrial cytopathy).
DIAGNOSIS
Unverricht–Lundborg disease (previously termed
‘Baltic myoclonus’)
• Age of onset: 8–13 years.
• Pathology: widespread neuronal degeneration in the brain.
• Clinical features: severe myoclonus, little or no dementia.
• Diagnosis: clinical and genetic (i.e. DNA analysis:
mutation in the EPM1 gene).
Lafora body disease
• Age of onset: 11–18 years.
• Clinical features: partial occipital seizures, inexorable
dementia.
• Investigations: EEG – focal or multifocal posterior
epileptiform discharges, generalized discharges, and
progressive slowing of background rhythm.
• Diagnosis: Lafora bodies (periodic acid–Schiff [PAS]-
positive inclusions polyglucosan bodies]) on light
microscopy of skin, muscle, liver or brain biopsy (106).
DNA analysis: mutation in one of the four exons of the
EPM2A gene or non-coding regions of EPM2A.
Sialidosis
Type I
• Age of onset: 8–20 years.
• Clinical features: severe myoclonus, gradual visual failure
and cherry red macular spot; absence of dementia.
• Investigations: storage material in lymphocytes and other
cells; excess urine sialic acid-rich oligosaccharides.
• Diagnosis: severe deficiency of α-N-acetylneuraminidase
in leukocytes.
89
Type II
• Age of onset: 10–30 years.
• Clinical features: cherry red macular spot; dysmorphic
features.
• Investigations: storage material in lymphocytes and other
cells; excess urine sialic acid-rich oligosaccharides.
• Diagnosis: severe deficiency of α-N-acetylneuraminidase
in leukocytes; and partial β-galactosidase deficiency in
most cases.
Neuronal ceroid lipofuscinosis
Late infantile (Jansky–Bielschowsky disease)
• Age of onset: 2–4 years.
• Clinical features: severe seizures, rapid regression, fundal
changes of attenuated retinal vessels and macular degeneration.
• Investigations: ERG: absent B wave; VEP: enlarged.
• Diagnosis: curvilinear profiles on EM of skin, muscle,
rectum or brain biopsy; elevated urinary sediment
dolichol in 92% of cases.
Juvenile (Spielmeyer–Vogt disease)
• Age of onset: 4–10 years.
• Clinical features: visual failure, fundal changes of optic
atrophy, attenuated retinal vessels and macular
degeneration.
• Investigations: ERG: absent B wave; VEP: diminished.
• Diagnosis: fingerprint profiles on EM of skin, muscle,
rectum or brain biopsy; elevated urinary sediment
dolichol in 85% of cases.
Adult (Kuf’s disease)
• Age of onset: 12–50 years.
• Clinical features: progressive dementia, myoclonic
epilepsy, spasticity, ataxia, normal optic fundi.
• Investigations: VEP: marked photosensitivity at a low
frequency stimulation in some cases.
• Diagnosis: curvilinear profiles on EM of skin, muscle,
rectum or brain biopsy; elevated urinary sediment
dolichol in some cases.
Mitochondrial cytopathies (see p.162)
• Age of onset: any age.
• Clinical features: short stature, optic atrophy, deafness,
muscle weakness due to myopathy, stroke-like episodes,
lactic acidosis, intrafamily variation in age of onset and
clinical severity, maternal inheritance.
• Investigations: elevated blood or CSF lactate levels;
mitochondrial DNA mutations.
• Diagnosis: mitochondrial DNA mutation, ‘ragged-red’
fibers on skeletal muscle biopsy.
TREATMENT
Symptomatic relief of myoclonus and seizures
• Valproic acid.
• Clonazepam.
• 5-Hydroxytryptophan with carbidopa.
• Piracetam as an add-on agent.
N.B. Patients with the PMEs are particularly prone to
neurotoxic side effects, especially with phenytoin (which
should not be used) and the uncritical use of multiple
anticonvulsants.
90 Epilepsy

Specific therapy Genetic counselling

• Mitochondrial encephalomyopathies (see p.162).
• Neuronal ceroid lipofuscinosis: ?antioxidants. PROGNOSIS
• Biotin-responsive encephalopathy. The natural history of many of these disorders is not known
• Gaucher’s disease: bone marrow transplantation. but is usually one of progressive mental and physical
disability.

Kwan P, Brodie MJ (2000) Early identification of STATUS EPILEPTICUS

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 Chapter Four 91

Headache
HEADACHE ETIOLOGY (see Table 12)

CLINICAL HISTORY
CLINICAL CLASSIFICATION AND PREVALENCE OF • Types of headache: how many types of headache do you
DIFFERENT TYPES (see Table 11) suffer from?
• Length of history of headache: is this a new headache or
not; has it changed in character, severity or frequency?
• Features of the headache itself:
Table 11 Clinical classification and prevalence of – Location/site of headache.
different types of headache in the general population (%) – Onset.
– Type/quality of headache (throbbing, steady).
Primary % – Timing.
Muscle contraction/tension-type headache 69 – Severity.
Idiopathic stabbing headache 33 – Radiation.
(ice cream/ice pick headache) – Associated features (e.g. nausea, photophobia,
Migraine 16 phonophobia, symptoms of aura, fever, neurologic
Exertional headache 1 symptoms such as weakness, diplopia, clumsiness,
Cluster headache 0.1 disturbance of balance, altered cognitive function; altered
consciousness).
Secondary % – Exacerbating factors (e.g. physical activity, bright light,
Systemic infection 63 noise).
Head injury 4 – Relieving factors.
Drug induced headache 3 – Duration of headache.
Vascular disorders 1 – Predisposing factors.
Subarachnoid hemorrhage <1 – Premonitory features.
Brain tumor 0.1 • Family history.
• Medications/drugs.

Table 12 Etiology of headache

Children Adults Elderly
(3–16 years) (17–65 years) (65+ years)
Tension headache ++ +++ +
Migraine ++ +++ +
Idiopathic stabbing headache + + +
Exertional headache + ++ –
Cluster headache + ++ +
Post-traumatic ++ +++ +
Drug-induced headache – ++ ++
Cervicogenic (referred from neck) – + +++
Cranial arteritis – + +++
Subarachnoid hemorrhage + ++ +
Subdural hematoma +/– ++ ++
Brain abscess + + +
Brain tumor + ++ ++
Idiopathic intracranial hypertension +/– ++ –
Glaucoma – + ++
Paget’s disease of the skull – + ++
Cerebral venous sinus thrombosis +/– + +
Arnold–Chiari malformation +/– + +/–
92 Headache

PHYSICAL EXAMINATION • Neck stiffness.

• Fever or other signs of systemic illness (e.g. temporal • Upper cervical spine facet joints.
artery tenderness [107, 108]). • Papilledema (109).
• Conscious state. • Subhyaloid heamorrhage (110).
• Eye movements.
• Facial weakness.
107 • Limb weakness or incoordination.
• Gait disturbance.

Table 13 Differential diagnosis of primary headaches

Muscle Migraine Cluster

contraction/ headache
107 Lateral photograph of the forehead of a patient with giant cell tension headache
arteritis showing a visibly enlarged, tender, temporal artery (arrows).
Gender Male = female Female Male
predominance predominance
(9:1)
108
Pain
• Location Bilateral 2/3 hemicranial Orbit or temple
Orbit or frontal
• Type Steady tightness Throbbing Boring
• Severity Moderate Severe Very severe
• Duration Chronic, Hours to days 15–180 minutes,
usually daily often nocturnal

Aura None Often None

Nausea/vomiting None Often Uncommon

Photophobia, None Often Uncommon

phonophobia

Ipsilateral None Rare Typical

autonomic
features
108 Temporal artery in cross-section showing features of active giant
cell arteritis with fibroblastic proliferation in the intima (on the left of Periodicity Episodic or Episodic Clusters
the photograph), fibrinoid necrosis in the subintima, disruption of the chronic, (weeks to
internal elastic lamina, histiocytic proliferation, multinucleated giant cells, usually daily months)
1–8 attacks/day
and infiltration of adventitia by lymphocytes and plasma cells.

109 110

109 Ocular fundus showing papilledema in a patient with idiopathic 110 Ocular fundus showing subhyaloid hemorrhage in a patient with
intracranial hypertension. (Courtesy Mr M.Wade, Department of subarachnoid hemorrhage. (Courtesy Mr M.Wade, Department of
Medical Illustrations, Royal Perth Hospital, Australia.) Medical Illustrations, Royal Perth Hospital, Australia.)
 Headache 93

DIFFERENTIAL DIAGNOSIS • Subarachnoid hemorrhage (110): sudden onset, severe

Primary headaches (see Table 13)
Secondary headaches
• Meningitis: fever, meningismus (stiff neck) (see p.273,
291).
• Temporal arteritis (108): elderly, scalp tenderness, jaw
claudication, high ESR (see p.234).
• Idiopathic (benign) intracranial hypertension (109):
young, obese women, papilledema (see p.477).
headache, stiff neck, subhyaloid hemorrhage (see p.249).
• Cerebral venous sinus thrombosis (111, 112) (see
p.257).
• Subdural hemorrhage (113) (see p.177).
• Cerebral tumor: headache in early morning, neurologic
signs often present, personality change, seizures (see
p.357).
• Arnold–Chiari malformation (114) (see p.136).

111, 112 CT brain scan 111 112

with contrast (111) and MRI
brain scan (112),T1W post
contrast axial images showing
a filling defect at the torcula
due to venous sinus
thrombosis (the empty delta
sign, arrows).

113 CT brain scan, axial

image, showing a right
subdural hematoma as slight
hyperdensity over the
convexity of the right
cerebral hemisphere
(arrows).

114 MRI brain scan, sagittal

image, showing an
Arnold–Chiari malformation
(arrow).

113 114
94 Headache

INVESTIGATIONS (see Table 14)

Table 14 Investigation of the patient presenting with headache

Headache onset Abrupt Subacute Subacute Progressive Intermittent

(hours) (hours to days) (days to weeks) (may be abrupt)

Associated features*:
Unilateral headache + +
Bilateral headache + + + + +
Visual symptoms + +
Photophobia + +
Family history +
Personality change +
Seizures + +
Focal neurologic + + +
symptoms and signs
Fever + +
Neck stiffness + +
Papilledema +
Subhyaloid blood +
Coma + + + +
Rash +

Recurrent +

Suspect** Subarachnoid Meningitis Viral Structural Migraine

hemorrahge encephalitis intracranial
lesion

Think Is there a high index of suspicion for bacterial meningitis?

Are immediate blood cultures and empirical antibiotics required?

Imaging (CT or MRI) Subarachnoid Normal May be normal Lesion: Normal;

blood or normal (meninges may subdural hematoma not indicated
enhance) tumor, abscess except to exclude
other causes

Lumbar puncture: May be unsafe if there is evidence of raised intracranial pressure (see p.32), a mass, lesion, a swollen brain, a bleeding
diathesis or sepsis at the site of the lumbar puncture
Needs to be delayed at least 12 hours after onset of suspected subarachnoid hemorrhage, and if CT brain scan is
negative

Cerebrospinal fluid
Appearance Xanthochromia Turbid Clear or turbid Contraindicated Not indicated
RBC + 0 0 0
WBC <3 (normal) Polymorphs Lymphocytes <3 (normal)
Gram stain Negative Organisms Negative Negative
Protein Normal or raised Raised Raised Normal
Glucose Normal Low Normal or low Normal

Management Consult Antibiotics Acyclovir Consult Analgesics

Neurosurgery EEG Neurosurgery Antiemetic
and Neuroradiology HSV PCR Specific treatment:
(?surgery, ?GDC coil) ergotamine
Cerebral angiography sumatriptan

See p.249 See pp.273, 291 See p.292 See pp.177, 357 See p.95

* Not all need to be present

** Muscle contraction/tension-type headache is the most common cause of headache
+ Present
Blank: absent
 Migraine
Restrict to patients presenting with
• Atypical symptoms or signs indicative of organic
pathology.
• Certain physical signs, such as papilledema or a red
tender scalp vessel.
• Unremitting course which is unresponsive to
conventional treatment.
If suspicion of secondary headache consider
• Full blood count.
• ESR in patients over 50 years old.
• Blood biochemistry.
• CT or MRI brain scan (111–114): depends of the type
of headache and any associated features. For example,
sudden onset headache associated with loss of
consciousness suggests probable subarachnoid
hemorrhage or pituitary apoplexy in which case CT brain
scanning is the initial investigation of choice. Headache
coming on over several weeks which is worse in the
morning and on coughing suggests raised intracranial
pressure in which case a contrast enhanced CT scan
(?brain tumor) or MRI scan (?venous sinus thrombosis),
perhaps followed by angiography would be appropriate.
If an Arnold–Chiari malformation is suspected, then the
craniocervical junction and brain needs to be imaged by
high resolution CT or MRI scan. The imaging
requirements of headache with localizing features
requires a little more thought: for example pituitary
disease (MRI), ear disease (MRI for internal auditory
meatus, CT for middle and external ear problems) or
sinus disease (CT to diagnose plus look at the ostia), but
in any case it is essential to state all the relevant history
on the request card or the investigation may not answer
the problem.
DIAGNOSIS
Before a primary type of headache such as muscle
contraction/tension headache or migraine is diagnosed,
secondary headaches should be considered and eliminated
on clinical grounds or by appropriate investigations.
TREATMENT
• Explain the problem to the patient.
• Identify and avoid any precipitating factors.
• Institute appropriate specific treatment (see Table 14).
95
MIGRAINE
DEFINITION
A symptom complex, or syndrome, that manifests as discrete
episodes of headache associated with other features of
sensory sensitivity.
EPIDEMIOLOGY
Prevalence
Lifetime
• Women: 33% (95% CI: 31–37%).
• Men: 13% (95% CI: 12–16%).
1 year
• Women: 25% (95% CI: 23–29%).
• Men: 7.5% (CI: 7–9%).
• Higher in Caucasians than African Americans, than
Asians.
Age
• Onset is nearly always (90%) before age 50 years; 25%
begin in childhood.
• Peak incidence at age 10–12 for males and 14–16 years
for females.
• Peak prevalence at age 50 years for men and 35 years for
females.
• Attacks commonly increase in frequency at the
menopause, but may decrease (or become acephalgic).
Gender
• Children: M=F.
• Adolescents and adults: F>M = 2–3:1.
ETIOLOGY
Unknown.
Migraine without aura
A combination of genetic factors (possibly involving calcium
ion channel function) and environmental factors (e.g.
stress); first degree relatives of probands with migraine
without aura have a twofold increased risk of migraine
without aura compared with the general population; the
probandwise concordance rate is higher in monozygotic
(MZ) than dizygotic twins (0.43 [95% CI: 0.36–0.49] vs.
0.31 [95% CI: 0.26–0.36]).
Migraine with aura
Largely genetic; first degree relatives of probands with
migraine with aura have a fourfold increased risk of migraine
with aura compared with the general population; the pro-
bandwise concordance rate is higher in monozygotic than
dizygotic twins (0.50 [95% CI: 0.38–0.62] vs. 0.21 [95%
CI: 0.12–0.30]). However, environmental factors are also
important as the pairwise concordance rate is less than 100%
in MZ twin pairs (i.e. it is about 34% [95% CI: 23–45%]).
96 Headache
Familial hemiplegic migraine (FHM)
A rare autosomal dominant subtype of migraine with aura.
Genes for FHM map to chromosomes 19p13 and 1q but
some families with FHM do not link to either locus,
indicating genetic heterogeneity of FHM. The CACNa1A
gene at 19p13 encodes the α1A subunit (the ion conducting
part) of a brain specific P/Q type voltage-dependent
calcium channel, suggesting that migraine may be a ‘cerebral
calcium channelopathy’.
PATHOPHYSIOLOGY
Triggered by the action of a multitude of environmental and
biochemical factors on the cerebral cortex or hypothalamus
(the latter of which, in turn, is modulated by seasonal
patterns, diurnal and biologic clocks, and hormonal factors
and coitus); the premonitory symptoms of elation, yawning
or a craving for sweet foods, experienced by about 25% of
patients, suggest hypothalamic activation.
Triggers
• Emotional stress and tension.
• Relaxation after stress.
• Fatigue.
• Hormonal changes: fall in estradiol levels at menstruation
and midcycle.
• High dose estrogen-containing contraceptives.
• Strong sensory stimulation: bright or flickering light;
loud noise; strong smells; occipital nerve compression
(e.g. ‘swim-goggle migraine’).
• Head trauma, such as heading the ball in soccer
(‘footballer’s migraine’).
• Food idiosyncrasies/allergies: rich foods (e.g. chocolate,
fatty foods), red wines, specific dietary amines (cheese).
• Missing meals.
• Sleeping late in the morning.
• Meteorologic changes.
• Vasodilators, such as alcohol, monosodium glutamate,
and anti-anginal agents.
• Substance misuse.
• Physical activity (footballer’s migraine, coital cephalgia).
Trigeminovascular reflex (115)
The activated cerebral cortex and hypothalamus stimulate
brainstem nuclei, dorsal raphe nuclei (which contain
serotonin) and locus coeruleus (containing noradrenaline)
and trigger the trigeminovascular reflex which constitutes
serotonergic and noradrenergic pathways that project from
the brainstem to the cortical microcirculation and the spinal
trigeminal nucleus and spinal cord.
Axons of the first division of the trigeminal nerve, which
innervate the pain-sensitive intracranial structures,
depolarize as a result of direct neuronal activation or
vasodilatation of dural and cerebral arteries, or both, leading
to central transmission of nociceptive pain signals to bipolar
neurons in the trigeminal ganglion and on to the trigeminal
nucleus in its most caudal extent in the caudal medulla and
the dorsal horn of the spinal cord at C1 and C2 (accounting
for the commonly reported neck pain with migraine).
Impulses are then transmitted to the ventroposteriomedial
nucleus of the thalamus via the quintothalamic tract, from
where they are relayed to the cortex.
Stimulation of the trigeminal ganglion leads to the
release of powerful vasodilator neuropeptides such as
calcitonin gene-related peptide (CGRP) from trigeminal
neurons that innervate the cranial circulation. This peptide
is not only a vasodilator but it also mediates a sterile
neurogenic inflammation (vasodilatation and edema) within
the dura mater.
Migraine aura and headache
At the onset of aura, regional cerebral blood flow to the
clinically involved part of the brain is reduced by about 20%,
and reduced neuronal activity spreads in a wave across the
cerebral cortex, usually beginning in the occipital region and
slowly moving forward (spreading depression of Laeo).
Migraine headache begins while regional cerebral blood
flow is reduced. Platelets in the blood release serotonin (5-
hydroxytryptamine, 5-HT), and this leads to platelet
aggregation. During the headache, the level of a vasodilator
peptide, CGRP increases in the external jugular venous
blood, and some intracranial arteries (particularly those of
the dura mater) become dilated and inflamed. Vascular
dilatation and neurogenic inflammation is believed to be
responsible for the pulsatile nature of the headache.
Migraine attacks can be ameliorated by activating 5-
hydroxytryptamine 1D (5-HT1D) presynaptic receptors
within the vessel wall, thus blocking release of vasoactive
neuropeptides, causing vasoconstriction of certain cerebral
and dural arteries, and inhibiting depolarization of
trigeminal axons, functionally blocking activation of
trigeminal perivascular nerve terminals.
CLINICAL FEATURES
Precipitating factors
See Triggers, above.
Phase one: prodrome
• Occurs in 25–50% of migraineurs.
• Gradual onset and evolution over up to 24 hours.
• Lightheadedness, dulled perception, irritability,
withdrawal, cravings for particular foods (particularly
sweet foods), frequent yawning, elation and speech
difficulties.
115 Trigger factors
Hypohalamus Cortex
Thalamus
Dorsal
raphe Locus
Dura
Trigeminal nucleus coeruleus
ganglion
Blood
vessel Medulla
C1
C2
115 Diagram showing how the trigeminovascular pathway may be
activated to produce migraine headache.
 Migraine 97

Phase two: aura Associated features

• 15–25% of migraine attacks are associated with aura. • Scalp tenderness on the affected side (about two-thirds
• Visual symptoms most commonly: blurred vision, of cases).
flashing lights (photopsia) or shimmering zigzag lines of • Nausea (90% of patients).
light (fortification spectra), sometimes around an area of • Vomiting (60%).
impaired vision or blindness (scintillating scotoma) in a • Diarrhea (20%).
part of the visual field of one or both eyes (116). • Heightened awareness of sensations such as smell and
• Somatosensory: tingling or pins and needles, or less noise.
commonly numbness, in the face, arm, hand or leg. • Fluid retention at onset, and polyuria as headache
• Dysphasia: difficulty understanding and expressing speech. subsides.
• Gradual onset, symptoms ‘build up’ or progress over
5–10 minutes, then subside within 5–60 minutes. Duration
• Followed within 60 minutes by headache; the aura may • 4–72 hours.
continue into the headache phase. • Commonly 2–6 hours in children, and 6–24 hours in
adults.
Phase three: headache
Present in most, but not all migraine attacks (cf. ‘migraine Phase four: postdrome
without headache’ or ‘acephalgic migraine’). For up to 24 hours after the headache has subsided, most
migraineurs feel tired and ‘drained’ or ‘washed-out’, with
Site aching muscles. Others however, become euphoric for a
• Unilateral in two-thirds of patients, and bilateral in one- period of time.
third.
• Frontotemporal region commonly, spreading to occipital Periodicity with recurrence
region. Migraine is paroxysmal; clearly defined episodes recur as
often as 4–6 times each month.
Quality
• Throbbing/pulsatile. Family history
• Moderate to severe. Family history of migraine is present in more than half of
patients.
Aggravating factors
• Physical activity/movement. SPECIAL FORMS
• Bright light (photophobia, 80%). Migraine variants
• Loud noise (phonophobia). Less than 5% of migraineurs.

Retinal migraine
Monocular, rather than binocular hemianopic visual
disturbance.

116 Illustration of 116 Ophthalmoplegic migraine:

the type of visual • Paralysis of ≥1 of the ocular cranial nerves, usually the
aura a migraineur IIIrd nerve, at the height of a migraine headache.
may describe; in this • The paralysis usually resolves but may persist after
case shimmering recurrent episodes.
zigzag lines of light • This entity does not embrace a transient dilatation or
(fortification constriction (Horner’s syndrome) of one pupil as this is
spectra). quite commonly seen during severe migraine attacks.
• The cause of the cranial neuropathy in ophthalmoplegic
migraine is probably transient ischemia of the cranial
nerve.

Vertebrobasilar migraine
Gradual onset and evolution over several minutes of
brainstem, cerebellar and visual disturbances, often accom-
panied or followed by headache and syncope.

Hemiplegic migraine
• Hemiparesis preceding or occurring with a migraine
headache.
• A family history of hemiplegic migraine is often present
and the gene is located on chromosome 19 or 1.
98 Headache

Migrainous infarction Secondary

• Permanent focal neurologic symptoms persisting beyond
24 hours after the cessation of migraine headache.
Cranial CT or MRI scan shows features consistent with
cerebral infarction.
• The cause is probably arterial thrombosis, provoked by
arterial spasm and a procoagulant state (e.g. cigarette
smoking and the oral contraceptive pill).
Menstrual migraine
Just before menstruation, plasma estradiol (rather than
progesterone) levels fall rapidly below about 20 ng/ml
which sets in motion a series of changes (perhaps through
prostaglandins) that culminate in the onset of migraine in
about 60% of women migraineurs and exclusively at that
time in about 14%. Migraine is relieved by pregnancy in
about 60% of women, many, but not all, of whom have a
history of menstrual migraine.
Migraine in childhood
• Headache and vomiting are common but the child may
be unable to describe the symptoms and may simply
appear pale, ill, limp, and inert, complaining of poorly
localized abdominal pain.
• Fever up to 38.5°C (101.3°F) may be present so that the
suspicion of appendicitis or mesenteric adenitis often
arises.
• Rather than accept a label of ‘bilious attacks’ or ‘periodic
syndrome’, recurrent headaches or vomiting attacks in
children which may develop at times of excitement or
stress should be considered as possibly migrainous and
not psychosomatic.
DIFFERENTIAL DIAGNOSIS
Abrupt onset of headache (‘thunderclap headache’)
Primary
• Cluster headache.
• Benign exertional or sex headache.
• Idiopathic stabbing headache.
Secondary
• Subarachnoid hemorrhage.
• ‘Sentinel headache’ (enlargement of a cerebral aneurysm
without rupture).
• Intracerebral hemorrhage.
• A precipitous rise in blood pressure: drug induced
headache.
• Head injury.
• Acute obstruction of the CSF pathways.
• Drug-rebound headache: a periodic daily bilateral
headache that has gradually increased in frequency, and
changed in character from the typical migraine
headaches, in concurrence with increasing consumption
and misuse of analgesic drugs, particularly those which
also contain caffeine.
• Systemic infection.
• Giant cell arteritis.
• Raised intracranial pressure: idiopathic intracranial
hypertension, brain tumor.
Vertebrobasilar migraine
Neurocardiogenic syncope.
Migraine aura without headache
(acephalgic migraine)
• TIA.
• Epileptic seizure.
• Arteriovenous malformation.
• Mitochondrial DNA disorders (e.g. MELAS, see p.162).
• Cerebral autosomal dominant arteriopathy with
subcortical infarction and leukoencephalopathy
(CADASIL) (see p.261).
INVESTIGATIONS
• Should only be necessary if headache is suspected to be
secondary to another disorder.
• ‘Alarm symptoms’ include:
– Onset above age 50 years.
– Aura without headache.
– Aura symptoms of acute onset without spread.
– Aura symptoms that are very brief (<5 mins) or unusually
long (>60 min).
– Aura symptoms that are stereotyped (i.e. always at the
same body site).
– Sudden increase in migraine frequency or change in
migraine characteristics.
– High fever.
– Abnormal neurologic examination.
• The role of imaging in patients with suspected migraine is
to exclude structural causes for the headache such as AVMs
or tumors. A contrast-enhanced CT scan is satisfactory for
this, and is usually normal (unless there is an AVM or
tumor). If MRI is performed, the T2W image occasionally
shows areas of altered signal in the white matter which may
be residual ischemic changes following a recent or
prolonged attack, or may rarely be due to CADASIL. The
appearance is non-specific however.

Unilateral headache DIAGNOSIS

• Cluster headache. Clinical
• Temporal arteritis. • At least 5 attacks.
• Glaucoma. • Attacks last 4–72 hours if untreated or unsuccessfully
• Temperomandibular joint disease. treated.
• Internal carotid or vertebral artery dissection. • At least two of:
• Structural intracranial lesion. – Unilateral headache.
– Pulsating headache.
Continuous or daily headache – Moderate or severe headache.
Primary – Headache aggravated by routine physical activity.
• Tension headache: just headache, and sometimes mild • At least one of:
photophobia and phonophobia but no other features of – Nausea, with or without vomiting.
sensory sensitivity. – Photophobia.
• Mixed migraine/tension headache. – Phonophobia.
 Migraine
TREATMENT
Avoid precipitating/triggering factors
Identify these by keeping a diary if necessary.
Treatment of the acute migraine attack
Ancillary measures
• Rest in a quiet dark room.
• Intravenous fluids if severely dehydrated.
Non-specific analgesics and antiemetic/prokinetic compounds
• Treat as early as possible (e.g. aspirin 600–900 mg or
ibuprofen 400–800 mg, together with metoclopramide
10 mg), and wait 40 minutes. If headache persists, try a
specific treatment such as ergotamine 1 mg capsule or
sumatriptan 50 mg tablet, and wait >1 hour. If headache
persists, repeat. (See below.)
• Anti-emetic and prokinetic compounds (e.g.
metoclopramide 10 mg or domperidone 10–20 mg) if
nausea and vomiting are a problem. Metoclopramide is
preferable because it improves the oral absorption of
other drugs (which is impaired in migraine attacks) and
may have a favorable central effect. If vomiting is severe,
suppositories of domperidone, prochlorperazine, or
chlorpromazine may be helpful.
• Simple analgesic drugs:
– Aspirin 2 or 3 × 300 mg chewable tablets (600–900 mg)
orally.
– Paracetamol (acetaminophen) 2 × 500 mg tablets (1g)
orally.
– Compound codeine-containing analgesic (e.g. codeine
15–30 mg) but may cause or exacerbate nausea.
• Non-steroidal anti-inflammatory drugs:
– Ibuprofen.
– Naproxen: oral, rectal.
– Diclofenac: oral (potassium salt-rapid absorption),
intramuscular.
– Ketorolac: intramuscular.
• Other non-specific drugs:
– Chlorpromazine: intramuscular, but long term considera-
tions (e.g. tardive dyskinesia).
– Narcotic analgesic use is highly controversial, not
evidence-based, and is associated with prominent adverse
effects and a high risk of dependency. Most patients who
require narcotics are misusing analgesics or ergots.
– Lignocaine infusion: may be indicated for prolonged
severe migraine unresponsive to other therapy or for
rebound headache (for the latter, all analgesics are
withheld during the infusion). Procedure: a 12-lead EKG
is obtained and examined before and 30–60 minutes
after starting the infusion. Lignocaine is delivered by a
pump device at a rate of 2 mg/min (no bolus is given).
The patient is attached to a bedside cardiac monitor, and
a rhythm strip is obtained every 5 minutes for the first
30 minutes, then every 15 minutes for 3 hours, and
thereafter every 2 hours. Pulse rate and blood pressure
are measured every 5 minutes for the first 30 minutes,
then every 15 minutes for 3 hours, and thereafter every
2 hours while the patient is awake. The infusion is
maintained until the patient has been headache free for
at least 12 hours. The duration of infusion should not
exceed 14 days. Contraindications include significant
heart disease (e.g. severe sinoatrial, atrioventricular, or
intraventricular heart block), epileptic seizures, or allergic
reaction to lignocaine.
99
Specific antimigraine agents
Ergot alkaloids:
• Alpha adrenergic agonists with potent 5-HT1 receptor
affinity. Also stimulants of dopamine D2 receptors in
brainstem and gut (vomiting and diarrhea), and vascular
adrenergic and 5-HT2 receptors (vasoconstriction).
• Ergotamine exists in several forms:
– 1 mg capsule of ergotamine tartrate, or combined with
caffeine.
– 2 mg suppository of ergotamine tartrate combined with
caffeine 100 mg.
– 2 mg tablet of ergotamine tartrate combined with
caffeine and an antiemetic.
• Dihydroergotamine mesylate can also be given orally
(absorbed erratically), or more effectively, by suppository
(1–2 mg), inhalation (0.36 mg), sublingual (1–2 mg),
intramuscular (0.5–1 mg) and intravenous (0.5–1 mg)
routes.
• Effective in about half of cases.
• If two doses at intervals of 2–6 hours are ineffective, no
more should be given for that attack.
• Limitations include poor oral and rectal bioavailability
(<3%); frequent, long-lasting adverse effects (nausea,
vomiting, diarrhea, muscle cramps, malaise, cold/ting-
ling fingers and toes); and risk of headache and ergotism
(generalized vasospasm, causing acral cyanosis, digital
necrosis, intermittent claudication, and tissue infarction)
with chronic recurrent use (>1 day per week).
• The drug of choice in a limited number of migraine
sufferers who have infrequent or long duration headaches
and are likely to comply with dosing restrictions. For
most migraine sufferers requiring specific migraine
treatment, a triptan is generally a better option from both
an efficacy and side-effect perspective.
Triptans:
Selective and potent agonists of 5-HT1B, 1D, 1F, and to
some extent 5-HT1A receptors. Antimigraine effects are
mediated by:
• Inhibition of firing of cells in trigeminal nuclei (5-HT1B or
D receptors in the brainstem: second generation triptans).
• Inhibition of dural neurogenic inflammation and plasma
extravasation (presynaptic 5-HT1D receptor stimulation
on trigeminal neurons).
• Vasoconstriction of meningeal, dural, cerebral or pial vessels
(stimulation of presynaptic vascular 5-HT1B receptors).
First-generation triptans: sumatriptan:
• A specific and selective agonist of 5-HT1D presynaptic
receptors on cranial blood vessels, inhibiting trigeminal
neuronal firing at the trigeminal nerve ending.
• Available as subcutaneous injection (6 mg), oral tablets
(25, 50 and 100 mg), nasal spray (20 mg), and rectal
preparations.
• Subcutaneous sumatriptan injection (6 mg):
– Bioavailability: 96%.
– Therapeutic plasma levels: within 10 minutes.
– 79% of patients improved at 2 hours after injection
(‘therapeutic gain’ [TG]: active minus placebo = 52%);
71% (TG: 51%) improved within 1 hour.
– 60% of patients pain-free at 2 hours after injection (TG:
42%); 43% (TG: 35%) pain-free after 1 hour.
(Continued overleaf)
100 Headache
First-generation triptans: sumatriptan (continued):
• Oral sumatriptan tablets (100 mg):
– Bioavailability: 14%.
– Therapeutic plasma levels: within 30–90 minutes.
– 59% (95% CI: 57–60%) of patients improved at 2 hours
after tablets(TG: 33%).
– 29% (27–30%) of patients pain-free at 2 hours (TG 26%).
• Oral sumatriptan is more effective than conventional
treatment with aspirin and metoclopramide or oral ergo-
tamine plus caffeine, particularly in the second and third
attacks, suggesting greater consistency for sumatriptan.
• Recurrence of headache occurs within 24–48 hours in
about one-third of responders to sumatriptan (and any
other acute antimigraine drug). Repeated drug adminis-
tration is usually effective, but the headache may recur
again.
• Adverse effects of sumatriptan are common but are
usually mild and short-lived. The most frequent are
tingling, paresthesias, and warm sensations in the head,
neck, chest, and limbs; less frequent are dizziness,
flushing, and neck pain or stiffness. The risk and intensity
is greater with the fixed subcutaneous formulation.
‘Chest-related symptoms’ include short-lived heaviness
or pressure in the arms and chest, shortness of breath,
chest discomfort, anxiety, palpitations, and, very rarely,
chest pain. The mechanism is unknown. The risk of
sumatriptan-induced myocardial ischemia in the absence
of coronary artery disease appears to be acceptable (e.g.
no greater than the risk of exercise-induced myocardial
ischemia in sportsmen).
Second-generation triptans:
• Zolmitriptan 2.5 mg, 5 mg: similar to oral sumatriptan.
• Naratriptan 2.5 mg: slower action and perhaps fewer and
less severe adverse effects, but lower efficacy.
• Rizatriptan 10 mg, 40 mg: better efficacy and
consistency, and similar tolerability.
• Almotriptan 12.5 mg: similar efficacy, better consistency
and tolerability.
• Eletriptan 20 mg, 40 mg and 80 mg: 80 mg orally is
more effective than sumatriptan 100 mg orally with
similar consistency but lower tolerability.
• Frovatriptan: possibly lower efficacy than oral sumatriptan.
Advantages over oral sumatriptan:
• Higher bioavailability: 45–75%.
• More rapid therapeutic plasma levels: within 30–60
minutes.
• Greater potency at 5-HT1B/D receptor sites.
• Increased lipophilicity and brain penetration (hence,
direct attenuation of excitability of cells within the
trigeminal nuclei of the brainstem, as well as vasocon-
striction and peripheral inhibition of trigeminal peri-
vascular terminals).
• Cheaper alternatives for patients who do not respond to
oral sumatriptan.
None of these agents is consistently effective in all patients
and all attacks, and some cause disturbing adverse effects.
Rizatriptan 10 mg, eletriptan 80 mg, and almotriptan
12.5 mg provide the highest likelihood of success.
Ergotamine and sumatriptan should not be prescribed for
patients with suspected coronary artery disease, Prinzmetal
variant angina, or uncontrolled hypertension.
Prevention
Non-pharmacologic
• Avoid precipitating factors (e.g. dietary-chocolate,
oranges, monosodium glutamate).
• Stress reduction through relaxation exercises and tapes,
meditation, yoga, swimming and similar strategies will
reduce migraine frequency in many patients.
• Regular exercise such as swimming.
• Acupuncture in short courses by an experienced therapist
can be a useful adjunct to other strategies in some
patients.
Pharmacologic
• The indication for prophylactic therapy is when the
patient needs it. This is usually when the migraine attacks
are frequently interfering with their life and recurring
every 2 weeks or so and not responding quickly and
adequately to acute treatment.
• Efficacy is limited: at most about half of patients will have
a reduction in attack frequency of half or more.
• Adverse effects occur commonly.
• The choice of prophylactic agent is primarily determined
by the patient and which potential adverse effects are
most acceptable (see Table 15).
• Discuss the adverse effect profile of each drug with the
patient and determine their preference. Asthma (beta
blockers) and weight gain (pizotifen [pizotyline] and
valproate) are by far the major concerns.
• Establish realistic expectations with the patient before
starting: the medication may reduce the frequency of
attacks but uncommonly abolishes attacks, and so
occasional breakthrough attacks requiring acute
treatment will occur.
• Start slowly, with dosage increments every 7–10 days to
minimize adverse effects.
• Encourage patients to persist for at least 3 months to
adequately trial the drug and because most adverse
effects become less prominent with time.
• Follow on with a drug free interval to reassess the
frequency and severity of migraine attacks.
Menstrual migraine
• Try standard prophylactic (interval) therapy, as above,
before hormone manipulation.
• Continuous bromocriptine therapy, 2.5 mg tds, added
to the existing prophylactic regime may be beneficial.
Adverse effects, such as light-headedness and nausea can
be minimized by gradual introduction of medication,
beginning with 1.25 mg daily and followed by daily
incremental 1.25 mg increases over 1 week to full dosage
(i.e. 25 mg tds).
• Non-steroidal anti-inflammatory drug, such as diclofenac
(enteric coated) 50 mg bd commencing 24 hours before
anticipated menstruation (to attempt to counteract the
overflow of prostaglandin from the contracting uterus).
• Application of a gel containing 1.5 mg estradiol to the
skin 48 hours before the expected onset of menstruation.
• Subcutaneous implantation of estradiol pellets, starting
with 100 mg, inhibits ovulation and maintains estradiol
levels, while regular monthly periods can by induced by
cyclical oral progestogens. Depoprovera, a different oral
contraceptive pill, or 3 monthly cycles of the oral
contraceptive pill are alternative strategies.
 Muscle Contraction/Tension-type Headache 101

• Tamoxifen citrate, 10–20 mg daily preceding and during MUSCLE CONTRACTION/TENSION-

menstruation may help; tamoxifen competes at estrogen TYPE HEADACHE
and anti-estrogen binding sites and is a calcium channel
blocker. However, the anti-estrogenic effect in young
women, such as osteoporosis, is an obvious problem with DEFINITION
this strategy. An episodic or chronic continuous headache due to
sustained muscle contraction.
CLINICAL COURSE
• Migraine is paroxysmal. Clearly defined episodes of EPIDEMIOLOGY
migraine recur as often as three or six times each month • Prevalence:
but sufferers remain symptom-free between attacks. – Episodic tension-type headache: 38% 1 year period
• The frequency of migraine attacks may increase until it prevalence.
develops into chronic daily headache (transformed – Chronic tension-type headache: 2.2% 1 year period
migraine), often as the result of stress or the over-use of prevalence.
ergotamine or analgesics. • Age:
• Migraine symptoms frequently change over time. – Any age.
• The severity of the attacks often diminish with time and – Onset before 10 years of age in 15%.
in some patients the attacks cease in latter years, – Peak prevalence 30–39 years of age.
particularly after the menopause in women. • Gender: F > M: 1.2:1.
• In some women however, attacks increase in frequency
at the menopause. ETIOLOGY
• Remission occurs in 70% of pregnancies. Unknown. Perhaps, at least in part, a disorder of the CNS
• For young women, below the age of 25 years, the with probable trigeminal activation and sensitization of
relative risk of ischemic stroke among migraineurs is second-order trigeminal neurons and some peripheral
increased (compared with age-matched controls), component. Generation of nitric oxide may have a role in
particularly among those taking the oral contraceptive central sensitization.
pill, but the absolute risk is extremely small (17–50 per
100 000 per year).

Table 15 Adverse effects of propyhlactic agents in migraine

Agent Dose Adverse effects

β-adrenoreceptor blockers
Propranolol 40–240 mg/day Tiredness, exercise intolerance, postural hypotension, vivid dreams,
Metoprolol 100–200 mg/day probably contraindicated in asthmatic patients
Anti-epileptic drugs
Sodium valproate 400–800 mg/day Drowsiness, tremor, weight gain, abnormal liver enzymes, risk of
teratogenicity in pregnant women
5-HT receptor antagonists
Pizotifen (pizotyline) 0.5–3 mg nocte Drowsiness, sedation, weight gain
Methysergide 1–4 mg/day Drowsiness, leg cramps, small (0.5%) risk of retroperitoneal or pleural
fibrosis if treatment is not stopped for 1 month every 4–6 months and
screened with physical examination, CXR, and renal function
Non-selective calcium channel blockers
Flunarizine Constipation; rare extrapyramidal adverse effects with flunarizine
Verapamil 40–120 mg tds Effective in preventing cluster headache
Vitamins
Riboflavin (vitamin B2) 400 mg/day Diarrhea, polyuria
Herbal medicines
Feverfew
Non-steroidal anti-inflammatory drugs
Naproxen Small risk of peptic ulceration
Hormonal manipulation
Antidepressants
Amitriptyline 50–150 mg/day Drowsiness, dry mouth, blurred vision
Dothiepin Useful for concurrent tension-type headaches
102 Headache
Predisposing factors
Genetic factors
First degree relatives of probands with chronic tension
headache have about three times the risk of chronic tension
headache than the general population, suggesting the
importance of genetic factors in chronic tension headache.
Physical abnormalities:
• Imbalance of bite: some patients have an uneven bite that
throws strain on one temperomandibular joint and leads to
the development of a clicking noise in the joint and pain
radiating from the affected joint over the face and head
(Costen’s syndrome). Dental attention is required to correct
the bite and it is necessary to reduce excessive jaw clenching
(bruxism) and the underlying anxiety state.
• Cervical spondylosis: degenerative changes in the cervical
spine may lead to spasm of cervical muscles which may re-
spond to manipulative or other therapy for the neck problem.
• Eye strain: refractive errors or ocular imbalance may be a source
of tension and should be corrected. At school or at work, the
patient should sit in a comfortable chair which is adjusted to
the height appropriate for the desk (to ensure good posture)
with light adjusted to the correct angle for comfort.
• Prolonged fasting, as occurs for the traditional Jewish Day of
Atonement fast (Yom Kippur), is a strong precipitator of a
nonpulsating, bilateral, frontal headache of mild to moderate
intensity, particularly among chronic headache sufferers. The
mechanism may include metabolic changes, such as
hypoglycemia or the accumulation of certain metabolites but
the headache tends to occur within 18 hours of fasting.
Psychologic factors
• Stress may be clearly associated with exacerbations of head-
ache in some patients and may be helped by readjustment of
stresses, alteration of life-style or psychologic counselling.
• Sleep disturbance is a major perpetuating factor in
patients with intermittent muscle contraction headache,
which contributes to it becoming chronic.
• Chronic tension-type headache is usually, but not always,
related to or exacerbated by anxiety or depression (as
well as sleep disturbance).
PATHOPHYSIOLOGY
• Constant involuntary tightening or overcontraction of the
frontal, temporal and occipital muscles, induced mentally or
physically, may be the cause in some patients who experience
some relief by learning to relax the appropriate muscles.
• Psychogenic mechanisms are relevant in other patients.
• Some form of sensitization with second-order trigeminal
neurons is likely to be involved.
CLINICAL FEATURES
• Site: usually bilateral, and diffuse or at the vertex of the
head, around the head, or in the neck or occiput.
Occasionally unilateral.
• Nature: non-pulsatile, tight, pressing, heavy or band-like
sensation.
• Onset: may occur during times of fatigue, stress, or anxiety.
• Timing: episodic, but may become constant, occurring
all day every day, for months and even years.
• Exacerbating and relieving factors: episodic headache
may be relieved by relaxation or analgesics. Chronic daily
headache is not relieved by analgesics and excessive
medication may itself induce or exacerbate headache.
• Associated symptoms: nausea may be present, but not
vomiting or sensory sensitivity to head movement, light or
sound (although one of the latter pair is acceptable). Patients
are commonly polysymptomatic and may have a fear of an
underlying brain tumor or other medical ailment.
DIFFERENTIAL DIAGNOSIS
• Migraine: muscle contraction/tension-type headaches
occur in about half of migraine sufferers, often as a
background pain, but are not usually unilateral and are
not accompanied by sensitivity to light, noise or physical
motion, nor vomiting or visual disturbance (as migraines
are). Sometimes migraine is gradually transformed into
chronic muscle contraction/tension-type headache, but
more frequently it is episodic muscle contraction/ten-
sion-type headache which becomes chronic. In both
instances overuse of drugs frequently plays a role in
aggravating the disorder. Discontinuation of daily drug
intake often results in improvement.
• Cervicogenic pain: muscle contraction/tension-type
headache may also occur as a result of pain referred from
the neck.
• Chronic drug-induced (analgesics or ergotamine)
headache (often in a migraineur).
• Raised intracranial pressure.
INVESTIGATIONS
Not necessary unless a secondary headache is suspected.
DIAGNOSIS
Based on the history.
Episodic tension-type headache:
A At least 10 previous headaches episodes fulfilling criteria
B–D listed below. Number of days with such headache
<180/year (<15/month).
B Headache lasting from 30 minutes to 7 days.
C At least 2 of the following pain characteristics:
– Pressing/tightening (non-pulsating) quality.
– Mild or moderate intensity (may inhibit, but does not
prohibit activities).
– Bilateral location.
– No aggravation by walking stairs or similar routine
physical activity.
D Both of the following:
– No nausea or vomiting (anorexia may occur).
– Photophobia and phonophobia are absent, or one but
not the other is present.
E At least one of the following:
– History, physical and neurologic examinations, and
appropriate investigations do not suggest headache
associated with head trauma, vascular disorders, non-
vascular intracranial disorder, substances or their
withdrawal, non-cephalic infection, metabolic disorder,
or disorders of the cranium, neck, eyes, ears, nose,
sinuses, teeth, mouth, or other facial or cranial structures.
– One of the disorders mentioned in E above is present,
but tension-type headache does not occur for the first
time in close temporal relation to the disorder.
Chronic tension-type headache
A Average headache frequency >15 days/month
(180 days/year) for >6 months fulfilling criteria B–D
listed below.
 Cluster Headache (Migrainous Neuralgia)
B At least 2 of the following pain characteristics:
– Pressing/tightening (non-pulsating) quality.
– Mild or moderate severity (may inhibit, but does not
prohibit activities).
– Bilateral location.
– No aggravation by walking stairs or similar routine
physical activity.
C Both of the following:
– No vomiting.
– No more than one of the following: nausea, photophobia
or phonophobia.
D As for E above.
TREATMENT
Reassurance
Prompt and convincing.
Consider discontinuing or minimizing heavy
analgesic intake
For patients in whom episodic tension-type headache or, less
frequently, migraine become transformed into chronic
tension-type headache, overuse of analgesic drugs frequently
plays a role in aggravating the disorder, and discontinuation
of daily drug intake often results in improvement.
Relaxation exercises, psychotherapy and
biofeedback training
A course in relaxation training may be highly beneficial in a
well motivated patient. They are now conducted by
psychologists, physiotherapists, and many hospitals and
community health centers. Various forms of biofeedback
may assist relaxation but do not make a substantial impact.
Pharmacotherapy
• Tricyclic antidepressants: amitriptyline, in particular, may be
very helpful, commencing with one-half of a 25 mg tablet
at night and gradually increasing to three tablets (75 mg) as
a single nocturnal dose, provided there are no adverse effects
such as drowsiness and confusion. If effective, an improve-
ment will usually be noticed within 2 weeks. Treatment
should be continued for about 6 months and then gradually
phased out to see whether it is still necessary or whether
improvement can be maintained with relaxation alone.
• Anxiolytics, such as the benzodiazepines, have a limited
role. They should be used for short periods only, and
under supervision, because of the risk of habituation,
dependency and drug-induced headache.
• Sodium valproate, 200–400 mg three times daily, may
help control chronic tension-type headache.
117
103
CLUSTER HEADACHE
(MIGRAINOUS NEURALGIA)
DEFINITION
A rare form of primary headache marked by recurrent
episodes, lasting 15–180 minutes, of excruciating unilateral
periorbital pain and associated autonomic features, that tend
to occur once or twice a day in bouts or clusters, lasting
from weeks to months at a time, separated by remission
periods of months or 1–2 years.
EPIDEMIOLOGY
• Incidence: 6 (3–10)/100 000/year.
• Lifetime prevalence: 0.3 (95% CI: 0.2–0.6)/1000.
• Age: any age, but unusual in children and most common
20–50 years of age.
• Gender: mainly men (ratio 10:1).
ETIOLOGY AND PATHOPHYSIOLOGY
• A neurovascular disorder, which is hypothesized to be
generated in the CNS in pacemaker or circadian regions
of the hypothalamic gray matter. The trigeminal/cervical
nuclear overlap is also central to the pathogenesis (see
Migraine, p.95). Activation of the trigeminovascular
system (i.e. release of calcitonin gene-related peptide
[CGRP] from peripheral terminals of trigeminal
nociceptive neurons, which supply cephalic blood vessels)
underlies symptoms of cluster headache. Increases in
neuropeptide markers of this system rapidly return to
normal after treatment with sumatriptan.
• The mechanism by which nitroglycerine can induce a
headache attack in cluster headache patients which is
indistinguishable from a spontaneous attack is at least
partly due to activation of the trigeminovascular system.
CLINICAL FEATURES
• Severe, boring, unilateral periorbital pain that may radiate
upwards over the frontotemporal region and downwards
to the face, jaw, neck and shoulder.
• Edema of the ipsilateral eyelid.
• Redness of the ipsilateral eye (conjunctival injection).
• Watering of the ipsilateral eye (lacrimation).
• Miosis with or without ptosis ipsilaterally in about 20%
of cases (117); permanent partial Horner’s syndrome
(ptosis and miosis) ipsilaterally in about 5% of patients.
• Swelling, dilatation, and tenderness of the superficial
temporal vessels occasionally.
• Rhinorrhea and a blocked nostril ipsilaterally.
• Temporal spacing of attacks: the pain usually lasts 15
minutes to 2 hours and recurs once or twice a day, often
at night at the same time, for several weeks (active
periods), followed by an attack-free period (remission
period).
• Vasodilators, notably alcohol, nitrates and calcium
channel blockers, may precipitate attacks during the
active period, but not in remission periods.
117 Facial photograph during an attack of cluster headache showing
unilateral eyelid edema, ptosis, miosis and conjunctival injection of the
right eye.
104 Headache
DIFFERENTIAL DIAGNOSIS
Primary short-lasting headaches with prominent
autonomic features
Chronic paroxysmal hemicrania (CPH)
• Frequent brief attacks of excruciating unilateral orbital,
supra-orbital or temporal pain (distribution of
ophthalmic division of trigeminal nerve) that last 2–45
minutes and recur five or more times daily (periods with
lower daily frequency may occur). The pain is usually
stabbing or boring, but may be throbbing as it builds up.
• At least one associated autonomic symptom, such as
conjunctival injection, lacrimation, nasal congestion,
rhinorrhea, ptosis or eyelid edema.
• Attacks usually (but not always) resolve rapidly within
days of initiating treatment with indomethacin in an
adequate dose of up to 150 mg/day orally.
• Age of onset: usually in the twenties, but may occur in
children.
• Gender distribution: F>M (3:1).
• Pathophysiology: unknown.
• Secondary causes include cavernous sinus meningioma,
gangliocytoma of the sella turcica, frontal lobe tumor,
arteriovenous malformation, intracranial hypertension,
connective tissue disease, and pancoast tumor.
• Distinguished from cluster headache by the shorter dur-
ation and higher frequency of attacks, the female pre-
ponderance, and the selective response to indomethacin.
Episodic paroxysmal hemicrania (EPH)
• Extremely rare.
• Frequent brief attacks of very severe, unilateral orbital
and/or temporal headache lasting from 1–30 minutes,
and recurring three of more times a day.
• Accompanying ipsilateral autonomic features.
• Age of onset: 12–51 years.
• Gender distribution: F=M.
• Absolute response to indomethacin.
• May evolve from a disorder with distinct intervals into a
chronic unremitting form identical to CPH.
Short-lasting unilateral neuralgiform headache with
conjunctival injection and tearing (SUNCT) syndrome
• Rare.
• Males predominate: M>F (17:2).
• Paroxysms of unilateral moderately severe orbital or
temporal stabbing or throbbing pain lasting between 5
and 250 seconds (i.e. <5 minutes).
• Average about 28 attacks a day (range 3–100).
• Conjunctival injection is often present and prominent;
other autonomic features may occur such as lacrimation,
sweating of the forehead and rhinorrhea.
• Precipitating factors, such as mechanical movements of
the neck, are common.
• Pathogenesis: most likely central activation of the trige-
minovascular reflex, rather than a peripheral vasculitis.
• SUNCT syndrome may be secondary to posterior fossa
lesions such as homolateral cerebellopontine angle
arteriovenous malformations.
• Refractory to all treatments so far described, including
indomethacin.
Cluster-tic syndrome
• Cluster headache.
• Additional symptoms of trigeminal neuralgia (see p.509),
which are always on the same side, in the same division,
and can be provoked by the same stimuli.
Primary short-lasting headaches with few or no
autonomic features
Trigeminal neuralgia (see p.509)
• Gender: F>M.
• Pain: V2/V3>V1, in the territory of supply of the
maxillary (V2) and mandibular (V3) branch of the
trigeminal nerve (i.e. cheek and jaw) more commonly
than the ophthalmic branch (V1) (i.e. forehead),
stabbing, and very severe.
• Attack duration: less than 1 second.
• Attack frequency: few to many/day.
Idiopathic stabbing headache
• Gender: F>M.
• Pain: any part of the head, stabbing, and severe.
• Attack duration: less than 1 second.
• Attack frequency: few to many/day.
• Responds to indomethacin.
Hypnic headache
• Rare.
• Age: elderly (67–84 years).
• Gender: M>F (5:3).
• Pain: generalized, throbbing, and moderately severe.
• Attack duration: 15–30 minutes.
• Attack frequency: 1–3 per night, often awakening patient
from sleep.
• Responds to lithium carbonate 600 mg at bedtime.
Cough headache
A bilateral headache of sudden onset, lasting less than 1
minute, and precipitated by coughing, in the absence of any
intracranial disorder, such as a Chiari type I malformation.
Benign exertional headache
A bilateral throbbing headache, lasting from 5 minutes to
24 hours, specifically provoked by physical exercise and
unassociated with any systemic or intracranial disorder, such
as subarachnoid hemorrhage, sinusitis and brain metastases.
Headache associated with sexual activity
• Bilateral headaches precipitated by masturbation or
coitus, in the absence of any systemic or intracranial
disorder, such as subarachnoid hemorrhage.
• Three types are recognized:
– A dull ache in the head and neck that intensifies as sexual
excitement increases.
– A sudden, severe, explosive headache occurring at orgasm.
– A postural headache, resembling that of low CSF
pressure, developing after coitus.
Other secondary or longer-lasting unilateral
headaches
Migraine (see p.95)
• Women are affected more commonly than men.
• Headache often lasts a lot longer, up to 72 hours.
 Cluster Headache (Migrainous Neuralgia)
• Migraine causes people to want to remain still in a quiet
dark room whereas cluster headache is so severe that
patients often pace the floor restlessly or wander
outdoors to seek relief in the cold night air.
Giant cell (cranial) arteritis (see p.234)
• Age >50 years at onset.
• New onset of localized headache, that may be unilateral,
bilateral or occipital.
• Claudication of the jaw or tongue during eating.
• Symptoms of systemic upset (fever, sweats, malaise,
weight loss, polymyalgia).
• Scalp and temporal artery tenderness or decreased
temporal artery pulse.
• Elevated ESR >50 mm/hour.
• Biopsy showing necrotizing arteritis.
• Responds within 24 hours of commencing prednisolone
60 mg/day.
Glaucoma
• Recurrent attacks of pain in the eye and forehead, that
may be precipitated by sitting in the dark, mydriatics or
emotional upset.
• Accompanying features include vomiting, visual
impairment, cloudiness of the cornea, discoloration of
the iris, a dilated pupil and circumcorneal injection.
• An arcuate scotoma and pallid cupped disc are charac-
teristic of narrow-angle glaucoma, which is often familial.
• Tonometry is necessary to confirm elevated intra-ocular
pressure.
Acute sinusitis (frontal, ethmoidal, maxillary)
• A dull, aching, throbbing pain over the affected sinus,
worse on bending or with the head in a certain position
in bed.
• The pain is temporarily eased by decongestant nasal drops
and antibiotics and seldom lasts more than 1–2 weeks.
• Usually associated with coryza and purulent nasal
discharge.
Cervicogenic headache (see p.101)
Facial trauma with soft tissue injury
Pituitary adenoma (see p.379)
Pseudoaneurysm within the cavernous sinus (see pp.354, 508)
Ipsilateral vertebral artery aneurysm (see p.249)
Occipital lobe arteriovenous malformation (see p.245)
Upper cervical meningioma (see p.375)
INVESTIGATIONS
Nil usually, unless secondary causes of headache need to be
excluded: blood count (thrombocythemia), ESR (cranial
arteritis), chest x-ray (pancoast tumor), vasculitic
investigations, and CT or MRI brain scan. Should the pain
become bilateral, a lumbar puncture may be indicated to
exclude intracranial hypertension.
DIAGNOSIS
Diagnostic criteria
Episodic
A At least 5 attacks fulfilling criteria B–D.
B Severe, unilateral orbital, supraorbital and/or temporal
pain lasting 15–180 minutes if untreated.
105
C Headache associated with at least one of the following
signs which have to be present on the painful side:
conjunctival injection, lacrimation, nasal congestion,
rhinorrhea, forehead and facial sweating, miosis, ptosis,
eyelid edema.
D Incidence of attacks ranging from one attack on alternate
days to 8 attacks/day.
E History and/or physical and neurologic examinations do
not suggest other disorders associated with head trauma.
Chronic
Attacks occur for more than 1 year without remission, or
with remission lasting less than 14 days. The attacks are
clinically indistinguishable from episodic cluster headache.
TREATMENT
Acute attack
• Oxygen 100% at 6–8 l/min often affords relief within
10 minutes, or
• Sumatriptan 100 mg po or 0.6 mg subcutaneous
injection (a 5-hydroxytryptamine (5HT1D) receptor
agonist) aborts the pain in most cases.
Prophylactic
During the susceptible period, regular medication can be
taken in anticipation of attacks:
• Ergotamine tartrate 1–2 mg (e.g. one-half of a 2 mg
suppository) daily, or as a nocturnal dose.
• Methysergide 1–2 mg three times daily, as for migraine,
if ergotamine is ineffective.
• Verapamil 40–120 mg tds for the duration of the cluster
(e.g. 14 days).
• Prednisone 50 mg daily, for 3 days and then reduced
rapidly to a dose (usually about 25 mg a day) that is just
sufficient to prevent the attacks. This is effective in about
80% of cases in whom it should be maintained for the
duration of the bout before weaning off slowly.
Chronic cluster headache
• Lithium carbonate, 250 mg two or three times daily, the
dose being adjusted to maintain a blood level of
0.5–1.2 mmol/l. Adverse effects include confusion and
tremor.
• Verapamil in large doses.
Chronic paroxysmal hemicrania
• Indomethacin, 25 mg three times daily, increasing to 50
mg tds after 1 week if there is no response. Occasional
patients require higher doses or slow-release
indomethacin preparations at night to treat break
through headaches.
• Other agents that may be effective include naproxen,
calcium channel blockers such as verapamil,
acetazolamide 250 mg tds, and possibly oxygen for
longer attacks.
CLINICAL COURSE
The headaches usually recur once or twice a day, often at
night, for a period of 4 weeks to 4 months. Remission is
then usual, until the next cluster ensues, months or
1–2 years later.
106
FURTHER READING
HEADACHE
Goadsby PJ (1999) Short-lasting primary
headaches: focus on trigeminal autonomic
cephalgias and indomethacin-sensitive
headaches. Curr. Opin. Neurol., 12: 273–277.
Lance JW (2000) Headache and face pain. Med. J.
Aust., 172: 450–455.
Van Gijn J (1999) Pitfalls in the diagnosis of sud-
den headache. Proc. R. Coll. Physicians. Edin.
29: 21–31.
MIGRAINE
Bahra, Matharu MS, Buchel C et al. (2001) Brain-
stem activation specific to migraine headache.
Lancet, 357: 1016–1017.
Bateman DN (2000) Triptans and migraine.
Lancet, 355: 860–861.
Boyle CAJ (1999) Management of menstrual mi-
graine. Neurology, 53 (Suppl 1): S14–S18.
Ducros A, Denier C, Joutel A, et al. (2001) The
clinical spectrum of familial hemiplegic mi-
graine associated with mutations in a neuronal
calcium channel. N. Engl. J. Med., 345:
17–24.
Ferrari MD (1998) Migraine. Lancet, 351:
1043–1051.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ
(2001) Oral triptans (serotonin 5-HT1B/1D
agonists) in acute migraine treatment: a meta-
analysis of 53 trials. Lancet, 358: 1668–1675.
Gervil M, Ulrich V, Kyvik KO, et al. (1999) Mi-
graine without aura: a population-based twin
study. Ann. Neurol., 46: 606–611.
Goadsby PJ, Ferrari MD, Olesen J, et al. for the
Eletriptan Steering Committee (2000) Eletrip-
tan in acute migraine: A double-blind, place-
bo-controlled comparison to sumatriptan.
Neurology, 54: 156–163.
Goldstein DJ, Roon KI, Offen WW, et al. (2001)
Selective seratonin 1F (5-HT 1F) receptor ag-
onist LY334370 for acute migraine: a ran-
domized controlled trial. Lancet, 358:
1230–1234.
Headache
Hand PJ, Stark RJ (2000) Intravenous lignocaine
infusions for severe chronic daily headache.
Med. J. Aust., 172: 157–159.
Hoffman EP (2001) Hemiplegic migraine –
downstream of a single-base change. N. Engl.
J. Med., 345: 57–59.
Launer LJ, Terwindt GM, Ferrari MD (1999) The
prevalence and characteristics of migraine in a
population-based cohort. The GEM study.
Neurology, 53: 537–542.
Montagna P (2000) Molecular genetics of mi-
graine headaches: A review. Cephalgia, 20:
3–14.
Silberstein SD, for the US Headache Consortium
(2000) Practice parameter: Evidence-based
guidelines for migraine headache (and evi-
dence-based review). Neurology, 55: 754–763.
Tfelt-Hansen P, Saxena PR, Dahlof C, et al.
(2000) Ergotamine in the acute treatment of
migraine. A review and European consensus.
Brain, 123: 9–18.
Ulrich V, Gervil M, Kyvik KO, et al. (1999) Evi-
dence of a genetic factor in migraine with aura:
A population-based Danish twin study. Ann.
Neurol., 45: 242–246.
MUSCLE CONTRACTION/TENSION-TYPE
HEADACHE
Goadsby PJ (1999) Chronic tension-type
headache: where are we? Brain, 122:
1611–1612.
Hand PJ, Stark RJ (2000) Intravenous lignocaine
infusions for severe chronic daily headache.
Med. J. Aust., 172: 157–159.
Holroyd KA, O’Donnell FJ, Stensland M, et al.
(2001) Management of chronic tension-type
headache with tricyclic antidepressant medica-
tion, stress management therapy and their
combination. A randomized controlled trial.
JAMA, 285: 2208–2215.
Ostergaard S, Russell MB, Bendtsen L, Olesen J
(1997) Comparison of first degree relatives
and spouses of people with chronic tension
headache. BMJ, 314: 1092–1093.
Russell MB, Ostergaard S, Bendsten L, Olesen J
(1999) Familial occurrence of chronic tension-
type headache. Cephalgia, 19: 207–210.
Schwartz BS, Stewart WF, Simon D, Lipton RB
(1998) Epidemiology of tension-type
headache. JAMA, 279: 381–383.
Tomkins GE, Jackson JL, O’Malley PG, et al.
(2001) Treatment of chronic headache with
antidepressants: a meta-analysis. Am. J. Med.,
III: 54–63.
Welch KMA (2001) A 47-year-old woman with
tension-type headaches. JAMA, 286:
960–966.
CLUSTER HEADACHE
Ekbom K (1991) Treatment of acute cluster
headache with sumatriptan. N. Engl. J. Med.,
325: 322–326.
Goadsby PJ, Edvinsson L (1994) Human in vivo
evidence for trigeminovascular activation in
cluster headache. Brain, 117: 427–434.
Goadsby PJ, Lipton RB (1997) A review of parox-
ysmal hemicranias, SUNCT syndrome and
other short-lasting headaches with autonomic
feature, including new cases. Brain, 120:
193–209.
Leone M, D’Amico D, Frediani F, et al. (2000)
Verapamil in the prophylaxis of episodic clus-
ter headache: A double-blind study versus
placebo. Neurology, 54: 1382–1385.
May A, Bahra A, Büchel C, Frackowiak RSJ,
Goadsby PJ (1998) Hypothalamic activation
in cluster headache attacks. Lancet, 352:
275–278.
 Chapter Five
Vertigo
VERTIGO
DEFINITION
An illusion of movement.
EPIDEMIOLOGY
Incidence: very common.
ETIOLOGY AND PATHOPHYSIOLOGY
Peripheral (most common)
Inner ear (semicircular canals, utricle, saccule)
• Benign paroxysmal positional vertigo (25% of cases).
• Vestibular neuronitis (‘viral’ labyrinthitis).
• Ménière’s disease.
• Benign recurrent vertigo.
• Trauma (including perilymph fistula): head injury.
• Infection: otitis media, syphilis.
• Vascular lesions.
Vestibular nerve
• Meningitis.
• Acoustic neuroma and other cerebello-pontine angle
tumors (usually cause unsteady gait and rarely cause
vertigo, particularly if there is no deafness).
• Ototoxins: aminoglycosides, frusemide (furosemide)
(cause imbalance rather than vertigo).
Central
• Tumors (usually posterior fossa).
• Vertebro-basilar ischemia (but may also cause infarction
of the labyrinth): cerebellar or brainstem infarction.
• Vascular malformation in brainstem (VIII nucleus)
• Multiple sclerosis involving brainstem.
• Trauma to brainstem.
• Basilar migraine (may also cause end organ or peripheral
involvement).
• Arnold–Chiari malformation.
• Syringobulbia.
• Drugs (alcohol, anti-epileptic drugs, barbiturates).
• Complex partial seizures can cause vertigo but almost
always with other more typical symptoms.
• Vertigo is rarely, if ever, due to cervical spondylosis.
CLINICAL FEATURES AND DIAGNOSIS
‘Doctor, I’m dizzy’ is one of the most common symptoms
in neurologic practice.
Is it vertigo or another cause of dizziness such as
pre-syncope?
• Encourage the patient to describe the dizzy sensation in
their own words.
• A symptom of relative movement, whether it is one of self
or of the environment, is usually indicative of vertigo and
107
of an underlying vestibular pathology. A sensation of
spinning is the most commonly described vertiginous
symptom, and is attributed to semicircular canal involve-
ment. Linear sensations of rocking, tilting and sudden
dropping are also valid descriptors of vertigo and probably
reflect involvement of the otolith organs (utricle and
saccule) which sense linear motion.
• Vertigo due to a vestibular disorder tends to be episodic,
and triggered or aggravated by head movements, rather
than postural changes alone. Conversely, constant dizziness,
persisting for months and years, that is not associated with
or aggravated by head movements does not usually have a
primary vestibular cause; more commonly it has a
psychiatric basis. Moving or large field visual stimuli, such
as large cinema screens and supermarket aisles, may induce
visual vertigo. Sometimes this leads to secondary
agoraphobia (e.g. avoidance of large shopping complexes)
and a misdiagnosis of a primary psychiatric disorder.
• Associated symptoms include nausea, vomiting and
ataxia, due to the vertigo. The risk of psychologic
complications, such as panic disorder and depression
increases in proportion to the chronicity of vestibular
symptoms. This makes assessment difficult as an
underlying vestibular disorder may be overlooked in
patients with prominent psychiatric complaints.
• If doubt remains after taking the history, reproduce in
the patient the sensations of physiologic vertigo (rotation
on the spot with eyes closed) and lightheadedness
(hyperventilation) which can be compared with the
patient’s presenting symptoms.
Is the vertigo due to a peripheral (labyrinthine) or
central (CNS) lesion?
A neurologic examination targeted to an assessment of
standing and walking balance, eye movements, hearing,
otoscopy, and the Dix–Hallpike maneuver is important to
elicit focal neurologic signs and exclude central pathology.
Labyrinthine
• Vertigo generally more prominent than ataxia and
nystagmus (exception: bilateral vestibular failure).
• Auditory symptoms common.
• Nystagmus, typically a mixed torsional (ocular motion in
the frontal plane, sometimes incorrectly referred to as
rotatory) and horizontal nystagmus that beats away from
the side of the lesion, is readily suppressed by visual
fixation and abates quickly as the acute vertigo settles.
• No focal neurologic features.
• Positive Dix–Hallpike maneuver in patients with benign
positional vertigo (see p.110): mixed torsional and
upbeating nystagmus begins after a short latent period,
is accompanied by moderately severe vertigo, fatigues
after up to 30 seconds, and is often less marked with
repeated maneuvers (habituation).
108 Vertigo
CNS
• Ataxia and nystagmus are often more prominent than
vertigo. Vertigo may occasionally be severe, as in lateral
medullary infarcts.
• Auditory symptoms rare.
• Focal neurologic features may be present (e.g. diplopia,
dysarthria, dysphagia, visual field loss, hemisensory or
hemimotor disturbance).
• Nystagmus may be unidirectional, bidirectional, or
vertical (upbeating or downbeating).
• Other central eye movement abnormalities are often
present (e.g. gaze palsy, skew deviation [vertical misalign-
ment of the eyes]).
What is the cause of the vestibular lesion?
Duration of vertigo
• Attacks lasting seconds only, particularly if they are
associated with head movements or postural changes, are
highly suggestive of either an uncompensated peripheral
vestibular lesion or benign positional vertigo (see p.110).
• Episodes lasting minutes may occur in migraine and,
rarely, vertebro-basilar ischemia.
• Vertigo of hours duration occurs in conditions such as
Ménière’s disease (see p.111).
• Vertigo that develops over several hours and gradually
resolves over a period of days to weeks is typical of
vestibular neuronitis (see p.111).
Associated features
Other clinical features associated with the vertigo are often
a clue to the cause (see below).
Migraine
• A common cause of vertigo, particularly in younger age
groups.
• May occur as an aura preceding a migraine headache, or
even as an isolated phenomenon (benign recurrent
vertigo).
• Rarely, patients can present with chronic fluctuating
spontaneous and positional vertigo, punctuated by
intermittent headaches.
Vertebrobasilar ischemia
• Rarely presents with isolated vertigo.
• Very occasionally a patient presents with intermittent,
isolated vertigo of minutes duration but this does not
usually persist as the sole manifestation for prolonged
periods. Generally, there are other focal neurologic
symptoms present.
• Likewise, exceptional patients with cerebellar infarcts may
present with apparently isolated vertigo, however the
degree of gait ataxia is usually more severe and prolonged
than would be expected from the nature of the vertigo.
• These patients are usually much older and often have
multiple vascular risk factors compared with the typical
patient with vestibular neuronitis.
• Contrary to previous claims, vertigo that is triggered by
head extension is almost never due to vertebral artery
occlusion by cervical osteophytes. Most patients with
head-extension vertigo have peripheral vestibular
disorders, particularly benign positional vertigo.
Multiple sclerosis
• Demyelination in the brainstem, involving the VIII
nucleus, may cause an acute vestibulopathy that may
superficially resemble vestibular neuronitis.
• A careful history and examination will usually detect
other CNS features of demyelination (see p.340).
Acoustic neuromas
• Arise from the vestibular nerve (hence are more correctly
termed vestibular schwannomas) but do not usually
present with vestibular symptoms because of the very
gradual loss of vestibular function that allows central
compensation.
• The most common presentation is with unilateral tinnitus
and hearing loss (see p.383).
Multi-sensory dizziness or disequilibrium
• A syndrome which tends to occur in the elderly and
manifests with disequilibrium and vague, non-specific
dizziness when walking.
• It is a deafferentation syndrome caused by multiple
sensory deficits such as visual impairment, peripheral
neuropathy, vestibular deficits and cervical spondylosis.
• Patients often have lower limb orthopedic impairments
that will accentuate the disability.
• An important syndrome to recognize because sedative
and vestibular suppressant drugs have the potential to
exacerbate the problem.
Bilateral vestibular failure
• Most commonly caused by aminoglycoside antibiotics
such as gentamicin ototoxicity, which may have occurred
in the setting of non-toxic blood levels and normal renal
function.
• Ataxia and motion-induced oscillopsia are the usual
presenting symptoms.
• Oscillopsia is a to-and-fro movement of the visual
environment which, in this instance, is due to failure of
the vestibulo-ocular reflex. These symptoms do not
usually become apparent until the patient starts to
mobilize and for this reason the diagnosis is often not
made until after the patient is discharged from hospital.
• Vertigo is not a common or pronounced feature because
the vestibular loss is almost always bilateral and symmetric.
Perilymph fistula
• An abnormal communication between the perilymph
compartment of the inner ear and middle ear caused by
a labyrinthine rupture in the region of the round or oval
windows.
• May be associated with head injury, barotrauma or
middle ear surgery.
• Presenting symptoms include fluctuating hearing loss,
ataxia, episodic vertigo (often triggered by exertion or
Valsalva maneuver), tinnitus and aural pressure.
• The diagnosis is often difficult to make. A positive fistula
test accompanied by vertigo and nystagmus in response
to pressure insufflation of the ear canal may suggest the
diagnosis but is neither specific nor sensitive.
• Surgical exploration is often required when the index of
suspicion is high, particularly if there is significant hearing
loss.
 Vertigo
DIFFERENTIAL DIAGNOSIS
Lightheadedness or presyncope (see p.59)
• Postural hypotension.
• Cardiac arrhythmia.
• Impaired cardiac output.
• Vaso-vagal attacks.
• Hyperventilation and anxiety.
• Anemia.
• Hypoglycemia.
Other
• Migraine (see p.95).
• Complex partial seizure (see p.69).
• Vertebrobasilar ischemia (see p.181).
INVESTIGATIONS
• CT brain scan. If central pathology is suspected, CT is
used, but it may miss some pathologies, such as
demyelination and ischemia. Specific contrast imagery
should only be used if there are auditory features to
suggest VIIIth nerve pathology.
• MRI brain scan. If CT is negative and central pathology
still suspected, MRI can be used.
• Audiometry. To document the presence and patterns of
hearing loss.
• Brainstem auditory evoked potentials (see p.42). These
have traditionally been used to exclude VIIIth nerve and
brainstem pathology, however MRI is now the gold
standard.
• Other tests of vestibular function, such as caloric and
rotational chair testing, may be indicated.
• Otorhinolaryngologic (ear, nose and throat) assessment.
This should be considered if there are significant auditory
signs (hearing loss, tinnitus pressure or aural fullness,
particularly if asymmetric), or signs of suppurative middle
disease.
CLINICAL COURSE
Sudden unilateral loss of vestibular function usually causes
acute, severe vertigo that persists for hours to days. Even
without recovery of the underlying vestibular deficit,
resolution of the severe disabling symptoms occurs as a
result of equilibration of the tonus in the brainstem
vestibular nuclei via the CNS process known as compensation.
During this recovery period the spontaneous symptoms
resolve, but patients may continue to complain of short-
lived episodes of vertigo induced by head or body motion.
Persistent motion-induced symptoms following an acute
vestibular insult reflect incomplete central compensation. In
contrast, recurrent spontaneous episodes of vertigo indicate
an unstable vestibular lesion resulting from active underlying
pathology. Such conditions demand specific medical or
surgical treatment.
TREATMENT
General
• Reassure the patient that, although the symptoms are
severe, the underlying cause is often not dangerous.
109
• Vestibular suppressant drugs should be reserved for the
treatment of acute vertigo that is accompanied by severe
autonomic or vegetative symptoms. Suitable drugs
include prochlorperazine, promethazine and chlorpro-
mazine. Chronic treatment with vestibular suppressant
drugs should be avoided if possible because of the risk of
development of drug-induced Parkinsonism and tardive
dyskinesia (see p.129). There is also some anecdotal
evidence that prolonged drug therapy may retard the
process of CNS compensation.
• Physical treatment programmes are often helpful for
patients with persistent motion-induced vertigo following
an acute vestibular insult who have failed to compensate
fully. Customized vestibular rehabilitation programmes are
often more effective than generic techniques such as the
Cawthorne–Cooksey exercises. Exercise programmes are
designed to induce the symptoms and, by a process of
habituation, are able to promote central compensation and
thereby reduce the persistent symptoms.
• Treatment of psychiatric complications is important and,
for this reason, a psychologist is a useful member of the
vestibular rehabilitation treatment team.
• Urgent referral to an otorhinolaryngologist is indicated if
auditory or vestibular symptoms are triggered by pressure
changes (barotrauma or Valsalva maneuver), a feature
which suggests the possibility of a perilymph fistula.
Migraine (see p.95)
• Anti-migraine therapy can lead to a dramatic relief in
some cases. In otherwise unexplained cases of recurrent
vertigo, an empirical trial of prophylactic migraine therapy
(e.g. pizotifen (pizotyline), propanolol and verapamil) is
often indicated, particularly if there is a history of
headache.
• The vertiginous aura of migraine does not respond to
interval therapy with drugs such as ergotamine or the
triptans.
Ménière’s disease (see p.111)
• Can be problematic to treat.
• Salt restriction and diuretic therapy are the major medical
treatment modalities.
• Betahistine, a vasodilator, can also be helpful. It has been
proposed that this medication improves blood flow to
the inner ear though the exact mechanism of action
remains unclear.
• Surgery is sometimes indicated when medical therapy
fails.
– The rationale for endolymphatic sac decompression is to
reduce the pressure in the endolymph compartment.
– Labyrinthectomy or vestibular nerve section is often
performed when sac surgery fails, but is reserved for
unilateral cases.
– More recently, local gentamicin ablation via a series of
injections into the middle ear cavity, has proved to be a
useful and less invasive management option.
Multi-sensory dizziness or disequilibrium
• Avoid sedative and vestibular suppressant drugs which
may exacerbate the problem.
• Balance rehabilitation programs may improve function.
110 Vertigo
BENIGN PAROXYSMAL
POSITIONAL VERTIGO
DEFINITION
Episodic rotational vertigo of brief duration induced by
head movement.
EPIDEMIOLOGY
• Incidence: at least 10 per 100 000 per year. One of the
most common vestibular conditions, accounting for
more than 25% of presentations in patients with
peripheral vestibular disorders.
• Age: occurs predominantly in older age groups with a
mean age of onset of 55 years.
• Gender: men and women are affected equally.
ETIOLOGY AND PATHOPHYSIOLOGY
Most cases in the elderly are due to cupulolithiasis of the
posterior semicircular canal. Degenerated otoconial deposits or
crystals, which are thought to arise from the utricular matrix,
form a heavy mass of sediment in the posterior semicircular canal
and, in response to a provocative head movement, result in
excessive displacement of the sensory organ, or cupula, via a
plunger effect. A predisposing cause is identified in a small num-
ber of patients: head trauma: 15%; vestibular neuronitis: 18%.
CLINICAL FEATURES
• Brief episodes of rotational vertigo occur associated with
specific head positions such as head extension, lying
down or turning over in bed.
• There is a latency of up to 45 seconds before symptoms
begin.
• Vertigo lasts for less than a minute.
• Symptom fatiguability occurs with repeated head movement.
• Vertical-torsional nystagmus accompanies the vertigo.
• Dix–Hallpike maneuver.
In the Dix–Hallpike maneuver the head of the sitting patient
is tipped back and rotated 45° to one side, and the patient is
moved briskly to the supine position so that the head remains
at about 45° below the horizontal. It has been traditionally
taught that the head is positioned over the edge of the couch,
but it is easier to perform and more comfortable for the patient
if the head is positioned over the back of a pillow. The patient is
instructed to report any vertigo and to keep their eyes open.
After a short latent period of up to 5 seconds or more, the
patient with a positive test complains of vertigo and manifests
nystagmus which is a mixed upbeating and torsional nystagmus
that fatigues up to 30 seconds later. The patient is then moved
quickly to the sitting position with the head kept in the same
plane. The nystagmus may reverse in this position. The
maneuver is then repeated with the head turned 45° in the
opposite direction. The vertigo and nystagmus is often less
marked with repeated maneuvers (habituation).
Nystagmus that does not have all of these characteristics
may be seen in unusual variants of benign positional vertigo
involving semicircular canals other than the commonly
involved posterior canal, but can also be a rare presenting
feature of central lesions in the posterior fossa (e.g. non-
fatiguing downbeating nystagmus). A positive Dix–Hallpike
maneuver requires the presence of a typical nystagmus
response. The complaint of dizziness without associated
nystagmus during positional testing is non-specific in nature.
DIFFERENTIAL DIAGNOSIS
• Post head trauma vertigo.
• Ménière’s disease.
• Vestibular neuronitis.
• Migraine.
• Complex partial seizure.
• Vertebrobasilar ischemia.
INVESTIGATIONS
Electronystagmography shows a reduced vestibular response
on the affected side.
DIAGNOSIS
This is usually a clinical diagnosis. The Dix–Hallpike maneuver
will induce, after a latent interval of 1–2 seconds, vertigo and
mixed torsional and vertical nystagmus will be observed. The
nystagmus and vertigo increase and then decline over a period
of 10–20 seconds. If the Dix–Hallpike test is repeated the
vertigo and nystagmus are reduced (i.e. fatiguability). Tests such
as electronystagmography are used only occasionally.
TREATMENT
Acute episodes
• Meclizine 25–50 mg 3 times/day.
• Diazepam 5–10 mg 1–3 times/day.
• Anti-emetics such as prochlorperazine 25 mg suppository.
Recurrent episodes
Physical exercise therapy: The principle of this treatment is to
have the patient repeat head movement maneuvers in order to
induce adaptation of the symptoms. The repeated head
movement is thought to induce loosening and dispersion of the
sediment in the cupula of the posterior semicircular canal. One
form of physical therapy described in 1988 (the liberatory
maneuver) involves moving the seated patient quickly from
sitting to lying with the affected ear down, then quickly over so
the other ear is down, and then back to the sitting position.
Another form of therapy (the canalith repositioning
procedure) involves a 5-position cycle in which the patient’s
head is moved about in such a way as to displace theoretically
any loose material in the posterior semicircular canal into the
utricle of the vestibular labyrinth. The first step is to move
the patient from a sitting to a reclining position, and extend
the patient’s head over the end of the table at a 45° angle.
The second step is to turn the patient’s head to the opposite
side. The next step is to roll the patient over onto that side.
The head is slightly angled while the patient is looking down
at the floor. The fourth step is to return the patient to a
sitting position. The final step is to tilt the patient’s chin
down. The time spent in each position is equal to the latency
plus the duration of the positional nystagmus observed
during the initial diagnostic Dix–Hallpike maneuver. The 5-
position cycle is repeated until no positional nystagmus is
elicited during any of the position changed or until a total of
five cycles has been performed.
A surgical procedure to plug, and effectively paralyse, the
offending canal is available but is rarely required.
CLINICAL COURSE AND PROGNOSIS
Spontaneous resolution occurs in most cases. Episodes may
last only a few days, but some patients can experience
recurrent episodes for 2 months or more. In some cases,
episodes occur recurrently for more than a year, and in
others it can persist chronically.
 Ménière’s Disease
VESTIBULAR NEURONITIS
DEFINITION
Acute onset of a usually singular episode of vertigo without
associated deafness or tinnitus. It is also known as acute
peripheral vestibulopathy, and vestibular neuritis.
EPIDEMIOLOGY
• Age: usually occurs in the fourth to sixth decades of life.
• Gender: M=F.
ETIOLOGY AND PATHOPHYSIOLOGY
• The aetiology is unknown, but is assumed to be viral in
most cases.
• A reactivation of herpes simplex virus type 1 (HSV-1)
infection is likely in some cases, based on recent studies
which have detected HSV-1 DNA in about 60% of
human vestibular ganglia and nuclei. The various patterns
of HSV-1 infection of vestibular structures are compatible
with virus migration from the vestibular ganglia to the
vestibular nuclei and from the ipsilateral to the
contralateral vestibular nucleus via commissural fibers.
CLINICAL FEATURES
• Vertigo that develops suddenly or over several hours
associated with nausea, vomiting and ataxia. Vertigo is
aggravated by any head movement.
• Torsional nystagmus to the side opposite the lesion is
observed.
• Hearing is preserved.
DIFFERENTIAL DIAGNOSIS
• Ramsay Hunt syndrome (herpes zoster infection of the
VIIIth cranial nerve).
• Post head trauma vertigo.
• Drug-induced vertigo, e.g. aminoglycosides.
• Internal auditory artery ischemia: may also cause a similar
syndrome, particularly in older age groups.
• Acute labyrinthitis: suspect when vertigo is accompanied
by prominent auditory symptoms. This can occur in its
bacterial form as a complication of suppurative middle
ear disease or as a result of viral infection.
INVESTIGATIONS
Electronystagmography shows a reduced vestibular response
on the affected side.
DIAGNOSIS
• Usually a clinical diagnosis. The Dix–Hallpike maneuver
will induce vertigo and torsional nystagmus will be
observed.
• Tests such as electronystagmography are used only
occasionally.
TREATMENT
• Meclizine 25–50 mg 3 times/day.
• Diazepam 5–10 mg 1–3 times/day.
• Anti-emetics such as prochlorperazine 25 mg suppository.
CLINICAL COURSE AND PROGNOSIS
Gradually resolves over a period of days to weeks in most
cases. Less than 10% of cases experience recurrent episodes.
111
MÉNIÈRE’S DISEASE
DEFINITION
• Recurrent episodes of severe vertigo associated with
unilateral hearing loss and tinnitus, with spontaneous
recovery within hours or days.
• Also known as endolymphatic hydrops.
EPIDEMIOLOGY
• Age: most frequent in the fifth decade of life.
• Gender: M=F..
ETIOLOGY AND PATHOPHYSIOLOGY
An increase in the volume of the endolymphatic fluid in the
semicircular canals. Most cases are idiopathic, but some
cases are attributed to acoustic trauma, congenital inner ear
abnormalities, syphilis, or vascular disorders associated with
hypertension or diabetes.
CLINICAL FEATURES
• Sudden onset of intense vertigo which may take many
hours to resolve.
• Unilateral tinnitus and decreased hearing associated with
a sensation of fullness and increased pressure in the ear.
• Horizontal-torsional nystagmus beating toward the
affected ear is observed.
• There may be a previous history of recurrent vertigo
accompanied by fluctuating auditory symptoms (tinnitus,
hearing loss and aural fullness). If so, the hearing may
have recovered between attacks but there is usually a
stepwise or gradual loss of hearing, classically involving
the low frequencies in the early stages.
• Drop attacks (otolithic crises of Tumarkin) can occur in
uncontrolled cases.
• Vestibular hydrops (recurrent vertigo without auditory
accompaniments) has been described, but this rarely
occurs as an isolated phenomenon for prolonged periods.
Many chronic cases of so called ‘vestibular hydrops’ have
other causes such as migraine.
DIFFERENTIAL DIAGNOSIS
• Post head trauma vertigo.
• Benign paroxysmal positional vertigo.
• Migraine.
• Complex partial seizure.
• Vertebrobasilar ischemia.
• Cogan’s syndrome.
INVESTIGATIONS
• Audiometry shows low frequency hearing loss initially,
with high frequency hearing loss occurring later.
• Electronystagmography shows a reduced vestibular
response on the affected side.
DIAGNOSIS
The diagnosis is primarily clinical with supportive evidence
from audiometry and electronystagmography.
112 Vertigo

TREATMENT • Medical labyrinthectomy using aminoglycoside drugs

Acute episodes given either systemically or intratympanically, can be used
• Meclizine 25–50 mg 3 times/day. in patients with either unilateral or bilateral disease.
• Diazepam 5–10 mg 1–3 times/day. • Sectioning of the VIIIth nerve on the affected side.
• Anti-emetics such as prochlorperazine 25 mg supposi- • Shunting procedure from the semicircular canals to the
tory. mastoid region and subarachnoid space.
• Salt restriction and diuretic therapy have been used to try
and prevent attacks, but there is no conclusive evidence CLINICAL COURSE AND PROGNOSIS
of their efficacy. • Recurrence of attacks is a hallmark of the disease.
• Many patients experience decremental hearing loss with
For severe cases recurrent episodes. Initially hearing loss in the low
For severe cases with recurrent disabling episodes unrelieved frequencies is observed. As the disease progresses, high
by medical therapy there are a number of options: frequency hearing loss is seen.
• Surgical labyrinthectomy is usually reserved for strictly • Contralateral involvement occurs in 20–30% of cases.
unilateral cases.

FURTHER READING BENIGN PAROXYSMAL POSITIONAL MÉNIÈRE’S DISEASE

VERTIGO
Brandt T, Bronstein AM (2001) Cervical vertigo.
J. Neurol. Neurosurg. Psychiatry, 71: 8–12.
Halmagyi GM, Cremer PD (2000) Assessment
and treatment of dizziness. J. Neurol. Neuro-
surg. Psychiatry, 68: 129–136.
Neuhauser H, Leopold M, von Brevern M, et al.
(2001) The interrelations of migraine, verti-
go, and migrainous vertigo. Neurology, 56:
436–444.
Sloan PD, Coeytaux RR, Beck RS, Dallara J
(2001) Dizziness: state of the science. Ann.
Intern. Med., 134: 823–832.
VERTIGO Saeed SR (1998) Diagnosis and treatment of
Froehling DA, Bowen JM, Mohr DN, et al. Ménière’s disease. BMJ, 316: 368–72.
(2000) The canalith repositioning procedure Vesterager V (1997) Tinnitus – investigation and
for the treatment of benign paroxysmal posi- management. BMJ, 314: 728–731.
tional vertigo: a randomised controlled trial.
Mayo Clin. Proc., 75: 695–700.
Furman JM, Cass SP (1999) Benign paroxysmal
positional vertigo. N. Engl. J. Med., 341:
1590–1596.
VESTIBULAR NEURONITIS
Arbusow V, Strupp M, Wasicky R, et al. (2000)
Detection of herpes simplex virus type 1 in
human vestibular nuclei. Neurology, 55:
80–882.
 Chapter Six 113

Movement Disorders
DYSTONIA ETIOLOGY
Dystonia is a symptom or sign of an inherited or acquired
brain disease, that usually involves the basal ganglia; it is not
DEFINITION a psychologic disturbance.
A syndrome of intermittent or continuous sustained muscle
contractions, frequently causing twisting and repetitive Inherited primary or idiopathic dystonias
movements or abnormal postures of virtually any part of the • Early-onset primary torsion dystonia (generalized):
body. – Autosomal dominant inheritance.
– Sporadic.
EPIDEMIOLOGY – X-linked.
Common, but the correct diagnosis is frequently delayed. • Adult-onset primary dystonia (focal).
• Incidence – focal dystonia: 1 (0.1–4)/100 000/year. • Dopa-responsive dystonia (Segawa disease).
• Prevalence (per million population): 391.
– Generalized dystonia: 62. Acquired secondary or symptomatic dystonias
Idiopathic: 34 (USA); 50 (Israel – Ashkenazi Jews). Drugs
Symptomatic: 28. • Dopamine receptor-blocking (antipsychotic/neuroleptic)
– Focal dystonia: 329. drugs: acute dystonic reactions and tardive dystonias.
Idiopathic: 296. • Dopaminergic (antiparkinsonian) drugs: dystonic dyskinesias.
Cranial dystonia (86). • Anti-epileptic drugs.
Spasmodic dysphonia (52). • Antidepressants.
Spasmodic torticollis (89).
Writer’s cramp* (69). Metabolic disorders
Symptomatic 33. • Wilson’s disease.
• Mitochondrial cytopathy.
* Writer’s cramp appears the most common in clinical • Leigh disease.
neurologic practice, and may have been underdiagnosed in • Glutaric aciduria.
prevalence studies. • Methylmalonic acidemia.
• Homocystinuria.
• Age: any age. • Metachromatic leukodystrophy.
• Gender: M=F. • Pelizaeus–Merzbacher disease.
• GM1 and GM2 gangliosidosis.
PATHOLOGY • Neuronal ceroid lipofuscinosis.
No consistent pathological changes have been identified in • Juvenile dystonic lipidosis.
primary dystonia, but when focal brain lesions are identified, • Lesch–Nyhan syndrome.
the basal ganglia (particularly the putamen) or rostral
midbrain are usually involved. Other neurodegenerative disorders
• Huntington’s disease.
PATHOPHYSIOLOGY • Parkinson’s disease.
One of the main neurophysiologic mechanisms of dystonia • Progressive supranuclear palsy.
is defective control of inhibitory interneurones in the • Multiple system atrophy.
cerebral cortex, brainstem and spinal cord. Functional • Hallevorden–Spatz disease.
imaging and animal model studies suggest reduced • Progressive pallidal degenerations.
inhibition of cortical motor output leads to the generation • Neuroacanthocytosis.
of excess motor activity during voluntary movement. Other • Ataxia telangiectasia.
studies have identified abnormal activation of group 1a • Familial basal ganglia calcification.
inhibitory interneurones in the spinal cord, with loss of
normal reciprocal inhibition, co-contraction of agonists and Cerebral palsy
antagonists, and tonic or phasic co-contraction. Genetic • Kernicterus.
studies have reaffirmed that dystonia is mostly inherited as • Perinatal brain injury.
an autosomal dominant condition with reduced penetrance. • Brain malformations.
A number of families with generalized and focal dystonia
have been described, and at least 12 different genotypes Trauma
identified to date. • Head trauma.
• Peripheral (limb and spine) trauma.
114 Movement Disorders
Infections
• Viral encephalitis.
• Cerebral toxoplasmosis.
Focal basal ganglia lesions
• Stroke.
• Brain tumor.
• Arteriovenous malformation.
• Toxins (exposure to manganese, carbon disulfide).
Toxins
• Manganese.
• Carbon disulfide.
• Wasp sting.
The chances of identifying an underlying pathologic
cause for dystonia depends on the age of onset and the
distribution of the dystonia (see below).
CLINICAL FEATURES
Dystonia
Muscle contractions that are prolonged (often twisting a
part of the body into characteristic postures), and
commonly intermittent (causing repetitive, often rhythmic
jerks into dystonic postures) but are sometimes continuous,
causing constant twisted postures.
Initially, movements and postures appear only during
specific movements (action dystonia) and subside with rest.
Voluntary movements are accompanied by ‘overflow’ of
muscle spasms and dystonic postures spreading to adjacent
muscle groups not normally recruited in the task. If the
syndrome progresses (as is common with children but rare in
adults), the initial action dystonia becomes evident at rest and
then spreads to affect other parts of the body. Dystonia is
therefore usually considered a ‘mobile’ movement disorder
because fixed postures and persistence of dystonia at rest occur
only in severe, advanced dystonia and hemiplegic dystonia.
Associated rhythmic postural tremors and myoclonus
(jerky movements), at about 3 Hz or at faster rates, similar
to those of benign essential tremor, are superimposed on
the dystonic postures in many patients. Combinations of
these movements frequently lead to misdiagnosis.
Spasms are relieved by ‘sensory tricks’ or ‘gestes
antagonistique’, in which tactile stimuli applied to or near
the affected body part relieve the muscle spasm. Movements
also disappear during rapid eye movement sleep and deep
(stage three and four) sleep.
HISTORY
The clinical features (and course) are determined by the
patient’s age, anatomic distribution of the dystonia and its
cause.
Age of onset
• Childhood-onset: commonly inherited and usually
autosomal dominant; an underlying pathologic cause can
be identified in up to about 40% of cases; dystonia usually
starts in the feet and legs, with a disorder of gait, and
progresses to become generalized or multifocal; speech
tends to be involved early. It progresses slowly over about
10 years from a focal action dystonia to a generalized
dystonia.
• Adolescent-onset: an underlying cause in 30% of patients;
intermediate progression.
• Adult-onset dystonia: usually sporadic; an underlying
cause in about 10% of patients; dystonia usually starts in
body parts other than the legs and frequently remains
focal or segmental; rapid progression.
Distribution of dystonia
• Typically, dystonia begins in one part of the body as a
focal action dystonia. The legs are commonly affected
first in children (onset before 13 years of age), less
commonly in adolescents (onset 13–20 years of age), and
very rarely in adults (onset after age 20 years). The
dystonia progresses to a multifocal or generalized
dystonia in about 60% of children, 35% of adolescents,
and 3% of adults.
• Hemidystonia: any age; an underlying pathologic cause
can be identified in over 80% of cases (usually a
structural basal ganglia lesion such as stroke, tumor or
AVM).
• Segmental, multifocal or generalized dystonia: commonly
inherited; an underlying cause in about 45% of patients.
• Focal dystonia: underlying cause found in less than 10%.
Etiology of dystonia
Drug-induced dystonia
Neuroleptic antipsychotics and anti-emetics produce two
types of dystonic reaction: acute dystonic reactions and
tardive dystonias.
• Acute dystonic reactions or oculogyric crises (see below)
follow exposure to D2 receptor antagonists (half of cases
occurring within 48 hours, and 90% within 5 days of
exposure) and most commonly in young men. The
dystonia particularly affects the eyes, jaws, neck and
trunk. Pre-treatment with anticholinergics reduces the
risk of oculogyric crises. Oculogyric crises resolve with
anticholinergics and withdrawal or reduction of the
offending drug.
• Tardive (‘delayed’) dystonia occurs in 1.5–2% of patients
receiving long term neuroleptic therapy. Less frequently,
levodopa, dopamine antagonists and selective serotonin
reuptake inhibitors may also produce dystonia. The latency
between drug exposure and onset of dystonia ranges from
3 weeks to 40 years, with 20% occurring in the first year.
Tardive dystonia most commonly affects the cranial, neck
and trunk muscles. Paradoxical dystonia (worse at rest and
relieved by movement) may occur. Treatment is based on
withdrawal of the offending drug if possible. Remission
rates are low (10–20%) and may take up to 5 years after
drug withdrawal. Treatment with tetrabenazine and
anticholinergics is helpful in about half of cases.
Past history of relevance
• Abnormal perinatal history.
• Delayed milestones.
• Precipitating illness.
• Seizures.
Family history of dystonia
PHYSICAL EXAMINATION
Physical signs which may be a clue to an underlying cause
of secondary dystonia:
• Intellectual impairment.
• Defects of vision, hearing, or sensation.
• Kayser–Fleischer rings (118).
 Dystonia
• Abnormalities of optic fundi or eye movements.
• Loss of postural reflexes.
• Pyramidal, cerebellar, or sensory signs.
• Hepato-splenomegaly.
SPECIAL SYNDROMES
Early onset primary torsion dystonia (generalized)
• Autosomal dominant inheritance.
• GAG deletion in DYT1 gene on chromosome 9 (9q34)
which codes for the ATP-binding protein torsin A.
• Penetrance: about 30-40%.
• Expression of dystonia in relatives: highly variable.
• Age of onset: 12.5 years (mean), 4–44 years (range).
• Onset: in one limb in 90% of patients; it is rare to begin
in the neck or larynx unless the onset is in adulthood.
The dystonia spreads to the trunk but rarely affects
cranial muscles. A past or family history of an action
tremor is common.
Adult-onset focal dystonia syndromes
Spasmodic torticollis (cervical dystonia)
• Torsion or tilting of the head due to sustained
contraction of neck muscles (119).
• Associated tremulous or jerky head movements are
common.
• Neck pain is common, affected muscles may
hypertrophy.
• Arm or oromandibular dystonia and blepharospasm
occur in a small percentage of patients.
Cranial dystonia
Blepharospasm:
• Bilateral orbicularis oculi muscle spasm results in inability
to maintain eye opening.
• Sometimes associated with cervical or oromandibular
dystonia.
Oromandibulfacial dystonia (Meige syndrome)
• Forceful opening, closure or lateral deviation of the jaw.
• Closure, pursing or retraction of lips.
• Protrusion of tongue.
Spasmodic dysphonia (laryngeal dystonia)
• Adductor spasm or vocal cords: strained speech, glottal
stops and variation of voice pitch.
118
118 Typical appearance of a corneal Kayser–Fleischer ring in Wilson’s
disease (arrows).
115
• Abductor spasm of vocal cords: whispering dysphonia
(rare).
• Spasm false vocal cords: inspiratory breathing dystonia.
Writer’s cramp (arm dystonia)
• Writing provokes stiffness, spasm or tremor of digits and
hand, with overflow of muscle activity to proximal arm
muscles.
• Resolves completely with cessation of writing.
• May affect other fine manual tasks in 25% of cases.
Dopa-responsive dystonia with diurnal variation
(Segawa’s disease)
• Autosomal dominant inheritance (5–10% of inherited
childhood dystonias) with reduced penetrance.
• Gene defects: several autosomal dominant mutations in-
volving the gene GCH1 coding for the enzyme guanine
triphosphate (GTP) cyclohydrolase I on chromosome
14q. The enzyme is involved in the synthesis of tetrahy-
drobiopterin (BH4) in the metabolic pathway manu-
facturing dopamine and serotonin. The clinical picture
results from dopamine deficiency. Other genetic defects
include autosomal recessive mutations in the gene for
tyrosine hydroxylase, which also interrupts dopamine
synthesis.
• Children and adolescents affected.
• F>M: 3:1.
• Lower limb dystonia: usually starts in the legs as an
equinovarus deformity causing walking difficulties.
• Fluctuates diurnally, being less in the morning and be-
comes worse as the day goes on, or becomes noticeable
in the afternoon and evening, particularly with exercise.
• Other features: postural instability; later progression to
a parkinsonian syndrome.
• Responds to small doses of levodopa.
• Many cases are misdiagnosed as ‘cerebral palsy’.
119
119 Photograph of a patient with focal cervical dystonia (spasmodic
torticollis). (Courtesy of Dr AM Chancellor,Tauranga, New Zealand.)
116 Movement Disorders
Paroxysmal kinesigenic dystonia
• Autosomal dominant inheritance.
• Childhood-onset.
• Brief (seconds to minutes) attacks of dystonia (or chorea)
precipitated by sudden movement, that occur several
times a day.
• Consciousness is preserved.
• Anti-epileptic drugs, such as carbamazepine and
phenytoin, are effective.
Paroxysmal non-kinesigenic dystonia
• Autosomal dominant inheritance.
• Childhood-onset.
• Infrequent episodes of dystonia without loss of
consciousness, which are not precipitated by movement,
and which last many minutes to hours.
• Clonazepam is sometimes effective.
Myoclonic dystonia
• Autosomal dominant inheritance.
• Childhood-onset.
• Dystonia combined with fast myoclonic jerks.
• Alcohol relieves the myoclonus but has less effect on the
dystonia.
Acute dystonic reactions
• Uncommon.
• Tends to affect children and adolescents more than adults.
• Usually drug-induced: occurs within a few hours (or less
often, days) after one or a few normal doses of:
phenothiazines (e.g. prochlorperazine, chlorpromazine);
butyrophenones (e.g. haloperidol); metoclopramide;
antihistamines; tetrabenazine; chloroquine; amodiaquine.
• Dystonia of head and neck muscles causing neck
retraction, opisthotonos, trismus, tongue protrusion,
spasmodic torticollis, choking and oculogyric crisis.
• Can be painful and is frightening.
• A family history of similar reactions may be present.
• Fever and tachycardia may be present.
• Differential diagnosis includes tetanus, but acute dystonia
often resolves in 1 or 2 hours or following i.v.
anticholinergic (e.g. benztropine 1–2 mg [lower dose in
children] or diazepam [5–10 mg i.v.]).
• A second exposure to the offending drug may be well
tolerated.
CLASSIFICATION
Dystonia may be classified according to age at onset,
anatomic distribution, or cause (primary, inherited, or
secondary, symptomatic dystonia).
According to age of onset
• Early onset primary torsion dystonia
• Adult onset focal dystonia
According to anatomic classification
Focal dystonia
Confined to only one part of the body. Examples include:
• Orbicularis oculi and neighboring facial muscles:
blepharospasm (involuntary spasms of eye closure).
• Jaw and mouth: oromandibular dystonia.
• Tongue: lingual dystonia.
• Pharyngeal muscles: dystonic dysphagia.
• Laryngeal muscles: laryngeal dystonia (spasmodic
dysphonia): vocal cord adduction, which gives rise to a
strangled speech, or vocal cord abduction, causing a
whispering dysphonia.
• Sternocleidomastoid, posterior neck, and indeed all
cervical muscles: cervical dystonia (spasmodic torticollis).
• Hand, forearm and arm: brachial dystonia (writer’s
cramp and other occupational cramps).
• Back and trunk: axial dystonia (causing scoliosis, lordosis,
kyphosis, or tortipelvis).
• Foot, leg and thigh: foot and leg dystonia.
Axial dystonia
Confined to neck or back.
Segmental dystonia
Involves ≥2 adjacent body parts. For example:
• Cranial dystonia (Meige or Brueghel’s syndrome):
combination of blepharospasm and oromandibular and
lingual dystonia.
• Craniocervical dystonia (cranial dystonia and spasmodic
torticollis).
• Craniocervical dystonia with dystonic arms.
• Oromandibular dystonia.
Hemidystonia
Confined to >1 body part (i.e. arm and leg) on the same
side; uncommon, caused by a structural lesion of the
contralateral basal ganglia.
Multifocal dystonia
≥2 non-contiguous parts (e.g. eyes, neck, and one leg):
• Dystonia responsive to levodopa.
• Myoclonic dystonia responsive to alcohol.
Generalized dystonia
Whole body, or most of it including all limbs and axial muscles.
Paroxysmal dystonia
• Paroxysmal kinesigenic dystonia responsive to anti-
epileptic drugs.
• Paroxysmal non-kinesigenic dystonia responsive to
clonazepam.
According to etiology (see Etiology, p.113)
DIFFERENTIAL DIAGNOSIS
(see Etiology, p.113)
Other movement disorders
• Wilson’s disease (see p.157).
• Huntington’s disease (see p.417).
• Parkinson’s disease (see p.420).
• Gilles de la Tourette’s syndrome (see p.130).
• Essential tremor (see p.119).
• Tardive dyskinesia (see p.129):
– Continuous involuntary choreiform movements of the
orobuccolingual and masticatory muscles.
– Present in about 20% of patients on long term
antipsychotic medication.
– Dopamine receptor hypersensitivity is probably responsible.
– Difficult to treat; withdrawal of the responsible
antipsychotic drug may induce a remission, but this can
take months or even years, and may be impractical if the
patient has a serious underlying psychiatric disorder.
 Dystonia 117

– Increased doses of dopamine antagonists (e.g. INVESTIGATIONS (see Table 16)

tetrabenazine) paradoxically may lead to improvement,
presumably by depleting presynaptic dopamine, but may
also cause depression.
– Baclofen, benzodiazepines, and calcium-channel blockers
may be effective; anticholinergic make tardive dyskinesia
worse.
• Psychological movement disorders.
• Exclude Wilson’s disease (see p.157) if onset is before
age 50 years: screen with slit lamp examination of the
eyes and serum ceruloplasmin. If any doubt, perform a
liver biopsy to measure the copper content.
• MRI of the brain if suspect basal ganglia structural lesions
(i.e. stroke, post-traumatic hemorrhage, tumor, AVM, or
metabolic or degenerative disorders) (120, 121).
• Blood or genomic DNA: PCR-RFLP of GAG deletion
in DYT1 dystonia gene on 9q34 (e.g. 128 bp fragment).

Table 16 Investigation of patients with dystonia 120

Idiopathic dystonia Symptomatic
dystonia
Onset in Onset in Onset at
childhood or adult life any age
adolescence
Blood
Full blood count and erythrocyte
sedimentation rate + + +
Urea and electrolytes, glucose, liver
function, calcium, phosphate + + +
Ceruloplasmin concentration + + +
Syphilis serology + + +
Antinuclear antibodies + +
Acanthocytes (neuroacanthocytosis) + +
Creatine kinase +
Uric acid +
Hypoxanthine-guanine
phosphoribosyltransferase activity +
Amino acid concentration +
White blood cell lysosomal enzymes +
Alpha-fetoprotein + 121
DNA analysis + + +
Urine
Amino acids (concentration) +
Organic acids +
Oligosaccharides +
Mucopolysaccharides +
24 hour copper excretion +
Cerebrospinal fluid + +
Biopsy
Skin +
Muscle (ragged red fibers of
mitochondrial cytopathy) +
Bone marrow +
Other
Slit lamp examination of the eyes
(Kayser–Fleischer rings) + + +
CT or MRI scan of the brain + + +
Nerve conduction studies and EMG + +
120, 121 Cranial CT scan (120) and MRI T2W
EEG + +
image (121) of a patient with right hemidystonia
Electroretinography +
showing a slit-like area in the left putamen (low
Evoked potentials + +
density on CT and high density on MRI, arrows)
* Wilson’s disease should be excluded in all patients with symptom onset representing necrosis due to previous hypertensive
before the age of 50 years hemorrhage.
118 Movement Disorders
DIAGNOSIS
• Is it dystonia? Clinical (see above).
• Is there a cause for the dystonia? Etiology, clinical and
laboratory investigations (see Table 16, above).
TREATMENT
Most dystonias can be controlled to some extent, often after
a trial of several medications (as with the treatment of
migraine), but their underlying cause cannot often be cured.
General
• Physiotherapy: helps prevent dystonic muscles developing
contractures.
• Speech and occupational therapy: provide aids to
communication and mobility. Mechanical braces are
usually not helpful and may lead to problems such as skin
ulceration as the dystonic spasms fight the constraint.
• Psychotherapy (supportive): often useful for this
distressing condition.
• Psychiatric assessment and intervention: if secondary
depression occurs.
Specific
Childhood- and adolescent-onset segmental, multifocal and
generalized dystonia
• Levodopa 100 mg and carbidopa 25 mg, one tablet
twice daily. Build up to two tablets three times daily for
3 months. If responsive, continue long term. N.B.
Adverse effects of long term levodopa that are seen in
Parkinson’s disease do not occur.
• Anticholinergic agents: if no response to levodopa, start
benzhexol (trihexyphenidyl) in low dose (2.5 mg twice
daily) and increase slowly (by 2.5 mg a day every 7–14
days) up to a dose that is effective or causes intolerable
adverse effects such as dry mouth, blurred vision, urinary
hesitancy, anorexia, weight loss, forgetfulness, confusion,
behavioral change, hallucinations and chorea. Young
people may tolerate doses up to 180 mg a day. About
half of patients benefit from anticholinergics.
• Benzodiazepines (e.g. diazepam), often in high dose,
seem to relax dystonic spasms.
• Baclofen, orally in high dose, or intrathecally in much
lower doses.
• Carbamazepine.
• Dopamine receptor antagonists and neuropletics such as
phenothiazines, haloperidol (2–6 mg/day), tetrabenazine
and pimozide (alone or in combination with
anticholinergic drugs or benzodiazepines) may dampen
down excessive movements by causing a degree of drug-
induced parkinsonism but they may also lead to tardive
dyskinesia. Tetrabenazine, which depletes the brain of
dopamine, carries less risk of inducing tardive dyskinesia
but it may cause depression.
• Risperidone (1.5–3 mg/day), a neuroleptic with high
affinity for 5-HT2 receptors, may be effective in patients
with idiopathic segmental dystonia partly insensitive to
haloperidol.
• Combination of low dose tetrabenazine (25 mg three
times daily), pimozide (gradually increasing the dose up
to 12 mg daily) and benzhexol (trihexyphenidyl)
(gradually increasing to the maximum tolerable dose).
Adult-onset focal dystonia
• Anticholinergic agents: effective in about one in five
people. Large doses (40–120 mg benzhexol [trihexy-
phenidyl] daily) may be required and a long latent
interval of weeks to months may elapse before improve-
ment occurs.
• Botulinum toxin A (BTX-A), injected in small doses into
the dystonic muscle(s), with or without EMG guidance,
is effective within 7–10 days in 80–90% of patients with
focal dystonias such as blepharospasm, spasmodic
torticollis, and spasmodic dysphonia. It is taken up by
peripheral nerve terminals and prevents calcium-
dependent release of acetylcholine, resulting in chemical
denervation and paralysis of the injected muscle, and
reduction or abolition of the dystonic spasms. The effect
lasts for about 2–4 months when terminal sprouting
restores muscle end plate neurotransmission. Up to 5%
of initially responsive patients may subsequently not
respond, due to incorrect storage of the toxin,
underdosing, injection of inappropriate muscles, a
worsening or change in the pattern of dystonia (possibly
with involvement of deep, inaccessible muscles),
development of contractures, altered perception of
response, and the development of immunity. Immunity
is associated with very frequent injections, ‘booster’
injections, and higher doses. Higher doses of BTX-F may
be effective with few adverse effects.
• Facial nerve section is a possible treatment of last resort
for blepharospasm in those in whom anticholinergic
drugs and botulinum toxin are ineffective and who are
prepared to have a permanent facial palsy, but it is
fortunately hardly ever done. Chemical myotomy is
another alternative.
• Peripheral nerve or root section for torticollis is rarely
indicated.
• Thalamotomy for stable hemidystonia can be useful but
bilateral thalamotomy for generalized dystonia is rarely
contemplated, mainly because of the risk of
compromising speech.
• Pallidotomy and pallidal stimulation are currently being
evaluated in the treatment of dystonia with encouraging
results.
Curative
Identify, treat and eliminate the underlying cause.
NATURAL HISTORY
• Primary (idiopathic) dystonia of childhood- or
adolescent-onset tends to progress in the first 5 years of
the illness, more slowly over the next 5 years and very
slightly, if at all, in adulthood.
• Idiopathic adult-onset focal dystonia does not tend to
progress.
• About 1 in 20 (5%) patients with any form of idiopathic
dystonia may experience a spontaneous improvement or
even resolution. This is most likely in the first 5 years of
the illness. Although subsequent relapses are common,
some patients experience remissions lasting years or
decades.
• The estimated risk for children or siblings of familial cases
developing clinical dystonia is about 20%; the risk for
sporadic cases is lower at about 8–14%.
 Essential Tremor (ET) 119

ESSENTIAL TREMOR (ET) • It is thought that the cerebellum introduces an error in

DEFINITION
A low frequency (4–9 Hz) postural tremor which is absent
at rest and not associated with the clinical signs of
parkinsonism or other neurologic deficits.
EPIDEMIOLOGY
• Incidence: 8 (95% CI: 4–14)/100 000/year.
• Prevalence (lifetime): 0.3–1.7%.
• Age of onset: bimodal: young adults (median about 15
years) and elderly.
• Gender: M=F.
PATHOLOGY
No characteristic pathological or biochemical findings.
ETIOLOGY
• Hereditary: autosomal dominant inheritance (50% of
patients) via a penetrant autosomal dominant gene. The
responsible gene(s) remain unknown.
• Sporadic: probably the same entity as hereditary ET.
PATHOPHYSIOLOGY
• Unknown.
• A central source of oscillation that is influenced by
somatosensory reflex pathways.
• Enhanced olivocerebellar oscillation and activation of
cerebellothalamocortical pathways probably have an
important role in the generation and transmission of the
tremor because:
– Functional imaging studies (PET and functional MRI)
reveal increased olivary glucose metabolism and increased
blood flow bilaterally in the cerebellum and red nuclei
and contralaterally in the globus pallidus, thalamus and
primary sensorimotor cortex of patients with essential
tremor.
– Lesions of the ipsilateral cerebellum diminish essential
tremor.
– Ventrointermediate thalamotomy or microstimulation
reduce tremor.
the timing of muscle bursts during voluntary movement,
and repeated corrective movements lead to tremor.
CLINICAL FEATURES
Tremor
• Postural or action tremor of the finger, hands and
forearms when they are held outstretched against gravity,
or used for specific, usually visually-guided, manual tasks
(‘position-specific postural tremor’).
• Variable kinetic component (tremor during any form of
movement).
• 4–12 cycles per second.
• Bilateral, but may be asymmetric.
• Other body parts involved in about half of cases: the
head (40%), tongue, lips, voice (15–20%), face, and
trunk; and postural tremor of lower limbs (15%).
• Visible.
• Persistent, but the amplitude may fluctuate.
• Exacerbated by emotional upset such as excitement and
anger.
• Improved temporarily by alcohol, in small quantities, in
about half of patients.
• Relatively longstanding (i.e. longer than 5 years).
• Froment’s sign (a rhythmic resistance to passive
movements of a limb about a joint when there is a
voluntary action of another body part).
DIFFERENTIAL DIAGNOSIS (see Tables 17, 18)
Intention or ‘terminal’ tremor due to
cerebellar disease
• Slower (3–5 cycles per second).
• Principally in a horizontal plane.
• Not present at rest.
• Increases with action and progressively increases during
a voluntary movement (terminal or intention tremor).
• Unlike kinetic tremor, which is tremor during any form
of movement; ‘intention’ or ‘terminal’ tremor is the
pronounced exacerbation of kinetic tremor toward the
end of goal-directed movement.
• The head may be affected, but usually as titubation
(repetitive nodding or ‘yes-yes’).
• May be incapacitating.
• Responds to propranolol and diazepam.

Table 17 Common tremors classified according to frequency and behavior

Frequency (Hz) Behavioral characteristics Disease locus Disease processes
2.5–3.5 Postural/kinetic Cerebellar/brainstem Alcoholic degeneration, multiple sclerosis,
trauma
4–5 Rest Substantia nigra/striatum Parkinson’s disease, drugs (neuroleptics,
?MPTP)
Rest/postural/movement/kinetic Red nucleus
Postural/kinetic Cerebellum
5.5–7.5 Postural/kinetic ?Cerebellum Essential tremor, Parkinson’s disease,
?Cerebrum–cerebellum drugs (valproate, lithium, antidepressants)
8–12 Postural/kinetic ?Cerebellum Enhanced physiologic tremor,
essential tremor, drug intoxications
120 Movement Disorders

Table 18 Common tremors classified according to clinical characteristics and distribution

Clinical characteristics Distribution Causes
Rest tremor Limbs, head, jaw Parkinson’s disease
Midbrain disease
Postural tremor Arms (when outstretched) Physiologic tremor
Essential tremor
Dystonic tremor
Cerebellar tremor
Neuropathic tremor
Task-specific action tremor During particular tasks Isolated voice tremor
Jaw tremor
Writing tremor
Intention tremor Approaching target Cerebellar disease
During purposeful movements Midbrain disease
Standing tremor Legs, trunk Orthostatic tremor

Parkinsonian tremor • Drug withdrawal:

• Typically 6 (3–7) cycles per second. Alcohol. Barbiturates.
• Present at rest. Benzodiazepines. Opiates.
• Not increased with posture or action. • Metabolic:
• Involves the limbs and head. Hypoglycemia. Metabolic encephalopathies.
• ‘Pill rolling’ character. Pheochromocytoma. Thyrotoxicosis.
• Exacerbated by emotion. • Exaggerated physiologic response:
• Responds to levodopa and anticholinergic medications. Anxiety. Fatigue.
Fright. Strenuous exertion.
Alcohol withdrawal
• 6–10 cycles per second. Management is directed to correction of the underlying
• Head and limbs involved. medical illness or cessation of any contributing drug. If
• Periodic: appears 8–12 hours after last drink. idiopathic EPT becomes inconvenient or socially
• Responds to diazepam and chlordiazepoxide. embarrassing, propranol may be helpful.

Metabolic derangements, such as thyrotoxicosis Primary orthostatic tremor

• 10–20 cycles per second. • Isolated, high frequency (14 Hz) bilaterally synchronous
• Head and upper limbs involved. tremor of legs and trunk when standing still.
• Symptoms and signs of metabolic disturbance. • May not be detected easily without palpation of the leg
• Responds to correcting metabolic disturbance. muscles.
• Patients may only complain of unsteadiness when
Enhanced physiologic tremor (EPT) standing.
A rapid 8–12 Hz small amplitude, barely visible, postural • Responds to clonazepam and, in some cases,
tremor, typically of the upper limbs, which occurs as a pramipexole; ET does not respond to clonazepam.
normal phenomenon during muscle contraction. EPT
manifests as a postural and kinetic hand tremor. It can be Isolated position-specific or task-specific tremors
difficult to distinguish between EPT and early stages of (including occupational tremors and primary
hereditary ET in a young person. There is no current writing tremor)
reliable way of making this distinction but the family history • Have the appearance of localized ET but the task
can be a clue. specificity of dystonia.
• May respond to anticholinergics.
Causes
• Drugs: Rubral tremor
Adrenergic drugs. Amiodarone. • A severe tremor with features of a parkinsonian rest
Amphetamines. Antipsychotic drugs. tremor and marked exacerbation during movement.
Caffeine. Cimetidine. • Not always associated with lesions of the red nucleus but
Corticosteroids. Cyclosporine A. may result from lesions of the ipsilateral cerebellar
Lithium. Oral hypoglycemics. dentate nucleus or superior cerebellar peduncle in the
Serotonin reuptake inhibitors. midbrain (dentato-rubral tracts).
Sodium valproate. Theophylline. • Most commonly seen in multiple sclerosis.
Thyroxine. Tricyclic antidepressants.
 Essential Tremor (ET)
Dystonia
• Highly asymmetric postural tremor is probably a form of
dystonia (see p.113).
• Isolated voice tremor may be due to laryngeal dystonia
and other dytonias of the vocal apparatus.
Psychogenic
• Unphysiologic variations in tremor frequency (>1 Hz).
• Unusual and inconsistent behavioral characteristics.
• Spontaneous remissions.
• Psychiatric or social factors (multiple somatizations,
secondary gain, litigation or compensation pending).
DIAGNOSIS
A clinical diagnosis based on the long duration of
symptoms; positive family history; lack of rigidity,
bradykinesia or other neurologic signs; symmetry; and
alcohol responsiveness.
Diagnostic criteria (predominantly for
research purposes)
Definite ET
• Characteristic bilateral tremor on maintaining posture,
typically of the outstretched upper limbs of more than 5
years duration. It is absent at rest, not made strikingly worse
with movement and is not associated with extrapyramidal
or cerebellar signs (see Clinical features, above).
• No definite evidence of sudden onset.
• No direct or indirect trauma to the brain, spinal cord or
relevant part of the peripheral nervous system in the
preceding 3 months.
• No recent exposure to tremorgenic drugs.
• Not in a state of drug withdrawal.
• Normal neurologic examination other than tremor.
• No history or clinical evidence suggestive of psychogenic
origins of tremor.
• No evidence of stepwise deterioration.
Probable ET
• Tremor: same as above (for definite ET).
• Duration more than 3 years.
• No evidence of isolated or localized tremors such as
primary orthostatic tremor, isolated voice tremor,
isolated position-specific or task-specific tremor, or
isolated tongue or chin tremor.
Possible ET
Type 1
Patients satisfy the criteria for definite or probable tremor
but exhibit other neurologic disorders (such as
parkinsonism, dystonia, myoclonus, peripheral neuropathy,
or restless legs syndrome) or other neurologic signs of
uncertain significance (i.e. hypomimia, decreased arm swing,
mild bradykinesia in isolation).
Type II
Monosymptomatic and isolated tremors of uncertain
relation to ET.
Task-specific tremors and isolated tremors of the voice,
tongue, head and legs have all been considered part of the
spectrum of ET but it may be that the label ‘ET’ is not
appropriate for these diverse disorders whose etiologies are
not yet known.
121
TREATMENT
Not all patients require treatment; only those severely
affected.
Medical
Propranolol and primidone have been shown in controlled
trials to afford a partial reduction in tremor amplitude in
about two-thirds of cases, and are the mainstay of treatment.
• Propranolol 10–40 mg mane or bd (up to about
240–320 mg/day), or metoprolol 25 mg twice daily
with 25 mg increments to effect or until a maximum of
50 mg three times daily, leads to variable improvement.
About half of patients experience a reduction in tremor
amplitude of up to 50%. The effect is greatest on postural
limb tremor. However, not all patients are helped and
the tremor is seldom abolished. There is little point in
prescribing a nocte dose. Adverse effects and relative
contraindications for propranolol include heart failure,
bradycardia, hypotension and asthma. The mechanism of
action of propranolol is thought to be blockade of
peripheral skeletal muscle β2 receptors. Selective β1
blockade is less effective than propranolol.
• Primidone (Mysoline) 50–250 mg daily if necessary, if
propranolol is ineffective or contraindicated. May be as
effective as beta blockers but adverse effects are common.
Care is required when introducing primidone because of
nausea, sedation and unsteadiness, which may be
sufficiently severe to warrant stopping the drug. A low
starting dose minimizes adverse effects, particularly if taken
in the evening before retiring. There appears to be no
added benefit to increasing the daily dose beyond 250 mg.
• Clonidine (an alpha adrenergic agent) in doses of
0.1–0.9 mg daily.
• Patients with alcohol responsive tremors may find
judicious use of alcohol to be helpful before social
engagements.
• Other drugs that may be helpful but also have adverse
effects include clonazepam (see Table 19), alprazolam,
flunarizine, clozapine, nicardipine and carbonic
anhydrase inhibitors such as methisnozole and
acetazolamide. Gabapentin is currently undergoing
evaluation for the treatment of tremor.
Table 19 Effective tremorlytic drugs
Disease/disorder Effective drugs
Enhanced physiologic β-blockers, alcohol
tremor
Essential tremor β-blockers, alcohol, primidone,
phenobarbitone (phenobarbital)
‘Kinetic-predominant’ Clonazepam
essential tremor
Primary orthostatic tremor Clonazepam
Parkinson’s disease Levodopa, dopamine agonists,
(rest tremor) anticholinergics, amantadine,
selegiline
Parkinson’s disease ?β-blockers, ?alcohol
(postural tremor)
Multiple sclerosis Isoniazid, clonazepam
122 Movement Disorders

Botulinum toxin CHOREA

Botulinum toxin can be injected locally into the splenius
capitus to reduce ‘no–no’ tremor without adverse effects
(e.g. weakness), but it does not work well when injected DEFINITION
into forearm muscles for wrist tremor (it causes wrist Involuntary, abrupt, irregular, arrhythmic and purposeless
weakness). movements of variable amplitude and usually involving the
face, hands and feet, which flow randomly from one body
Surgical treatment part to another.
• Stereotactic thalamotomy is usually employed only for
the most severe tremors because of the significant risks PATHOLOGY
of adverse effects (dysarthria, weakness, dysequilibrium, Basal ganglia lesions, such as infarction, hemorrhage, tumor,
and persistent paresthesia), particularly with bilateral and calcification, and caudate nucleus atrophy (Hunting-
operations. About 70–90% of patients experience some ton’s disease, 122).
relief from tremor.
• Thalamic stimulation with chronically implanted ETIOLOGY AND PATHOPHYSIOLOGY
electrodes, positioned with the use of intraoperative Hereditary neurologic disorders
recordings in the nucleus ventralis intermedius of the • Huntington’s disease (see p.417).
thalamus, confers lower risk. High frequency (100–200 • Benign familial chorea.
Hz) stimulation, controlled by a subcutaneously • Familial paroxysmal choreoathetosis.
implanted box on the chest wall, is thought to produce • Focal paroxysmal kinesigenic choreoathetosis.
its beneficial effect by inducing depolarization block. • Dentato-rubro-pallido-luysian atrophy (DRPLA).
Good results have been achieved in the vast majority of • Wilson’s disease.
patients (up to 88% with parkinsonian tremor and 68% • Cerebellar degenerations.
with ET). It is hoped that the benefits will be maintained • Neuroacanthocytosis.
with longer term follow-up.
A randomized comparison of thalamotomy and Vascular
thalamic stimulation found that both were effective in • Stroke: basal ganglia infarction or hemorrhage (hemi-
relieving drug resistant tremor but thalamic stimulation chorea, hemiballism).
produced greater functional improvement. Bilateral • Polycythemia rubra vera.
thalamic stimulation may have a lower complication rate • Essential thrombocythemia.
than bilateral thalamotomy. Dysarthria and aphonia • Vasculitis.
complicate up to 20–25% of bilateral thalamic lesions (or
stimulators), though with stimulation speech improves Immune-mediated
when the stimulator is switched off. • Sydenham’s (rheumatic) chorea: a complication of beta
hemolytic streptococcal infection.
PROGNOSIS • Systemic lupus erythematosus.
• ET is slowly progressive but seldom becomes severe. • Antiphospholipid antibody syndrome.
• Other neurologic impairments do not occur. • Encephalitis lethargica.

Metabolic/hormonal
• Hormone replacement therapy.
• Oral contraceptives (rare and reversible).
• Pregnancy (chorea is rare and stops within weeks of
delivery but may recur in subsequent pregnancies).
• Thyrotoxicosis.
• Hypocalcemia/hypoparathyroidism.
• Hyperglycemia.
• Fahr’s syndrome.
• Hallervorden–Spatz disease.
• Lesch–Nyhan syndrome.
• Ataxia telangiectasia.
• Kernicterus (neonatal hyperbilirubinemia).

Toxic
• Drugs:
Amiodarone. Amphetamines.
Antihistamines. Bromocriptine.
Butyrophenones. Carbamazepine.
Dopamine receptor-blocking drugs
(e.g. metoclopramide, phenothiazines).
Flunarizine. Flupenthixol.
L-dopa. Nomifensine.
Oral contraceptives (rare and reversible).
Phenobarbitone (phenobarbital). Phenytoin.
• Carbon monoxide poisoning.
 Chorea
Structural: brain tumor (basal ganglia)
Other
• Brain anoxia.
• Cerebral palsy.
CLINICAL FEATURES
History
• Age: onset in children and adolescents (e.g. Sydenham’s
chorea, benign familial chorea, kernicterus); adulthood
(e.g. Huntington’s disease).
• Chorea:
– Precipitants: sudden movement or startle (e.g. focal
paroxysmal kinesigenic choreoathetosis); alcohol, caffeine,
emotion, stress (e.g. familial paroxysmal choreoathetosis).
– Duration: brief paroxysms of chorea, tonic, dystonic or
athetoid movements lasting only a minute or two and
may be unilateral or bilateral (e.g. focal paroxysmal
kinesigenic choreoathetosis).
– Course: progressive (e.g. Huntington’s disease, kernicterus).
• Other history:
– Past history: kernicterus; cerebral palsy; stroke; streptococ-
cal infection; previous episodes of chorea with pregnancy;
use of the oral contraceptive pill or in other circumstances.
– Family history: chorea; dementia; suicide.
– Medications: oral contraceptives, other drugs and
duration of exposure.
– Systemic enquiry: pregnant or not?
Physical examination
Chorea
• Abrupt, unpredictable, fleeting, irregular, purposeless
movements make the patient appear restless and fidgety.
The patient may try to disguise the involuntary
movements by terminating them with a semipurposeful
or purposeful voluntary movement.
• The movements may affect any or many parts of the
body. Hemichorea suggests a unilateral basal ganglia or
subthalamic lesion. Exceptionally wild, flinging
movements of an arm or leg on one side is called
hemiballismus and is usually caused by a lesion,
commonly vascular, in the subthalamic nucleus of Luys.
• Speech may become slurred, swallowing impaired, the
hands clumsy, the gait unsteady, and falls occur.
• Ask the patient to hold their tongue out and arms out
and observe for choreiform movements.
• Ask the patient to grip your right index finger with their
left hand and your left index finger with their right hand
tightly and constantly. Observe for a ‘milk-maid’ grip
characterized by intermittent irregular flexion and
relaxation (chorea) of the patient’s fingers.
Other features
• Subcortical dementia (Huntington’s disease).
• Depression/behavioral, affective or psychotic disorder
(Huntington’s disease).
• Other movements: dystonia, tics, dyskinesia (neuro-
acanthocytosis), athetosis (kernicterus).
• Depressed tendon reflexes (subclinical motor neuropathy:
neuro-acanthocytosis).
122 Pathology specimen of a patient with Huntington’s disease
showing atrophy of the caudate nuclei and frontal lobes, and
secondary dilatation of the frontal horns of the lateral ventricles.
123
DIFFERENTIAL DIAGNOSIS
Other hyperkinetic movement disorders:
• Ballism (perhaps a severe form of chorea): abrupt,
irregular, large amplitude, random movements, usually
of the arm, due to a lesion of the subthalamic nucleus of
Luys, that is usually vascular.
• Myoclonus (see p.124): brief, shock-like muscle jerks of
abrupt onset and offset.
• Tics (see p.130): repetitive simple and complex stereo-
typed movements, particularly affecting the face and
upper body, which can be suppressed by an effort of will.
• Tremor (see p.119): a rhythmic sinusoidal movement,
which may be present at rest (rest tremor), during the
maintenance of certain positions (postural tremor), during
any active movement (kinetic or action tremor), or during
specific movements (task-specific action tremor).
• Dystonia (see p.113): a syndrome of sustained muscle
contractions and spasms resulting in twisting or repetitive
movements superimposed on abnormal postures.
• Athetosis (literally ‘no fixed position’): twisting and
writhing movements of distal limbs and fingers, generally
regarded as a distal expression of dystonia.
• Idiopathic orofacial dyskinesia (see p.129).
• Cerebellar ataxia (see pp.437, 441, 444).
INVESTIGATIONS
Blood
• Full blood count (polycythemia rubra vera).
• Peripheral blood smear (acanthocytes).
• ESR (vasculitis).
• Antinuclear antibody (systemic lupus erythematosus).
• Anticardiolipin antibody.
• Activated partial thromboplastin time (lupus anticoagulant).
• Creatine phosphokinase.
• Thyroid function tests (thyrotoxicosis).
• Serum calcium (hypocalcemia).
• Copper and ceruloplasmin (Wilson’s disease).
• Antistreptolysin O and anti-DNAase B titers (Syden-
ham’s rheumatic chorea).
• DNA analysis for Huntington’s disease (expanded CAG
trinucleotide repeat on chromosome 4) and the DRPLA
mutation.
Imaging
CT or MRI brain scan (basal ganglia lesion such as an
infarct, hemorrhage, tumor, calcification; caudate nucleus
atrophy [Huntington’s disease]).
122
124 Movement Disorders

TREATMENT MYOCLONUS
Identify and remove the underlying cause if possible.

Symptomatic control of chorea DEFINITION

Dopamine receptor antagonists
• Tetrabenazine, oral, 12.5 mg twice daily, increasing
gradually if necessary and if tolerated, to 50 mg three
times daily.
• Haloperidol, oral, 0.5 mg three times daily, increasing
gradually if necessary and if tolerated to 10 mg three
times daily or more.
• Thiopropazate, oral, 5 mg three times daily, increasing
as required and tolerated to 30 mg three times daily.
• Pimozide, oral, 2 mg daily, increasing as required and
tolerated to 20 mg daily.
Sudden, very brief, shock-like involuntary movements
caused by muscular contractions (positive myoclonus) or
inhibitions (negative myoclonus). Myoclonus is a primarily
descriptive term; it is not a diagnosis. (see Tables 20, 21).
EPIDEMIOLOGY
• Incidence: 1.3 per 100 000 person years.
• Prevalence: 8.6 per 100 000 population (lifetime).
• Age: any age; incidence and prevalence increase with
increasing age.
• Gender: M>F.

Adverse effects include depression, drowsiness, PATHOPHYSIOLOGY

parkinsonism and tardive syndromes.
Tetrabenazine is a synthetic benzoquinolone that depletes
presynaptic storage of monoamines and blocks postsynaptic
dopamine receptors. It has the advantage over conventional
neuroleptic dopamine antagonists that it rarely causes a
dystonic reaction and has not been reported to caused
tardive dyskinesia. The most common adverse effects are
drowsiness (about one-third of cases), parkinsonism (about
one-quarter), depression (one-sixth), and insomnia, nervous-
ness/anxiety, or akathisia (each about one-tenth of cases), all
of which can be controlled with reduction in dosage.
Sodium valproate
An abnormal electric discharge in the neuraxis (commonly
the cerebral cortex or brainstem reticular formation) leads
to a loss of normal inhibitory influences, an abnormally
rapid and hypersynchronous recruitment of multiple motor
units, and brief (<100 ms) ‘shock-like’ myoclonic jerks.
Epileptic myoclonus (see Table 21)
• Cortical reflex myoclonus: a fragment of focal or
localization-related epilepsy, due to the paroxysmal
depolarization shift, an excessively long excitatory post-
synaptic potential that induces a rapid burst of action
potentials in the neurone. The EEG signal is high ampli-
tude multiple and rapid spikes followed by a slow wave.

Phenytoin
Focal paroxysmal kinesigenic choreoathetosis.

Clonazepam
Familial paroxysmal choreoathetosis.

Prednisolone Table 20 Anatomic classification of myoclonus

Antiphospholipid antibody syndrome. Prednisolone may Myoclonus Anatomic origin Etiology
help, but is unproven. type

PROGNOSIS Focal Cerebral Vascular (AVM)

The prognosis depends on the cause. cortex Inflammatory (encephalitis)
Hemichorea and hemiballismus due to stroke usually resolve Tumor
within a few weeks or months. Brain stem Vascular, demyelination, tumor
(‘palatal
myoclonus’)
Spinal cord Vascular (ischemia)
Inflammatory (myelitis)
Tumor
Compression
Generalized/ Cortical or Anoxia (post hypoxic myoclonus)
multifocal brainstem Encephalitis
Creutzfeldt–Jakob disease
Metabolic encephalopathy
Spinocerebellar degenerations
Tay–Sachs disease
Lafora body disease
Whipple’s disease
Celiac disease
Drugs and toxins
Idiopathic (‘benign essential
myoclonus’)
 Myoclonus 125

• Reticular reflex myoclonus: a fragment of a type of
generalized epilepsy, which originates in a hyperexcitable
caudal brainstem reticular formation. A generalized spike
discharge, frequently associated with, but not time-
locked to, the jerk, usually follows the first EMG sign of
myoclonus.
• Primary generalized epileptic myoclonus: a fragment of
primary generalized epilepsy, originating diffusely from
the cerebral cortex, which is driven diffusely and syn-
chronously by subcortical inputs that trigger paroxysmal
events.
Non-epileptic myoclonus
Segmental myoclonus: hypothesized to originate from the
spinal cord or brainstem from hyperactive alpha motor
neurones that have lost normal inhibitory inputs.
ETIOLOGY
• Genetic: various forms of familial myoclonic epilepsy.
• Acquired: diffuse brain damage: hypoxia, encephalitis,
metabolic disturbances.
Physiologic myoclonus (in normal people)
• Benign hypnagogic myoclonus (hypnic jerks): sudden,
singular jerks on falling asleep.
• With anxiety or exercise.
• Hiccoughs (singultus).
Essential myoclonus (no known causes and
no other neurologic deficit)
• Hereditary:
– Autosomal dominant inheritance with variable
penetrance.
– Onset before 30 years, usually in first or second decade.
– Men and women are affected equally.
– Non-disabling myoclonus, generalized or focal, with a
predilection for the face, trunk, and proximal limb
muscles.
– Myoclonus is reduced or absent at rest, absent in sleep,
and exacerbated by stress and movement.
– Sometimes associated with ET.
• Sporadic: similar to above but no family history.
• Nocturnal myoclonus (periodic movements of sleep).
Epileptic myoclonus (epileptic seizures
accompanied by myoclonus)
• Generalized epileptic myoclonus:
– More common in children and adolescents than adults.
– Infantile spasms.
– Lennox–Gastaut syndrome.
– Juvenile myoclonic epilepsy (see p.86).
• Myoclonus associated with isolated spike discharges in
the motor cortex:
– Idiopathic stimulus-sensitive myoclonus.
– Isolated epileptic myoclonic jerks.

Symptomatic myoclonus
Static myoclonic encephalopathies
Myoclonus following an acute brain insult.

Table 21 Descriptive classification of myoclonus

Stimulus sensitive Non-stimulus sensitive
Cortical reflex Reticular reflex Periodic Rhythmic Irregular
Site Face, distal limb Face, proximal limb Face, limb Eyes, palate, limb Face, limb
Laterality Unilateral Bilaterally Bilateral usually Symmetric usually Unilateral
or bilateral synchronous or bilateral
Rhythmicity Irregular Irregular Periodic Rhythmic Irregular
Provoking factors Action, various Action, various None None Indefinite
stimuli stimuli
Duration of Short Short Relatively long Long Indefinite
EMG discharge (100–400 msec)
Spread Rostral to caudal Bulbar to rostral None None None
EEG Spike, contralateral Spike, no relation Can be associated No correlate No correlate
central, time with myoclonus with PSDs
locked to myoclonus
Cortical SEP Giant Not enhanced Not enhanced Not enhanced Not enhanced
Long latency reflex Enhanced Enhanced Not enhanced Not enhanced Not enhanced
Main causes PME Post anoxic CJD Pontine lesion PME
Post anoxic PME SSPE Essential
CJD Spinal Spinal
Alzheimer’s disease
PME: Progressive myoclonic epilepsy and allied diseases; CJD: Creutzfeldt–Jakob disease; SSPE: Subacute sclerosing panencephalitis;
PSD: Periodic synchronous discharge. Spinal myoclonus is sometimes stimulus sensitive
126 Movement Disorders

Post-hypoxic (chronic) action myoclonus: CLINICAL FEATURES

• Myoclonic jerks in isolation or repetitively. History
• Induced by attempts at voluntary movements (action or • Exposure to drugs, toxins or anoxia.
intention myoclonus) or by some types of sensory • Current and past medical problems: epileptic seizures.
stimuli. • Family history.
• Associated with spikes in the EEG.
Examination
Post-hypoxic (acute) myoclonus: Myoclonus
• Generalized, rhythmic, and stimulus-sensitive myoclonus. Involuntary, sudden, very brief, shock-like movements of
• Occurs as an acute effect of hypoxia while the patient is the face, limbs or trunk which tend to be isolated,
in, or recovering from, coma. asymmetric, repetitive and irregular.
• Frequently transient.
• Causes includes: head injury, thalamotomy and stroke. Anatomic site:
• A poor prognostic sign when it occurs in the recovery • Generalized (involving the whole body).
phase of hypoxic coma. • Regional/multifocal (confined to two or more
contiguous regions).
Progressive myoclonic encephalopathies • Focal/segmental (confined to one region).
A progressive brain disorder characterized by myoclonus
with or without seizures. Activation: myoclonus may occur at rest (‘spontaneous
myoclonus’) or be induced by a stimulus such as a sudden
Inborn errors of metabolism: noise, flash of light, or touch (reflex myoclonus) or
• Gaucher’s disease. voluntary movement (action myoclonus), or some
• Hexosaminidase deficiency (GM2 gangliosidosis) (see combination of these factors.
p.172).
Temporal pattern: sporadic or repetitive/periodic, rhythmic
Infectious encephalopathies: or irregular: examples of rhythmic myoclonus include palatal
• Subacute sclerosing panencephalitis (see p.304). myoclonus, or symmetric flexion of the limbs or trunk; the
• Herpes simplex encephalitis (see p.295). latter typically occurs in progressive brain disorders such as
• Arbovirus encephalitis (see p.293). SSPE and infantile spasms (infants with brain damage and
• Creutzfeldt–Jakob disease (see p.330). violent movements).
• Post-encephalitic parkinsonism (see p.420).
Associations:
Progressive myoclonic epilepsies (see p.87). • Other forms of generalized epilepsy; a series of myoclonic
jerks may precede tonic-clonic seizures.
Progressive myoclonic ataxias: a syndrome comprising • Lapses in contraction of muscles (negative myoclonus),
myoclonus, progressive cerebellar ataxia with infrequent or which may cause falls (akinetic attacks) or asterixis: the
absent epileptic seizures and little or no cognitive ‘flapping tremor’ of various encephalopathic states.
dysfunction due to diseases such as mitochondrial disease,
spinocerebellar degenerations, and celiac disease. Other neurologic signs
• Cognition.
Metabolic encephalopathies: • Cerebellar function.
• Dialysis dementia. • Extrapyramidal function.
• Hepatic encephalopathy (see p.452).
• Hypoglycemia. SUBTYPES (see Table 20, p.124)
• Non-ketotic hyperglycemia. Focal myoclonus
• Hypocalcemia. Myoclonus restricted to one muscle group or body part.
• Hyponatremia.
• Renal failure. Cortical myoclonus
• Respiratory failure. • A form of focal motor seizure due to an abnormal focal
electric discharge in or near the motor cortex.
Toxic encephalopathies: • May be spontaneous or precipitated by action, muscle
• Heavy metal poisons. stretch and particularly touch and photic stimulation
• Bismuth. (stimulus-sensitive).
• Methyl bromide. • Manifests as one or more myoclonic jerks of a limb or the
• Strychnine. face on the side contralateral to the cortical discharge.
• Lithium. • If repetitive and regular, it is synonymous with epilepsia
• Beta-lactams. partialis continua.

Degenerative disorders:
• Alzheimer’s disease (see p.407).
• Wilson’s disease (see p.157).
• Huntington’s disease (see p.417).
• Progressive supranuclear palsy (see p.432).
 Myoclonus
Brainstem (palatal myoclonus/nystagmus)
• Regular, slow, continuous, rhythmic (1–3 times per
second) contraction of the soft palate which may give rise
to a rhythmic clicking in the ear and difficulty with
speaking and swallowing.
• Sometimes the ocular, facial and diaphragmatic muscles
may be involved.
• Movements do not cease during sleep.
• Caused by a lesion in the brainstem that may involve the
triangular pathway between the red nucleus in the mid-
brain, the ipsilateral inferior olivary nucleus in the lower
medulla, and the contralateral dentate nucleus in the
cerebellum (Guillain–Mollaret’s triangle).
• Onset usually 10–12 months after the precipitating cause
and remains permanently.
Hemifacial spasm
• Involuntary painless muscle twitching around one eye.
• Exacerbated by eye closure.
• May gradually spread to involve the other facial muscles
ipsilaterally and lead to additional twitching of the corner
of the mouth and platysma.
• Mild weakness around the corner of the mouth may be
present but no other signs.
• Causes include facial nerve compression by a cerebello-
pontine angle mass which needs to be excluded by CT
or MRI scan, particularly if there is an absent ipsilateral
corneal reflex or sensorineural deafness.
• Although not a classical subtype of myoclonus, it is in-
cluded here for completeness and to highlight the over-
lap between some involuntary movement syndromes.
Segmental myoclonus
• Restricted to one part of the body innervated by the
brainstem or spinal cord.
• May be caused by brainstem or spinal cord trauma,
arteriovenous malformation, tumor and transverse
myelitis.
• Distinguish from cortical epileptic discharges causing
simple partial motor seizures, epilepsia partialis continua
and cortical myoclonus, which may be evident on the
EEG.
Nocturnal ‘myoclonus’ (periodic leg movements of sleep)
• Abrupt, rather stereotyped, withdrawal movements,
usually of one leg but sometimes one arm, synchronously
or asynchronously, followed by a brief tonic contraction
which can occur intermittently throughout the night,
during non-REM sleep, every 30 seconds for up to
several hours.
• Most common in the elderly.
• Not epileptic.
• Quite benign but can disrupt sleep.
• May be associated with restless legs syndrome.
Multifocal myoclonus
Usually caused by widespread cortical pathology.
127
Generalized myoclonus
• Usually arise from the brainstem.
• May be stimulus-sensitive, especially to sound.
• Treatment may be difficult and is based on the use of
anticonvulsants (e.g. clonazepam, sodium valproate,
primidone), often in combination.
DIFFERENTIAL DIAGNOSIS
Myoclonus or not?
• Clonus: a series of rhythmic, uniphasic or monophasic
(i.e. unidirectional) contractions and relaxations of a
group of muscles, thus differing from myoclonus, which
are shock-like contractions of a group of muscles that are
irregular in rhythm and amplitude and, with few
exceptions, asynchronous and asymmetric in distribution;
and also differing from tremors, which are always
diphasic or bidirectional.
• Asterixis: sudden pauses of muscular activity (a form of
negative myoclonus): the basis of the ‘flapping tremor’
of various encephalopathic states.
• Tics (see p.130): simple motor tics are rapid brief jerks
involving a single group of muscles, usually of the head
and arms, which appear very much like myoclonus.
However, unlike myoclonus, they can be suppressed for
short periods at the expense of increasing tension and
distress to the patient. Complex motor tics involve
sequences of movements that persist far too long to be
confused with myoclonus.
• Startle reflexes: an exaggerated startle response is a quick
jerk involving the face, head, neck, and sometimes the
proximal limbs. Although myoclonus may occasionally
be triggered by startle, usually it is spontaneous or
elicited by other stimuli.
• Chorea (see p.122): choreiform movements are abrupt,
unsustained, irregular and non-stereotyped movements
of variably changing speed that seemingly flow at random
from one muscle group to another, whereas myoclonic
movements are repetitive and stereotyped in both
direction and degree.
• Dystonia (see p.113): a syndrome of excessive muscle
contractions, which frequently cause twisting and
repetitive movements, or abnormal postures. Quick
movements can occur in dystonia, but their association
with slower movements or postures distinguishes them
from myoclonus.
• Tremor (see p.119): a rhythmic and sinusoidal oscillation
of one body part in relationship to another. Although
myoclonus can be rhythmic, the movement form
resembles the appearance of a ‘square wave’ temporal
pattern, with a distinguishable interval between each
movement.
• Fasciculations: appear as muscle twitches which do not
result in the movement of a whole muscle (as does
myoclonus), and result from spontaneous firing of motor
units or bundles of muscle fibers, usually in the setting
of peripheral nerve disease.
• Cerebellar ataxia: in patients with moderate or severe
action myoclonus, it is difficult to determine if cerebellar
signs are present as well, unless the myoclonus can be
controlled with drug therapy.
128 Movement Disorders

INVESTIGATIONS Specific medication for myoclonus

First line • Sodium valproate, benzodiazepines (clonazepam) and
• Electrolytes. lamotrigine are the most effective conventional drugs.
• Glucose. Valproate use may be limited by gastrointestinal effects,
• Renal function. sedation and liver toxicity. Clonazepam can be limited by
• Hepatic function. sedation, imbalance, behavioral changes, and tolerance.
• Drug and toxin screen. • Piracetam may be useful.
• Brain imaging: CT or MRI scan. • Serotonin precursors may be used for post-hypoxic
• EEG (123): generalized spike wave discharges, photo- myoclonus or progressive myoclonic epilepsy.
sensitivity, focal (particularly posterior) epileptiform • Phenytoin has a deleterious effect.
discharges, vertex spikes in REM sleep, may be found in • In contrast to the general principle of monotherapy in
most of the disorders that cause the progressive epilepsy, polytherapy may produce additional benefit in
myoclonic epilepsy syndrome. Slowing of background the treatment of severe myoclonus, although drug
activity occur in all forms of PME but is usually much toxicity needs to be avoided.
more prominent and early in those diseases with diffuse
neuronal damage and storage compared with those Physical therapy
diseases with restricted neuronal degeneration.
Social rehabilitation
Second line
• Polygraphic EEG–EMG monitoring and back-averaging: PROGNOSIS
the most essential and useful electrophysiologic Depends on the cause; myoclonus may occur as a transient
technique to try and show a relationship between a or persistent phenomenon in many conditions such as viral
cortical spike and a muscle contraction. EEG-EMG encephalitis, suppurative meningitis, intoxications with
backaveraging techniques can be used to detect EEG strychnine and tetanus, and metabolic disorders such as
potentials that are not present in routine EEG uremia and anoxic encephalopathy.
recordings. This technique increases the signal-to-noise
ratio and records preceding EEG waveforms that are
time-locked to the myoclonus.
• Somatosensory-evoked potentials (SEP): useful for
further investigating the pathophysiology of myoclonus.
Giant somatosensory-evoked potentials may be found in
stimulus-sensitive, cortical reflex myoclonus caused by
most of the disorders that cause the progressive
myoclonic epilepsy syndrome.
• Copper studies: Wilson’s disease.
• Enzyme activities: storage diseases.
• Genetic testing: mitochondrial disease, Huntington’s
disease, spinocerebellar ataxias.
• Chromosomal fragility: ataxia-telangiectasia.
• Spinal imaging: segmental pathologic condition.
• Tissue biopsy: storage disease, mitochondrial disease.

DIAGNOSIS
Clinical and electrophysiologic.
123
TREATMENT
The myoclonus may not be severe enough to warrant
symptomatic treatment. Treatment of the underlying cause
(e.g. renal failure) may obviate the need for specific
treatment. Anti-epileptic treatment for seizures may reduce
the myoclonus.

123 EEG, 8 channel, sleep recording, in a young adult with myoclonic

seizures, showing trains of fast spikes followed by a single slow wave
(multispike and wave).
 Dyskinesias
DYSKINESIAS
DEFINITION
Abnormal dystonic and choreoathetoid involuntary
movements that may occur spontaneously, after a sudden
voluntary movement, after prolonged physical exertion, or
during sleep, which occur during full consciousness, and are
of variable duration.
EPIDEMIOLOGY
Prevalence
• Tardive dyskinesia: about 20% of patients on long-term
antipsychotic medication.
• Paroxysmal dyskinesia: rare, except when associated with
late stage Parkinson’s disease.
Age of onset
• 21 years (mean); range 1–60 years (paroxysmal
kinesogenic dyskinesia [PKD]).
• 30 years (mean); range 1–77 years (paroxysmal non-
kinesogenic dyskinesia [PNKD]).
• 13 years (mean); range 1–29 years (paroxysmal exertion-
induced dyskinesia [PED]).
• Idiopathic paroxysmal dyskinesias have a younger age of
onset compared with secondary dyskinesias.
• Gender: F<M = 3:5 (i.e. about 60% as common in
women than men).
CLASSIFICATION
Continuous dyskinesias
Tardive dyskinesia.
Paroxysmal dyskinesias
Kinesigenic (Paroxysmal kinesigenic dyskinesia)
Abrupt onset of episodes of abnormal involuntary move-
ments after a sudden voluntary movement.
Non-kinesigenic (Paroxysmal non-kinesigenic dyskinesia)
Spontaneous onset of attacks of abnormal involuntary
movements.
Exertion-induced dyskinesia
Attacks of abnormal involuntary movements precipitated by
prolonged physical exertion.
Hypnogenic dyskinesia
Attacks of abnormal involuntary movements occurring only
during sleep.
ETIOLOGY
Tardive dyskinesia
Long term antipsychotic medication.
Paroxysmal kinesigenic dyskinesia
Familial: 65% of cases, usually autosomal dominant
inheritance with complete or incomplete penetrance. Linked
to the pericentromeric region of chromosome 16.
PATHOPHYSIOLOGY
Tardive dyskinesia
Dopamine receptor hypersensitivity.
129
Paroxysmal kinesigenic dyskinesia
• Decreased inhibitory influences of the medial globus
pallidus and substantia nigra on the thalamus, or
• Damage to the thalamic reticular nucleus itself, thus
making the thalamus more sensitive to superficial or deep
sensory input.
Paroxysmal hypnogenic dyskinesia (PHD)
May be associated with frontal epilepsy.
CLINICAL FEATURES
Tardive dyskinesia
Continuous involuntary movements of the orobuccolingual
and masticatory muscles of a choreiform nature.
Paroxysmal dyskinesis
Precipitating factors
Paroxysmal kinesigenic dyskinesia (PKD):
• Sudden voluntary movement of a limb; orofacial
movements such as yawning and talking; movements
associated with startle or hyperventilation.
Paroxysmal exertion-induced dyskinesia (PED):
• Walking, running for 5–15 minutes.
Paroxysmal hypnogenic dyskinesia (PHD):
• Sleep.
Prodromal symptoms immediately prior to onset of attack
Muscle tension; tingling; numbness; dizziness.
Site of involvement
Limbs, often unilaterally; oromandibular and facial muscles:
dysarthria or anarthria.
Nature of involvement
Dystonia and/or choreoathetosis or athetosis.
Associated symptoms
Pain in the affected body part sometimes; perhaps sleep
disorders (e.g. sleep apnea, narcolepsy).
Exacerbating factors
Paroxysmal kinesigenic dyskinesia (PKD):
• Stress; fatigue; menses; alcohol; cold; heat.
Duration of attacks
From seconds up to several hours to days. Attacks may
become shorter or longer with time.
SPECIAL FORMS
Superior oblique myokymia, causing paroxysmal diplopia or
‘shimmering of vision’.
DIFFERENTIAL DIAGNOSIS
• Epileptic seizures (movement-induced seizures, reflex
epilepsy or subcortical epilepsy): paroxysmal dyskinesias
are dystonic or choreoathetoid with preserved conscious-
ness, a normal EEG during attacks, and absence of a post
ictal state.
• Psychogenic: attacks associated with or triggered by
hyperventilation and odors.
130 Movement Disorders
INVESTIGATIONS
Cranial CT and MRI scan: often normal.
TREATMENT
The precipitating circumstance is the most important factor
in determining the underlying mechanism of the paroxysmal
movement disorder, the natural history and response to
treatment. Long lasting attacks suggest a good response to
medication.
Tardive dyskinesia
• Difficult to treat.
• Withdrawal of the responsible antipsychotic drug may
induce a remission, but this can take months or even
years, and may be impractical if the patient has a serious
underlying psychiatric disorder.
• Increased doses of dopamine antagonists (e.g. tetra-
benazine) paradoxically may lead to improvement,
presumably by depleting presynaptic dopamine, but may
also cause depression.
• Baclofen, benzodiazepines, and calcium-channel blockers
may be effective; anticholinergics make tardive dyskinesia
worse.
Paroxysmal dyskinesias
Almost all patients with PKD improve with anti-epileptic drugs
in contrast to only one-quarter of patients with PNKD. Short-
lasting (and non-kinesigenic) attacks generally fail to
improve with medication. Carbamazepine and phenytoin
seem more effective than other anti-epileptic drugs in PKD
and clonazepam in PNKD. Drugs that enhance GABAergic
neurotransmission, such as benzodiazepines, valproic acid, and
phenobarbitone (phenobarbital), increase the latency to the
onset of attacks and reduce the severity, while drugs that
impair GABAergic transmission decrease the latency.
• Clonazepam (PNKD).
• Tetrabenazine (PKD).
• Lorazepam (PHD).
• Chronic stimulation of the ventro intermediate (Vim)
thalamus may impove dystonic paroxysmal non-
kinesigenic dyskinesia.
TOURETTE SYNDROME (TS)
DEFINITION
A genetically determined chronic neuropsychiatric disorder
that develops in children and adolescents and is
characterized by multiple motor and vocal tics (quick,
involuntary movements that occur repeatedly and non-
rhythmically in the same way) which last more than 1 year
and cause considerable social, vocational and functional
impairment. It is commonly associated with obsessive–com-
pulsive behavior, attentional and executive dysfunction, and
aggressive behavior. The syndrome was first described in
1825 by Dr Georges Gilles de la Tourette.
EPIDEMIOLOGY
• Prevalence: 3–10/1000; much more common than
previously appreciated; many cases are mild and do not
come to medical attention or are not recognized.
• Tics: common during childhood development (4–12%
of children aged 6–12 years), and possibly more common
in children with learning problems. The relationship
between such tics and the disorder of TS remains unclear.
Commonly, tics are transient and disappear.
• Age of onset: before age 21, usually 2–15 years.
• Gender: M>F (3:1); as yet unexplained.
PATHOLOGY
Limited histopathologic data have failed to identify any
definitive pathologic changes in the striatum (124).
ETIOLOGY AND PATHOPHYSIOLOGY
• Commonly familial and inherited as an autosomal
dominant trait with reduced penetrance and variable
expression.
• A linkage has been found to chromosome 18 in some
families.
• No evidence for genetic linkage at the dopamine D2 or
D3 receptor loci has been found.
• It is hypothesized by some that the TS genetic locus is
common and is involved in normal brain development,
and that the occurrence of the clinical disorder TS
represents an excessive expression or abnormal
persistence of normal developmental characteristics. The
appearance of the typically associated clinical features of
TS (i.e. tics, obsessive–compulsive behavior, inattention,
and hyperactivity) commonly occurs during normal
childhood development (as a form of ‘developmental’ or
‘physiological’ TS) and reflects normal synaptogenesis in
basal ganglia and limbic regions. The medical disorder
TS differs only quantitatively from this process.
• Other hypotheses are that:
– TS is a basal ganglia disorder characterized by striatal
dopamine receptor hypersensitivity.
– TS is a cingulate and orbitofrontal cortex disorder
characterized by dysfunction of the central endogenous
opioid system in limbic and orbitofrontal basal
ganglia/thalamic loops.
• Reports of TS following head trauma, carbon monoxide
poisoning, neuroleptic drugs, other toxic and metabolic
encephalopathies, Creutzfeldt–Jakob disease, Hunting-
ton’s disease, and encephalitis lethargica are more likely
to be coincidental than causal.
 Tourette Syndrome (TS)
CLINICAL FEATURES
Chronic, multiple motor and vocal tics
Tics involving the face or neck (e.g. repeated eye blinking
and throat clearing) is the most common initial feature.
Other common initial symptoms include complex move-
ments such as touching, striking or hitting, and jumping.
Tics are brief stereotyped movements (motor tics) or
sounds produced by moving air through the nose, mouth
or throat (vocal tics). They are classified as motor and vocal,
and simple and complex, although the boundaries of these
are not well defined:
• Simple motor tics: eye blinking, facial grimacing, neck
jerking, shoulder shrugging.
• Complex motor tics: facial gestures, smelling, groaning
behaviors, touching, stamping, hitting or biting oneself,
jumping.
• Simple vocal tics: sniffing, coughing, throat clearing,
grunting, snorting, barking.
• Complex vocal tics: repeating words or phrases out of
context, palilalia (increasingly rapid repetition of a word
or phrase), echolalia (repetition of words), and coprolalia
(foul language).
With time, the tics become more prominent and involve
the shoulders and arms, followed by the legs. Involvement
of the muscles of respiration causes vocal tics such as
grunting, barking or coughing noises which interrupt
conversation. The expulsion of air imparts an explosive
quality to the speech and occasional associated hissing
sounds.
Some patients develop repetitive involuntary explosive
stereotyped verbal utterances during compulsive expiration,
which may consist of obscene expletives (coprolalia).
Patients may also repeat the last word or sentence of others’
(echolalia) or their own speech (palilalia), repeat motor acts
(echopraxia) and sometimes obscene (copropraxia) and
other gestures.
The tics occur many times a day (usually in bouts) nearly
every day, or on again, off again for more than a year. There
124
124 Brain of a drug addict showing basal ganglia (globus pallidus)
disease bilaterally due to the use of illicit drugs.Tics are occasionally
due to organic basal ganglia disease.
131
are periodic changes in the type, number, frequency, and
location of the tics, and in the waxing (increasing) and
waning (decreasing) of their severity. Symptoms will some-
times mysteriously disappear for weeks or months at a time.
Although tics are described as being quick, involuntary
movements that occur repeatedly and non-rhythmically in
the same way, they are not strictly ‘involuntary’. Most
people with TS have some control over their symptoms.
However, this control, which can be exerted from seconds
to hours at a time, tends to delay more severe tics. They
become irresistible and must eventually be executed; some
people wait until they are in private before doing so.
Associated disorders, behaviors and consequences
Coexist in about half of all patients.
Obsessive–compulsive disorder (about 50% of cases)
The presence of obsessions or compulsions causing marked
distress or interfering with normal functioning. Obsessions
are recurrent persistent ideas, thoughts, impulses or images
that are intrusive and inappropriate and cause anxiety or
distress. They are a product of the person’s own mind and
are not simply excessive worries about real-life problems.
Examples include fear of contamination, need for symmetry,
and pathologic doubt. Compulsions are repetitive behaviors
or mental acts that a person feels driven to perform, often in
response to an obsession. The aim of them is to prevent or
reduce anxiety or distress, not to provide pleasure or grati-
fication. Examples include checking, washing, counting,
needing to ask or confess, and symmetrizing or being precise.
Attention deficit disorder (ADD)
Characterized by five or more of the following: failure to
give attention to details or making careless mistakes in
schoolwork, work, or other activities; frequent difficulty
organizing tasks and activities; easy distractibility by
extraneous stimuli; failure to follow through on instructions
and finish work or duties; often leaving seat in classroom or
in other situations in which remaining seated is expected;
difficulty playing or engaging in leisure activities quietly;
talking excessively.
Sleep disorders
Sleep talking, insomnia, nightmares, enuresis, and
somnambulism.
Other types of behavior
• Learning difficulties.
• Hyperactivity.
• Self-injury.
• Antisocial behavior.
• Aggressive behavior.
• Inappropriate sexual activity.
• Lack of discipline.
These disorders and behaviors may wax and wane and
may persist even after the tics have largely disappeared. Many
patients are left-handed or ambidextrous and have minor
neurologic abnormalities. A family history of tics, obses-
sive–compulsive behavior, or ADD is commonly present.
132 Movement Disorders

DIFFERENTIAL DIAGNOSIS Tourette disorder (TD)

Normal variants (i.e. physiologic) 1 Criteria 1–5 for Tourette syndrome are satisfied.
• Tics are common in children between the ages of 2 Tics cause distress or significant impairment in social,
2–6 years but most are transient and disappear. academic, occupational, or other important areas of
• ‘Colds’ or ‘allergies’: some of the most common tics, functioning.
such as eye blinking, sniffing, throat clearing, and cough-
ing are commonly ascribed to ‘colds’ and ‘allergies’. Clinical features increasing confidence for the
• ‘Nervous habits’: tics such as facial grimaces or head jerks diagnosis of TS or TD
are often considered to be ‘nervous habits’. 1 Multiple tic types that vary over time.
2 Tics wax and wane in severity.
Developmental basal ganglia syndrome 3 Coprolalia.
Primary (hereditary) 4 A positive family history of TS or TD.
Primary tic disorders:
• Tourette syndrome. N.B. The type or severity of tic is not considered in the
• Chronic motor tic disorder. diagnosis of TS. For example, coprolalia is not required for
• Chronic vocal tic disorder. the diagnosis; it occurs in less than one-third of clinic
• Transient tic disorder. populations and in less than 5% of affected members of
studied TS pedigrees.
Related primary neuropsychiatric disorders:
• Primary obsessive–compulsive disorder. TREATMENT
• Primary ADD. Education and counselling of the patient and family.
• Developmental stuttering.
Psychologic support
Inherited neurologic disorders Promote the child’s self-esteem and competency and
• Huntington disease. provide support in the challenges of school or work and in
• Neuroacanthocytosis. social relationships.
• Torsion dystonia.
Pharmacologic intervention
Secondary (symptomatic) Symptomatic treatment of TS with drugs can be helpful but
• Autisms, pervasive developmental disorder. improvements are usually incomplete and short-lasting.
• Mental retardation.
• Fetal alcohol syndrome. Tics
• Intrauterine infection or exposure to illicit drugs (124). Neuroleptics with dopamine-blocking activity are most
• Perinatal asphyxia. widely used. Those with a greater selectivity for the
• Carbon monoxide toxicity. dopamine D2 receptor subtype, such as haloperidol,
• Encephalitis. pimozide and sulpiride can be effective in reducing the
• Head trauma. frequency and severity of tics for patients with severe
• Stroke. symptoms. Medication needs to be administered carefully
• Post-infectious (immune-mediated). and in small doses to obtain the maximum benefit and the
• Sydenham’s chorea. minimum number and degree of adverse effects; tardive
dyskinesia often develops with prolonged usage. Other
Tic-inducing drugs effective treatments include tetrabenazine, a dopamine-
• Neuroleptic agents. depleting agent, and clonidine, which is a central α2
• Stimulants. adrenergic receptor antagonist and is thought to reduce
presynaptic release of noradrenaline.
INVESTIGATIONS • Pimozide, beginning with 0.5 mg daily and increasing
• Blood: DNA analysis. by 0.5 mg increments to as high as 10 mg daily if
• EEG: abnormal in many cases although non-specifically. necessary, is effective in up to 80% of cases. Adverse
effects include sedation, weight gain, depression, and
DIAGNOSIS restless legs.
Tourette syndrome (TS) • Haloperidol, for patients who fail to respond to pimozide
1 Multiple (two or more) motor and/or vocal tics. because the risk of long term adverse effects such as
2 Onset in the first two decades of life. tardive dyskinesia is greater with haloperidol than
3 Tics present for more than 1 year. pimozide. Starting dose 0.5 mg three times daily by
4 Tics are not caused by tic-inducing drugs (e.g. stimulants mouth, increasing to as much as 10 mg three times daily
or neuroleptic agents), other environmental insults to the if necessary.
brain (e.g. perinatal hypoxia, intrauterine infection, or • Trifluoperazine or thiothixene can be effective in
exposure to alcohol), or to hereditary neurologic refractory cases.
disorders that may produce tics (e.g. neuroacanthocytosis • Clonidine may help a few: increasing up to 6 micrograms
or Huntington’s disease). per kg daily, oral, in three divided doses, but sedation can
5 There is no evidence of significant brain dysfunction (e.g. occur. Withdrawal must be slow to avoid rebound
mental retardation, pyramidal tract signs, or seizures) hypertension.
other than tics. • A combination of neuroleptics may be required.
 Neuroleptic Malignant Syndrome 133

• Naltrexone, an opiate antagonist, has improved attention NEUROLEPTIC MALIGNANT

and reduced the number of tics in a double-blind SYNDROME (NMS)
randomized trial.
• Botulinum toxin reduces urge and tic frequency.
DEFINITION
Obsessive–compulsive disorder A rare but potentially life-threatening complication of
Obsessive–compulsive disorder can be controlled with anti- neuroleptic drug treatment.
depressant medication, and drugs with serotonin reuptake
blocking activity, such as clomipramine and fluvoxamine, EPIDEMIOLOGY
appear to be the most effective. • Incidence: 0.2% of patients treated with neuroleptics.
• Age: all ages, particularly young and middle-aged adults;
Attention deficit disorder mean age 40 years.
ADD can be treated with psychostimulant medications, but • Gender: M=F.
when patients have combined features of ADD and TS,
stimulant drugs tend to worsen the tics. Desipramine has ETIOLOGY
been shown in a recent double-blind controlled trial to be D2 dopamine receptor antagonists
useful in the treatment of ADD in TS without a Neuroleptic drugs
deterioration in tic severity. • Phenothiazines: chlorpromazine;
• Butyrophenones: haloperidol – most common.
PROGNOSIS
• TS is a lifelong illness. Non-neuroleptic antiemetic, anesthetic and sedative drugs
• Many people experience remissions of symptoms • Metoclopramide.
(particularly tics), commonly in the late teens and early • Prochlorperazine.
twenties, which may be complete, or incomplete and • Droperidol.
followed by subsequent relapses. • Promethazine.
• Lifelong medical treatment with pimozide or haloperidol
is often required but many patients can be restored to a Withdrawal of dopamine agonists
full active life in the community, without any (anti-parkinsonian medication)
compromise to life expectancy. Infrequent.
• A person with TS has about a 50% chance of passing the
gene to his or her children. However, only about 10% of Risk factors
children who inherit the TS gene will have symptoms • Previous episodes (one-third develop subsequent
severe enough to seek medical attention. episodes on re-challenge).
• Dehydration.
• Agitation.
• Rapid rate and parenteral route of neuroleptic
administration.
• Pre-existing organic brain disease or mood disorders,
particularly if taking lithium.

PATHOPHYSIOLOGY
• An acute reduction in brain dopamine activity; probably
dopamine receptor blockade in the hypothalamus,
caudate and pallidum primarily.
• Commonly due to an increase in dose of neuroleptic
drugs within the therapeutic range, rather than a toxic
manifestation.
• Infrequently, withdrawal of anti-parkinsonian medication
precipitates NMS.

CLINICAL FEATURES
Rapid onset, usually within a few days of starting treatment
with a dopamine receptor antagonist (16% within 24 hours,
66% within 1 week, 96% within 30 days), but sometimes
after stopping treatment.

History
Often there is a history of psychiatric illness, requiring
treatment with a neuroleptic. Occasionally, recent with-
drawal of anti-parkinsonian medication has taken place.
134 Movement Disorders

Physical examination INVESTIGATIONS

• Altered level of consciousness with confusion and • Full blood count (leukocytosis).
agitation (often precedes rigidity and fever). • Serum creatine kinase: elevated (but may be normal).
• Muscle rigidity in all muscle groups ± opisthotonos, • Urinary myoglobin: detected (myoglobinuria).
tremor and dyskinesia. • Arterial blood gases (hypoxia and ?respiratory ?metabolic
• Autonomic dysfunction (hypertension or hypotension). acidosis).
• Hyperthermia (>38°C [100.4°F], fever, diaphoresis). • Culture urine and blood to exclude a septic focus.
• Tachycardia. • EEG: non-focal, generalized slow wave activity in half of
• Tachypnea. cases (125).
• Dehydration is common.
• Ocular abnormalities (oculogyric crises, internuclear DIAGNOSTIC CRITERIA
ophthalmoplegia, and conjugate gaze paresis) occur All five items required concurrently:
infrequently. 1 Treatment with neuroleptics within 7 days of onset
• Extensor plantar responses may be present. (2–4 weeks for depot neuroleptics).
2 Hyperthermia (>38°C [100.4°F]).
ATYPICAL FORMS 3 Muscle rigidity.
NMS may follow cessation of prolonged therapy (6 weeks) 4 Five of the following:
with metoclopramide. – Change in mental status.
– Tachycardia.
DIFFERENTIAL DIAGNOSIS – Blood pressure instability (hypertension or hypotension).
Encephalopathy – Tachypnea or hypoxia.
Primary central nervous system disorders – Diaphoresis or sialorrhea.
• Infection (viral encephalitis, HIV, post-infectious – Tremor.
encephalomyelitis). – Incontinence.
• Tumor. – Creatine phosphokinase elevation or myoglobinuria.
• Stroke. – Leukocytosis.
• Trauma. – Metabolic acidosis.
• Seizures. 5 Exclusion of other drug-induced, systemic, or neuropsy-
• Severe dystonic reaction. chiatric illnesses.
• Akinetic mutism.
TREATMENT
Systemic disorders Early recognition
• Infection (septicemia, tetanus, rabies).
• Metabolic derangement. Discontinue offending drug
• Endocrinopathy (thyrotoxicosis, pheochromocytoma).
• Autoimmune disease (SLE, polymyositis). Supportive
• Heatstroke (history of physical exertion, and absence of • Intravenous fluids for rehydration.
diaphoresis and rigidity). • Temperature reduction.
• Malignant hyperthermia. • Nasogastric feeds.
• Toxins (carbon monoxide, phenols, strychnine, lithium, • Monitor for complications.
cocaine, designer drugs [e.g. ecstasy (methylenedioxy- • Consider early transfer to an intensive care unit.
amphetamine)]).
• Food-related allergic reactions.
• Substance abuse (salicylates, dopamine inhibitors and
antagonists, stimulants, monoamine oxidase inhibitors,
anesthetic agents, anticholinergics, alcohol or sedative 125
withdrawal).
• Serotonin syndrome: this is a potentially fatal hypersero-
toninergic state commonly precipitated by coadministra-
tion of either tryptophan or a selective presynaptic
serotonin reuptake inhibitor (drugs known to increase
serotonin, e.g. clomipramine) with a monoamine oxidase
inhibitor (MAOI, e.g. tranylcypromine). Typical features
include confusion, agitation, restlessness, hypomania,
fever, diaphoresis, shivering, tremor, myoclonus, hyper-
reflexia and incoordination, which coincide with the
addition of, or an increase in the dose of, these drugs.
Spontaneous resolution often occurs within 24 hours of
removing the added agent.

Psychiatric disorder
Catatonia.

125 EEG showing non-specific generalized slow wave activity.

 Further Reading 135

Specific • Mortality has declined in recent years although fatalities

• May be required in more severe cases.
• Benzodiazepines intravenously (e.g. midazolam;
diazepam 30 mg in divided doses over 24 hours) may
help with muscle rigidity.
• Intravenous dantrolene (0.5–3 mg/kg bodyweight
i.v./6–8 h or 100–200 mg/day po).
• Dopamine agonists: amantadine; bromocriptine
(2.5–20 mg/8 h po); levodopa/carbidopa.
• Electroconvulsive therapy may be successful in some
cases during and after NMS.
PROGNOSIS
• The syndrome lasts 7–10 days in uncomplicated cases
receiving oral neuroleptics, recovering spontaneously
without the need for specific drugs.
• It may develop earlier and take longer to resolve in
patients with schizophrenic disorders.
• Residual cerebellar damage may occur as a sequelae of
the hyperpyrexia.
still occur.
• Neuroleptics may be reintroduced safely in the
management of most patients who have recovered from
an episode of NMS but a significant risk of recurrence
does exist, dependent in part on the time elapsed since
recovery and the dose and potency of the neuroleptic.
PREVENTION
• A careful drug history, physical examination, and
laboratory evaluation should be obtained prior to
neuroleptic administration.
• Indications for neuroleptics should be clear.
• Increases in dose should be made judiciously based on
symptom response, with alternative methods (e.g.
interpersonal interventions, benzodiazepines) used to
optimize behavioral control and sedation.
• Patients should be sedated and monitored to prevent
agitation, exhaustion and dehydration.

FURTHER READING
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Deuschl G (2000) New treatment options for
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136 Chapter Seven
Developmental
Diseases of the
Nervous System
ARNOLD–CHIARI MALFORMATION
DEFINITION
A number of developmental anomalies of the hindbrain,
base of skull, and upper cervical canal characterized by
caudal displacement of the cerebellar tonsils, and sometimes
more of the cerebellum and lower brainstem, through the
foramen magnum into the cervical spinal canal.
CLASSIFICATION OF CHIARI MALFORMATIONS
Type I
Cerebello-medullary malformation
Herniation of the cerebellar tonsils below the foramen
magnum into the cervical spinal canal with elongation of
the medulla (126, 127). Meningomyelocele is rare.
Hydrocephalus (see p.468) and syringomyelia (see p.541)
may develop, the latter in up to 50% of cases (128–130).
126
126 MRI brain sagittal T1W image of a 40 year old lady with altered
sensation to pain and temperature over the right chest from T4 to T9,
showing Chiari malformation with herniated cerebellar tonsils (arrow)
within the foramen magnum and reaching the midlevel of the posterior
arch of C1, cervical syrinx (arrowheads), and syringobulbia (short
arrow) with the tract extending upwards in the midline of the ventral
medulla to the pontomedullary junction.
Type II
Cerebello-medullary malformation with meningomyelocele
Cerebellum and medulla are displaced inferiorly and are
deformed (131). The medulla is elongated and often folded
upon itself in an S-shaped pattern or overlies the cervical
cord, which may be small with upward directed roots.
Meningomyelocele (protrusion of spinal cord/cauda equina,
dura and arachnoid through a defect in the vertebral lamina,
forming a cystic swelling) is invariably present (see p.140).
Type III
Cerebellar herniation with a high cervical or occipito-cervical
meningomyelocele
Includes cervical spina bifida, cerebellar herniation through
the defect, and an open, dystrophic posterior fossa. Rarely
compatible with post-natal life.
127
127 Chiari type I malformation: midline sagittal MR T1W imaging
(TR=500 ms,TE=15 ms) showing caudal displacement of cerebellar
tissue, with herniation of the cerebellar tonsils below the foramen
magnum (arrow).
 Arnold–Chiari Malformation 137

128 129 128, 129 MRI cervical and upper thoracic

spine, sagittal T1W images, showing herniated
cerebellar tonsils (arrow) and a large syringo-
hydro-myelia (arrowheads) extending down
to the upper end plate of T9.

130 MRI thoracic spine, axial gradient echo

image, showing large hyperintense (white,
arrows) central syringo-hydro-myelia
occupying most of the thoracic spinal cord
in cross-section.

Type IV 130
Cerebellar hypoplasia only
May be related to or equivalent to Dandy–Walker
malformation.

EPIDEMIOLOGY
• Incidence: uncommon.
• Age of onset of symptoms: type II: infancy, type I: teens
or young adulthood.
• Gender: M=F.

PATHOLOGY
• Caudal descent of the cerebellar tonsils.
• Medulla and pons elongated.
• Medulla and cerebellum occlude foramen magnum.
• Remainder of cerebellum, which is small, is also
displaced, obliterating the cisterna magna.
• Fibrosis of arachnoid tissue around herniated brainstem
and cerebellum.
• A kink or spur in the upper cervical spinal cord, pushed
posteriorly by the lower end of the fourth ventricle. In this
type of malformation, a meningomyelocele is nearly always
found, and hydromyelia of the cervical cord is common. • Aqueduct stenosis.
• Hydrocephalus (due to aqueduct stenosis or CSF
Associations outflow obstruction at base of the brain).
Bony abnormalities • Syringomyelia and syringobulbia (126, 128–130).
• Posterior fossa: small. • Lumbosacral meningocele or meningomyelocele (see
• Foramen magnum: enlarged and grooved posteriorly. p.140).
• Base of skull: flattened or infolded by the cervical spine. • Filum terminale: lower spinal cord may extend to the
• Fused cervical vertebrae (Klippel–Feil syndrome). sacrum.
• Spinal dysraphism (see p.139). • Others, such as fusion of the corpora quadrigemina, cysts
of the foramen of Magendie, upward herniation of the
CNS abnormalities cerebellum through an abnormally large tentorial notch,
• Developmental abnormalities of the cerebrum: poly- enlargement of the mass intermedia, fusion of the
microgyria. thalami, and hydromyelia.
138 Developmental Diseases of the Nervous System
ETIOLOGY AND PATHOPHYSIOLOGY
• Unknown.
• Probably a failure of coordinated development of the
brainstem, cerebellum and upper cervical spinal cord.
• Arnold–Chiari malformations are traditionally viewed as
a congenital anomaly but may be acquired. One
hypothesis is that the CSF pressure difference between
the spinal and cranial compartments causes tonsillar
herniation. Others suggest that a mismatch between the
volume of the posterior fossa and its tissue contents may
produce downward herniation of the cerebellar tonsils.
CLINICAL FEATURES
Chiari type 1 malformation
May be asymptomatic or cause symptoms and signs of
progressive dysfunction of the:
• Cerebellum (progressive cerebellar ataxia),
• Medulla (spastic quadriparesis), or
• Lower cranial nerves (dysphagia),
at any time during life, sometimes being delayed until adult
life.
Other progressive symptoms include those of:
• Raised intracranial pressure (e.g. headache) due to
hydrocephalus (see p.468), and
• Syringomyelia (see p.541).
Symptoms occasionally arise acutely, such as headache or
vertigo and ataxia following neck extension (e.g. dental
extraction and chiropractic manipulation), coughing,
sneezing and Valsalva maneuver (inducing hindbrain
herniation); and syncope on exertion.
Examination findings include:
• A short ‘bull’ neck in about 25% of cases.
• Low hairline.
• Torsional or downbeating nystagmus with neck extension.
• Permanent signs of cerebellar, medulla, high cervical
cord or lower cranial nerve dysfunction.
Downbeat nystagmus is usually in the primary position of
gaze, and increases in gaze slightly below horizontal,
especially in gaze down and laterally. It is due to a disturbance
of the vestibulo-cerebellar pathways and is highly suggestive
of a craniocervical junction disorder such as Arnold–Chiari
malformation, basilar invagination or ankylosing spondylitis.
However, it may also be seen in cerebellar disease (when
other cerebellar eye signs are usually present), drug intoxi-
cation (phenytoin, carbamazepine, lithium), brainstem
encephalitis, magnesium depletion, communicating hydro-
cephalus, Wernicke’s encephalopathy, multiple sclerosis,
vascular disease and as a paraneoplastic phenomenon. It may
coexist with periodic alternating nystagmus.
Chiari type II malformation
Usually presents in infancy with:
• Progressive enlargement of the head, due to
hydrocephalus, and
• Spinal meningomyelocele.
Diagnosis may be delayed until the spinal cord is
compressed at the cranio-cervical junction causing:
• Spastic quadriparesis (limb spasticity, hyperreflexia and
extensor plantar responses).
• Cerebellar ataxia (predominantly affecting the legs and
later the arms).
• Downbeat nystagmus.
• Weakness and wasting of the tongue, sternomastoid and
trapezius muscles due to lower cranial nerve palsies (XI
and XII).
• Recurrent vocal cord paralysis, laryngeal stridor, or
respiratory obstruction during physical activity, due to
periodic venous congestion in the medulla.
Some remain asymptomatic well into adult life and
present later with pain in the back of the head, neck,
shoulders and upper limbs, exacerbated by head movement
and cough, sneeze or strain (‘hindbrain hernia headache’).
This may be followed by the evolution of weakness and
spasticity in the limbs, gait ataxia and difficulty swallowing.
Clinical features of syringomyelia (see p.541) may also
coexist.
DIFFERENTIAL DIAGNOSIS
• Multiple sclerosis.
• Tumor of the high cervical cord or lower medulla
(foramen magnum).
• Motor neuron disease (Chiari I may present with
progressive severe bulbar palsy and generalized
hyperreflexia due to severe stretch injury to lower cranial
nerves [caused by caudal displacement of medulla]
and/or direct brainstem compression).
• Autosomal dominant cerebellar ataxia of late onset.
• Dandy–Walker syndrome: a developmental anomaly with
cystic dilatation of, or near, the fourth ventricle. It causes
obstructive hydrocephalus, cerebellar and/or brainstem
signs.
INVESTIGATIONS
MR scan of the brain and cervical spinal cord is the
investigation of choice
Chiari I malformation
• T1W midline sagittal MRI (or myelography) shows the
inferior displacement of the cerebellar tonsils, the tips
lying in the C1–C2 region (126, 127).
• The tonsils may lie up to 5 mm below the foramen
magnum in normal individuals – this is a fairly frequent
finding.
• The tonsils usually appear ‘pointed’ rather than rounded
as in the normal.
• The position of the brainstem and fourth ventricle and
the rest of the brain should appear normal in
uncomplicated type 1.
• Syringomyelia may be present in 20–73% of cases (126,
128–130).
• May be associated with C2 and C3 fusion (Klippel–Feil
syndrome), short clivus or odontoid or C1 abnormalities.
Chiari II (the Arnold–Chiari malformation)
Midline sagittal and axial images of the brain and spinal cord
are required.
Brain:
• The cerebellar tonsils, vermis and brainstem are herniated
through the foramen magnum and the fourth ventricle
outlets are obstructed causing hydrocephalus (131).
• The cervicomedullary junction may be kinked.
 Rachischisis (Dysraphism)
• The frontal horns of the lateral ventricles are squared-off.
• The fourth ventricle is compressed.
• The aqueduct is stretched.
• The superior aspect of the cerebellum is herniated
superiorly through the tentorial hiatus (which is
enlarged), i.e. the whole posterior fossa is too small.
• Corpus callosum agenesis or partial abnormalities are
frequent.
• Heterotopias and abnormal gyral patterns are common.
Spinal cord:
• A lumbosacral myelomeningocele is nearly always present
(see p.140).
• The cord is nearly always tethered.
• A lipoma of the filum terminale may be present.
Less optimal imaging techniques:
• Plain skull and cervical spine x-rays may show cranial
enlargement, a small posterior fossa with low tentorial
insertion and dural sinuses, basilar impression (platy-
basia), enlargement of the foramen magnum, elongation
of cervical arches, widened cervical canal, fusion of
cervical vertebrae, and Klippel–Feil anomaly.
• Myelography followed by CT scanning of the cranio-
cervical junction (the contrast material in the subarach-
noid space helps to reveal the abnormality).
• Vertebral angiography.
TREATMENT
• The meningomyelocele and hydrocephalus should be
treated promptly in an affected infant.
• When signs of progressive neurologic deficit appear in
later life, hydrocephalus (if present) should be treated
surgically by shunting and suboccipital craniectomy and
upper cervical (C1) decompression laminectomy may
help decompress the region.
• If clinical progression is slight or uncertain, a conserva-
tive approach is recommended, with ongoing obser-
vation and reassessment.
131
131 Chiari II malformation.T1W midline sagittal view of the brain and
upper cervical cord shows marked abnormality of the brainstem and
cerebellum with downwards displacement of the cerebellum and no
true fourth ventricle.
139
RACHISCHISIS (DYSRAPHISM)
DEFINITION
Defective closure of the neural groove (dysraphism).
EPIDEMIOLOGY
• Incidence: the incidence varies widely from one country
to another and is about 1 per 1000. The disorder is more
likely to occur in a second child if one child has already
been affected (the incidence rises from 1 per 1000 to
40–50 per 1000). Abnormalities of closure of the
cranium are more frequent than defects of closure of the
vertebral arches. Even so, spina bifida occulta is found in
5% of the normal population. Meningomyelocele is 10
times more frequent than meningocele.
• Age: infants and children predominantly.
ETIOLOGY AND PATHOPHYSIOLOGY
Some degree of failure occurs during the first 3 weeks of
fetal development of the folding and fusion of the dorsal
midline structures of the primitive neural tube with its
normal covering of meninges, bone and skin. Genetic and
environmental factors are thought to interact. A genetically-
determined variant of the 5,10- methylenetetrahydrofolate
reductase gene that specifies a product with reduced enzyme
activity is associated with NTDs. Folic acid reduces the risk
of NTDs, not by correcting a simple nutritional deficiency
but by overcoming the reduced activity in the conversion of
5,10-methylenetetrahydrofolate to 5 methyltetrahydrofolate.
PATHOLOGY
Brain
Anencephaly
Absence of cranial vault and its contents (132). The
undeveloped brain lies in the base of the skull as a small
vascular mass without recognizable nervous tissue. It is the
most frequent of the rachischises. It has many associations
with other conditions in which the vertebral laminae fail to
fuse. It is incompatible with life.
132
132 Pathologic specimen, sagittal section, of a dead fetus with
anencephaly, showing absence of the cranial vault and its contents.
140 Developmental Diseases of the Nervous System

Cranial meningocele dilated fourth ventricle, expands in the midline, causing the
Meninges protrude through a defect in the skull. occipital bone to bulge posteriorly and to displace the
tentorium and torcula upward. In addition, the corpus
Meningoencephalocele callosum may be deficient or absent, and there is dilatation
Meninges and brain parenchyma protrude through a defect of the aqueduct, third and lateral ventricles.
in the skull.
Spinal cord
Dandy–Walker syndrome In the spine, dysraphism is most common in the lumbo-
A failure of development of the midline portion of the sacral area.
cerebellum. A cyst-like structure, representing the greatly
Spina bifida occulta
• Closure defect, due to failure of fusion, of one or more
133 vertebral arches.
• The spinal cord remains inside the vertebral canal and
there is no external sac.
• A congenital dural sinus tract occasionally communicates
the skin with the lumbar CSF sac via the incompletely
closed vertebral arch, and predisposes to recurrent
bacterial meningitis.
• Lipomas or dermoids in the cauda equina region may be
present and may not become symptomatic until later life.
• A skin dimple, vascular anomaly or tuft of hair may be
present over the site of the lesion in the low back in the
midline (133).
• Tethering of the spinal cord: may become symptomatic
in children and sometimes adolescents (see p.142).

133 Photograph of the low back of a patient with spina bifida occulta
showing a tuft of hair over the site of the spina bifida occulta, and a
vertical midline scar following surgical resection of a cauda equina
lipoma that was causing neurologic symptoms and signs.

134 135 136

134, 135 MRI lumbosacral spine, sagittal T1 (134) and dual echo T2W (135) images showing a
lumbosacral meningomyelocele and narrowing of the elongated lumbar cord with cord
tethering.There is no lipomatous or other soft tissue mass related to the spinal dysraphism. Disc
degeneration is noted incidentally at L2/3 and L3/4.

136 MRI cervical spine, sagittal T1W image, of the same patient in 134, 135, showing inferior displacement of the medulla and cerebellum and
elongation of the medulla (Chiari II malformation).
 Rachischisis (Dysraphism)
Meningocele
Meninges (dura and arachnoid) protrude through a defect
in the vertebral arch as a cystic CSF-filled dural sac. The
cord remains in the canal. Seldom are there any neurologic
consequences.
Meningomyelocele
Meninges and spinal cord or (more commonly the cauda
equina) roots protrude through the defect in the neural arch
as a dural sac containing spinal cord or roots closely applied
to the fundus of the cystic swelling (134, 135) . It may be
associated with overlying dermal defects, Arnold–Chiari
malformation (136), or hydrocephalus. Motor, sensory and
bladder disturbances are common.
Spina bifida aperta (myeloaraphia/rachischisis)
Exposed neural tube without overlying leptomeninges,
vertebral arch or dermis. The dural sac is open and neural
tissue is exposed on the back. Severe neurologic deficits are
always present.
Diastematomyelia
A septum (bony spicule or fibrous band) protrudes into the
spinal canal from the body of one of the thoracic or upper
lumbar vertebrae and through the spinal cord in an
anterior–posterior direction, thus dividing the spinal cord into
two for a variable vertical extent (137, 138). The division of
the cord may be complete, each half with its own dural sac and
set of nerve roots. This longitudinal fissuring and doubleness
of the cord is referred to as diplomyelia. With growth this leads
to a traction myelopathy. Often associated with spina bifida.
Associations
• Hydrocephalus as a result of aqueduct stenosis.
• Posterior fossa abnormalities.
• Syringomyelia.
• Klippel–Feil syndrome (fusion of cervical vertebrae or of
atlas and occiput).
137, 138 Diastematomyelia. 137
T2W midline sagittal (137),
and T1W axial (138) MRI of
the lumbar spine show a
bony bar (arrow) across the
center of the spinal canal
with neural tissue
(arrowheads) passing round
it. Note also the spinal canal
is abnormally wide and the
visible vertebral bodies and
posterior elements are
misshapen.
141
• Congenital dislocation of the odontoid process and atlas.
• Platybasia and basilar impression.
Complications
• Recurrent ascending bacterial meningitis due to the
presence of a sinus tract from skin to lumbar CSF.
• Progressive hydrocephalus from an often associated
Chiari malformation.
CLINICAL FEATURES
Cranial meningoencephalocele
Small encephaloceles protruding into the nasal cavity may
cause no neurologic signs unless innocently snipped off,
when CSF rhinorrhea may result. Larger occipital
encephaloceles may be associated with blindness, ataxia, and
mental retardation.
Lumbosacral meningomyelocele
Lumbosacral polyradiculopathy
The child is typically born with a lumbosacral meningo-
myelocele covered by delicate, weeping skin; sometimes it
may have ruptured in utero or during birth. If the sac
contains elements of spinal cord or cauda equina, there is
neurologic dysfunction appropriate to the level of the lesion.
If lumbosacral, the legs do not move unless the sac is
stroked, which may elicit involuntary movements of the
legs. The deep tendon reflexes are absent, there is no
response to pinprick over the lumbosacral dermatomes and
urine constantly dribbles. If entirely sacral, bladder and
bowel sphincters are affected but the legs are not.
Progressive spastic weakness of the leg muscles
Stretching of the spinal cord, which is securely attached to
the lumbar vertebrae, during the period of rapid
lengthening of the vertebral column (see Tethered cord
syndrome, p.142).
Acute or progressive cauda equina syndrome
Sudden or repeated stretching of the implicated sensory and
motor nerve roots.
Syringomyelia (see p.541)
Spina bifida occulta
No clinical symptoms. May have overlying tuft of hair
(133), discoloration, dimple or dermal sinus.
138
142 Developmental Diseases of the Nervous System

Tethered cord syndrome DIAGNOSIS

• Derives from adhesion of the conus to one of the lower lum-
bar vertebrae resulting in malascent of the conus medullaris.
• Causes:
– Intradural fibrous adhesions.
– Diastematomyelia.
– Intradural lipomas.
– Dermal sinus tracts.
– Tight filum terminale.
• Clinical features:
– Onset: may be delayed until adolescence or even later if
low traction on conus; may require additional mechanical
triggers if low traction on conus.
– Progressive sensorimotor (segmental) deficits in the
lower limbs (in about three-quarters of cases).
– Severe pain: perineogluteal region and non-dermatomal
leg pain (three-quarters).
– Cutaneous stigmata of spinal dysraphism, such as
subcutaneous lipoma, midline hypertrichosis, sacral nevus
(two-thirds).
– Bowel and bladder dysfunction (two-thirds).
– Mild upper motor neuron signs coexisting with
symptoms of conus dysfunction (one-sixth).
Pre-natal
• Amniotic fluid alpha-fetoprotein and acetylcholinesterase
immunoassay (removed at 15–16 weeks of pregnancy);
blood contamination is a source of error.
• Uterine ultrasound.
Post-natal
Clinical ± radiologic (see Features, above).
TREATMENT
Prevention
• Genetic screening could identify women who will require
folic acid supplements to reduce their risk of having a
child with a NTD.
• Folic acid supplementation during pregnancy.
• Termination of pregnancy if the diagnosis is established
at 16 weeks pregnancy and parents agree to a termination.
Conservative
If high spinal lesions and total paraplegia, kyphosis,
hydrocephalus, and other major congenital anomalies,
because of poor prognosis (see below).

Associated hydrocephalus Meningomyelocele

• Rapid increase in head size. Excise in the first few days of life if the objective is to
• Downward deviation of the eyes (‘setting sun’ eyes) due prevent fatal meningitis.
to upgaze paresis as a result of pressure on the posterior
commissure in the rostral midbrain. Hydrocephalus
Ventriculoperitoneal or ventriculoatrial shunt is used if
INVESTIGATIONS hydrocephalus needs to be decompressed.
Meningoceles/meningomyeloceles
• Plain x-rays of the relevant part of the spine are useful to PROGNOSIS
delineate the vertebral abnormalities (e.g. lumbosacral spine Less than 30% of patients with high spinal lesions and total
x-rays may show failure of fusion of one or more vertebral paraplegia, kyphosis, hydrocephalus and other major
arches, hemivertebrae, block vertebrae, diastematomyelia). congenital anomalies survive beyond 1 year. 80–90% of the
• CT brain scan (+/– intrathecal contrast) may further survivors are totally dependent on others for their care because
delineate bony elements and soft tissues (ideally with 2D of some degree of intellectual handicap and paraplegia.
and 3D reconstructions) and may reveal enlarged
ventricles due to hydrocephalus.
• MRI spine (midline sagittal T1 and T2W plus axials of
the relevant part) is the investigation of choice for
imaging the cord, meningocele contents (cord elements
or just CSF) and associated abnormalities such as
tethering of the cord, lipomas of the filum terminale, or
dermoids in the cauda equina region (134, 135).
• Beware of the dangers of lumbar puncture: iatrogenic
damage to the spinal cord by a needle inserted into a
spinal cord that is tethered to the margin of one of the
low lumbar or sacral vertebral bodies.

Diastematomyelia
• Plain x-rays may demonstrate the bony spur plus
associated anomalies.
• CT with intrathecal contrast will demonstrate the
relationship of the bony spur to the cord, nerve roots
and thecal sac.
• MRI is really the investigation of choice (see
Meningocele). It will demonstrate the position of the
cord-tethering and splitting (137, 138).
 Tuberous Sclerosis
TUBEROUS SCLEROSIS
DEFINITION
Tuberous sclerosis complex (TSC) is a neurocutaneous
syndrome characterized by intellectual handicap, epileptic
seizures, and hamartomas affecting multiple organs systems,
including skin, kidney, brain and heart.
EPIDEMIOLOGY
• Prevalence: 3.7 per 100 000 population in Scotland, but
may be as high as 8–9 per 100 000.
• Age: infancy and childhood.
• The disease may be present clinically and radiologically
at birth but is usually not recognized until 2–3 years of
age when delay in reaching milestones of natural
maturation, mental retardation, or epileptic seizures
become evident. Adenoma sebaceum appear later, usually
between 4–10 years of age, and progress thereafter.
• Gender: M=F.
PATHOLOGY
The TSC affects all tissues, including the lymphatic system,
with the possible exceptions of the peripheral nervous
system, meninges, skeletal muscle and pineal gland.
Brain
Cortical tubers and subependymal nodules
Macroscopically, the brain is normal in size but may show
areas (5 mm–3 cm [0.2–1.2 in]) of broadening, unnatural
whiteness, and firmness on the surface of the cerebral cortex
(‘cortical tubers’). Their cut surface reveals a lack of demarc-
ation of cortex from white matter and the presence of white
flecks of calcium (‘brain stones’). The surface of the lateral
ventricles may be encrusted with white or pink-white masses
(‘subependymal nodules’) resembling candle gutterings.
Rarely, nodules of abnormal tissue are seen in the basal
ganglia, thalamus, brainstem, cerebellum and spinal cord.
Microscopically, the tubers are composed of interlacing
rows of plump fibrous astrocytes (like an astrocytoma but
lacking in glial fibrillar protein). The structure of the
cerebral cortex and ganglionic structures is diffusely
disturbed with gliosis and the presence of atypical
monstrous neurons and giant glial cell forms. Nodules
composed of masses of subependymal glial cells intermixed
with distorted neurons or giant glial cells protrude into the
ventricles. These gliomatous deposits may obstruct the
foramina of Monro or the aqueduct or floor of the fourth
ventricle, causing hydrocephalus.
The cortical tubers and subependymal nodules both
show histologic evidence of abnormal growth and
migration, and occasionally they give rise to subependymal
giant-cell astrocytomas. Neoplastic transformation of
abnormal glial cells usually takes the form of a large-cell
astrocytoma, but may, less commonly, give rise to a
glioblastoma or a meningioma. Calcification may occur.
143
Skin
• Hypomelanotic macules are the first skin lesions to
appear in about 90% of cases of TSC. They vary from a
few millimeters to several centimeters in size, have an
oval ash leaf shape with one end round and the other
pointed, are arranged in a linear fashion over the trunk
or limbs, contain sweat glands, and become pink when
rubbed. Because of the reduced number and function of
melanoblasts, which normally absorb light in the
ultraviolet range, these lesions are more readily seen with
a Wood’s lamp, which transmits only ultraviolet rays.
• Adenoma sebaceum are small, red-pinkish-yellow, wart-
like skin lesions with a smooth glistening surface, about
2 mm in size, which tend to be limited to the nasolabial
folds, cheeks, and chin; sometimes also involving the
forehead and scalp. They are angiofibromas characterized
by hyperplasia of connective and vascular tissue.
• Shagreen patches are thick, slightly elevated, flesh-
colored yellowish skin, 1–10 cm (0.4–4 in) in diameter,
with a ‘pigskin’, ‘orange peel’, or ‘elephant hide’ appear-
ance, over the lower trunk, most often in the lumbosacral
region. These are plaques of subepidermal fibrosis.
• Subungual fibromas are fibromatous involvement of the
nail bed, which usually appear at puberty and continue
to develop with age. Other skin changes include café-au-
lait spots, fibroepithelial tags (soft fibromas), and port
wine hemangiomas.
Other
There is an increased incidence of:
• Glial tumors.
• Hydrocephalus.
• Spina bifida.
• Rhabdomyomas of the skeletal muscle and heart.
• Endocrine tumors.
• Cyst formation in the kidneys, pancreas, and liver.
• A honeycomb appearance of the lung.
• Phakomas of the retina: composed mainly of neuronal
and glial components.
ETIOLOGY AND PATHOPHYSIOLOGY
• Familial (i.e. inherited as an autosomal dominant or
recessive trait) in about 40% of cases, and sporadic (i.e.
new mutations) in at least 60% of cases.
• Genetic heterogeneity: mutations in two genes. One
gene, TSC1, is located on the long arm of chromosome
9 (9q34), and a second gene, TSC2, on chromosome
16p13.3.
• About 50% of TSC families show genetic linkage to
TSC1 and 50% to TSC2.
• Among sporadic cases, mutations in TSC2 are more
frequent and often accompanied by more severe
neurologic deficits.
• Multiple mutational subtypes have been identified in the
TSC1 and TSC2 genes.
• The TSC1 (chromosome 9) and TSC2 (chromosome
16) genes encode distinct proteins, hamartin and tuberin,
respectively, which are widely expressed in the brain and
may interact as part of a cascade pathway that modulates
cellular differentiation, tumor suppression, and intra-
cellular signalling. Tuberin has a GTPase activating
protein-related domain that may contribute to a role in
cell cycle passage and intracellular vesicular trafficking.
144 Developmental Diseases of the Nervous System
CLINICAL FEATURES
Clinically extremely variable with manifestations ranging from
very severe illness to absence of symptoms (i.e. the forme
fruste). Considerable variation is also observed within families.
• The usual presenting features in childhood are delay in
reaching milestones, progressive intellectual handicap and
epileptic seizures that are difficult to control, but only
one aspect may be prominent. Over half of affected
individuals have normal intelligence and a quarter do not
have seizures.
• The seizures initially take the form of salaam spasms (i.e.
flexion myoclonus with hypsarrhythmia [irregular
dysrhythmic bursts of high-amplitude spikes and slow
waves in the EEG]), later becoming atypical absence or
more typical generalized seizures.
• Focal neurologic deficits and seizures may arise as a result
of brain tumors.
• Dystonia and athetosis may also occur.
• Behavioral and affective disorders are present in about
half of patients.
• Hypomelanotic macules may be visible on the skin using
a Wood’s light.
• Adenoma sebaceum typically occurs in childhood over the
cheeks and bridge of the nose in a butterfly distribution
(139). In some patients it may be more subtle and
restricted to a few lesions in the nasolabial folds.
• Gingival and subungual (beneath the fingernails)
fibromas begin to appear in adolescence (140).
• Phakomata (white nodules) appear in the retina on
ophthalmoscopy.
• Other congenital abnormalities such as spina bifida and
hydrocephalus may be present.
• Family history may be revealing.
139
DIFFERENTIAL DIAGNOSIS
• Mental retardation:
– Acquired destructive lesions: obstructive hydrocephalus.
– Chromosomal abnormalities.
– Multiple congenital anomalies: rubella.
– Developmental abnormality of the brain.
– Metabolic and endocrine disease: cretinism.
– Progressive neurodegenerative disease: lipidoses.
– Psychosis.
• Epilepsy (see p.65).
• Adenoma sebaceum: acne vulgaris.
• Other neurocutaneous syndromes:
– Sturge–Weber syndrome (see p.151).
– Von Hippel–Lindau disease (see p.392).
– Neurofibromatosis (see p.147).
– Ataxia telangiectasia (see p.444)
INVESTIGATIONS
CT scan or MRI scan
CT scan (141–144) or, preferably, MRI scan (145) of the
brain may reveal:
• Cortical and subcortical tubers (50% calcified on CT, 3%
enhance on MR).
• Subependymal nodules (80% calcified on CT, 30%
enhance on MR).
• White matter lesions: seen on MRI as curvilinear or
wedge-shaped bands radiating from the ventricles; 12%
enhance.
• Atrophy and enlarged ventricles.
• Giant cell astrocytoma: usually near the foramen of
Monro (145). These are larger than the other subepen-
dymal nodules and grow and obstruct the foramina. On
CT or MR a prominent enhancing nodule near the
foramen of Monro is likely to be a giant cell astrocytoma.
140
140 Ungual fibroma adjacent to the lateral border of the nail bed
of the left great toe and third toe in a patient with tuberous
sclerosis. (Courtesy of Dr AM Chancellor,Tauranga, New Zealand.)
139 Photograph of the face of a patient with tuberous sclerosis
showing diffuse small adenoma sebaceum (pink, wart-like
angiofibromas) throughout the cheeks, chin and forehead, and larger
lesions in the nasolabial fold on the left. (Courtesy of Dr AM
Chancellor,Tauranga, New Zealand.)
 Tuberous Sclerosis 145

141 142 143

141–143 CT scan of the brain, non-contrast, axial slices, showing small white calcified subependymal nodules in the temporal horns bilaterally
(141), frontal horn of the right lateral ventricle and posterior horn of the left lateral ventricle (142), and the lateral ventricles bilaterally (143)
in a patient with tuberous sclerosis.

144 145

145 T1W axial MRI post-contrast showing a

mass at the foramen of Monro (arrow) with
marked contrast enhancement and mixed
signal features in a patient with tuberous
sclerosis.There is secondary hydrocephalus
144 CT scan of the brain, non-contrast, axial slices, showing small white calcified subependymal (the lateral ventricles are very large).
nodules in the frontal horn of the right lateral ventricle, and the lateral ventricles bilaterally
(arrows), not to be confused with the calcified pineal gland centrally (short arrow) and calcified
choroid plexus laterally (arrowheads). (Courtesy of Dr AM Chancellor,Tauranga, New Zealand.)
146 Developmental Diseases of the Nervous System

EKG PREVENTION
Counselling of affected individuals against childbearing.
Echocardiograph
?Cardiac rhabdomyoma. PROGNOSIS
• Slow progression, mainly in cognitive function,
Abdominal ultrasound ultimately leading to death in adolescence or early adult
Liver, kidneys. life.
• Status epilepticus is now a less common cause of death,
Blood with better control of epilepsy.
DNA analysis for mutations in the TS genes located on • Malignant gliomas cause a significant minority of deaths.
chromosomes 9 (TSC1) and 16 (TSC2). • Incomplete forms of TS may have a better prognosis.

DIAGNOSIS
Definite TSC
Two major diagnostic features or one major plus two minor
features.

Probable TSC
One major plus one minor feature.

Possible TSC
One major or two or more minor features.

Major diagnostic features

• Facial angiofibromas (adenoma sebaceum).
• Ungual fibromas.
• Retinal hamartomas.
• Hypomelanotic macules (three or more).
• Shagreen patch.
• Renal angiomyolipoma.
• Cardiac rhabdomyoma.
• Pulmonary lymphangiomatosis.
• Subependymal nodules.
• Subependymal giant cell astrocytomas.
• Tubers.

Minor diagnostic features

• Dental enamel pits in deciduous or permanent teeth.
• Bone cysts.
• Renal cysts.
• Gingival fibromas.
• Hamartomatous rectal polyps.

The diagnosis of people with minimal disease expression

(the forme fruste) can be very difficult. In children the
phenotype is often incomplete or not fully assessable. Hence
mildly affected subjects, at risk for severely affected
offspring, may remain undiagnosed. The detection of
(small) mutations in the TS genes located on chromosomes
9 (TSC1) and 16 (TSC2) has recently become possible and
may be helpful in the diagnosis of ambiguous cases.

TREATMENT
Symptomatic
• Epilepsy: anti-epileptic medication. It is rarely helpful to
attempt tumor excision, particularly in severely affected
individuals.
• Raised intracranial pressure: partial tumor excision or
ventricular decompression.
• Adenoma sebaceum: dermabrasion of facial lesions may
benefit patients who are not mentally impaired but they
regrow slowly.
 Neurofibromatosis
NEUROFIBROMATOSIS
DEFINITION
The neurofibromatoses are a group of neurocutaneous
syndromes primarily affecting tissues derived from the neural
crest. They consist primarily of two distinct
neuroectodermal disorders (phakomatoses) which are
inherited as autosomal dominant traits and characterized by
localized overgrowths of ectodermal and mesodermal
elements in the nervous system and skin.
CLASSIFICATION
• Neurofibromatosis 1 (NF-1): the more common type,
also previously called peripheral and von Reckling-
hausen’s neurofibromatosis. The responsible gene is
located on chromosome 17q11.2, and is believed to
function as a tumor suppressor gene. The protein
product of the NF1 gene is called neurofibromin, a
protein that negatively regulates signals transduced by
Ras proteins.
• Neurofibromatosis 2 (NF-2): the less common type, also
previously called central neurofibromatosis. The gene is
located on chromosome 22q12.
EPIDEMIOLOGY
• Incidence:
– NF-1: 1 in 2500 live births.
– NF-2: 1 in 33 000 live births.
• Prevalence:
– NF-1: 1 in 5000.
– NF-2: 1 in 210 000.
• Age:
– NF-1: pigmentary lesions are nearly always present at
birth but neurofibromas are infrequent then. Both
lesions increase in number during late childhood and
adolescence.
– NF-2: symptoms usually begin in the ‘teens or early
twenties’, but occasionally as early as the first and as late
as the seventh decade of life.
• Gender: M=F.
PATHOLOGY
Skin
• Hyperpigmented lesions (café-au-lait patches) which are
characterized by an excess of melanosomes in the
malpighian cells, which accounts for the dark color (there
is no excess of melanocytes) and abnormally large
melanosomes in some of the basal cells of the epidermis.
• Skin tumors: the collagen and elastin of the dermis is
replaced by a loose arrangement of elongated connective
tissue cells.
Nervous system
• Nerve tumors: composed of a mixture of fibroblasts and
Schwann cells, except optic gliomas which contain a
combination of astrocytes and fibroblasts.
• There is an increased incidence of brain tumors such as
gliomas, meningiomas, and acoustic neuromas.
• Malignant degeneration of tumors occurs in 2–5% of
cases, peripherally they become sarcomas and centrally,
astrocytomas or glioblastomas.
147
ETIOLOGY AND PATHOPHYSIOLOGY
Autosomal dominant inheritance or spontaneous mutation.
About 50% of cases have no family history.
NF-1
NF-1 is caused by a mutation of the NF-1 gene located on
chromosome 17q11.2; 50–70% of patients inherit the
mutation as an autosomal dominant trait and 30–50% (i.e.
the remainder) of patients represent a new mutation. Full
penetrance is exhibited.
The NF-1 gene codes for a large cytoplasmic protein of
2818 acids. The NF-1 gene product, neurofibromin,
contains a small region in the central part of the protein that
bears sequence similarity with a family of proteins that
regulate the proto-oncogene p21-ras. These p21-ras regu-
latory proteins are collectively termed guanosine triphos-
phatase (GTPase)-activating proteins (GAPs). Since p21-ras
can transform cells, neurofibromin (which downregu-
lates/inhibits p21-ras activity) suppresses the growth of cells.
The identification of somatic mutations in NF-1 from tumor
tissue suggests that NF-1 is probably a tumor suppressor
gene. The mutation probably results in a loss of NF-1 gene
expression, which leads to a loss of neurofibromin.
Neurofibromin is hypothesized to function as a tumor
suppressor (negative growth regulator) by:
• Inactivating the p21-ras proto-oncogene, thus reducing
cell proliferation in some cell types, such as Schwann cells
and astrocytes (in astrocytomas).
• Regulating microtubule signal transduction in the
cytoskeleton.
• Influencing progression through the cell cycle and
promoting growth arrest at the ‘commitment’ stage of
the cell cycle, causing cells to exit from the cell cycle and
remain in G0/G1.
The loss of neurofibromin causes a loss of suppression of
cell growth, predisposing to particular benign and malignant
neoplasms, which arise primarily from cells of neural crest
origin (e.g. neurofibromas, neurofibrosarcomas, optic
gliomas, and pheochromocytoma) and also immature
myeloid cells (e.g. juvenile myelomonocytic leukemia, and
the monosomy 7 syndrome, a childhood variant of myelo-
dysplasia). The exact mechanism remains uncertain however.
NF-2
Inactivating mutations of both alleles of the NF-2 gene on
chromosome 22q12.1, consistent with the tumor suppressor
gene hypothesis. The gene product is merlin.
CLINICAL FEATURES
Clinical expression is very variable.
NF-1 type
Skin pigmentation
Multiple (more than 5) brown skin macules appear shortly
after birth, usually on the trunk, but can occur any place on
the body, and vary in size from a millimeter or two to
several centimeters, and in color from a light to a dark
brown (café-au-lait spots). Axillary and inguinal freckles or
diffuse pigmentation also occur.
148 Developmental Diseases of the Nervous System
Skin neurofibromas
These appear in late childhood or early adolescence. They
are situated in the dermis and form discrete, soft or firm
papules which are flesh-colored or violaceous, vary in size
from a few millimeters to 1 or more centimeters, and come
in all shapes: flattened, sessile, pedunculated, conical and
lobulated. When pressed, the soft tumors tend to invaginate
through a small opening in the skin: ‘buttonholing’.
Plexiform neuromas
Overgrowth of subcutaneous tissue, often in the face, scalp,
neck and chest, which feel like a bag of worms or strings to
palpation. The underlying bone may enlarge. If there is
overlying hyperpigmentation which extends to the midline,
suspect an intraspinal tumor at that level.
More deeply located neurofibromas
Firm discrete nodules may attach to a nerve which may
compress the spinal cord, nerve roots, brachial or
lumbosacral plexus, and peripheral nerves and cause pain
and muscle weakness in the distribution of innervation of
the relevant nerves. For example, neurofibromas developing
on spinal nerve roots may extend through the intervertebral
foramen in dumb bell fashion and compress the spinal cord
(146–149). If not, they may attain considerable size in the
posterior mediastinum or retroperitoneal space.
Vestibulocochlear (VIIIth cranial) nerve sheath neurofibroma
Nerve deafness, dizziness, headache, staggering.
Meningioma (see p.374)
Glioma (see p.364)
Optic nerve glioma (see p.372)
Progressive monocular blindness, optic atrophy, nystagmus,
enlargement of the optic foramen, abnormal contour of sella
turcica, and failure to thrive (if the hypothalamus is
invaded).
Lisch nodules
Nodules appear as small whitish pigmented iris hamartomas.
Choroidal abnormalities
Bright, multiple, patchy regions at and around the entire
posterior pole of most, if not all, eyes when viewed by
infrared monochromatic light examination (but are not seen
under conventional ophthalmoscopic examination or
fluorescein angiography). These regions correspond to
hypofluorescent areas on indocyanine-green angiography.
Other tumors
• Ganglioneuromas.
• Pheochromocytomas.
• Carcinoid tumor of the intestine.
Other features or associations
• Macrocephaly.
• Cortical dysplasias.
• Heterotopias.
• Aqueduct stenosis.
• Learning disabilities.
• Intellectual decline.
• Speech impediments.
• Headache.
• Epileptic seizures.
• Short stature.
• Cranial bone defects with pulsating exophthalmos.
• Bone cysts.
• Bone hypertrophy.
• Pathologic fractures (pseudoarthrosis).
• Bony malformations of the spine.
• Kyphoscoliosis.
• Syringomyelia.
• Stroke (ischemic).
Patients with NF-1 may have Schwann cell tumors on
any nerve, but bilateral acoustic neuromas are virtually non-
existent in families with this disorder.
NF-2 type
Bilateral or multiple acoustic neurilemmomas
• The hallmark.
• The first symptom is usually unilateral loss of hearing,
which is often first noticed when using a telephone.
There may be a history of intermittent ringing or roaring
in one or both ears or some unsteadiness, particularly
when walking at night on uneven ground (when visual
cues are eliminated).
• Other symptoms include vertigo, facial weakness, sensory
change, headache, seizures, or a change in vision.
• Symptoms are usually caused by pressure on the
vestibulocochlear and facial nerve complex.
Other features
• Multiple CNS tumors:
– Neurilemmomas on cranial and spinal nerves.
– Intracranial and intraspinal meningiomas.
– Astrocytoma of the optic nerve, brainstem, spinal cord.
• One or more café-au-lait spots; skin changes are less
common than in type 1.
• Subcutaneous neurofibromas.
• Lens opacity or cataracts.
TERMINOLOGY
Because NF-1 and NF-2 may have both central and
peripheral nervous system manifestations, the terms used
previously – ‘peripheral neurofibromatosis’ (for von
Recklinghausen’s form) and ‘central neurofibromatosis’ (for
bilateral acoustic neuroma) – have been discarded as
misleading and confusing.
DIFFERENTIAL DIAGNOSIS
• Normal patches of skin pigmentation: 10% of the
population have one or more café-au-lait spots, but not
more than six spots, particularly exceeding 1.5 cm
(0.6 in) in diameter.
• Multiple lipomas.
• Sporadically occurring tumors of the nervous system:
meningiomas, schwannomas, neurofibromas and gliomas.
 Neurofibromatosis
146
146 Cervical spine x-ray, oblique lateral view, showing enlargement of
the C2/3 intervertebral foramen (arrow) caused by a neurofibroma
developing on the C3 spinal nerve root and extending through the
intervertebral foramen.
148
148 MRI cervical spine, coronal T1W image, after gadolinium contrast
injection, showing the same lesion in 147 as a well circumscribed, dumb
bell-shaped, high intensity, contrast-enhancing neurofibroma (arrow)
measuring 4 cm (1.6 in) laterally in the coronal plane, extending from
the upper cervical spinal cord at C2 through the C2/3 intervertebral
foramen.The upper cervical spinal cord is displaced to the left (to the
right in the image) and compressed to a crescentic shape.
149
147
147 MRI cervical spine, sagittal T1W image showing a well
circumscribed, low-density, neurofibroma (arrow) measuring 2 cm
(0.8 in) in diameter in the anterior-posterior plane and 2.5 cm (1 in) in
the rostral-caudal plane which is compressing the upper cervical spinal
cord at C2.
149
149 MRI cervical spine, axial T1W image at the level of C2/3, after
gadolinium contrast injection, showing the same lesion as in 147, 148
as a well circumscribed, high intensity, contrast-enhancing neurofibroma
(arrows) extending from the upper cervical spinal cord at C2 (which is
displaced to the left [to the right in the image]) through the C2/3
intervertebral foramen.
150 Developmental Diseases of the Nervous System
INVESTIGATIONS
NF-1
• Slit lamp examination of irides.
• Neuropsychologic assessment of IQ.
• Visual evoked potentials.
• Molecular DNA analysis.
• 24-hour urinary catecholamines if pheochromocytoma
suspected.
• Imaging:
– Bone dysplasias and pseudarthroses of the long bones are
best shown on plain radiography occasionally combined
with CT.
– MRI is the investigation of choice for brain and optic nerve
abnormalities though CT can be used (contrast enhanced).
– Optic gliomas (pilocystic astrocytomas pathologically)
are seen in 15–40% of patients with NF-1. MRI (or CT)
shows thickening and increased signal (on T2W image)
of the optic nerves (usually bilaterally) or chiasm with
variable enhancement. The signal alterations may extend
posteriorly along the optic pathways (see p.372).
– Areas of increased signal on T2W image are often seen
in the basal ganglia, cerebral peduncles, and hemispheric
white matter. The exact cause of these is debated, but
growth or new enhancement after adolescence may
indicate malignant gliomatous change and requires short
time interval follow-up scans.
– De novo cerebellar, brain stem and cerebral astrocytomas
are also seen in NF-1.
– Plexiform neurofibromas favor the Vth nerve and orbit,
are soft and elastic, and appear as enlarged nerves. These
may undergo sarcomatous change.
– Astrocytomas of the spinal cord also occur (MRI
demonstrates these best).
NF-2
• Audiometry.
• Molecular DNA analysis.
• Imaging:
– MRI is the investigation of choice for brain and spinal
lesions.
– Enhanced T1W MRI is the best technique to demon-
strate bilateral acoustic schwannomas. Any coincidental
meningiomas or schwannomas elsewhere in the brain
(Vth nerve is the next most common site) will be seen as
strongly enhancing (white) masses, and gliomas (e.g.
ependymomas) may also be seen.
– Other brain abnormalities include aqueduct stenosis,
polymicrogyria and pachygyria.
– In the spine, multiple nerve sheath tumors occur on the
nerve roots usually in the cauda equina. These may be
intra or extra dural.
– Other spinal abnormalities include dural ectasia (lateral
thoracic outpouchings of dura and scalloping of the
posterior surfaces of the vertebral bodies) and syringomyelia.
DIAGNOSIS
NF-1
Clinical
Two or more of the following clinical criteria:
• Six or more café-au-lait macules whose greatest diameter is:
– >5 mm (>0.2 in) in prepubertal individuals, and
– >15 mm (>0.6 in) in postpubertal individuals.
• Two or more neurofibromas of any type or one plexi-
form neurofibroma.
• Freckling in the axillary or inguinal regions.
• Optic glioma (see p.372).
• Two or more Lisch nodules (iris hamartomas).
• A distinctive osseous lesion such as sphenoid dysplasia or thin-
ning of long-bone cortex with or without pseudoarthrosis.
• A first-degree relative (parent, sibling, or child) with NF-1
by the above criteria.
Molecular DNA analysis
NF-2
Clinical
One of the following clinical criteria:
• Bilateral vestibulocochlear (VIIIth cranial) nerve tumors
imaged by CT or gadolinium-enhanced MRI scan.
• A first-degree relative (parent sibling or child) with NF-2
and either a unilateral VIIIth nerve tumor, or any two of the
following: neurofibroma, meningioma, glioma, schwan-
noma, or early- (juvenile) onset posterior subcapsular
lenticular opacity.
Molecular DNA analysis
Mild and severe phenotypic subtypes of NF-2 can be defined
using age at onset of symptoms (≥20 years vs. <20 years),
number of associated intracranial tumors (<2 tumors vs. ≥2
tumors), and spinal tumors (absent vs. present).
It is important to distinguish between NF-1 and NF-2
because the genetic basis and natural history are distinct. It
is also important to differentiate between NF-2 and the
sporadic unilateral acoustic neuroma, the latter of which is
not inherited, it tends to develop later in life, and raises far
fewer problems in management (see p.383).
TREATMENT
• Most people do not experience any functionally disabling
complications.
• Surgical resection or decompression of tumors is indicated
for gliomas and meningiomas and when neurofibromas
compress cranial and peripheral nerves or spinal cord. The
skin tumors should not be excised unless they are
cosmetically objectionable or increase in size, suggesting
malignant change. Plexiform neuromas of the face should
be dealt with by an experienced plastic surgeon because
they may involve cranial nerves superficially or affect the
underlying bone by eroding it (a pressure effect) or
causing it to hypertrophy from increased blood supply.
• Treatment of acoustic neuroma (see p.383).
• Genetic counselling for patient and family, including
presymptomatic diagnosis of family members.
PROGNOSIS
NF-1
A progressive disease but the prognosis varies with the grade of
severity, being more favorable in those with only a few lesions.
NF-2
• Bilateral acoustic neuromas are inherited in an autosomal
dominant pattern with penetrance of over 95%, so that for
any offspring of an affected parent the risk that these tumors
will develop is about 50%. There are marked inter-family
differences in tumor susceptibility and disease severity.
• The mean age at death is about 35 years. Almost all deaths
are a result of a complication of neurofibromatosis.
 Sturge–Weber Diseases (Encephalotrigeminal Vascular Syndrome)
STURGE–WEBER DISEASE
(ENCEPHALOTRIGEMINAL
VASCULAR SYNDROME)
DEFINITION
A rare, congenital and sporadic neuroectodermal
degeneration (phakomatosis) characterized by:
• A cavernous or capillary cutaneous hemangioma (port
wine stain) on one side of the face, but sometimes
asymmetrically bilateral, in the distribution of the
ophthalmic division of the trigeminal nerve, together
with,
• A venous hemangioma of the meninges, usually
ipsilateral to the skin lesion, and
• Atrophy, gliosis and calcification of the underlying
cerebral cortex.
In 1879, W Allen Sturge described a child with sensori-
motor seizures contralateral to a facial ‘port wine mark’, and
in 1922 and 1929, Parkes Weber radiographically demon-
strated the atrophy and calcification of the cerebral hemi-
sphere homolateral to the skin lesion.
EPIDEMIOLOGY
• Incidence: uncommon. Isolated facial port wine stains
without neurologic complications occur in about 1 in
5000 births.
• Age: present from birth.
• Gender: M=F.
PATHOLOGY
• Capillary or cavernous hemangiomatous malformation
within but not always limited to the ophthalmic division
of the trigeminal nerve; in some cases, additional divi-
sions of the trigeminal nerve and other body parts are
involved (150).
• Venous hemangioma of the leptomeninges in the
parieto-occipital region. When the skin lesion involves
the ophthalmic division of the trigeminal nerve, the
venous hemangioma is usually present in the occipital
lobes, whereas a facial nevus is more often associated with
involvement of the parietal and frontal lobes.
• Atrophy of the subcortex of the brain on the side of the
facial lesion, beneath the large number of abnormal
blood vessels in the meninges, probably due to stagna-
tion of blood flow and consequent hypoxia. In some
cases, a band of calcification develops within the lesion
in the second and third layers of the cerebral cortex.
ETIOLOGY AND PATHOPHYSIOLOGY
• Unknown.
• Sporadic usually; familial occurrence is exceptional.
• Intrauterine developmental malformation.
• There seems to be a close correlation between the mal-
development of the embryonic vasculature of the eyelid
and forehead and that of the parieto-occipital parts of the
brain.
151
CLINICAL FEATURES
• Cutaneous angiomatosis (vascular nevus) on one side of
the face and scalp involving the first (ophthalmic)
division of the trigeminal nerve.
– Present at birth.
– Deep red (port wine nevus).
– Varies in its extent (150): it may be limited to only the
upper eyelid and forehead or may extensively involve the
entire head and even other parts of the body.
– Involvement of the upper eyelid nearly always indicates
an associated brain lesion. Nevi lying entirely below the
upper eyelid or high on the scalp are not usually
associated with a brain lesion, but can occasionally be
associated with a vascular malformation of the meninges
overlying the brainstem and cerebellum.
– Margins may be flat or raised.
– Surface may elevated or irregular due to soft or firm
papules, composed of vessels.
• Epileptic seizures (partial and secondary generalized),
which usually begin in infancy or early childhood, some-
times followed by transient postictal (Todd’s) or permanent
paralysis, are usually the first neurologic symptom.
• Intellectual handicap in some cases.
• Hemiparesis, hemisensory defect, and homonymous
hemianopia contralateral to facial nevus in severe cases,
may arise abruptly or insidiously. The arm and leg may
be small.
• Angiomatosis of choroid of eye with abnormal distension
and enlargement of the eyeball (buphthalmos) ipsilateral
to the lesion, sometimes with later glaucoma, causing
blindness.
• Megalencephaly due to impaired cerebral venous return
has been reported.
• Hypertrophy of the face in some cases: increased
cutaneous vascularity may result in an overgrowth of
connective tissue and underlying bone.
150
150 Facial photograph showing a cutaneous capillary hemangioma
(port wine stain) on one side of the face in the distribution of the
ophthalmic and maxillary divisions of the trigeminal nerve.
152 Developmental Diseases of the Nervous System

DIFFERENTIAL DIAGNOSIS TREATMENT

• Facial nevi, especially the flat midline ones: of no
neurologic significance.
• Elevated strawberry nevi: of no neurologic significance.
• Epidermal nevus syndrome: an epidermal nevus or linear
sebaceous nevus is associated with a variety of hemicranial
and neurologic abnormalities, such as thickening of the
skull bones, unilateral cerebral atrophy, porencephalic
cyst, leptomeningeal hemangioma and arteriovenous
malformation ipsilateral to the nevus.
• Hemangioma of the trunk or upper or lower limb
associated with a spinal cord vascular malformation
(Klippel–Trenaunay syndrome).
• Hemangioblastoma of the retina and cerebellum (von
Hippel-Lindau disease, see p.392).
• Familial telangiectasia (Osler–Rendu–Weber disease, see
p.153).
• Symptomatic control of complications such as epileptic
seizures (with anti-epileptic medications), and glaucoma
if they arise.
• Laser therapy may reduce the size and intensity of the
skin lesion.
• The brain lesions are usually too extensive to be treated
surgically, though resection may be considered for
intractable epilepsy.
PROGNOSIS
• Most patients survive for many years, often with epileptic
seizures and some residual neuropsychologic deficit and
hemiparesis.
• Meningeal nevi do not enlarge to form a mass lesion and
they are rarely the source of subarachnoid or brain
hemorrhage.

INVESTIGATIONS
Skull x-ray
Uusually negative just after birth but when it is taken at the
end of the second year reveals characteristic parieto-occipital
cortical calcification, often as parallel lines, ‘railroad tracks’
or ‘tramline calcification’.

Cranial CT
Cranial CT scan at an earlier age shows a ‘tramline’ pattern
of intracranial, usually parieto-occipital, hyperdensity (due to
calcification) of the cerebral cortex on the side of the brain
beneath meningeal angiomatosis (151); atrophy of that side
of the brain and abnormal deep cerebral venous drainage.

MR scanning
MRI may show more abnormalities including:
• Accelerated myelination in the affected hemisphere in the
early stages of the condition. 151
• Abnormal low signal in the white matter on the side of
the port wine stain.
• Enhancement of the pia mater overlying the affected
cortex probably due to ischemia (which is the underlying
lesion).
• Abnormal draining deep cerebral veins.
• Abnormalities on both sides of the head though more
pronounced on the side of the cutaneous abnormality.

Cerebral angiography
The abnormal meningeal vessels, which are predominantly
veins, are not well seen (in contrast to arteriovenous
malformations) because the drainage of the hemisphere
ipsilateral to the port wine stain is all to the deep cerebral
veins, there being no cortical drainage (152, 153).
Prominent focal dilatation of the deep veins and apparent
strictures of the venous sinuses may be present.

151 CT brain scan (with contrast) showing an area of serpiginous

calcification in the right parietal lobe at the junction of cortex with
white matter (arrows), typical of Sturge–Weber syndrome.
 Hereditary Hemorrhagic Telangiectasia (HHT) (Osler–Rendu–Weber Syndrome) 153

152 HEREDITARY HEMORRHAGIC

TELANGIECTASIA (HHT)
(OSLER–RENDU–WEBER SYNDROME)

DEFINITION
A group of autosomal dominant inherited disorders
characterized by multiple telangiectases involving the skin,
mucous membranes, viscera (particularly the gastrointestinal
[nose, pharynx, gut] and genito-urinary tracts) and occasion-
ally the nervous system. Rendu first recognized the combin-
ation of hereditary epistaxis and telangiectases in 1896 as a
specific distinct entity from hemophilia. Osler and Weber
produced prominent case reports in the following decade.

EPIDEMIOLOGY
• Prevalence: 1 in 2350 (France) to 1 in 40 000 (England).
• Age: children and adults.
• Gender: M=F.

PATHOLOGY
Telangiectases
• Range from small focal dilatations of postcapillary venules
to large, markedly dilated and convoluted venules which
extend through the entire dermis, have excessive layers of
smooth muscle without elastic fibers, and often connect
directly to dilated arterioles. Perivascular lymphocytes.
• Bright red or violaceous.
152 Lateral view of the venous phase of a right carotid angiogram • Blanch under pressure.
(same patient as in 151) demonstrating the grossly abnormal venous • Range in size from that of a pinhead to >3 mm (0.1 in).
drainage of the right hemisphere – the anterior half of the sagittal sinus • Tendency to bleed.
is absent (arrowheads indicate missing sinus) as is the deep venous • Skin, gastrointestinal tract.
drainage, consequently the blood drains via enlarged cortical and peri-
cavernous veins (arrows). Arteriovenous malformation
• Direct connections between arteries and veins, lacking
capillaries.
153 • Brain (5–10%).
• Spinal cord.
• Pulmonary (5–15%): predilection for lower lobes.
• Gastrointestinal tract.

Aneurysm
Intracranial.

ETIOLOGY AND PATHOPHYSIOLOGY

• Autosomal dominant inheritance.
• Gene locus: chromosome 9q33-q34 in some families,
and chromosome 12q in other families.
• The gene for HHT at chromosome 9q3 is endoglin.
Endoglin encodes an integral membrane glycoprotein
that is the most abundant protein on endothelial cells to
bind transforming growth factor β. Transforming growth
factor β modulates several processes of endothelial cells,
including migration, proliferation, and adhesion and the
composition and organization of the extracellular matrix.
• The fundamental lesion is probably a dysplasia of the
vessel wall.
• Bleeding is thought to be due to the mechanical fragility
of the vessel.
• Pulmonary arteriovenous malformations create a right-to-
153 Lateral view of the venous phase of a left carotid angiogram left shunt that may lead to cerebral hypoxia and polycythemia
(same patient) showing the grossly abnormal venous drainage of the and may allow the passage of paradoxical emboli
left hemisphere – all via the deep veins, there being no communication (thrombotic, septic) from the systemic venous circulation or
to the superficial system.The port wine stain was on the left. right heart to the brain causing stroke and cerebral abscess.
154 Developmental Diseases of the Nervous System

CLINICAL FEATURES Gastrointestinal arteriovenous malformations,

• Severe or recurrent episodes of: telangiectases, angiodysplasias
– Epistaxis. • Endoscopy.
– Upper or lower gastrointestinal hemorrhage. • Angiography.
– Hematuria. • CT for liver lesions.
– Sudden focal neurologic dysfunction: stroke syndrome
due to intracranial or intraspinal hemorrhage, or arterial DIAGNOSIS
obstruction by paradoxical embolism of thrombus from Clinical
the systemic venous circulation or right heart to the brain. Any two of the following:
• Iron deficiency anemia. • Recurrent epistaxis.
• Progressive focal neurologic dysfunction: enlargement of • Telangiectases elsewhere than in the nasal mucosa.
the intracranial or intraspinal vascular lesions, or • Evidence of autosomal dominant inheritance (the disease
occurrence of brain abscess due to embolism of septic is found in heterozygotes but penetrance may be
material to brain via pulmonary fistulae. incomplete).
• Epileptic seizures: arteriovenous malformation. • Visceral involvement.
• Family history.
• Dyspnea, fatigue, cyanosis, polycythemia, clubbing, chest Molecular DNA
bruit. Mutation of the endoglin gene on chromosome 9q3, in
• Telangiectases on lips, tongue, palate, nasal mucosa, face, some cases.
conjunctivae, trunk, nail beds, finger pulps (154, 155).
• Cerebral and spinal telangiectases are usually TREATMENT
asymptomatic. Nasal telangiectases
• Humidification.
INVESTIGATIONS • Packing.
• Full blood count. • Transfusion.
• Iron studies if microcytic, hypochromic anemia. • Estrogen therapy.
• Septal dermoplasty.
Brain arteriovenous malformation • Laser ablation.
• CT brain scan. • Cautery eradicates a bleeding lesion, but satellite ones
• MRI brain scan. tend to form.
• MR angiography.
Skin telangiectases
Pulmonary arteriovenous malformation • Topical agents: oxidized cellulose (Oxycel or Gelfoam)
• Chest x-ray (156–158). applied to the lesion.
• Arterial blood gases and finger oximetry. • Laser ablation.
• High resolution helical CT (159, 160).
• Pulmonary angiography.

154 155

154, 155 Telangiectases of the upper and lower lips (154) and
tongue (155) in a patient with hereditary hemorrhagic telangiectasia.
 Hereditary Hemorrhagic Telangiectasia (HHT) (Osler–Rendu–Weber Syndrome) 155

156 157

156, 157 Chest x-ray. Posterior–anterior (156) and lateral (157)

views showing a pulmonary arteriovenous malformation in the left
anterior mid zone (arrow, 156) and the anterior aspect of the left
lower lobe (arrow, 157).

158 159

160

158 Chest x-ray posterior–anterior showing a pulmonary

arteriovenous fistula (arrows). (Reproduced with permission from
Hankey GJ,Warlow CP [1994] Transient Ischaemic Attacks of the Brain
and Eye. WB Saunders, London.)
159, 160 Chest CT scan, images in the axial plane, at the level of the
mid thorax (159) and the right hemidiaphragm (160) showing a
pulmonary arteriovenous malformation in the left anterior mid zone
(arrow, 159) and the anterior aspect of the left lower lobe (arrow, 160).
156 Developmental Diseases of the Nervous System

Pulmonary arteriovenous malformation Gastrointestinal arteriovenous malformation

• Embolotherapy. • Transfusion.
• Surgical resection. • Photocoagulation.
• Ligation of arterial supply. • Estrogen-progesterone therapy.
• Antibacterial prophylaxis at the time of a dental or
surgical procedure. PROGNOSIS
The telangiectases first appear during childhood, enlarge
Central nervous system arteriovenous malformation during adolescence, and may assume spidery forms,
(see p.245) resembling the cutaneous telangiectases seen with liver
• Neurovascular surgery. cirrhosis, in late adult life.
• Embolotherapy.
• Stereotactic radiosurgery.

FURTHER READING
ARNOLD–CHIARI MALFORMATION
Ikusaka M, Iwata M, Sasaki S, Uchiyama S (1996)
Progressive dysphagia due to adult Chiari I
malformation mimicking amyotrophic lateral
sclerosis. J. Neurol. Neurosurg. Psychiatry,
357–358.
Koehler PJ (1991) Chiari’s description of cerebel-
lar ectopy (1891). J. Neurosurg., 75:
823–826.
Sahuquillo J, Rubio E, Poca MA, et al. (1994)
Posterior fossa reconstruction: a surgical tech-
nique for the treatment of Chiari I malforma-
tion and Chiari I/syringomyelia complex: pre-
liminary results and magnetic resonance imag-
ing quantitative assessment of hindbrain mi-
gration. Neurosurgery, 35: 874–885.
Santamarta D, Kusak ME, De Campos JM, Sierra
JM (1999) Increased cerebrospinal fluid flow
through the foramen of Magendie after de-
compression for Chiari I malformation. J.
Neurol. Neurosurg. Psychiatry, 66: 799.
TUBEROUS SCLEROSIS
Crino PB, Henske EP (1999) New developments
in the neurobiology of the tuberous sclerosis
complex. Neurology, 53: 1384–1390.
O’Callaghan FJK (1999) Tuberous sclerosis. BMJ,
318: 1019–1020.
NEUROFIBROMATOSIS
Créange A, Zeller J, Rostaing-Rigattieri S, et al.
(1999) Neurological complications of neu-
rofibromatosis type 1 in adulthood. Brain,
122: 473–481.
Huson SM (1999) What level of care for the neu-
rofibromatoses? Lancet, 353: 1114–1116.
Yasunari T, Shiraki K, Hattori H, Miki T (2000)
Frequency of choroidal abnormalities in neu-
rofibromatosis type 1. Lancet, 356: 988–992.
HEREDITARY HEMORRHAGIC
TELANGIECTASIA
Guttmacher AE, Marchuk DA, White RI Jr
(1995) Hereditary haemorrhagic telangiecta-
sia. N. Engl. J. Med., 333: 918–924.
Maher CO, Piepgras DG, Brown RD Jr., et al.
(2001) Cerebrovascular manifestations in 321
cases of hereditary hemorrhagic telangiectasia.
Stroke, 32: 877–882.
 Chapter Eight 157

Inherited Metabolic
Diseases of the
Nervous System of
Adult Onset
WILSON’S DISEASE (WD) Microscopic
(HEPATOLENTICULAR • Marked hyperplasia of protoplasmic astrocytes
DEGENERATION) (Alzheimer type II cells) in the cerebral cortex, basal
ganglia, brainstem nuclei, and cerebellum.
‘ • Nerve cell loss and some degree of degeneration of
When trouble is sensed well in advance, it can be easily remedied; if myelinated fibers in lenticular nuclei, substantia nigra,
you wait for it to show itself, any medicine will be too late because and dentate nuclei are usually apparent.
the disease will have become incurable. As the doctors say of a
wasting disease, to start with it is easy to cure but difficult to ETIOLOGY AND PATHOPHYSIOLOGY
diagnose; after a time, unless it has been diagnosed and treated at Genetic
the outset, it becomes easy to diagnose but difficult to cure. Autosomal recessive inheritance. Therefore, it is not sex-
Machiavelli 1513 linked (it occurs equally in men and women), and in order
to inherit it, both parents must carry a Wilson’s disease
DEFINITION gene, which each passes to the affected child. If both parents
A rare autosomal recessive disease caused by a gene defect have the WD gene, then the chance of the child getting WD
on chromosome 13 that results in a disorder of (i.e. receiving an abnormal gene from each parent) is 25%.
hepatobiliary copper excretion that leads to the deposition All children of a person with WD will receive a WD gene
of free copper in nearly all the body's tissues, particularly the from the affected person. 50% of children of a carrier will
liver, brain, kidneys and cornea. receive a WD gene, since the carrier has one normal and one
abnormal gene.
EPIDEMIOLOGY The gene defect, designated ATP7B, spans an 80 kb
• Prevalence: 1:30 000 (30 per million) are affected; 1:100 region of chromosome 13q14.3 and encodes a copper
individuals in the general population carry the Wilson’s transporting ATPase.
disease gene (i.e. have one normal and one abnormal More than 50 unique mutations in ATP7B, a relatively
gene). large gene, have been found to cause Wilson’s disease to date.
• Age: onset: 8 to >50 years. Most are spontaneous mutations in the gene and are single
– Neurologic and psychiatric presentations somewhat later base transversions or deletions. A substantial number of other
than hepatic. cases are simply transmitted from generation to generation.
• Gender: M=F. Although only one gene is involved in Wilson’s disease,
many different mutations cause various defects in its
PATHOLOGY product, a copper-transporting ATPase. The existence of
Varies with rate of progress of the disease. different alleles and combinations of two alleles (intralocus
genetic heterogeneity) explains much of the variability in
Macroscopic Wilson’s disease among different families. For example,
Lenticular (putaminal and pallidal) nuclei: mutations that result in complete absence of the gene
• Frank cavitation (rapidly and advancing fatal form). product are associated with development of liver disease at
• Shrinkage and light-brown discoloration (more chronic a particularly early age.
form). Because most patients are compound heterozygotes,
containing different mutations of the WD gene on each
allele, genetic screening for this disease is complicated.
However, in a particular family, if the precise mutation is
identified, a genetic diagnosis is possible. Individuals
heterozygous for the WD gene (i.e. only one abnormal
158 Inherited Metabolic Diseases of the Nervous System of Adult Onset
gene; carriers) may manifest mild abnormalities in copper
metabolism but do not develop the disease; one normal
allele is adequate for disease prevention.
Hepatic copper metabolism and pathogenesis of WD
Disruption of one of the genes controlling copper
metabolism, located on chromosome 13, leads to a
reduction in the rate of biliary excretion of copper, and an
accumulation of excess copper in the body (e.g. in the liver,
and extrahepatic sites such as Descemet’s membrane in the
cornea and the basal ganglia of the brain). The role of
ceruloplasmin is unclear.
CLINICAL FEATURES
• Variable: asymptomatic or a range of hepatic, neurologic
and psychiatric symptoms.
• No two patients are ever quite the same, even in a sibship.
Neurologic and psychiatric disease
Insidious onset and progressive course.
The four main clinical categories
• Pseudosclerotic, with tremor of the limbs (postural and
intention) that closely resembles that seen in multiple
sclerosis and which can be severe enough to be described
as ‘wing-beating’, titubation of the head, incoordination,
limb ataxia, and dysarthria (seen most commonly in
adults).
161
162
• Parkinsonian, with rigidity and bradykinesia of the
tongue, lips, pharynx, larynx and jaw; dysarthria,
dysphagia, hoarseness and drooling.
• Choreic movements of the limbs.
• Dystonic postures of the limbs, with hypertonia and
rigidity; the latter two subgroups being more common
in children.
Other features
• Kayser–Fleischer (K–F) rings (161, 162):
– A golden brownish coloration on the outer margin
(limbus) of the cornea present in virtually all patients
with neurologic and 80% with hepatic WD.
– Almost diagnostic of WD.
– Gonioscopic examination provides earliest detection, and
later may be seen through an auroscope or ophthalmo-
scope or with the unaided eye.
– Slit lamp examination is necessary to demonstrate
definitely copper granules in Descemet’s membrane.
• Loss of motor control: bizarre spontaneous movements.
• Change in personality and behavior (argumentative,
excessively emotional).
• Depression.
• Cognitive decline (dementia).
• Seizures (rare).
• Occasional autonomic dysfunction, causing hyperhidrosis
and exophthalmos.
Ultimately, the ‘classic syndrome’ develops: dysarthria,
dysphagia and drooling, rigidity and slowness of movements
of the limbs, fixed flexed postures, fixity of facial muscles
with mouth constantly agape, giving an appearance of
grinning or a ‘vacuous smile’; slow saccadic eye movements,
a virtual anarthria (bulbar extrapyramidal syndrome); and
tremor in repose which increases when the limbs are
outstretched (coarse, ‘wing-beating’ tremor).
In most neurologic cases, the liver lesion plays a relatively
minor role.
161, 162 Kayser–Fleischer ring. A 1–3 mm thick brown ring (but
may be green, yellow, blue, ruby red, or a mixture of these colors)
of sulfur–copper complexes in Descemet’s membrane at the
corneal margin.
163 Sunflower cataract.
163
 Wilson’s Disease (WD) (Hepatolenticular Degeneration) 159

Liver disease • Hereditary ceruloplasmin deficiency: mutations of the

May take many forms: ceruloplasmin gene on chromosome 3q; autosomal
• Asymptomatic. recessive phenotype; dementia, involuntary movements
• Chronic active hepatitis. and diabetes; iron deposition in the brain and liver
• Cirrhosis. instead of copper.
• Fulminant hepatitis with massive necrosis; there does not • Pseudo-K–F rings have been described in:
appear to be a significant increased risk of hepatocellular – Primary biliary cirrhosis.
carcinoma. – Chronic active hepatitis.
• Pallor of mucous membranes (hemolytic anemia). – Progressive intrahepatic cholestasis of childhood.
• Jaundice. – Intraocular copper foreign body.
• Sunflower cataracts (163). – Multiple myeloma.
• Azure lunulae of the nailbeds. – Infestation with Schistosoma japonicum and African
• Hepatocellular carcinoma is rare, in contrast to hemo- trypanosomiasis.
chromatosis. – Copper therapy.

DIFFERENTIAL DIAGNOSIS INVESTIGATIONS

More than half of patients are initially suspected to have a Patient
disease other than WD. • Slit lamp examination for K–F rings: may be absent early
• Parkinson’s disease: WD mainly affects the bulbar in disease, invariably present in patients with neurologic
musculature and spreads caudally. or psychiatric symptoms.
• Psychiatric disease: anxiety; depression; schizophrenia. • Full blood count: hemolytic anemia, thrombocytopenia.
• Multiple sclerosis. • Liver function tests: abnormal.
• Encephalitis. • Serum ceruloplasmin: <200 mg/l (<20 mg/dl) (in 95%
• Myasthenia gravis. of patients); sensitivity 95% (normal levels
• Thyrotoxicosis. [200–300 mg/l; 20–30 mg/dl] in 5% of patients);
• Hypothyroidism. specificity high but level also decreased in 20% of
heterozygote carriers.
• Serum copper: low, <15.7 μmol/l (<100 μg/dl);
normally decreased in proportion to serum cerulo-
plasmin; markedly elevated in fulminant Wilsonian
hepatitis.
• DNA analysis: gene defect on chromosome 13.
• 24-hour urinary copper excretion: >1.6 μmol (>100 μg)
in 24 hours (normal <0.8 μmol [<50 μg]); completeness
164 of collection is important.
• 24-hour urinary copper excretion post-penicillamine: high,
>25.1 μmol (>1600 μg); may also be increased in
cholestatic disorders.
• Cranial CT scan: normal or may show atrophy of the
caudate nuclei and brainstem, with hypodense areas in
the basal ganglia, dentate nuclei and thalami.
• MRI brain: normal or increased signal intensity on T2W
image in the above areas (164), atrophy of the caudate
nuclei and scattered areas of increased signal in the brain-
stem, midbrain, red nucleus, periaqueductal gray matter
and external capsules. Generalized atrophy may occur.
• Liver biopsy: copper concentration: high, >3.9 μmol/g
(>250 μg/g) dry weight (normal <0.8 μmol/g
[<50 μg/g]); can be intermediate in heterozygotes,
cholestatic disorders; can be elevated in primary biliary
cirrhosis, childhood cirrhosis.
– Histology: steatosis, glycogen nuclei, fibrosis, chronic
active hepatitis, cirrhosis.
– Rhodanine histochemistry: positive, present in some but
not all nodules; may be negative early in disease
– Electron microscopy: stage specific mitochondrial and
lysosomal alterations.
• Failure to incorporate 64Cu into ceruloplasmin.
• Aminoaciduria: present and persistent in most but not all
cases.

164 T2W MR brain scan, axial section through the basal ganglia Relatives
showing high signal in the lateral parts of the basal ganglia (arrows) Screening by clinical, biochemical and genetic assessment.
due to Wilson’s disease.
160 Inherited Metabolic Diseases of the Nervous System of Adult Onset

DIAGNOSIS Grandchildren of WD patients have a 1/400 chance of

Clinical and laboratory evidence of: having the disease: all children of the patient are carriers;
• K–F rings. from the patient’s child, grandchildren have a 50% chance
• Low serum ceruloplasmin and copper. of inheriting a gene (1/2); from the other parent, a normal
• High urine copper excretion over 24 hours. person, they have a 1/200 chance of inheriting the gene
• High hepatic copper content on liver biopsy. (1/2 × 100).

The abundance of specific mutations of the gene on Presymptomatic screening

chromosome 13 and their location at multiple sites across
the genome have limited molecular genetic diagnosis to
kindreds of known patients. The DNA-based diagnostic test
can be done only in siblings of an index patient whose
diagnosis was made according to phenotypic criteria and
only if DNA from both patients is available.
Presymptomatic risk
Siblings of WD patients have a 25% chance of having the
disease. Since both of a sibling’s parents are carriers, 1/4
have the disease, 2/4 will be carriers, and 1/4 will have no
WD gene.
Children of WD patients have a 1/200 chance of having
the disease: from the patient, their children will definitely
inherit the abnormal gene; for the patient’s spouse, a normal
person, the chance of carrying the gene is 1/100 and the
chance they will pass it on is 1/2.
All siblings, aunts, uncles, children, nieces, nephews and
cousins should be screened for WD, because those with
even mild or non-apparent WD will ultimately become
seriously ill if not treated.
The most appropriate screening test is 24-hour urine
measurement of copper, which should be performed in
asymptomatic individuals at about age 5 years and again at
age 15 years. Blood ceruloplasmin is helpful but is normal
in 5–10% of WD patients. Screening can begin for low
ceruloplasmin and abnormal liver function tests at age
2 years. Ophthalmologic assessment for K–F rings can be
diagnostic but they do not have to be present to have WD.
TREATMENT (see Table 22)
WD is a manifestation of copper toxicosis and, in most
cases, symptoms can be prevented or reversed by achieving
and maintaining a negative copper balance.

Table 22 Recommended treatment of, and pharmacologic agents for,Wilson’s disease

Recommended treatment
Clinical status Recommended treatment
Asymptomatic Maintenance therapy
Penicillamine
Trientine
Zn salts
Neurologic/psychiatric symptoms Penicillamine
Trientine
BAL (can use in conjunction with oral therapy)
Tetrathiomolybdate (experimental)
Chronic active hepatitis, or Penicillamine
Hepatic insufficiency Trientine
Fulminant hepatic failure Orthotopic liver transplantation
Chelation therapy and plasmapheresis pendingtransplantation
Pharmacologic agents
Agent Daily adult dose Mode of action
Penicillamine* 1–2 g orally in 2–4 divided doses Chelator
Possible inducer of metallothionein (MT)
Trientine hydrochloride 1.2–2.4 g orally in 2–4 divided doses Chelator
Zinc salts 600 mg of metallic zinc orally Prevents copper absorption by inducing intestinal MT;
in three divided doses may also induce hepatic MT
British antilewisite (BAL) (dimercaprol) 3 ml of 10% BAL in peanut oil i.m. Chelator
Tetrathiomolybdate** Up to 2 mg/kg orally in divided doses Chelator
* Administered with supplemental pyridoxine 25 mg orally daily **Experimental
 Wilson’s Disease (WD) (Hepatolenticular Degeneration)
Presymptomatic
• Reduction of dietary copper to less than 1 mg/day:
avoid copper-rich foods (liver, mushrooms, cocoa,
chocolate, nuts and shellfish).
• Zinc sulfate, 200 mg orally, three times daily, blocks
copper absorption from the gut. Adverse effects:
epigastric pain, nausea, vomiting, and sideroblastic
anemia.
Symptomatic
Medical
Limit dietary copper to less than 1 mg/day (see above).
Chelating agents:
Penicillamine (a copper chelator) can be taken orally. Begin
with 250 mg orally twice a day before food and increase
slowly over a few weeks to 1.0–2.0 g daily in 2–4 divided
doses. Add pyridoxine 25 mg daily, particularly during
pregnancy, a growth spurt, malnutrition or prolonged
intercurrent illness. Pyridoxine deficiency, due to d-
penicillamine, can be detected early by the presence of
abnormal tryptophan metabolites in the urine. About 10%
develop penicillamine sensitivity (rash, arthralgia, fever,
leukopenia): temporarily reduce the dose or try a course of
cortisone. Reinstitute in low dose (250 mg daily) with small,
widely spaced increases. If the penicillamine sensitivity
persists or if severe immune-mediated reactions (lupus-like
or nephrotic syndromes) occur, the drug should be
discontinued and zinc acetate (50 mg elemental zinc 5 times
daily) or trientene substituted.
Triethylene tetramine dihydrochloride (trientine, TETA)
is as effective as penicillamine and has fewer adverse effects,
but is expensive. It is taken orally, 1.2–2.4 g daily in 2–4
divided doses before food. It is poorly absorbed from the
gut. TETA reduces intestinal copper absorption and
increases urinary copper excretion. Add zinc acetate 50–150
mg as a single dose at night (separate from the ingestion of
trientene tablets) to prevent zinc deficiency. Toxic reactions
are rare: sideroblastic anemia, reactivation of penicillamine-
induced lupus, colitis and duodenitis.
Metal to metal antagonists:
Zinc sulfate or acetate can be used if penicillamine or
trientene toxicity occurs. Doses are taken orally, 200 mg
three times daily. It blocks copper absorption from the gut.
Toxic reactions are rare: nausea, epigastric pain, vomiting,
sideroblastic anemia. It is useful for maintenance therapy,
treatment of the pregnant patient, and the initial as well as
maintenance treatment of the presymptomatic patient. It
does not seem to be optimal for initial treatment because it
is somewhat slow acting and may take several months to
control copper toxicity.
Ammonium tetrathiomolybdate blocks intestinal
absorption of copper and binds copper present in tissues.
Early studies suggested it may depress bone marrow and
cause serious epiphyseal deformities in growing animals (and
presumably children). A safe and effective initial treatment
in a recent open study of 33 patients.
Metal-binding agent:
British antilewisite (BAL) (dimercaprol): if advanced
neurologic lesions which have failed to respond to other
treatments. Crosses the blood–brain barrier better than
chelating agents.
161
• Monitor clinical response, full blood count, proteinuria,
and urine copper excretion.
• A further 8% or so show no response to treatment.
• The appropriate drug needs to be continued for the
patient’s lifetime.
In about 20% of patients, chelation treatment results in
an initial worsening of neurologic symptoms before
improvement begins, and a few (1–2%) may deteriorate
rapidly once treatment is started. This is thought to reflect
the mobilization of copper from tissues, e.g. liver, and its
redistribution in the brain, and for the redistribution of
copper within neurons themselves.
Chelating agents have been used during pregnancy in
WD patients without teratogenic effects.
Surgical
Liver transplantation: cures WD by removing the site of the
metabolic lesion; chelation therapy need not be continued.
If there is irreversible liver damage due to acute and chronic
liver failure its place in the management of advanced
neurologic disease is less clear.
CLINICAL COURSE AND PROGNOSIS
Course and prognosis vary greatly. Untreated, the course is
invariably progressive and fatal. Most patients reach a
terminal stage with severe dystonia and contractures, though
a few may become akinetic. The disease may last from a few
months (it tends to run a more acute course in younger
patients) to many years with occasional periods of relative
remission. With treatment, most patients improve or recover
completely, but some do not. Some get worse before they
get better (about 25%), some get worse and do not get
better, remaining permanently disabled, and some die,
fortunately very few. Pseudosclerotic patients have a better
prognosis than the dystonic.
PREVENTION
Younger siblings can now be identified by means of
molecular DNA techniques as normal, heterozygous or
presymptomatic carriers of the WD gene. For the latter and
relatives detected by screening (see above), prophylactic
treatment can be started. Experience to date shows that
such patients remain in good health so long as they take
their medication.
162 Inherited Metabolic Diseases of the Nervous System of Adult Onset

HALLERVORDEN–SPATZ DISEASE MITOCHONDRIAL (OXIDATIVE

PHOSPHORYLATION) DISEASES

DEFINITION
An autosomal recessive inherited condition characterized by
iron deposition in the basal ganglia and progressive pyramidal
and extrapyramidal signs. Also known as pigmentary degener-
ation of the globus pallidus, substantia nigra and red nucleus.
DEFINITION
A clinically, biochemically and genetically diverse group of
disorders that result from structural, biochemical, or genetic
derangement of mitochondria.

EPIDEMIOLOGY EPIDEMIOLOGY
• Incidence: rare. • Incidence: not uncommon; being recognized with
• Age: late childhood or early adolescence. increasing frequency.
• Gender: M=F. • Prevalence:at least 1 in 50 000.
• Age: any age.
ETIOLOGY AND PATHOPHYSIOLOGY • Gender: either sex.
• Autosomal recessive inheritance.
• No known biochemical defect. STRUCTURE AND FUNCTION OF MITOCHONDRIA
AND THEIR DNA
PATHOLOGY Every mammalian cell contains multiple (about 800)
Deposits of iron in the basal ganglia: mitochondria, the main function of which is to generate
• Macroscopic: intense brown pigmentation of the globus energy for cellular processes by producing ATP through
pallidus, substantia nigra (particularly the anteromedial oxidative phosphorylation. For this task, the extensively
parts) and red nucleus. folded inner membrane of the mitochondrion is equipped
• Microscopic: granules and larger amorphous deposits of iron with the respiratory chain, a redox system whose com-
mixed with calcium in the walls of small blood vessels or free ponents (complexes I–V) are encoded by two separate
in the tissue; loss of neurons and medullated fibers in the genetic systems; 13 subunits are encoded on mitochondrial
most affected regions; and swollen axon fragments. DNA and more than 67 on nuclear DNA. Each mito-
chondrion contains 2–10 molecules of its own, extra-
CLINICAL FEATURES chromosomal mitochondrial DNA.
• Spastic quadriparesis, with hyperreflexia and Babinski signs.
• Rigidity. Mitochondrial DNA (mtDNA)
• Dysphagia and dysarthria. • Distinct from DNA in the cell nucleus, it is 16 569 base-
• Dystonia. pairs long, a closed circular and double-stranded
• Choreoathetosis. molecule that encodes 13 protein subunits of four
• Cognitive decline. biochemical complexes and the 24 structural RNAs and
• Ataxia and myoclonus in some patients. 22 transfer RNAs that are required for the
intramitochondrial translation of the protein-coding unit.
DIFFERENTIAL DIAGNOSIS • Almost exclusively inherited maternally because the
• Wilson’s disease. spermatocyte contributes virtually no mitochondria to
• Other dystonias. the zygote at fertilization.
• Mitochondrial disease: Leigh disease. • Does not recombine; mutations accumulate sequentially
• Neuroaxonal dystrophy. through maternal lineages.
• Has a very high mutation rate (10 times as frequent as
INVESTIGATIONS nuclear DNA) and has no introns, so that a random
• Serum iron studies: normal. mutation will usually strike a coding DNA sequence.
• CT brain scan: normal or symmetric non-enhancing areas • Mutations may occur in each type of mitochondrial gene.
of reduced density in the lenticular nuclei. • Different populations (normal and mutant mtDNA) can
• MRI brain: reported to show low signal in the basal coexist in the same cell (heteroplasmy) because each cell
ganglia (lentiform nucleus) on T2W image possibly due contains multiple mitochondria, and because each
to the iron deposition, and increased signal in the mitochondrion contains 2–10 DNA molecules. This
periventricular white matter. However, this is rather non- condition, allows an otherwise lethal mutation to persist.
specific as these features also occur in Wilson’s disease Homoplasmy is the presence of either completely normal
and a number of other more common conditions. or completely mutant mitochondrial DNA.
• When cells replicate, the proportions of mutant and
DIAGNOSIS normal molecules can shift as mitochondrial DNA is
Clinical and radiologic. partitioned into daughter cells because mitochondria
segregate randomly to daughter cells at each mitotic
TREATMENT division (mitotic segregation). The resulting cell
• Supportive. generation might inherit different amounts of coexisting
• L-dopa (levodopa) may provide temporary symptomatic mtDNA populations (mosaicism).
relief.
• Iron chelating agents are not helpful.

PROGNOSIS
Slowly progressive over 10–20 years.
 Mitochondrial (Oxidative Phosphorylation) Diseases 163

• The phenotypic expression of a pathogenic mutation
exhibits a threshold effect, depending on the relative
proportion of the mutant to the complementing wild
type genome. The proportion of mutant mitochondrial
DNA required for the occurrence of a deleterious
phenotype (clinical disease), known as the threshold
effect, varies among people, organ systems and tissues,
and depends on the delicate balance between oxidative
demand and supply.
• Histochemistry: cytochrome c oxidase (complex IV)
negative fibers.
• Electron microscopy: structurally abnormal mitochondria
containing paracrystalline inclusions (condensations of
mitochondrial creatine kinase between mitochondrial
inner and outer membranes).
• Biochemical studies: defective oxidative phosphorylation.
• mtDNA analysis usually positive for one of the
recognized mutations.

ETIOLOGY AND PATHOPHYSIOLOGY CLINICAL FEATURES

• Gross structural rearrangements (single deletions, Mitochondrial DNA mutations cause an extensive array of
multiple deletions, or duplications) or point mutations clinical disorders because virtually all tissues in the body
in mitochondrial DNA. depend to some extent on oxidative metabolism and are
• Mitochondrial mutations can be inherited maternally and prone to be affected by mitochondrial DNA mutations.
by mendelian patterns. A minority of patients fit neatly into well defined syndromes
• An autosomal dominant locus on chromosome 10 can such as MELAS, MERRF, CPEO, or the KSS (see below).
predispose to deletions of mitochondrial DNA.
• Mutations with the potential to cause a lethal impairment Neurologic
of oxidative phosphorylation (gross structural defects or N.B. Common and typical features are shown in italics.
point mutations in critical regions) are viable only if they
are heteroplasmic. Brain:
• The majority of the milder, missense mutations in • Generalized (and partial) seizures.
protein-coding genes are homoplasmic. • Myoclonus: spontaneous and stimulus-sensitive.
• Ataxia.
It can be difficult to link a mutation to a clinical disease • Dementia.
for several reasons: • Stroke-like episodes in a young person.
• Mitochondrial DNA is highly polymorphic. • Dystonia.
• There is a dissociation between the genotype and the • Psychiatric disorder (particularly depression).
phenotype.
• Different mutations can be associated with the same Cranial nerves:
phenotype. • Optic neuropathy: optic atrophy, peripheral pigmentary
• The same mutation can be associated with different retinopathy, cataracts.
phenotypes. • Sensorineural deafness.
• Epigenetic factors (e.g. alcohol and tobacco use) can • Aminoglycoside deafness.
affect clinical manifestations.
Spinal cord: myelopathy.
Even so:
• Mitochondrial encephalomyopathy phenotype: tRNA Peripheral nerves: peripheral neuropathy; usually
mutations predominate. asymptomatic.
• Leber’s hereditary optic neuropathy phenotype: protein-
coding gene mutations predominate. Muscle:
• Myopathy: mild and proximal; gross wasting and
The mechanism of stroke-like episodes in MELAS weakness are rare.
syndrome (see below) is probably a combination of defects • Hypotonia.
in neuronal metabolism as well as in cerebral vasculature. • Chronic progressive external ophthalmoplegia: evolves
slowly, hence diplopia is uncommon.
PATHOLOGY • Fatiguability and exercise intolerance.
MELAS syndrome (see p.164) • Recurrent myoglobinuria.
Brain
• Light microscopy: diffuse fibrillary gliosis with abundant Systemic
gemistocytes, focal evidence of ischemic neuronal injury Stature: short.
and edema.
• Electron microscopy: bizarre enlarged mitochondria and Eyes:
changes consistent with cellular edema. Strongly reactive • Cataracts.
succinate dehydrogenase staining in cerebral blood • Pigmentary retinopathy.
vessels.
• Mitochondrial DNA analysis: point mutation at nucleotide Ears: hearing loss.
position 3243 of the mitochondrial tRNA Leu(UUR)
gene in most (82%) of brain mitochondria in one study. Heart:
• Cardiac conduction defects and heart block.
Muscle • Cardiomyopathy.
• Modified Gomori trichrome stain: proliferation of
subsarcolemmal mitochondria (ragged-red fibers).
164 Inherited Metabolic Diseases of the Nervous System of Adult Onset

Endocrine: • Ptosis (165, 166).

• Diabetes mellitus. • Progressive external ophthalmoplegia.
• Hypoparathyroidism. • Atypical pigmentary retinopathy.
• Growth/multiple hormone deficiency. • Deafness (166).
• Cerebellar ataxia.
Gastrointestinal: • Heart block.
• Episodic nausea and vomiting. • Diabetes mellitus.
• Hepatopathy. • CSF protein elevated above 1 g/l (100 mg/dl).
• Intestinal pseudo-obstruction.
• Exocrine pancreatic dysfunction. Myoclonus, cortical blindness and hemiparesis are not
• Villous atrophy. features of KSS.

Renal: Etiology:
• Glomerulopathy. • Spontaneous (i.e. usually not maternally inherited),
• Proximal nephron dysfunction, with aminoaciduria, heteroplasmic deletions of the mitochondrial genome at
phosphaturia and glycosuria. high levels are found in 80% of cases.
• The most frequent deletion (30–50% of cases) is a 4.9 kb
Hematologic: sideroblastic anemia/pancytopenia. deletion (‘common deletion’) that spares the origins of
replication.
Other: lactic acidosis.
Prognosis:
Family history for evidence of mendelian or maternal • Many patients die in the third and fourth decade of life.
inheritance.
B. Transfer RNA mutation
CLASSIC PHENOTYPES Mitochondrial encephalomyopathy, lactic acidosis, and stroke-
I. PRIMARY MITOCHONDRIAL DNA MUTATIONS like episodes (MELAS) syndrome
A. Mitochondrial DNA rearrangements Clinical and biochemical features:
Chronic progressive external ophthalmoplegia (CPEO) • Onset at any age.
• Clinical features: • Stroke-like events causing subacute focal brain dysfunction.
– Ptosis (165, 166). • Seizures and/or migraine headache.
– Ophthalmoplegia. • Lactic acidosis.
– Limb myopathy. • Other clinical and laboratory features: retinitis
– Variable constellation of other clinical and laboratory pigmentosa, cerebellar ataxia, myopathy, cardiomyopathy,
features. diabetes, proximal renal tubule defects, and lactic
• Etiology: most commonly sporadic, large, single acidemia and hyperalaninemia.
deletions in mitochondrial DNA.
Etiology:
Kearns–Sayre syndrome (KSS) • Inherited maternally.
A form of CPEO. • A point mutation at nucleotide position 3243 in the tRNA
Clinical features: Leu(UUR) gene in 80% of cases but this mutation is not
• Onset before age 20 years. specific for MELAS syndrome; it has multiple phenotypic
effects.

165 Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome

Clinical and pathologic features:
• Myoclonus.
• Epileptic seizures: myoclonic epilepsy, generalized
seizures, or focal seizures.
• Cerebellar ataxia.
• Mitochondrial myopathy with ragged-red fibers.
• Variable constellation of other clinical and laboratory
features: dementia, optic neuropathy, deafness, corticospinal
tract degeneration, peripheral neuropathy, myopathy,
proximal renal tubule dysfunction, cardiomyopathy and
166 lactic acidemia plus hyperalaninemia.
• Maternal relatives may be asymptomatic or have partial
clinical syndromes, including lipomas in a characteristic
‘horse collar’ distribution and cardiovascular disease.

Etiology: mutations at nucleotide positions 8344 and 8356

in the tRNA Lys gene.

165, 166 Ptosis, progressive external ophthalmoplegia and

sensorineural deafness in a patient with Kearns–Sayre syndrome.
 Mitochondrial (Oxidative Phosphorylation) Diseases
C. Missense mutations
Neuropathy, ataxia, and retinitis pigmentosa and
maternally inherited Leigh disease
Clinical features:
• Proximal muscle weakness.
• Sensory neuropathy.
• Ataxia.
• Retinal pigmentary degeneration.
• Developmental delay.
• Dementia.
• Epileptic seizures.
Etiology:
• Inheritance: maternal.
• Mutation: heteroplasmic missense point mutations at
nucleotide position 8993 in the ATPase 6 gene.
Leber’s hereditary optic neuropathy (LHON) (see p.491)
II. NUCLEAR DNA MUTATIONS
Nuclear DNA mutations causing multiple mtDNA
rearrangements
Autosomal dominant chronic progressive external
ophthalmoplegia: (chromosome 10q23.3-24.3 locus)
Autosomal recessive chronic progressive external
ophthalmoplegia
INVESTIGATIONS
Laboratory
• Full blood count: may reveal pancytopenia.
• Urea, electrolytes and creatinine: renal tubular dysfunc-
tion may be seen as part of the Fanconi syndrome.
• Plasma glucose: commonly elevated (diabetes).
• Creatine kinase: normal or mildly increased.
• Blood organic acid (lactate and pyruvate), amino acid,
and carnitine concentrations: lactic acidosis, raised
lactate : pyruvate ratio.
• Urine (24-hour collection) organic acid, amino acid, and
carnitine concentrations: increased lactate, pyruvate and
alanine or a generalized aminoaciduria.
• EKG: cardiac conduction defects.
• Audiography: sensori-neural hearing loss.
167
167 Skeletal muscle biopsy, stained with modified Gomori trichrome,
showing a ragged-red fiber with large pink subsarcolemmal aggregates
of mitochondria (arrow).
165
• CSF protein: elevated.
• CSF organic and amino acids: elevated lactate.
Neurophysiology
• Nerve conduction studies: may demonstrate a peripheral
(predominantly axonal) neuropathy.
• EMG: normal or mildly myopathic.
Imaging
• Brain CT or MRI: basal ganglia calcification or focal
signal abnormalities.
– MELAS syndrome causes cortical infarct-like lesions (but
in an atypical distribution for normal arteriovascular
territories) usually affecting the posterior parts of the
cerebrum. These lesions may disappear in time leaving only
mild sulcal dilatation. Leigh’s disease causes periaqueductal
gray and putaminal abnormal signal intensity, swollen
caudates on MRI, and low density in the putamina on CT.
• Phosphorus-31 nuclear magnetic resonance spectros-
copy: lactate may be detected in the abnormal areas.
Histology
• Open skeletal muscle biopsy is diagnostic, although occa-
sional patients with mitochondrial myopathy due to
mtDNA mutations and those with LHON may have
normal biopsies.
• Histochemical analysis typically reveals ragged-red fibers
on Gomori trichrome staining, which reflect mitochondrial
proliferation (167). These fibers stain strongly for
succinate dehydrogenase (SDH, complex II), and often
stain negatively for COX (complex IV) in CPEO, KSS, or
MERFF but positively in MELAS. COX-negative fibers
are normal over age 40 years and the proportion increases
with age, but does not normally exceed 5%. Ragged-red
fiber-positive and SDH-positive and COX-negative fibers
may also be seen in inflammatory myopathies.
• Ultrastructural analysis may show intramitochondrial
paracrystalline inclusions (168).
• Biochemical analysis of isolated mitochondria or muscle
tissue by enzyme studies, polarography, or spectroscopy
may identify the site(s) of the defect within the
respiratory chain, and this can help to direct molecular
genetic analysis.
168
168 Electron microscopy of skeletal muscle showing a
subsarcolemmal collection of mitochondria with paracrystalline
inclusions.
166 Inherited Metabolic Diseases of the Nervous System of Adult Onset
Molecular genetic analysis
Molecular genetic studies of DNA derived from blood
(platelets, white cells), hair follicles, urine or muscle are
analysed for mitochondrial DNA mutations: virtually all
point mutations can be detected readily in available tissues,
such as leukocytes, but major structural mutations, such as
deletions, require the analysis of skeletal muscle. Analysis is
necessary for genetic counselling.
DIAGNOSIS
• Mitochondrial disease should be considered in any
patients with an unexplained multi-system neurologic
disorder, particularly if there are eye signs and deafness.
• The diagnosis is straightforward when the clinical
findings indicate a well defined mitochondrial cytopathy
syndrome. In less clear cut cases diagnosis can be difficult
and, to be certain, the diagnosis should be supported by
at least two laboratory investigations, including serum
lactate analysis, muscle biopsy biochemistry and
histochemistry, and mitochondrial DNA studies on
muscle or other tissues.
• There is no overall screening test that is sensitive and
specific for the presence of mtDNA mutations.
Sequencing the entire mtDNA region is impractical.
TREATMENT
• Therapeutic trials have been limited with no adequate
controlled studies.
• Various agents that naturally act as cofactors in the
electron transport, or are designed to bypass decreased
respiratory chain complex activity by providing an
additional redox system have been assessed; these include
coenzyme Q10 (ubidecarenone), succinate, vitamin K3
(menadione), vitamin C, thiamine, vitamin B2
(riboflavin), dichloroacetate, and idebenone 1, a novel
quinone, among others.
• Corticosteroids have been associated anecdotally with
improvement and with fatal metabolic acidosis.
• Gene therapy is a future hope.
PROGNOSIS
Variable.
ADRENOLEUKODYSTROPHY (ALD)
DEFINITION
An X-linked recessive peroxisomal disorder characterized by
an excessive accumulation and deposition of unbranched, very
long chain saturated fatty acids (VLCFAs) with more than 22
carbon atoms in many tissues and body fluids, leading to
adrenal failure and demyelination in the brain and spinal cord.
The disease ranges from the rapidly progressive childhood
cerebral form, which is characterized by diffuse demyelination
in the cerebral hemispheres and leads to total disability during
the first decade, to the milder adrenomyeloneuropathy
(AMN), which is a distal axonopathy that most severely
involves the distal aspects of the long tracts in the spinal cord
and which is compatible with survival to the eighth decade.
EPIDEMIOLOGY
• Prevalence: 1/20 000 males.
• Age: children, adolescents and young adults.
– ALD affects children; AMN which is a milder form of
ALD, affects adults, with onset at 20–30 years of age.
• Gender: males and heterozygous females (sex-linked
recessive).
PATHOLOGY
ALD
• Massive and diffuse demyelination, often asymmetrically,
in various parts of the cerebral hemipheres, beginning
most commonly in the parieto-occipital region, and later
involving the brainstem, optic nerves and spinal cord
(169).
• Perivascular infiltration with lymphocytes and macro-
phages, resembling that seen in multiple sclerosis.
• Degradation products of myelin are visible in macro-
phages in recent lesions, namely sudanophilic demye-
lination. Axis cylinders are damaged but to a lesser degree.
• Adrenal gland cortex atrophy.
• Abnormally large amounts of VLCFAs in histiocytes in
brain and adrenals.
• Testes show marked interstitial fibrosis and atrophy of
the seminiferous tubules.
• Electron microscopy shows characteristic lamellar
cytoplasmic inclusions in the macrophages of the brain
and adrenals and the Leydig cells of the testes.
AMN
• A distal axonopathy most severely involving the distal
aspects of the long tracts in the spinal cord.
• The inflammatory reaction is mild or absent.
ETIOLOGY AND PATHOPHYSIOLOGY
• X-linked recessive inheritance.
• The disease maps to chromosome Xq28.
• Mutations have been described spread over most of the
X-ALD gene, and have been of different types: missense,
nonsense, deletions and insertions.
• The gene product ALD-P encodes a 70 kDa peroxisomal
membrane protein PMP70.
• The gene mutation is believed to result in an abnormality
in a peroxisomal VLCFA coenzyme A (CoA) synthetase
or ligase, ultimately resulting in impaired β-oxidation in
the peroxisomes and accumulation of VLCFAs in organs
such as the adrenals, brain and spinal cord.
 Adrenoleukodystrophy (ALD)
• The same mutation can cause ALD or AMN within the
same family but more commonly, the great majority of
X-ALD kindreds have different X-ALD gene mutations.
Additional factors presumably play a part in determining
the final phenotype.
CLINICAL FEATURES
The phenotypic presentation is extremely variable but
follows two broad patterns: a predominantly cerebral form
(ALD) occurs in about 35–50% of cases, and a spinal cord
form (AMN) in 28–40%. In addition, another 8% manifest
only as idiopathic Addison’s disease, and another 10% are
asymptomatic at diagnosis, but many of whom develop
some form of the disease later in life.
Heterozygous women may also develop symptoms that
resemble those of AMN, but they tend to develop later in
life (up to 10 years later) and the lower limb spasticity and
sensory deficits are milder.
The cause of the variable phenotypic expression is unclear
and no correlation between genotype and phenotype has
been found.
ALD
• Boys, less commonly adolescent and adult men.
• Pseudobulbar palsy: dysarthria; dysphagia; quadriparesis;
emotionalism.
• Dementia (i.e. progressive learning difficulties and
decline in scholastic performance).
• Personality change.
• Cortical blindness.
• Deafness.
• Ataxia.
• Seizures occasionally.
• Bronzing pigmentation of oral mucosa and skin around
nipples and over elbows, knees, and scrotum, before
becoming more diffuse.
• Rapidly progressive clinical course.
• Heterozygotes of ALD or AMN may be clinically
symptomatic.
• There may be a positive family history.
169
169 Brain, coronal section, showing massive, asymmetric demyelination
adjacent to the posterior horns of the lateral ventricles (arrows).
167
AMN
• Adult males.
• Chronic, progressive spinal cord syndrome (myelopathy)
characterized by spastic paraparesis, sphincter dysfunc-
tion, and sometimes mild sensory loss.
• Adrenal insufficiency (70%): generalized weakness,
weight loss, skin pigmentation, attacks of nausea and
vomiting; usually precedes the neurologic symptoms.
• Peripheral neuropathy: difficult to detect in presence of
prominent pyramidal signs.
• Uncommonly, dementia and cerebellar ataxia may occur.
• Heterozygote adult females (at least 20%) may develop,
in the fourth or fifth decade of life, a very slowly
progressive spastic paraparesis with mild sphincter and
sensory disturbance.
• A positive family history of slowly progressive spastic
paraparesis may be present.
DIFFERENTIAL DIAGNOSIS
ALD
• Multiple sclerosis.
• Diffuse cerebral sclerosis of Schilder (Schilder disease,
encephalitis periaxalis diffusa): non-familial; children and
young adults; large, sharply outlined, asymmetric focus
of myelin destruction, often involving an entire lobe or
hemisphere of the brain, typically extending across the
corpus callosum; dementia, pseudobulbar palsy, varying
degrees of hemiparesis and paraparesis, homonymous
hemianopia, cortical blindness, deafness; chronic
progressive or relapsing remitting course; no evidence of
adrenal atrophy or sex-linked male inheritance.
• Other leukodystrophies (globoid cell leukodystrophy of
Krabbe [see p.171], metachromatic leukodystrophy, see
p.169) which have a specific inherited biochemical defect
in the metabolism of myelin proteolipids and are
characterized clinically by progressive visual failure,
mental deterioration, and spastic paralysis; and patho-
logically by massive and more or less symmetrical
destruction of the white matter of the cerebral hemi-
spheres. Each may involve peripheral nerves as well as
CNS tissue.
AMN
• Hereditary spastic paraparesis.
• Multiple sclerosis.
• Spinal cord arteriovenous malformation.
• Spinal cord neoplasm.
• Dopa-responsive dystonia.
168 Inherited Metabolic Diseases of the Nervous System of Adult Onset
INVESTIGATIONS
• Urea and electrolytes: most patients have clinical or
biochemical evidence of impaired adrenal function and
reserves: low sodium and chloride levels and elevated
potassium levels.
• Adrenal function tests: serum cortisol levels decreased,
urinary excretion of corticosteroids reduced, plasma
ACTH increased, ACTH stimulation test negative: lack
of rise in 17-hydroxyketosteroids after ACTH stimulation.
• Plasma VLCFAs (C26:0): increased several fold. The
plasma VLCFA ratio C26:0/C22:0 is also increased
several-fold compared with values for control.
• Skin fibroblast concentrations of VLCFAs: increased.
• CT brain scan: shows symmetric areas of low density in
the parieto-occipital white matter, with later involvement
of the temporal, parietal and frontal lobes. This can
extend across the splenium of the corpus callosum and
into the cerebellum. Contrast enhancement may occur
around the periphery of the lesions. Occasionally there
may be calcification and mass effect in the white matter
lesions.
• MRI brain scan (170) in ALD shows increased signal on
T2W image, decreased on T1W image in the areas
outlined above, and loss of gray/white matter
differentiation. MRI is more sensitive than CT and may
also show extension into the long motor tracts and visual
pathways. Enhancement may occur at the edges of the
white matter lesions. Magnetic resonance spectroscopy
shows a diminution in the N-acetylaspartate peak and an
increase in the choline peak. In AMN, MRI brain is often
normal, but shows involvement of the spinal cord and
peripheral nerves.
• CSF protein may be elevated.
• Nerve conduction studies: often abnormal in AMN and
suggest a mixture of axonal loss and multifocal
demyelination.
• Molecular genetic analysis: for possible sequence
variations in the ALD gene by polymerase chain reaction
(PCR) amplification and single strand conformation
polymorphism (SSCP) analysis.
DIAGNOSIS
• Demonstration of excessive VLCFAs in plasma or skin
fibroblasts (a ketogenic diet can cause raised levels in
normals) in a patient with appropriate clinical and
neuroimaging findings and family history.
• The progressive childhood form of X-ALD may be
accompanied by ‘non-diagnostic’ concentrations of
plasma VLCFAs.
Presymptomatic screening
DNA analysis is the most reliable method for establishing the
carrier status in X-ALD kindred; about 10% of heterozygous
women have normal plasma VLCFA levels using current
assays. However, the distribution of mutations over the
whole coding region complicates such detection. Study of
the ALP-P expression in white blood cells or fibroblasts may
help circumvent this problem and identify heterozygous
women, particularly when the mutation is not identified.
TREATMENT
Adrenal insufficiency
Adrenal steroid replacement therapy: may prolong life,
increase general strength, and improve school performance
but does not alter neurologic disability.
Neurologic disability
Three therapeutic approaches are under current
investigation.
Dietary therapy
Attempts to lower the levels of saturated VLCFAs have
included diets enriched in monounsaturated fatty acids
(oleic acid), devoid of VLCFAs, supplemented with glycerol
(glyceryl) trioleate oil (GTO) and glycerol (glyceryl)
trierucate (GTE) (the 4:1 mixture of GTO and GTE oil is
popularly referred to as Lorenzo’s oil), and containing
erucic acid (an omega 9 mono-unsaturated 22-carbon fatty
acid), which competes with saturated fatty acids for the
microsomal fatty acid elongating enzyme system. Although
marked reduction of plasma levels of lignoceric (C24:0) and
hexacosanoic acid (C26:0) have been achieved, there has
been little or no effect on neurologic progression in patients
who are already neurologically affected. One explanation is
that little erucic acid crosses the blood–brain barrier and
enters the brain. At present, dietary therapy is of limited
value in correcting the accumulation of saturated VLCFAs
in the brains of patients with ADL.
Bone marrow transplantation
When undertaken at an early stage of the disease in child-
hood, long term benefits have been described in small series.
Immunosuppression
Experimental.
PROGNOSIS
• ADL: rapidly progressive and fatal disorder within 3–5
years after clinical symptoms are detected.
• AMN: slowly progressive course over years. About 35%
of patients will have substantial neurologic progression
during a 3 year period, and cerebral involvement may
develop in up to half at some point. The presence and
severity of adrenal insufficiency has no bearing on the
severity of the neurologic disease.
• Male siblings of the patient have a 50% risk of receiving
the ALD gene from their mother but because the
disorder is so clinically heterogeneous with various
phenotypes, the risk of a male sibling developing AMN
is less than 50%.
 Metachromatic Leukodystrophy (MLD) 169

METACHROMATIC – Caused by a mutation affecting the polyadenylation of

LEUKODYSTROPHY (MLD) the arylsulfatase mRNA.
– Low arylsulfatase is not accompanied by accumulation of
sulfatides in the organs, because the residual activity is sup-
DEFINITION posedly sufficient to ensure normal sulfatide metabolism.
An autosomal recessive lysosomal disorder characterized by – Memory disturbances, ataxia, fatigue, tremor or loss of
demyelination of the white matter in the CNS and the vision are present.
peripheral nerves. – Blood DNA analysis reveals homozygosity for the
pseudodeficiency allele.
EPIDEMIOLOGY • Multiple sclerosis.
• Incidence: rare (only 50 or so cases of adult form • Huntington’s disease.
described in the literature). • Parkinson’s disease.
• Age: late infantile form (age at onset, 1–2 years); juvenile
form (age at onset, 3–15 years); adult form (age at onset,
older than 16 years): mean age of onset 23 years; range
16–62 years. 170
• Gender: M=F.

PATHOLOGY
• Accumulation of sulfatides in the brain, peripheral nerves,
and non-neural organs.
• Demyelination of the periventricular white matter (171)
and peripheral nerves, with reduction of myelin sheath
thickness in peripheral nerve.

ETIOLOGY AND PATHOPHYSIOLOGY

• Deficiency of the enzyme arylsulfatase A (ASA), which
hydrolyses various sulfatides, including galactosyl
sulfatide and lactosyl sulfatide, the major sulfate-
containing lipids of the nervous system.
• Autosomal recessive inheritance.
• The gene is located on chromosome 22q13.
• Eight different MLD alleles:
– Type 0 alleles without residual activity of arylsulfatase;.
– Type R alleles with some residual activity of arylsulfatase.
• Late infantile form (age at onset, 1–2 years): homo-
zygosity for type 0 alleles.
• Juvenile form (age at onset, 3–15 years): compound
heterozygosity for type 0/type R alleles. 170 T2W axial MRI showing diffuse bilateral increased signal mainly in
• Adult form (age at onset, older than 16 years): the parieto-occipital white matter in adrenoleukodystrophy.The more
homozygosity for type R alleles. anterior white matter is beginning to look affected.

CLINICAL FEATURES
Late infantile form (age at onset, 1–2 years)
Gait and behavioral disturbance.
171
Juvenile form (age at onset, 3–15 years)
Gait and behavioral disturbance.

Adult form (age at onset, older than 16 years)

Progressive neurologic or psychiatric symptoms and signs,
which include any of:
– Dementia.
– Behavioral abnormalities: aggressiveness, irritability,
impaired social awareness, and inappropriate behavior.
– Ataxia.
– Paraparesis.
– Polyneuropathy.

DIFFERENTIAL DIAGNOSIS
• Pseudodeficiency of arylsulfatase:
– A common genetic polymorphism, with an estimated
gene frequency of 7.3%. 171 Brain, coronal section, showing extensive demyelination of the
periventricular white matter (arrows).
170 Inherited Metabolic Diseases of the Nervous System of Adult Onset

INVESTIGATIONS • Reduced myelinated fiber density and myelin sheath

Blood thickness.
• Arylsulfatase activity in leukocytes: decreased (less than • Ultrastructural examination reveals various types of
35–110 nmol/h per mg of protein). inclusion, mainly lamellar zebra-like bodies and tuffstone
• DNA analysis. bodies.

Urine
Accumulation of sulfatides in urinary sediment.
EMG
Slowing of nerve conduction velocities (NCV): mean
peroneal NCV: 25 m/s (range: 0–30 m/s [late infantile],
10–28 m/s [juvenile], 15–39 m/s [adult]; normal
44–57 m/s).
CT scan of the brain
Extensive areas of hypodensity in the white matter, especially
in the frontal lobes, which does not enhance (172, left).
MRI brain
Extensive increased signal in the white matter on T2W
image (172, right) due to diffuse demyelination of the peri-
ventricular white matter. The imaging features on CT and
MRI are non-specific.
CSF
Normal or slightly elevated protein concentration.
Skin biopsy
Decreased arylsulfatase activity in fibroblasts
(<270–770 nmol/h per mg of protein).
Peripheral (e.g. sural) nerve biopsy with
acidic cresyl violet staining
• Accumulation of sulfatides as brown metachromatic
deposits in Schwann cells and in large perivascular
macrophages.
• Segmental demyelination and remyelination with slight
onion bulb formation (less active in adult than late
infantile and juvenile forms).
DIAGNOSIS
• Progressive symptoms of mental deterioration, behavioral
abnormalities, or ataxia in combination with hypo-
myelination of the CNS and slowing of NCV.
• Decreased arylsulfatase activity in leukocytes or
fibroblasts (not specific).
• Increased amounts of sulfatides in urinary sediment.
• Morphologic demonstration of accumulation of
sulfatides in various tissues, e.g. sural nerve or brain.
• DNA analysis: to confirm or exclude a pseudodeficiency
state of arylsulfatase activity.
TREATMENT
Late infantile
Bone marrow transplantation: conflicting results.
CLINICAL COURSE AND PROGNOSIS
Late infantile form (age at onset 1–2 years)
• Rapid course.
• Fatal outcome.
Juvenile form (age at onset 3–15 years)
More protracted course.
Adult form (age at onset, older than 16 years)
• Slowly progressive.
• The interval between the onset of one symptom (e.g.
behavioral abnormality or ataxia) and the occurrence of
the second symptom is about 3.7 years (range
1–20 years). The third symptom occurs, on average,
2 years (range 0–7 years) later.
• In the final stages , most are demented, severely ataxic,
and have behavioral abnormalities. Psychosis is very rare.
• Death occurs 10 years (range 3–24 years) after onset of
symptoms.

172 172 CT brain scan (left);T2W MRI

(right) shows increased white
matter signal.
 Adult-onset Globoid Cell Leukodystrophy (Krabbe Disease) 171

ADULT-ONSET GLOBOID CELL PATHOLOGY

LEUKODYSTROPHY (KRABBE Macroscopic
DISEASE) A marked reduction in the cerebral white matter, which feels
firm and rubbery.

DEFINITION
A rare autosomal recessive disorder caused by deficiency of
the lysosomal enzyme galactosylceramide β-galactosidase (β-
galactocerebrosidase), resulting in accumulation of galacto-
cerebroside in the central and peripheral nervous systems,
particularly the white matter of the brain and causing
demyelination.
One of the leukodystrophies, a group of inheritable
diseases in which the abnormal metabolism of myelin
components leads to progressive demyelination.
EPIDEMIOLOGY
• Incidence: rare.
• Age: adult-onset: a rare variant of the more common
infantile-onset form of Krabbe disease.
• Gender: M=F.
ETIOLOGY AND PATHOPHYSIOLOGY
• Autosomal recessive inheritance.
• A variety of mutations of the human galactocerebrosidase
gene on chromosome 14q24.3-q32.1 have been
identified.
• Deficiency of the lysosomal enzyme galactosylceramide
β-galactosidase (β-galactocerebrosidase), which catalyses
lysosomal hydrolysis of myelin-specific galactolipids
including galactosylceramide (galactocerebroside) and
galactosylshingosine (psychosine), leads to the accumu-
lation of galactosylsphingosine (galactocerebroside) or
psychosine, which is neurotoxic to both the central and
peripheral nervous systems, resulting in demyelination of
the white matter of the brain and peripheral nerves.
Microscopic
• Widespread demyelination and astrocytic gliosis in brain,
spinal cord, and nerves.
• Perivascular infiltration of large multinucleated macro-
phages containing accumulated galactocerebroside
(globoid cells) (173).
• Tubular or crystalloid inclusions in Schwann cell
cytoplasm seen on electron microscopy.
• Large-fiber, demyelinating, sensorimotor polyneuropathy.
CLINICAL FEATURES
• Asymmetric spastic quadriparesis or hemiparesis, with
brisk or absent/depressed reflexes.
• Visual failure with optic atrophy.
• Cognitive decline/dementia in some patients.
• Cerebellar ataxia.
• Peripheral neuropathy.
• Developmental delay, deafness, rigidity and seizures with
infantile onset.
DIFFERENTIAL DIAGNOSIS
• Other lysosomal storage diseases: MLD, ALD, GM2
gangliosidosis.
• Multiple sclerosis.
• LHON.
• Wilson’s disease.
• Mitochondrial disease: Leigh disease.

173 Microscopic section, high power, of brain 173

white matter showing large histiocytes
containing galactocerebroside (globoid cells)
in a patient with Krabbe disease. (Courtesy
of Professor BA Kakulas, Royal Perth Hospital,
Australia.)
172 Inherited Metabolic Diseases of the Nervous System of Adult Onset
INVESTIGATIONS
• EEG: normal initially, eventually non-specific slow,
disorganized background. Occasional multifocal
paroxysmal or epileptiform discharges are seen but
generally there are no spikes.
• EMG: normal, or decrease in sensory and motor nerve
conduction velocity and evidence of denervation, consis-
tent with a large-fiber sensori-motor polyneuropathy.
• CSF: normal 0.15–0.45 g/l (15–45 mg/dl)or elevated
protein (0.7–4.5 g/l).
• CT brain scan: normal or symmetric non-enhancing areas
of reduced density in the internal capsule, basal ganglia
or deep white matter.
• MRI brain: T2W images, show abnormal high signal,
consistent with demyelination, in the periventricular
white matter of the frontal, parietal and occipital lobes
and cerebellar white matter.
• Nerve biopsy: large-fiber sensori-motor demyelinating
polyneuropathy may be seen. Electron microscopy
reveals clusters of electron-dense filamentous inclusions
surrounded by a plasma membrane within the Schwann
cell cytoplasm.
• White blood cell galactocerebrosidase activity: reduced.
• Cultured skin fibroblasts: markedly reduced galacto-
cerebrosidase activity.
• Molecular analysis of cloned galactocerebrosidase
complementary DNA (cDNA) may reveal mutations
within the gene for galactocerebrosidase. For example,
there may be a G283 → A transition (Gly95 → Ser), which
results in an inactive galactocerebrosidase enzyme, and a
G147 → C transversion located at the last base of exon 1
(-1 position of the 5´ splicing sequences), which results
mostly in abnormally spliced mRNA.
DIAGNOSIS
• Markedly reduced galactocerebrosidase activity in
leukocytes or fibroblasts.
• Typical inclusions in Schwann cell cytoplasm.
• Symmetric demyelinating lesions on MRI brain scan.
• Mutation in the galactocerebrosidase gene.
TREATMENT
• Supportive: there is no effective medical treatment.
• Bone marrow transplantation hasn’t proved effective but
may have a role if undertaken early in the disease.
• Genetic replacement therapy may be the way of the
future: reversal of the galactocerebrosidase deficiency in
cultured cells has been accomplished by SL3-3 recom-
binant retrovirus harboring a human galactocere-
brosidase cDNA.
PROGNOSIS
Progressive: can be slow or rapid.
LATE-ONSET GM2 GANGLIOSIDOSIS
DEFINITION
The GM2 gangliosidoses comprise a spectrum of disorders of
nervous system function, each characterized by a deficiency
of either β-hexosaminidase A (Hex A) alone or in com-
bination with a deficiency of β-hexosaminidase B (Hex B).
The classic infantile forms, Tay–Sachs disease and
Sandhoff disease, result in megalencephaly, blindness,
seizures, quadriparesis, and death in early childhood.
Late-onset GM2 gangliosidosis is a variant form of
Tay–Sachs disease characterized by onset of multisystem
neurologic symptoms and signs in adolescence or in early
adult life, and slower progression with survival into adult life.
EPIDEMIOLOGY
• Incidence: rare.
• Age: onset in adolescence or early adult life.
• Gender: M=F.
PATHOLOGY
Macroscopic
Enlargement of the brain.
Microscopic
• Loss of neurons and a reactive gliosis.
• Distension of remaining nerve cells throughout the CNS
with glycolipid (174).
ETIOLOGY AND PATHOPHYSIOLOGY
• Autosomal recessive inheritance.
• Deficiency of Hex A, which normally cleaves the N-acetyl
galactosylamine from gangliosides, resulting in
accumulation of GM2 gangliosides.
• A single point mutation in exon 7 of the Hex A gene,
whereby a G → A substitution at nucleotide 805 causes
the substitution of glycine at position 269 of the Hex A
α-chain with a serine (i.e. Gly269 → Ser substitution in
the α-chain). The effect of this mutation is that it results
in an α-chain with reduced stability, indirectly affecting
its association with the β-chain of hexosaminidase so that
it is not processed to mature Hex A.
Or:
• Compound heterozygosity for the functionally silent 4-
bp insertion in exon 11 (which leads to deficiency of the
α-chain mRNA and the absence of α-chain protein,
typical of the infantile form of the disease) and for a
mutation, T538 → C, resulting in the missense
Tyr180 → His. The effect of this mutation is to decrease
the stability of the α-chain and indirectly affect the
formation of mature Hex A.
CLINICAL FEATURES
Considerable clinical heterogeneity; features include:
• Progressive ataxia, dysarthria, incoordination and
irregular postural tremor: poor handwriting.
• Progressive proximal limb neurogenic muscle weakness:
may climb stairs by mounting one at a time rather than
by alternating the feet.
• Spasticity with or without Babinski signs bilaterally.
• Dystonia.
• Intellectual impairment.
• Seizures.
 Late-onset GM2 Gangliosidosis 173

• Myoclonus. Skin
• Intermittent psychosis in some patients. Cultured fibroblasts: preparation of poly A+ mRNA.
• Restricted vertical and horizontal pursuit (supranuclear
gaze paresis). MRI brain
• Slow or hypometric horizontal and vertical saccades. MRI may show white matter disease, and brain atrophy with
• Ocular dysmetria. widening of cerebellar sulci and atrophy of brainstem.
• Internuclear ophthalmoplegia (unilateral).
Nerve conduction studies and EMG
DIFFERENTIAL DIAGNOSIS • Absent or reduced amplitude sensory nerve action
• Multiple sclerosis. potentials.
• Friedreich’s ataxia. • Normal or near-normal motor nerve conduction
• Vitamin E deficiency. velocities.
• Neuroacanthocytosis. • Widespread chronic partial denervation.
• Syphilis.
Sural nerve biopsy
INVESTIGATIONS Chronic neuropathy with predominant axonal degeneration
Blood and regeneration.
• Full blood count and film, including acanthocyte screen.
• Urea and electrolytes. Rectal mucosal biopsy
• Glucose. Glycolipid distension of ganglion cells.
• Liver function tests.
• Vitamin E, B12 and folate. DIAGNOSIS
• Creatine kinase. • Plasma, leukocyte and fibroblast hexosaminidase activity
• Lipid and protein electrophoresis. assay.
• Lysosomal enzyme analysis: hexosaminidase A activity in • DNA analysis.
plasma and leukocytes: reduced; isolation of genomic
DNA from leukocytes. TREATMENT
Supportive and symptomatic.
Chest x-ray
PROGNOSIS
Cerebrospinal fluid Slow progression with survival into adult life.

174

174 Distension of nerve cells with glycolipid.

174 Inherited Metabolic Diseases of the Nervous System of Adult Onset

NIEMANN–PICK DISEASE ETIOLOGY AND PATHOPHYSIOLOGY

TYPE C (NP-C)
DEFINITION
A panethnic autosomal recessive neurovisceral storage
disease characterized by a unique error in cellular trafficking
of exogenous cholesterol, and resulting in a variable degree
of cognitive and behavioral decline, vertical supranuclear
ophthalmoplegia and ataxia. Previously termed atypical
juvenile lipidosis and juvenile dystonic lipidosis.
CLASSIFICATION
• Type A: early infantile NP who die in infancy; primary
sphingomyelinase deficiency.
• Type B: hepatosplenomegaly without nervous system
involvement; primary sphingomyelinase deficiency.
• Type C: slowly progressive neurologic disease.
• Type D: slowly progressive neurologic disease but
appears restricted geographically to Nova Scotia.
EPIDEMIOLOGY
• Incidence: underestimated, but rare. The adult variant
occurs in only 5% of patients with Niemann–Pick disease.
• Age: childhood, adolescence or early adulthood.
• Gender: M=F.
PATHOLOGY
Brain (175)
• Accumulation of unesterified cholesterol in lysosomes.
• Light microscopy reveals storage material in ballooned
cortical neurons.
• Electron microscopy reveals storage material as
membranous and osmiophilic granules in lysosomes.
• Axonal spheroids.
• Neurofibrillary tangles similar to those in Alzheimer’s
disease: stain positive with Alz50 antibody and consist of
paired helical filaments (in adults).
• No senile plaques.
Other tissues
Foamy histiocytes (lipid-laden macrophages) in bone
marrow, liver, spleen, skin, skeletal muscle and eye.
• Impaired intracellular homeostatic responses to
exogenous low-density lipoprotein (LDL)-derived
cholesterol due to a defect of intracellular cholesterol
esterification. The primary defect is still unknown.
• Abnormal egress of free cholesterol from lysosomes to
other cellular organelles such as plasma membrane and
the Golgi apparatus.
• Autosomal recessive inheritance.
• Primary genetic defect still unknown.
• Gene locus: linked to chromosome 18q11-12 in most
patients.
• Genetic heterogeneity.
CLINICAL FEATURES
Pre-school-onset
• History of prolonged neonatal jaundice.
• Hepatosplenomegaly: non-progressive.
• Dystonia: initially focal in hand or foot and may later
generalize.
• Ataxia, dysarthria and dysmetria.
• Vertical supranuclear gaze palsy:
– Impaired voluntary vertical saccades.
– Normal horizontal saccades and oculocephalic reflexes.
• Cognitive decline causing difficulty at school.
Adult-onset
• Progressive dementia and psychosis.
• Vertical supranuclear ophthalmoplegia (may not be
present in adult disease).
• Ataxia, dysarthria and dysmetria.
• Dystonia.
• Cataplexy may occur.
• Seizures can occur later in course.
DIFFERENTIAL DIAGNOSIS
School difficulty
• Attention deficit disorder.
• Other learning disabilities.
• Absence seizures.
• Early dementias (see immediately below).

175 175 Coronal

sections of the brain
at autopsy of a
patient with
Niemann–Pick
disease.
 Niemann–Pick Disease Type C (NP-C) 175

Dementia • Skin fibroblast cultures with LDL-derived tritiated oleate:

• Neuronal ceroid lipofuscinosis. – Severely delayed rate of cholesterol esterification.
• Leukodystrophies. – Filipin staining reveals accumulation of unesterified free
• Subacute sclerosing panencephalitis. cholesterol in lysosomes.
• HIV infection. – Reduced acid sphingomyelinase activity in some patients:
• Multiple sclerosis. a secondary phenomenon due to excessive cholesterol
• Psychosis. sequestration.
• Fluorescence microscopy may be useful to detect cells
Dystonia from patients with sphingolipidoses by the color and
• Idiopathic torsion dystonia. subcellular distribution of the fluorescence, by the
• Dopa-responsive dystonia. presence of red lysosomes.
• Wilson’s disease.
• Amino- and organic acidopathies (glutaric aciduria, mito- DIAGNOSIS
chondrial diseases). • Vertical supranuclear gaze palsy associated with various
• GM2 gangliosidosis. degrees of splenomegaly and other neurologic signs.
• Characteristic inclusions in lipid-laden cells in tissues such
Cataplexy as skin or liver.
• Other sleep disorders.
• Epilepsy (akinetic/atonic seizures). Definitive diagnostic test
• Syncope. • Skin fibroblast cultures with LDL-derived tritiated oleate:
• Periodic paralysis. severely reduced rate of cholesterol esterification. Filipin
staining reveals accumulation of free cholesterol in
Vertical supranuclear gaze palsy lysosomes.
• Dorsal midbrain syndrome (upgaze: posterior commis- • There is no correlation between the degree of the
sure, downgaze: rostral interstitial nucleus of the medial cholesterol esterification defect and the clinical severity
longitudinal fasciculus). of the disease.
• Tumors: pineal, tectal.
• Hydrocephalus. TREATMENT
• GM2 gangliosidosis. Specific
• Mitochondrial disease. • Nil available to date that is effective.
• Non-ketotic hyperglycinemia. • Neither low cholesterol diet nor cholesterol-lowering
• Maple syrup urine disease. medication has been shown to be effective to date.

Isolated splenomegaly Supportive

• Leukemia. • Physical therapy to maximize mobility and minimize
• Lymphoma. contractures.
• Histiocytosis. • Speech and swallowing therapy to avoid aspiration
• Storage diseases (Gaucher, Niemann–Pick types A and B). pneumonia.
• Infections. • Psychologic support.
• Anticholinergic medication for dystonia.
Severe neonatal jaundice • Protriptyline hydrochloride or clomipramine hydro-
• Biliary atresia. chloride for cataplexy.
• Congenital infections. • Anti-epileptic medication for epilepsy.
• Alpha1-antitrypsin deficiency. • Haloperidol or other antipsychotic drugs for psychotic
• Tyrosinemia. manifestations.
• Gastrostomy in late stages if swallowing no longer
INVESTIGATIONS possible.
• Blood: normal chemistry, hypercholesterolemia is not a
feature. Genetic counselling
• PCR-based DNA linkage study: linkage to the major • Parents who are both carriers of the disease gene have a
18q11-12 Niemann–Pick type C locus. 25% chance of having an affected child in each pregnancy.
• CT / MRI brain: may be normal or show multiple areas • Pre-natal diagnosis: cultured chorionic villus biopsy
of demyelination (high signal on T2W image), gliosis specimens or cultured amniotic cells with LDL-derived
and moderate atrophy. tritiated oleate for rate of cholesterol esterification.
• Proton magnetic resonance spectroscopy: decreased N- • Obligatory carriers of the gene that causes NP-C cannot
acetyl aspartate and increased choline in various parts of be detected by these methods because carriers have
brain of moderately to severely affected patients. cholesterol esterification and free cholesterol accumu-
• Brainstem auditory evoked potentials: absent acoustic lation in lysosomes that range between normal and half
reflex early in disease. the values of affected homozygotes.
• CSF: normal.
• Abdominal ultrasound: may show hepatosplenomegaly. PROGNOSIS
• Bone marrow aspirate: lipid-laden phagocytic foam cells • Pre-school onset: inexorable progression to death,
with numerous small cytoplasmic vacuoles (sea-blue usually in the teenage years.
histiocytes). • Progression is slower in patients with later onset.
176 Inherited Metabolic Diseases of the Nervous System of Adult Onset
FURTHER READING
GENERAL
Gray RGF, Preece MA, Green SH, et al. (2000)
Inborn errors of metabolism as a cause of neu-
rological disease in adults. An approach to in-
vestigation. J. Neurol. Neurosurg. Psychiatry,
69: 5–12.
WILSON’S DISEASE
Brewer GJ, Johnson V, Dick RD, et al. (1996)
Treatment of Wilson disease with ammonium
tetrathiomolybdate. Arch. Neurol., 53:
1017–1025.
Fink JK, Hedera P, Brewer GJ (1999) Hepatolen-
ticular degeneration (Wilson’s disease). The
Neurologist, 5: 171–185.
Pyeritz RE (1997) Genetic heterogeneity in Wil-
son disease: Lessons from rare alleles. Ann. In-
tern. Med., 127: 70–72.
MITOCHONDRIAL (OXIDATIVE
PHOSPHORYLATION) DISEASES
Leonard JV, Schapira AHV (2000) Mitochondri-
al respiratory chain disorders I: mitochondrial
DNA defects. Lancet, 355: 299–304.
Leonard JV, Schapira AHV (2000) Mitochondri-
al respiratory chain disorders II: neuro-
degenerative disorders and nuclear gene de-
fects. Lancet, 355: 389–394.
ADRENOLEUKODYSTROPHY
Bezman L, Moser AB, Raymond GV, et al. (2001)
Adrenoleukodystrophy: incidence, new muta-
tion rate, and results of extended family
screening. Ann. Neurol., 49: 512–517.
Ito R, Melhem ER, Mori S, et al. (2001) Diffu-
sion tensor brain MR imaging in X-linked
cerebral adrenoleuco dystrophy. Neurology, 56:
544–547
Moser HW (1997) Adrenoleukodystrophy: phe-
notype, genetics, pathogenesis and therapy.
Brain, 120: 1485–1508.
Moser HW (1999) Treatment of X-linked
adrenoleukodystrophy with Lorenzo’s oil. J.
Neurol. Neurosurg. Psychiatry, 67: 279–280.
Sawaya RA (2000) Adrenoleukodystrophy: a re-
view. The Neurologist, 6: 214–219.
Shapiro E, Krivit W, Lockman L, et al. (2000)
Long-term effect of bone-barrow transplanta-
tion for childhood-onset cerebral X-linked
adrenoleukodystrophy. Lancet, 356: 713–718.
METACHROMATIC LEUKODYSTROPHY
Chen C-S, Patterson MC, Wheatley CL, O’Brien
JF, Pagano RE (1999) Broad screening test
for sphingolipid-storage diseases. Lancet, 354:
901–905.
Hageman ATM, Gabreels FJM, de Jong JGN, et
al. (1995) Clinical symptoms of adult
metachromatic leucodystrophy and arylsul-
phatase A pseudodeficiency. Arch. Neurol., 52:
408–413.
ADULT-ONSET GLOBOID CELL
LEUKODYSTROPHY
Bernardini GL, Herrera DG, Carson D, et al.
(1997) Adult-onset Krabbe’s disease in sib-
lings with novel mutations in the galactocere-
brosidase gene. Ann. Neurol., 41: 111–114.
Satoh J-I, Tokumoto H, Kurohara K, et al. (1997)
Adult-onset Krabbe disease with homozygous
T1853C mutation in the galactocerebrosidase
gene. Unusual MRI findings of corticospinal
tract demyelination. Neurology, 49:
1392–1399.
LATE-ONSET GM2 GANGLIOSIDOSIS
De Gasperi R, Gama Sosa MA, Battistini S, et al.
(1996) Late-onset GM2 gangliosidosis: Ashke-
nazi Jewish family with an exon 5 mutation
(Tyr180ÆHis) in the Hex A a-chain gene.
Neurology, 47: 547–552.
NIEMANN-PICK DISEASE TYPE C
Chen C-S, Patterson MC, Wheatley CL, O’Brien
JF, Pagano RE (1999) Broad screening test
for sphingolipid-storage diseases. Lancet, 354:
901–905.
Lossos A, Schlesinger I, Okon E, et al. (1997)
Adult-onset Niemann-Pick type C disease.
Arch. Neurol., 54: 1536–1541.
Schiffmann R (1996) Niemann-Pick disease type
C. From bench to bedside. JAMA, 276:
561–564.
 Chapter Nine 177

Traumatic Diseases of
the Nervous System
SUBDURAL HEMATOMA
DEFINITION
Hemorrhage into the subdural space, usually caused by
rupture of bridging veins which pass from the pia-arachnoid
over the brain to a dural sinus.
EPIDEMIOLOGY
• Incidence: 6 (95% CI: 3–12) per 100 000 per year.
• Lifetime prevalence: 0.3 (95% CI: 0.2–0.6) per 1000.
• Age: all age groups but more frequent among the elderly.
The average age is about 65 years.
• Gender: M=F.
PATHOLOGY
Acute subdural hematoma (<3 days old)
A collection of fresh clotted blood in the subdural space,
frequently combined with epidural hemorrhage, cerebral
contusion and laceration (176, 177).
Subacute subdural hematoma (3 days–3 weeks old)
A mixture of subdural clot and liquid.
Chronic subdural hematoma (>3 weeks old)
• Almost entirely liquid (and some altered blood) in the
subdural space, encysted by fibrous membranes (pseudo-
membranes) which have grown from the dura.
• Bilateral in 20–25% of cases.
ETIOLOGY
• Head trauma causing rupture of small pial vessels:
particularly relevant in acute subdural hematoma; may
be minor in chronic subdural hematoma among elderly
alcoholics and patients on anticoagulants.
• Rupture of:
– A saccular or mycotic aneurysm of a major intracerebral
artery.
– An intracavernous aneurysm of the carotid artery.
– An aneurysm of the middle cerebral artery.
– An arteriovenous malformation; a vascular tumor.
• Moyamoya syndrome.
• Ventricular decompression for hydrocephalus.
• Dural metastases.
• Lumbar puncture.
Risk factors
• Older age: presumably cerebral atrophy makes the
bridging veins to the venous sinuses more vulnerable to
an acceleration/deceleration injury.
• Alcohol abuse.
• Bleeding diathesis: anticoagulant drug use, the most
common precipitant, accounting for about 25% of all
subdural hematomas, and 50% of those without obvious
trauma; thrombolytic treatment.
• CSF shunt.
• Epilepsy.

176 Autopsy specimen of 176 177

a fatal subdural hematoma
over the right hemisphere
(arrows).

177 Autopsy specimen of

a fatal subdural hematoma
over the parasagittal region
of one hemisphere,
beneath the dura, which
has been retracted.
178 Traumatic Diseases of the Nervous System
PATHOPHYSIOLOGY
Acute subdural hematoma
Caused by traumatic tearing of subdural cortical surface
vessels or bridging veins to the venous sinuses. Symptoms are
caused by an expanding fresh blood clot, compressing
underlying brain (causing focal neurologic signs) and raising
intracranial pressure (causing drowsiness and confusion),
leading to transtentorial herniation if not arrested.
Unlike arterial hemorrhage into the epidural space,
venous hemorrhage into the subdural space is usually
arrested by rising intracranial pressure.
Chronic subdural hematoma
Injury leads to hemorrhage from a subdural bridging vein
or cortical surface vessel into the subdural space over one
cerebral hemisphere and occasionally over both hemi-
spheres, interhemispheric (usually aneurysmal) or subcere-
bellar. The hemorrhage is under low pressure and may be
small and not of any clinical consequence.
Over the next few days, fibroblasts invade the clot, and
fine connective tissue membranes form over the inner
(cortical) and outer (dural) surfaces, so that at about
3 weeks, the hematoma becomes completely enclosed by
membrane and attached to the dura. During this time, the
clot progressively breaks up and liquefies.
The liquefied hematoma is resorbed in many cases but in
others it gradually enlarges, probably because of repeated
small hemorrhages from the fine, friable vessels in the
connective tissue membranes that have formed. Hemorr-
hage may be promoted by accumulation of fibrin degrada-
tion products in the liquefied hematoma, and depletion of
coagulation cascade components.
It is likely that there is a balance between resorption and
enlargement of the hematoma: if production exceeds resorp-
tion, the hematoma enlarges and acts as a space-occupying
mass, compressing the underlying brain (causing focal
neurologic signs) and eventually producing distortion and
herniation of the brain.
Chronic subdural hematomas tend to expand slowly,
allowing the brain to compensate to some extent, so that at
times the hematoma may be quite large with considerable
brain distortion before causing symptoms.
CLINICAL FEATURES
Depend on the site and size of the hematoma and maximum
brain compression, and the rate of hematoma enlargement.
Acute subdural hematoma
Supratentorial
Usually initial loss of consciousness (from the head trauma),
which may persist or be followed by a short lucid interval of
several hours where consciousness is regained, followed by
progressive headache, confusion and deterioration of conscious
state. Lateralizing neurologic signs may be present.
Infratentorial
Headache, vomiting, dysphagia, pupillary inequality, cranial
nerve palsies, truncal and gait ataxia, and, rarely, a stiff neck.
Chronic subdural hematoma
• Most patients are elderly.
• About half recall a head injury of varying severity.
• Subacute onset, over several days to weeks, of:
– Headache (present in about 80% of cases).
– Confusion, apathy, drowsiness and stupor.
– Decline in cognitive function and speed of thinking
(subacute dementia).
– Mild focal neurologic symptoms and signs (e.g.
incomplete hemiparesis, aphasia); all of which may
fluctuate, and may be transient.
• Patients presenting late may be in coma or have a hemiplegia.
• Seizures occur rarely, mostly in alcoholics or patients with
cerebral contusions.
SPECIAL FORMS
Subdural hygroma
• A collection of blood and CSF in the subdural space.
• Pathophysiology: thought to be due to a tear in the arach-
noid which permits CSF to pass from the subarachnoid
into the subdural space, where it may accumulate, presum-
ably due to a ball-valve effect of the arachnoidal tear.
• Etiologic factors:
– Head injury.
– Meningitis as an infant or young child.
– Ventriculoperitoneal shunting of a hydrocephalic brain.
– Pneumoencephalography (in the past).
• Clinical features: asymptomatic or confusion, drowsiness,
irritability and fever.
• CT brain scan shows a subdural fluid collection of the
same density as CSF. No contrast enhancement is seen
because there are no vascular membranes.
• Treatment: as for chronic subdural hematoma: aspirate
or drain the subdural fluid if symptomatic.
DIFFERENTIAL DIAGNOSIS
Acute epidural hemorrhage
• Usually a history or evidence of head trauma, or a
temporal or parietal skull fracture.
• Consciousness may not have been disturbed, or may have
been lost momentarily, followed a few hours or a day later (the
interval may be longer with venous bleeding) by headache of
increasing severity, with vomiting, drowsiness, confusion, and
seizures or signs of hemispheric dysfunction such as dysphasia
and hemiparesis. As coma develops, the pupil on the side of
the hematoma dilates (because the IIIrd nerve is compressed
in the tentorial notch by downward displacement of the
temporal lobe), bilateral corticospinal tracts signs may develop,
and signs of transtentorial herniation ensue (see p.44).
• X-ray of the skull may show a fracture line.
• CT or MRI scan of the brain establishes the diagnosis by
revealing a lens-shaped clot with a smooth inner margin (180).
• Lumbar puncture is contraindicated.
• Surgical evacuation of the clot and ligation of the bleeding
vessel (usually the middle meningeal artery) can be life-saving.
Alternatively, if the condition is advancing too rapidly for any
investigation to be done, the placement of burr holes on the
same side of the skull as the dilated pupil can also be life-saving.
Subarachnoid hemorrhage
Some chronic subdural hematomas may present with acute
headache, mimicking SAH (see p.249).
Transient ischemic attack or stroke
Subdural hematoma may rarely present with the abrupt onset
of focal neurologic signs, and they may be initially transient.
Subacute delirious reaction
Drug intoxication.
 Subdural Hematoma 179

Depression the inner table of the skull and the cortex. The mass
effect may cause midline shift and compression of the
Dementia ipsilateral lateral ventricle (181).
Alzheimer’s disease (see p.407). • Subacute subdurals (i.e. around 10–21 days old) may be
isodense with brain and difficult to identify unless
Brain tumor (see p.357) secondary features such as compression of the ipsilateral
ventricle, midline shift and loss of cortical sulci are
INVESTIGATIONS sought. Contrast may help to highlight subacute
Cranial CT scan subdurals (the vascular membrane will enhance making
• The imaging investigation of subdural hematomas is with the cortical margin more visible).
CT – this will exclude most acute and chronic subdurals • Chronic subdurals are hypodense (black) so are easier to
(178, 179), and acute extradurals (180), if the scan is see (179). They may also have mass effect depending on
carefully examined. their size.
• Acute subdural hematomas are hyperdense (white) • In cases of doubt a repeat CT scan 1 week or so later or
compared with normal brain, crescentic, lying between an MRI will sort it out.

178 Acute on chronic 178 179

subdural hematoma over
the left hemisphere. Note
the layer of higher density
sediment posteriorly
indicating some recent
hemorrhage
(arrowheads) and the
considerable midline shift.

179 Bilateral chronic

subdural hematomas (or
hygromas as sometimes
called [arrowheads]).
Note the absence of
cortical sulci and the
compressed lateral
ventricles indicating that
these are not just large
CSF spaces due to
atrophy.

180 Acute extradural 180 181

hematoma over the
right parietal lobe for
comparison. Note the
whiteness (indicating
fresh hemorrhage) and
the localized position
(subdurals tend to spread
more extensively over the
hemisphere).

181 Plain cranial CT scan

showing a recent subdural
hematoma (arrowheads)
as a high density (white)
over the right hemisphere
causing mass effect with
compression of the right
lateral ventricle and
midline shift.
180 Traumatic Diseases of the Nervous System
MRI
• MRI is more sensitive for detecting hematomas; the
properties of hemoglobin breakdown products give
signal changes that make even small subdurals stand out
quite clearly no matter what their age.
• The problem with using MR in the first instance is that
these patients are often confused and unwell, so they
move in the MR scanner and the end result may not be
diagnostic. It is better to go for the quick technique that
suits ill patients, which is CT.
EEG
Usually abnormal bilaterally, sometimes with reduced
voltage or electric silence over the hematoma (due to
dampening effects) and high-voltage slow waves over the
contralateral hemisphere, because of the displacement of the
brain to that side. Unilateral focal delta activity is also quite
non-specific.
CSF
Not indicated, but if done, the pressure may be normal or
elevated; the appearance may be clear and acellular, bloody
or xanthochromic, depending on the presence or absence
of recent or old contusions and subarachnoid hemorrhage;
and the protein may be relatively low.
Cerebral angiography
Shows displacement of cortical branches of the middle
cerebral arteries inward from the inner surface of the skull,
and contralateral displacement of the anterior cerebral artery.
DIAGNOSIS
• Suspect in any patient with recent onset of headache or
drowsiness, progressive impairment of memory or
intellect, or other symptoms suggestive of a space-
occupying lesion.
• Confirm by cranial CT scan, but beware that, after some
days, the density of the hematoma approaches that of
surrounding tissue and may be difficult to detect.
• If the CT appears normal and the index of suspicion is
high, MRI is the definitive investigation; bilateral carotid
angiography used to be.
TREATMENT
• Conservative, with careful observation, if there is no
definite neurologic compromise or significant radiologic
mass effect (e.g. if the maximum thickness is less than
1 cm [0.4 in]).
• Rapid correction of the coagulation status, if appropriate
(e.g. anticoagulant-associated subdural).
• Active neurosurgic intervention is indicated if neurologic
symptoms and signs are severe and progressing, and if
the clot is large enough to explain the clinical features.
Medical treatments such as mannitol and corticosteroids
are ineffective.
• The surgical options include:
– Making a simple twist drill hole that allows the subdural
fluid to escape
– Making one or two burr holes and washing out the
subdural space.
– Performing a formal craniotomy, which may be accom-
panied by excision of some of the subdural membrane.
• A burr hole or twist drill hole is a lesser undertaking than
a formal craniotomy.
• If the CT brain scan suggests that a significant amount
of actual clot is present or that the membranes have
created a loculated chronic subdural hematoma (CSDH),
a craniotomy may the most appropriate choice.
• A reduction of 20% of the volume of the subdural fluid
is all that is required to reduce the subdural pressure to
close to zero, which usually leads to clinical improve-
ment. In addition to reducing any pressure effects,
drainage allows washing out of the high concentration
of fibrin degradation products which have contributed
to the CSDH enlargement, thus shifting the balance
back in favor of resorption. It is uncommon for the brain
to immediately re-expand following its period of
compression. Post-operative CT brain scan usually
demonstrates some residual subdural fluid and air, and it
may take up to 6 months for the CT to show complete
resolution of the hematoma. The patient’s clinical course
is therefore more important for detecting complications
than the post-operative CT scan.
Complications
• Post-operative infection, particularly subdural empyema,
occurs in <1% of patients but can be fatal.
• Reaccumulation, presumably caused by bleeding from
the vascular outer membrane, occurs in 10–20% of
patients, and may lead to deterioration or failure to
improve post operatively. CT scan usually shows a new
collection of hyperdense or mixed density hematoma,
and redrainage is generally required.
• Epilepsy may occur in up to 10% of patients.
NATURAL HISTORY
Usually progressive or fluctuating clinical course, sometimes
with spontaneous resolution. If the level of consciousness
remains normal, spontaneous resolution may occur, even
with an acute onset. However, sudden deterioration may
occur days or weeks after onset.
PROGNOSIS
85–90% of patients make a good functional recovery with
appropriate treatment. The outcome correlates with the
patient’s neurologic condition at the time of diagnosis and
treatment: most patients with poor outcomes are
significantly impaired (e.g. comatose) before treatment.
FURTHER READING
Maurice-Williams RS (1999) Chronic subdural haematoma: an everyday
problem for the neurosurgeon. Br. J. Neurosurg., 13: 547–590.
Maurice-Williams RS (2001) Bedside treatment of chronic subdural
haematoma? Lancet, 357: 1308–1309.
Reinges MHT, Hasselberg I, Rohde V, et al. (2000) Prospective analysis of
bedside percutaneous tapping for the treatment of chronic subdural
haematomas in adults. J. Neurol. Neurosurg. Psychiatry, 69: 40–47.
Van Havenbergh T, Van Calenbergh F, Griffin J, Plets C (1996) Outcome
of chronic subdural haematomata, and analysis of prognostic factors. Br.
J. Neurosurg., 10: 35–39.
 Chapter Ten 181

Vascular Diseases of
the Nervous System
NEUROVASCULAR SYNDROMES: ANATOMIC (see Table 23) AND
CLINICAL (see Table 24) CLASSIFICATION

Table 23 Anatomic classification

Arterial territory Area supplied Typical syndrome if total territory involved

Internal carotid artery*

Ophthalmic artery Retina and optic nerve Monocular blindness or altitudinal field defect

Anterior choroidal artery Globus pallidus (internal) Contralateral hemiparesis, hemisensory loss, and homonymous hemianopia
Internal capsule(posterior limb)
Choroid plexus

Middle cerebral artery (MCA) Frontal lobe Contralateral central facial weakness, hemiparesis and hemisensory loss (arm>leg),
Parietal lobe homonymous hemianopia, and global aphasia (dominant hemisphere) or visual-spatial-
Superior temporal lobe perceptual dysfunction (non-dominant hemisphere)

Medial lenticulostriate Internal capsule Contralateral pure motor hemiparesis

Lateral lenticulostriate Putamen Contralateral hemiparesis, dysphasia (dominant hemisphere) or visual-spatial-

Globus pallidus (external) perceptual dysfunction (non-dominant hemisphere)
Caudate nucleus
Internal capsule
Corona radiata

Superior division of MCA Frontal and anterior parietal lobes Contralateral central facial weakness, hemiparesis and hemisensory loss, ipsilateral
deviation of head and eyes, and global or motor aphasia (dominant hemisphere)
Pre-rolandic branch Contralateral face and arm weakness, and motor aphasia (dominant hemisphere)
Rolandic branch Contralateral central facial weakness, hemiparesis and hemisensory loss; and
dysarthria (resembling lacunar syndrome)
Anterior parietal branch Conduction aphasia and bilateral ideomotor apraxia

Inferior division of MCA Inferior parietal and Homonymous hemianopia,Wernicke’s aphasia or agitated confusional state
lateral temporal lobes (dominant hemisphere), left visual neglect (right-sided lesion)
Posterior parietal branch
Angular branch
Posterior temporal branch
Anterior temporal branch
Temporal polar branch

Anterior cerebral artery Anterior and superior Contralateral foot and leg weakness or hemiparesis (leg>arm), abulia, incontinence,
medial frontal lobe grasp reflexes

Vertebrobasilar territory
Vertebral and basilar artery**
Brainstem and cerebellum
Various syndromes including diplopia, ophthalmoplegia, or gaze palsies;
vertigo, nausea and nystagmus; dysarthria, dysphagia, and bulbar weakness;
ipsilateral facial sensory loss and weakness (nuclear or infranuclear);
hiccoughs and respiratory failure; contralateral hemiparesis or tetraparesis,
contralateral or bilateral sensory loss, coma
Continued on page 182

* Complete internal carotid artery occlusion, if symptomatic, usually produces symptoms in the MCA territory, but the ophthalmic and anterior cerebral
artery territories can also be involved alone, or in combination with the MCA, depending on collateral supply.
** Basilar artery occlusion may also involve the territory of one or both posterior cerebral arteries.
N.B: Incomplete syndromes are common, and the symptoms of infarction and hemorrhage are similar.
182
Table 23 (continued)
Arterial territory
Basilar artery
Top of basilar artery
Superior cerebellar artery
Anterior inferior
cerebellar artery
Posterior inferior
cerebellar artery
Paramedian branches
Posterior cerebral artery
Paramedian
mesencephalic arteries
Thalamic-subthalamic
(thalamoperforating)
Posterior communicating artery
Polar arteries
(tuberothalamic)
Thalamo-geniculate
Posterior choroidal
arteries
* Complete internal carotid artery occlusion, if symptomatic, usually produces symptoms in the MCA territory, but the ophthalmic and
anterior cerebral artery territories can also be involved alone, or in combination with the MCA, depending on collateral supply.
** Basilar artery occlusion may also involve the territory of one or both posterior cerebral arteries.
N.B. Incomplete syndromes are common, and the symptoms of infarction and hemorrhage are similar.
Vascular Diseases of the Nervous System
Area supplied Typical syndrome if total territory involved
Rostral midbrain Variable pupillary abnormalities
Part of thalamus Ptosis or lid retraction
Inferior temporal, Supranuclear vertical gaze paresis
occipital lobes Somnolence
Hemiballismus
Amnesia
Cortical blindness
Midbrain (dorso-lateral), Ipsilateral Horner’s syndrome
superior cerebellar peduncle, Ipsilateral limb ataxia and tremor
superior cerebellum Contralateral spinothalamic sensory loss
Contralateral central facial weakness
Contralateral IVth nerve palsy sometimes
Base of pons Ipsilateral Horner’s syndrome
Rostral medulla Ipsilateral facial sensory loss (pain, temperature)
Rostral cerebellum Ipsilateral nuclear facial and abducens palsy
Cochlea Ipsilateral deafness and tinnitus
Vestibule Vertigo, nausea, vomiting and nystagmus
Ipsilateral ataxia of limbs and dysarthia
Lateral medulla, Ipsilateral Horner’s syndrome
inferior cerebellum Ipsilateral facial sensory loss (pain, temperature)
Vertigo, nausea, vomiting and nystagmus
Ipsilateral paralysis of palate (dysphagia)
Ipsilateral paralysis of larynx (dysphonia)
Ipsilateral ataxia of limbs
Contralateral hemisensory loss below neck
Paramedian pons Any of the lacunar syndromes:
Pure motor hemiparesis
Ataxic hemiparesis
Pure hemisensory loss
Hemiparesis-hemisensory loss
Internuclear ophthalmoplegia
Locked-in syndrome, if bilateral
Occipital lobe Contralateral homonymous hemianopia
Cortical blindness if bilateral
Inferior temporal lobe Amnesia (especially if bilateral)
Rostral medial midbrain Hemisensory-motor loss
Postero-medial Hemisensory loss, amnesia
thalamus inferiorly
Anterior lateral thalamus Hemisensory loss, amnesia
Ventrolateral thalamus Pure hemisensory loss
Anterior and posterior Hemisensory loss, amnesia
thalamus
182 T2W axial MRI of an infarct in the right hemisphere (arrow),
obtained at 12 hours after symptom onset, in a patient with a left
hemiparesis, visual-spatial-perceptual dysfunction and a left homonymous
hemianopia (a total anterior circulation syndrome). Note the altered
signal in gray and white matter and the mass effect.
 Neurovascular Syndromes 183

Table 24 Clinical features, anatomy, pathology, etiology, and prognosis of the four clinical stroke syndromes

Total anterior circulation Partial anterior circulation Lacunar syndrome Posterior circulation syndrome
syndrome (TACS) (182, 183) syndrome (PACS) (184–186) (LACS) (187) (POCS) (188–194)

Clinical features 1 Hemiparesis and Any combination of two of 1 Hemiparesis or Brainstem symptoms
hemisensory loss and preceding three in TACS 2 Hemisensory loss or and signs (e.g. diplopia,
2 Homonymous hemianopia and or (3) alone, or monoparesis 3 Hemisensorimotor vertigo, dysphagia, ataxia,
3 Cortical dysfunction loss or bilateral limb deficits,
(dysphasia or visual-spatial- 4 Ataxic hemiparesis hemianopia or cortical
perceptual dysfunction) blindness)
No hemianopia or
cortical dysfunction

Anatomy Fronto-temporal-parietal lobes Lobar Small deep lesion in Brainstem and/or cerebellum
or either corona radiata,
Thalamus/internal internal capsule,
capsule/occipital lobe thalamus or ventral
pons

Pathology Infarction (85%) or Infarction (85%) or Infarction (95–98%) or Infarction (85%) or

Hemorrhage (15%) Hemorrhage (15%) Hemorrhage (2–5%) Hemorrhage (15%)

Etiology Infarction: occlusion of ipsilateral Infarction: occlusion of Infarction: usually Infarction: occlusion of
ICA or MCA, and occasionally branch of MCA or PCA; perforating artery VBA or PCA, or branches;
PCA; by embolism from heart, by embolism from heart, microatheroma/ by in situ thrombosis or
aortic arch or carotid or aortic arch, or carotid or lipohyalinosis or embolism from heart,
vertebrobasilar arteries, vertebrobasilar arteries rarely arteritis or aortic arch or VBA
or in situ thrombosis embolism

Hemorrhage: any of possible Hemorrhage: any of Hemorrhage: any, Hemorrhage: any

causes (see p.238) possible causes (see p.238). but usually of possible causes (see p.238)
hypertensive small
vessel disease

Recurrence rates Low High in first 3 months Low but steady over High in first 2 months
12 months and steady over 12 months

Prognosis at Poor Fair Fair Fair

1 year
Dead 60% 15% 10% 20%
Dependent 35% 30% 30% 20%
Independent 5% 55% 60% 60%

ICA: internal carotid artery; MCA: middle cerebral artery; PCA: posterior cerebral artery;VBA: vertebrobasilar artery

182 183

183 Brain, coronal section showing necrosis of the right parietal and
temporal lobes, basal ganglia and internal capsule (arrow) due to an old
infarct in the right middle cerebral artery territory causing a total anterior
circulation syndrome. (Courtesy of Professor BA Kakulas, Department of
Neuropathology, Royal Perth Hospital, Australia.)
184 Vascular Diseases of the Nervous System

184 185 184,185 Plain cranial CT

scan showing hyperdensity
(due to blood clot) in the
origin of the left middle
cerebral artery (184,
arrow), and left
striatocapsular infarction in a
patient who presented with
a partial anterior circulation
syndrome (right hemiparesis
and dysphasia/cognitive
deficit) (185, arrow).

186 187

187 Brain at autopsy showing a lacunar infarct (arrow) in the internal

capsule of a patient with a previous lacunar syndrome. (Courtesy of
Professor BA Kakulas, Department of Neuropathology, Royal Perth
Hospital, Australia.)

186 Plain cranial CT scan showing a 188

homogenous area of high density due to
hemorrhage in the right frontal lobe of an elderly
man with amyloid angiopathy and a partial
anterior circulation syndrome (left hemiparesis
and cognitive/visual-spatial-perceptual
dysfunction).

188, 189 Eye signs of a patient with a posterior

circulation syndrome due to an embolus to the
top of the basilar artery causing midbrain
infarction (188). Note the lid retraction, skew
deviation, right internuclear ophthalmoplegia, and
upgaze palsy (189).
 Neurovascular Syndromes 185

189 190

189 Lid retraction, skew deviation, right internuclear ophthalmoplegia,

and upgaze palsy in a patient with a posterior circulation syndrome due
to an embolus to the top of the basilar artery causing midbrain
infarction (see also 188).

190 MRI brain scan,T2W image, showing an area of high attenuation,

consistent with recent infarction in the right lateral medulla (arrow).

191

192

191 MR angiogram showing patchy signal in the right vertebral artery

consistent with dissection of the right vertebral artery (arrow).

193
192 Autopsy specimen of brain, horizontal slice through the medulla
at the level of the olives, showing pallor in the right lateral medulla
(arrow).

193, 194 MRI scan,T2W image (193), and ventral surface of the
cerebellum and medulla at autopsy (194) showing infarction in the
right posterior inferior cerebellum (arrows) due to occlusion of the
posterior inferior cerebellar artery.

194
186 Vascular Diseases of the Nervous System

TRANSIENT ISCHEMIC ATTACKS (TIA) Somatosensory

OF THE BRAIN AND EYE Altered feeling on one side of the body, in whole or in part.

Visual
DEFINITION • Loss of vision in one eye, in whole or in part.
A clinical syndrome characterized by: • Loss of vision in the left or the right half of the visual field.
• Sudden onset of loss of focal brain or monocular function. • Bilateral blindness.
• Symptoms are thought to be due to inadequate brain or • Double vision*.
ocular blood supply as a result of arterial thrombosis or em-
bolism associated with disease of the arteries, heart or blood. Vestibular
• Symptoms last less than 24 hours. The 24 hour time A spinning sensation*.
limit for the duration of symptoms is purely arbitrary,
having more to do with the earth's rotation than biology; * In isolation these symptoms do not necessarily indicate
there is no qualitative difference between patients with transient focal cerebral ischemia.
TIA and mild ischemic stroke in terms of etiology and
prognosis, only a quantitative difference in terms of Non-focal neurologic symptoms
duration of symptoms. Non-focal neurologic symptoms are not neuroanatomically
localizing and are not due to TIAs unless accompanied by
EPIDEMIOLOGY additional focal neurologic symptoms.
• Incidence: about 50 per 100 000 per year (crude incidence). • Generalized weakness and/or sensory disturbance.
• Age: middle-aged and elderly; incidence increases with • Faintness and/or imbalance.
increasing age. • Altered consciousness or fainting, in isolation or with
• Gender: M=F (age <55 years), M>F (age 55–75 years), impaired vision in both eyes.
F>M (age >75 years). • Incontinence of urine or feces.
• Confusion or memory disturbance.
ETIOLOGY • A spinning sensation*.
A TIA is not a disease but a symptom of disease of the • Difficulty swallowing*.
arteries, heart or blood. • Slurred speech*.
• Double vision*.
Arterial disease (embolism/low flow) 75–80% • Loss of balance*.
• Extracranial large artery (aorta, carotid, vertebral)
atherothromboembolism 40–45%. * If these symptoms occur in combination, or with focal
• Intracranial large (e.g. middle cerebral, vertebrobasilar) neurologic symptoms, they may indicate transient focal
artery atheroma 5–10%. cerebral ischemia.
• Intracranial small (perforating) artery lipohyalinosis/
microatheroma 25% (‘lacunar’ TIA). Where is the TIA? (see Table 25)
• Non-atheromatous arterial disease (e.g. congenital,
arteritis, dissection) <5%. What is the cause of the TIA? (see Etiology [above]
and Stroke [p.192])
Cardiac disease (embolism) (see p.209) 20%
Table 25 Where is the TIA?
Hematologic disease (thrombo-embolism)
(see p.218) <5% Arterial Territory
Symptom Carotid Either Vertebro-
CLINICAL FEATURES basilar
Is it a TIA? Dysphasia +
• Sudden onset. Monocular visual loss +
• Loss of focal neurologic or monocular function. Unilateral weakness* +
• Symptoms maximal at onset: they do not spread or intensify. Unilateral sensory disturbance* +
• Symptoms resolve within 24 hours. Dysarthria** +
Homonymous hemianopia +
Focal neurologic symptoms and signs Unsteadiness/ataxia** +
Motor symptoms Dysphagia** +
• Weakness or clumsiness of one side of the body, in whole Diplopia** +
or in part. Vertigo** +
• Simultaneous bilateral weakness*. Bilateral simultaneous visual loss +
• Difficulty swallowing*. Bilateral simultaneous weakness +
Bilateral simultaneous sensory disturbance +
Speech/language disturbances Crossed sensory / motor loss +
• Difficulty understanding or expressing spoken language.
• Difficulty reading or writing. * Usually regarded as carotid distribution
• Slurred speech*. ** Not necessarily a TIA if an isolated symptom, only if associated
• Difficulty calculating. with >1 other symptom on the list
 Transient Ischemic Attacks (TIA) of the Brain and Eye 187

DIFFERENTIAL DIAGNOSIS consciousness, loss of personal identity, focal neurologic

TIA of the brain symptoms or epileptic features.
• Migraine aura (with or without headache): younger patients, • Labyrinthine disorders: benign recurrent vertigo, benign
positive symptoms (visual scintillations, tingling), spread or paroxysmal positional vertigo, acute labyrinthitis, Ménière’s
march of symptoms over minutes. disease.
• Partial (focal) epileptic seizures: symptoms are positive • Metabolic disorders: hypoglycemia, hyperglycemia,
(jerking, tingling), march over seconds, stereotyped hypercalcemia, (hyponatremia).
recurrences, usually respond to anti-epileptic drugs. • Hyperventilation or panic attacks, somatization disorder.
• Transient global amnesia: abrupt onset of loss of • Intracranial structural lesion: meningioma, tumor, giant
anterograde episodic memory for verbal and non-verbal aneurysm, arteriovenous malformation, chronic subdural
material, usually accompanied by repetitive questioning, hematoma.
which resolves within 24 hours. There is no clouding of • Acute demyelination: multiple sclerosis.
• Syncope.
• Drop attacks.
195 Ocular fundus 195 • Mononeuropathy/radiculopathy.
showing golden-orange • Myasthenia gravis.
cholesterol crystals • Cataplexy.
(Hollenhorst plaques)
in the cilioretinal artery TIA of the eye
(arrows). (Reproduced Retina
from Warlow, Dennis, Vascular:
van Gijn, Hankey, • Low retinal artery perfusion :
Sandercock, Bamford, – Internal carotid artery atherothromboembolism
Wardlaw [2000] Stroke: or other arterial disorders (195–197).
A Practical Guide to – Embolism from the heart.
Management, 2nd edn. – Retinal migraine.
Blackwell Scientific, • High resistance to retinal perfusion:
Oxford, UK.) – Intracranial arteriovenous malformation.
– Central or branch retinal vein thrombosis.
– Raised intraocular pressure (glaucoma).
– Raised intracranial pressure (blowing the nose).
196 Ocular fundus 196 – Increased blood viscosity.
showing an embolus in – Retinal hemorrhage (198).
a peripheral branch of
the inferior temporal Non-vascular:
arteriole (arrow). • Paraneoplastic retinopathy.
• Phosphenes.
• Lightning streaks of Moore.
• Chorioretinitis.
197 Ocular fundus
photograph of a patient Optic nerve
with inferior temporal Vascular (anterior ischemic optic neuropathy):
branch retinal artery • Systemic hypotension.
occlusion showing pallor • Arteritis (e.g. giant cell).
of the inferior half of • Malignant arterial hypertension.
the retina due to cloudy
swelling of the retinal
ganglion cells caused by
retinal infarction.The 197 198
inferior temporal
branch arteriole is
attenuated and contains
embolic material.

198 Ocular fundus

showing a small retinal
hemorrhage in a patient
complaining of transient
monocular visual
disturbance.
188 Vascular Diseases of the Nervous System

Non-vascular: Magnetic resonance angiography (MRA) or intra-arterial

• Papilledema. digital subtraction angiography (IA-DSA) (202–207)
• Optic neuritis and Uhthoff’s phenomenon. Used if duplex ultrasound evidence of >70% stenosis of
• Dysplastic coloboma. symptomatic carotid artery (perhaps lower threshold to >50%
stenosis if the duplex is unreliable and a true 70% stenosis
Eye/orbit could be underestimated as 50% stenosis), and the patient is
• Vitreous hemorrhage. fit and willing for carotid surgery/stent (205–207).
• Reversible diabetic cataract. Dynamic CT angiography is also under evaluation (208).
• Lens subluxation. N.B. Practice varies with some surgeons performing carotid
• Orbital tumor (e.g. optic nerve sheath meningioma): endarterectomy on the result of ultrasound alone.
gaze-evoked loss of vision.
Transthoracic echocardiography (TTE)
INVESTIGATIONS Used if there is any abnormality of the heart clinically, on
All patients EKG or chest x-ray, followed by transesophageal
• Full blood count: polycythemia, anemia, thrombocy- echocardiography (TOE) if necessary.
tosis/cytopenia.
• ESR: arteritis, infective endocarditis, myxoma, infections.
• Plasma glucose: diabetes, hypoglycemia.
• Plasma cholesterol: hypercholesterolemia. 199
• EKG: atrial fibrillation, left ventricular hypertrophy, silent
MI.
• Urinalysis: diabetes, renal disease, infective endocarditis,
arteritis.

Selected patients
Depending on patient’s symptoms, age, general physical
condition and willingness to be investigated and treated.

CT brain scan
CT is used to exclude a non-vascular cause of symptoms of
TIA of the brain (e.g. meningioma, arteriovenous malforma-
tion) that may present like a TIA about 1% of the time
(199). Not all patients with TIA need a CT brain scan, such
as those with TIAs of the eye and perhaps single carotid
territory TIAs. Patients with posterior circulation TIA or
multiple carotid territory TIAs, particularly if stereotyped,
are more likely to have a symptomatic intracranial structural
lesion and should undergo CT brain scan.

Duplex ultrasound of the neck vessels (200, 201)

If a carotid territory TIA is present and the patient is fit and
willing for carotid artery surgery or stenting (should imaging 199 Cranial CT scan of a patient presenting with symptoms
reveal a severe carotid stenosis on symptomatic side). suggestive, but atypical of a transient ischemic attack which
were due to this right frontal arteriovenous malformation.

200 201

200 Color doppler ultrasound of a tight internal carotid artery 201 Color doppler ultrasound of an internal carotid artery occlusion.
stenosis. Note the black outline of the arterial wall (arrowheads) The outline of the internal carotid artery is visible but there is no color
with a thin color jet in the center indicating the stenosis (arrow). signal within it, whereas the external carotid is clearly patent.
 Transient Ischemic Attacks (TIA) of the Brain and Eye 189

202 203 204

202, 203 Intra-arterial angiograms of fibromuscular 204 Angiogram of a patient with painful arm and
hyperplasia. Note the narrowed and beaded hand and intermittent blue fingers. It shows a cervical
appearance of the internal carotid artery (arrow). rib and subclavian artery compression (arrow).

205 206 207

205 Intra-arterial DSA of a tight internal carotid artery stenosis 208

(arrow).

206, 207 2D and 3D time of flight MRA of an internal carotid artery

stenosis (arrow). Note the ‘flow void’ at the point of stenosis which
may make it difficult to measure the exact degree of narrowing.

208 Spiral CT angiogram of an internal carotid artery stenosis

(arrow). Note the anatomic detail is good, but lots of calcification
(there is only a little in this example) may obscure the detail of the
lesion.
190 Vascular Diseases of the Nervous System
Transesophageal echocardiography (TOE)
Used for young patients (less than about 50 years) without a
history of cardiac disease and with unexplained TIA (or
ischemic stroke) to exclude left atrial myxoma or thrombus,
and ‘congenital’ cardiac defects such as patent foramen ovale
and atrial septal aneurysm. Also indicated in unexplained TIA
(and ischemic stroke) to identify complex plaque of the
ascending aorta and aortic arch.
Other tests
• Urea and electrolytes: if hypertensive, on antihypertensive
agents, or diabetic.
• Hemoglobin A1C: if elevated fasting plasma glucose.
• VDRL/RPR and TPHA: if increased pre-test probability
of meningovascular syphilis.
• Thyroid function tests: if atrial fibrillation or
hypercholesterolemia.
• Antinuclear antibody assay: if vasculitis suspected (e.g.
elevated ESR).
• Autoimmune screen.
• Blood cultures (infective endocarditis).
• HIV serology.
• Lipoprotein fractionation.
• 24-hour EKG.
• Transcranial doppler ultrasound (intracranial arterial
stenosis).
• Alpha 1-antitrypsin (arterial dissection/aneurysm).
• Temporal artery biopsy and leptomeningeal/cortical
biopsy (arteritis).
• Thrombophilia screen (see p.220): if unexplained TIA,
particularly if younger than 50 years of age, positive past
or family history of premature arterial or venous occlusive
disease, recurrent miscarriages, or an abnormality on the
blood film such as thrombocytopenia.
DIAGNOSIS
Based on the clinical history; there are usually no
confirmatory physical signs or investigations. There is
considerable inter-observer variation in the diagnosis of TIA,
even among experienced neurologists, particularly if the
patient has forgotten the symptoms, finds them difficult to
describe, or was frightened by the attack and more
preoccupied with the immediate outcome.
TREATMENT
Treat the underlying cause.
Giant cell arteritis (see p.234)
Steroids.
Infective endocarditis (see p.215)
Antibiotics.
Atherothromboembolism (see p.202)
Vascular risk factor control
• High blood pressure.
• Cigarette smoking.
• High serum cholesterol.
• Diabetes mellitus.
Antiplatelet therapy
• Reduces the risk of stroke, MI or vascular death by about
a quarter, irrespective of age, sex, and blood pressure; from
an average of about 8% to 6% per year.
• Absolute benefit is greatest in those who have a high rate
of vascular events, such as the elderly.
• Risks of hemorrhage are low and far exceeded by the
benefits.
• Aspirin is safe and effective in preventing subsequent
vascular events by about 13–25%; low dose aspirin
(75–150 mg) is as effective as higher doses and causes less
adverse effects such as dyspepsia and GI hemorrhage.
• Clopidogrel 75 mg/day is safe and marginally, but
significantly, more effective than aspirin (reduces vascular
events by about 10% more than aspirin, from an average
of about 6% to 5.4% per year) but is more costly. It is
associated with less gastrointestinal upset and bleeding
than aspirin in a dose of 325 mg per day, but has a slight
excess (about 1%) of diarrhea and skin rash than aspirin.
• Ticlopidine is also slightly (about 10% [CI: 2–18%]) more
effective than aspirin but is more costly and has a small but
important risk of thrombotic thrombocytopenic purpura
and neutropenia. It is also associated with a higher rate of
diarrhea and skin rash than clopidogrel. Clopidogrel has
superseded ticlopidine in many countries because it is of
similar efficacy (i.e. marginally but significantly better than
aspirin by about 10%) but is safer and in most countries
(e.g. Malaysia is an exception) less costly.
• Aspirin in combination with dipyridamole may be more
effective than aspirin alone, by about 15% (CI: 4–26%), but
further trials (e.g. European/Australasian Stroke Prevention
in Reversible Ichaemia Trial [ESPRIT]) are in progress.
• Anticoagulation with warfarin/coumadin is probably no
more effective and more hazardous than antiplatelet therapy
in secondary prevention of vascular events among patients
with TIA due to atherothromboembolism. This comparison
is also being studied in the ESPIRIT trial.
• Treatment should continue for at least 2 years after the
TIA, probably longer and probably for life if well-
tolerated.
Carotid endarterectomy
Carotid endarterectomy is effective in patients with recent
carotid territory TIA or mild ischemic stroke, who have severe
carotid stenosis (>80% European Carotid Surgery Trial
[ECST] method, >70% NASCET method of measurement)
and who are fit and willing for surgery. It reduces the 3 year
risk of stroke from 26.5% (8.8% per year) to 14.9% (5.0% per
year), a relative risk reduction of 44% (95% CI: 21–60%), and
absolute risk reduction of 11.6% (3.8% per year). The number
needed to treat (NNT) to prevent one stroke at 3 years is 9,
and to prevent one stroke each year is 26. Only up to about
16% of patients with recent carotid ischemia and severe
carotid stenosis on the symptomatic side benefit from carotid
endarterectomy. These are probably patients who score four
or more in the prognostic model below (see Table 26).
The net effectiveness of carotid endarterectomy is also
determined by the surgical perioperative stroke and death
rate. Referring doctors (and patients) should have access to
the perioperative stroke and death rate of their prospective
surgeon(s), derived from independent and rigorous audit.
However, interpretation of unusually high or low operative
risks must take into account the effects of chance and case-
mix. Otherwise, over-simplistic interpretation of crude results
may lead to unjustified criticism of individual surgeons, and
not to improvements in patient care. The decision to operate
should consider all the important prognostic factors for stroke
and perioperative stroke and death.
 Transient Ischemic Attacks (TIA) of the Brain and Eye
Table 26 Prediction model for benefit from carotid
endarterectomy among patients with recent carotid
ischemia and severe symptomatic carotid stenosis
Independent risk factors for stroke with best medical therapy
Ischemic events of the brain (as opposed to the eye) 1 point
Recent ischemic events (in the past 2 months) 1 point
Severe degree of carotid stenosis:
80–89% stenosis 1 point
90–99% stenosis 2 points
Carotid plaque irregularity 1 point
Independent risk factors for perioperative risk of stroke and death
• Female gender -0.5 points
• Systolic BP>24 kPa (180 mmHg) -0.5 points
• Peripheral vascular disease -0.5 points
Percutaneous transluminal carotid and vertebral
angioplasty/stenting
Carotid angioplasty with stenting is a promising alternative
to carotid endarterectomy that is still being evaluated in
clinical trials. It is however also being practised increasingly,
in the absence of robust evidence of safety and long term
efficacy, because it is thought to be associated with fewer
perioperative complications than carotid endarterectomy and
equal efficacy in preventing stroke (209–211). However, true
modest differences in the outcome of patients treated by
carotid angioplasty/stenting and carotid endarterectomy will
only be detected reliably by large randomized trials.
One trial in a single center without previous experience in
209
209–211 Selective carotid angiogram, subtraction views, showing a tight stenosis of the origin of the internal carotid artery (209, arrow), which
has been dilated by means of balloon catheter angioplasty (210) and dilated further with the deployment of a stent (211).
191
carotid angioplasty/stenting was stopped after only 17
patients had been randomized because of five peroperative
strokes among the seven patients treated with carotid stenting
(compared with no strokes among the 10 patients treated
with carotid endarterectomy). The only other completed trial
has been the Carotid And Vertebral Artery Transluminal
Angioplasty Study (CAVATAS) which randomized 504
patients with carotid artery stenosis (97% symptomatic) to
carotid endarterectomy (253 patients) or carotid angioplasty
(251 patients; stents were used in 26%). Safety data indicate
that the perioperative (within 30 days) rate of all stroke or
death was 9.9% among patients allocated carotid endarterec-
tomy and 10.0% among patients allocated carotid angioplasty.
The perioperative (within 30 days) rate of disabling stroke or
death was 5.9% among patients allocated carotid endarterec-
tomy and 6.4% among patients allocated carotid angioplasty.
There was a significant excess of cranial nerve palsy
amongst patients allocated carotid endarterectomy (8.7%)
compared with carotid angioplasty (0%, p<0.001) and a
significant excess of wound hematoma amongst patients
allocated carotid endarterectomy (6.7%) compared with
carotid angioplasty (1.2%, p<0.0015). Efficacy data, to date,
show that carotid restenosis is more common after carotid
angioplasty but is rarely symptomatic, within the first few
years. Most importantly, there is no difference in rate of stroke
during the first 3 years after carotid angioplasty or end-
arterectomy, but further follow-up is required and is ongoing.
Extracranial to intracranial bypass surgery
No longer practised outside research settings following con-
clusive evidence from a large randomized trial that the
balance of surgical risk and eventual benefit did not favor
surgery.
210 211
192 Vascular Diseases of the Nervous System
Cardiogenic embolism (see p.209)
Anticoagulation: warfarin (target INR 2.0–3.0), if major
cardiac source of embolism:
• Atrial fibrillation (non-rheumatic): reduces annual stroke
risk by two-thirds from about 12% to 4%.
• Recent (<3 months) myocardial infarction: treat for at
least 3 months, and continue longer if chronic AF or
other risk factor: large anterior MI or apex involvement;
mural thrombus; high risk (AF, heart failure, previous
embolic event).
• Dilated cardiomyopathy.
• Cardiac failure.
• Valvular heart disease: mitral stenosis or regurgitation;
mechanical prosthetic aortic or mitral valve.
• Complicated patent foramen ovale not closed surgically
(associated with atrial septal aneurysm or mitral valve
prolapse) – anticoagulation is controversial/unproven.
PROGNOSIS
As a group, TIA patients have an increased risk of stroke and
other serious vascular events of about 8–10% per year. The
risk of stroke is about 4–5% in the first month, 12% in the
first year, 29% over 5 years. The risk of a coronary event is
about 3% per year.
As individuals, TIA patients have a variable prognosis.
Independent predictors of an increased risk of stroke and
other cardiovascular events are:
• TIAs of the brain (compared with TIAs of the eye).
• Increasing age.
• Increasing number of TIAs in the previous 3 months (i.e.
multiple attacks).
• Peripheral vascular disease.
• Carotid stenosis >80%.
Other adverse prognostic factors may include: past history
of any TIA, left ventricular hypertrophy, carotid plaque
morphology (e.g. ulceration), impaired cerebrovascular reserve.
212
STROKE
DEFINITION
A generic term describing a clinical syndrome characterized
by the sudden onset of a focal neurologic deficit (or coma)
due to infarction of, or hemorrhage into or over, a part of
the brain. The deficit persists for longer than 24 hours or
leads to earlier death.
EPIDEMIOLOGY
• Incidence: 2 per 1000 per year.
• Age: any age but the incidence of stroke increases steeply
with age.
• Gender: M>F in middle age, F>M in old age.
• Burden: stroke is the third most common cause of death
(10–12% of all deaths) in developed countries and a
major cause of adult physical disability.
PATHOGENESIS
Cerebral infarction (75–80%)
• Large artery atherothromboembolism (50%):
– Extracranial (aorta, carotid, vertebral arteries) (40–45%).
– Intracranial (ICA, MCA, ACA, Vertebral, Basilar, PCA)
(5–10%).
• Small artery microatheroma/lipohyalinosis (lacunar
syndromes) (25%).
• Embolism from the heart (20%).
• Blood disease (thrombophilia) (<5%).
• Non-atheromatous arterial disease (e.g. dissection,
arteritis) (<5%).
Intracerebral hemorrhage (10–15%) (212)
• Hypertensive lipohyalinosis and microaneurysms (40%).
• Bleeding diatheses (e.g. antithrombotic drugs, thrombo-
cytopenia) (10%).
• Arteriovenous malformation (10%).
• Amyloid angiopathy (10%).
• Hemorrhagic transformation of cerebral infarct (10%).
• Aneurysm (8%).
• Intracerebral tumor (5%).
• Arteritis (<5%).
• Drugs: sympathomimetics (e.g. amphetamines, cocaine)
(<5%).
• Arterial dissection (<5%).
• Intracranial venous thrombosis (<5%).
Subarachnoid hemorrhage (5%)
• Aneurysm.
• Arteriovenous malformation.
Unknown (5%)
Vascular risk factors and diseases in first-ever
ischemic stroke*
• Hypertension (BP >21.3/12 kPa [160/90 mmHg] on
two occasions pre-stroke): 52%.
• Angina and/or past myocardial infarction: 38%.
212 Axial slice of the brain at autopsy showing bilateral basal ganglia
hemorrhage with rupture into the ventricles in a patient with severe
hypertension.
 Stroke 193

• Current smoker: 27%. – Self-audible bruits: internal carotid artery stenosis

• Claudication and/or absent foot pulses: 25%. (distal); dural arteriovenous fistula; glomus tumor;
• Major cardiac embolic source: 20%. carotico-cavernous fistula.
• Transient ischemic attack (TIA): 14%. • Medications/drugs:
• Cervical arterial bruit: 14%. – Blood pressure-lowering/vasodilators.
• Diabetes mellitus: 10%. – Hypoglycemic drugs.
• Any of the above: 80%. – Cocaine, amphetamines, ephedrine, phenylpropano-
lamine, ecstasy (methylenedioxyamphetamine).
* Sandercock PAG, Warlow CP, Jones LN, Starkey IR – Oral contraceptives; estrogens in men.
(1989) Predisposing factors for cerebral infarction: The – Allopurinol.
Oxfordshire Community Stroke Project. BMJ, 298: 75–80. – Interleukin 2.
– Deoxycoformycin (pentostatin).
CLINICAL FEATURES – L-asparaginase (asparaginase).
Is it a stroke? • Past medical history:
• Sudden onset. – Previous stroke or TIA.
• Loss of focal neurologic function (see TIA, p.186). – Vascular risk factors (see above).
• Symptoms and signs are maximal within a few seconds or – Recent myocardial infarction.
minutes, but sometimes evolve over a few hours or – Rheumatic fever.
progress in a stepwise fashion due to propagation of – Inflammatory bowel disease.
thrombus, recurrent embolization, or hemorrhagic – Celiac disease.
transformation of the infarct. Progression over more than – Irradiation of the head or neck.
a few hours or failure to improve after a few days, suggests – Recurrent deep venous thrombosis.
complications (e.g. brain edema, hydrocephalus) and an – Recurrent miscarriages.
alternative diagnosis (e.g. tumor). • Family history: (gene/chromosome location, if known)
• Symptoms persist beyond 24 hours (by arbitrary definition). – Connective tissue disorders:
Ehlers–Danlos syndrome type IV: (collagen 3A1).
Where is the stroke? (see Neurovascular Pseudoxanthoma elasticum.
syndromes, p.181) Marfan’s syndrome: (fibrillin).
Fibromuscular dysplasia.
What is the cause of the stroke? Familial mitral valve prolapse.
Infarction or hemorrhage? – Hematologic disorders:
There are no clinical features that reliably distinguish Sickle cell (SC) disease/trait.
intracerebral hemorrhage from infarction. Headache, coma Antithrombin III deficiency.
at onset, vomiting and rapid deterioration are more Protein C deficiency.
common with hemorrhage but may also occur with Protein S deficiency.
infarction. The sudden onset of severe headache associated Plasminogen abnormality/deficiency.
with neck stiffness or coma distinguishes subarachnoid Dysfibrinogenemia.
hemorrhage (SAH) from other causes (see SAH, p.249). Hemophilia and other inherited coagulation factor
deficiencies.
Clues to the cause of the ischemic and hemorrhagic – Others:
stroke, or alternative diagnosis Familial hypercholesterolemia.
Clinical history: Neurofibromatosis.
• Age, sex and race. Homocystinuria.
• Presenting complaint: Fabry’s disease.
– Onset, if gradual: consider low flow (hemodynamic) Hereditary cerebral amyloid angiopathy: Dutch type,
ischemic stroke; migraine; structural intracranial lesion; (amyloid precursor protein).
multiple sclerosis. Hereditary cerebral amyloid angiopathy: Icelandic type,
– Precipitating factors: standing up quickly, heavy meal, hot (cystatin C).
weather, hot bath, warming the face, exercise, valsalva Migraine.
maneuver, chest symptoms such as pain or palpitations, Familial cardiac myxoma.
starting or changing blood pressure-lowering drugs, head Familial cardiomyopathies.
turning – all suggest low flow; hypoglycemia. Mitochondrial cytopathy: (mitochondrial tRNA-leu).
– Injury to head or neck: vertebral/carotid artery dissec- CADASIL (cerebral autosomal dominant arteriopathy
tion, chronic subdural hematoma. with subcortical infarcts and leukoencephalopathy):
• Associated symptoms: (notch3 mutations, 19q12).
– Recent headache: carotid/vertebral dissection; giant cell Sneddon’s syndrome.
arteritis (or other vasculitis); migrainous stroke/TIA; Arteriovenous malformations.
intracranial venous thrombosis; structural intracranial lesion. Cerebral cavernous malformation: (7q22; genetic
– Epileptic seizures: cortical infarction or hemorrhage; heterogeneity).
intracranial venous thrombosis; mitochondrial cytopathy; Intracranial saccular aneurysms.
non-vascular intracranial lesion. Polycystic kidney disease: (polycystin).
– Malaise: inflammatory arterial disorders; infective Hereditary hemorrhagic telangiectasia-1: (endoglin).
endocarditis; cardiac myxoma; cancer; thrombotic Hereditary hemorrhagic telangiectasia-2: (activin
thrombocytopenic purpura; sarcoidosis. receptor-like kinase 1).
194 Vascular Diseases of the Nervous System
Examination:
• Body weight.
• Pulses:
– Present or absent (peripheral vascular disease).
– Tenderness (giant cell arteritis).
– Rhythm (atrial fibrillation).
• Blood pressure:
– Supine and erect (hypertension, postural hypotension).
– Both arms (subclavian steal or aortic dissection).
• Neck bruits*.
• Neck stiffness.
• Heart: murmurs (valvular heart disease).
• Eye:
– Conjunctival injection and rubeosis iridis (ischemic
oculopathy) (8, 9).
– Horner’s syndrome (carotid dissection).
• Ocular fundi: retinal emboli; hypertensive, diabetic or
ischemic retinopathy.
• Neurologic examination: impairments (see Neurovascular
syndromes, p.181), disabilities and handicaps. Observe
the patient attempting functional tasks such as those
required for everyday activities of daily living. These are
vital in assessing and monitoring the patient’s prognosis
and structuring an appropriate rehabilitation program.
*N.B. Listening for carotid bruits is not particularly helpful
as their absence does not exclude tight carotid stenosis and
their presence does not mean that the patient has tight
common or internal carotid artery stenosis; a carotid bruit
can be a normal finding in young adults; it can be due to
external carotid stenosis (which is irrelevant to the patient's
symptoms); it can be transmitted from the heart and great
vessels in patients with aortic or mitral valve disease, a patent
ductus arteriosus or coarctation of the aorta; and it can be
part of a diffuse neck bruit in patients with thyrotoxicosis
or a hyperdynamic circulation associated with pregnancy,
anemia, fever and hemodialysis.
Skin signs of underlying causes of TIA or stroke
• Finger clubbing(14): cancer; right to left intracardiac
shunt; pulmonary arterial venous malformation; infective
endocarditis; inflammatory bowel disease.
• Splinter hemorrhages: infective endocarditis; cholesterol
embolization syndrome; vasculitis.
• Scleroderma: systemic sclerosis.
• Livedo reticularis: Sneddon’s syndrome; systemic lupus
erythematosus; polyarteritis nodosa; cholesterol emboliz-
ation syndrome.
• Lax skin: Ehlers–Danlos syndrome; pseudoxanthoma
elasticum.
• Skin color: anemia; polycythemia; cyanosis (right to left
intracardiac or pulmonary shunt).
• Porcelain white papules/scars: Kohlmeier–Degos’ disease.
• Skin scars: Ehlers–Danlos syndrome.
• Petechiae/purpura/bruising: thrombotic thrombocyto-
penic purpura; fat embolism; cholesterol embolization
syndrome; Ehlers–Danlos syndrome.
• Oro-genital ulceration: Behçet’s disease.
• Rash: Fabry’s disease.
• Epidermal nevi: epidermal nevus syndrome.
• Café-au-lait patches: neurofibromatosis.
• Thrombosed veins, needle marks: i.v. drug abuse.
DIFFERENTIAL DIAGNOSIS OF STROKE
(IN ORDER OF FREQUENCY OF OCCURRENCE
IN GENERAL PRACTICE)
• Metabolic/toxic encephalopathy (hypoglycemia, non-
ketotic hyperglycemia, hyponatremia, Wernicke–Korsa-
koff syndrome, hepatic encephalopathy, alcohol and drug
intoxication).
• Functional/non-neurologic (e.g. hysteria).
• Epileptic seizure (postictal Todd’s paresis).
• Structural intracranial lesions (subdural hematoma,
tumor, arteriovenous malformation).
• Encephalitis (e.g. herpes simplex virus)/brain abscess.
• Head injury.
• Peripheral nerve lesion(s).
• Hypertensive encephalopathy.
• Multiple sclerosis.
• Creutzfeldt–Jakob disease.
INVESTIGATIONS
All patients
Immediate CT brain scan(213–217)
• To exclude non-stroke pathology (213–215):
– Unclear history of sudden onset of focal neurologic
symptoms (i.e. because of coma, dysphasia, confusion,
no witness);
– Atypical clinical features (i.e. gradual onset, seizures, no
clear focal neurologic signs); young patient (age
<50 years) with no vascular risk factors.
• To distinguish intracranial hemorrhage (216) from
cerebral infarction (CT must be done within about
10 days of stroke).
Intracranial hemorrhage is seen immediately as a
homogeneous area of high density; infarction, if seen, as an
area of low density. Within the first few hours of infarction,
there is loss of gray/white matter differentiation, slight
hypodensity and a little swelling (loss of visibility of the
sulci). The lesion is wedge-shaped if cortical and rounded if
subcortical. The occluded artery may appear hyperdense
(whiter) due to the presence of thrombus (this sign is
reliable if present, but its absence means little as far as
whether or not the artery is patent).
Within the first few days the infarct margins become clearly
demarcated, the infarct more hypodense (darker), and the
swelling increases (large infarcts may produce considerable
mass effect with midline shift and uncal herniation). After the
first week, the swelling subsides and the infarct becomes of
similar density to normal brain making it difficult to see
(fogging). Fogging lasts for a week or so. After several
months, the infarct is a shrunken black area (‘hole’).
Up to 50% of all infarcts will not be positively identified
by CT; larger and older infarcts are more likely to be visible
(but see above, fogging). Hemorrhagic transformation of
the infarct (HTI) can occur any time within the first few
weeks, but is most frequent within the first week and in
patients with large infarcts, high blood pressure, or who are
given antithrombotic and thrombolytic drugs. HTI may be
massive or minor (petechial); massive HTI may be
indistinguishable from a de novo primary intracerebral
hemorrhage (PICH) (217–219).
• To ascertain the likely cause of ischemic or hemorrhagic
stroke.
• Otherwise as for TIA patients (see p.186).
 Stroke 195

213 214 215

213 Plain cranial CT scan showing low density in the cortex and subcortex of the left frontal 216
lobe (arrows) and also in the periventricular regions of a patient who presented with sudden
onset of dysphasia and right hemiparesis and was diagnosed as having suffered an ischemic
stroke (but see 214, 215).

214, 215 Post contrast CT scan in the same patient as 213 showing ring enhancement of the
left frontal cortical/subcortical lesion (arrow) (214) and another ring enhancing lesion in the left
anterior temporal lobe (arrow) due to metastatic carcinoma (215).

216 Non-contrast cranial CT scan showing a focal area of high density in the frontal lobe on
the right due to hemorrhage secondary to amyloid angiopathy.

217, 218 Hemorrhagic transformation of an arterial infarct. CT scan (217) within 4 hours of
the stroke shows a high density (white) area in the left temporal lobe. Cerebral angiogram (AP
view) (218) 1 hour later shows occlusion of the left middle cerebral artery (arrow) and dilated
lenticulostriate arteries.These images are typical of early hemorrhagic transformation of an
arterial infarct, which can be difficult to differentiate from primary intracerebral hemorrhage.

219 Axial section of the brain at post mortem showing a large hemorrhagic cortical/subcortical
infarct in the right frontal lobe due to embolic occlusion of the right anterior cerebral artery and
pre-rolandic branch of the upper division of the right middle cerebral artery by an embolus
from the origin of the right internal carotid artery.

217 218 219

196 Vascular Diseases of the Nervous System
Selected patients
As for TIA patients (see p.188).
MRI brain scan
With or without diffusion and perfusion weighted imaging, if:
• A CT scan performed >10 days after stroke shows a low-
density area that could be infarction or resolving
hemorrhage and it is essential to distinguish them.
• CT scan is negative and it is crucial to be able to localize
the infarct. MRI is more sensitive in detecting infarcts
than CT (particularly brainstem and small subcortical
infarcts), but can be difficult to use in very sick, confused
patients and may show so many ‘holes’ in some patients
that it is just confusing. The evolution of the appearance
of infarction is similar to CT (including fogging). A
recent infarct is bright on T2W imaging (T2WI) and
dark on T1WI. An occluded artery shows up as an absent
‘flow void’, sometimes with a bright blob in it on T2WI
(the clot). Special sequences can show very early changes
of infarction (within minutes of the interruption of blood
flow) such as diffusion- or perfusion-weighted imaging
or spectroscopic imaging, but these are still being
evaluated.
• Arterial dissection suspected (N.B. catheter angiography
remains the gold standard).
• Trying to identify the response to thrombolytic therapy
(e.g. perhaps the greatest benefit is obtained with a large
diffusion/perfusion mismatch).
CSF examination
Useful if SAH is still suspected despite a normal CT scan
(must wait until at least 12 hours have elapsed since the
onset of stroke symptoms before doing the CSF
examination) or if positive blood VDRL or TPHA.
DIAGNOSIS
A clinical diagnosis, based on the sudden onset of a focal
neurologic deficit, which is correct about 95% of the time.
Factors that may reduce the reliability of the clinical
diagnosis of stroke include:
• Unclear history: impaired conscious level; dysphasia;
dementia.
• Unusual symptoms: persistent headache; personality
change.
• Unusual signs: fever; papilledema.
• Young age: less likely to have degenerative vascular
disease.
• Progressing neurologic signs.
The diagnosis of stroke can sometimes be confirmed by
CT or MRI brain scan, or at autopsy. The CT scan can be
normal in stroke, provided other causes of an apparent focal
neurologic deficit, such as multiple sclerosis and psychogenic
behavior, have been excluded.
TREATMENT
Organized and coordinated multidisciplinary
care (Stroke Unit)
Compared with conventional care in a general ward,
organized and coordinated care by an interested and trained
multidisciplinary team in a stroke unit reduces death and
dependency at 1 year after stroke from about 62.0% to
56.4%. This is an odds reduction of about 29% (odds ratio
(OR) 0.71), a relative risk reduction (RRR) of 9% (95% CI:
4% –14%) and absolute risk reduction (ARR) of 5.6%.
Therefore, treating 1000 patients in a stroke unit prevents
about 56 patients from dying or becoming dependent
compared to treating 1000 in a general ward. The number
of patients needed to treat (NNT) in a stroke unit to
prevent one from death or dependency is about 18.
Although preferable, a geographically dedicated stroke unit
is not necessary. There are insufficient data on the cost of
stroke unit care but it does not increase length of stay.
Patients with TIA and mild non-disabling stroke do not
need admission if facilities are available for rapid, appropriate
investigation and follow-up as an outpatient.
General
Assess, manage and monitor:
• Airway: care must be taken to maintain a patent airway
in patients with depressed consciousness or bulbar
dysfunction.
• Oxygen therapy: if the patient is hypoxic (oxygen
saturation <95%); of no benefit if hemoglobin is fully
saturated.
• Vital systemic signs: temperature, heart rate, blood
pressure, respiration, fluid input and output. Maintaining
fluid balance and preventing dehydration is essential.
• Vital neurologic signs: Glasgow coma scale, pupils, body
postures.
• Fever: should be investigated (MSU, CXR, blood
cultures, sputum culture and so on) and treated
appropriately; elevated temperature is an adverse
prognostic factor.
• Blood pressure (BP) rises transiently after stroke, especially
hemorrhagic stroke, and falls during the first 7 days.
Current empirical policy is not to initiate new
antihypertensive therapy for the first 7 days after stroke
because a reduction in blood pressure may substantially
lower cerebral blood flow in the ischemic penumbra
surrounding an infarct (because of loss of autoregulation in
ischemic brain) and lead to further ischemic brain damage,
particularly if there is a tight stenosis of the feeding artery.
Blood pressure should only be lowered, and cautiously at
that (by about 15% over 24 hours), in the presence of
hypertensive crises such as hypertensive encephalopathy, left
ventricular failure, aortic dissection, or intracerebral
bleeding, or if the blood pressure is very high and poses a
real risk of cerebral hemorrhage. We don’t know what level
of blood pressure is ‘too high’ but treatment is recom-
mended if: systolic BP >26.7–29.3 kPa (200–220 mmHg)
(ischemic stroke) or >24–26.7 kPa (180–200 mmHg)
(hemorrhagic stroke); or diastolic BP >16–17.3 kPa
(120–130 mmHg) (ischemic stroke) or >13.3–14.7 kPa
(100–110 mmHg) (hemorrhagic stroke).
Oral antihypertensive agents are recommended, such as
a diuretic, beta-blocker, ACE inhibitor (low dose) or
calcium-channel blocker; nifedipine capsules, and parenteral
medications should be avoided because of the rapid and
sometimes precipitous fall in blood pressure.
 Stroke
• Low blood pressure may reflect hypovolemia due to
excessive losses by sweating and insufficient intake by
mouth or tube, and should be corrected by raising the
foot of the bed and by fluid replacement via a safe route.
• Swallowing function: maintain fluid and electrolyte
balance and nutrition initially with i.v. saline and/or
nasogastric tube until swallowing function is assessed by
a trained nurse or speech pathologist and dietary
requirements by a dietician. Percutaneous endoscopic
gastrostomy tube is preferred for patients who require
feeding by tube for more than about 2 weeks.
• Bladder function: after attempted voiding, residual
bladder volume of urine is estimated by a nurse trained
in the use of bladder ultrasound. If the residual urine
volume is more than 100 ml, the bladder should be
emptied by catheter every 6–8 hours.
• Immobile patients: should be turned frequently (e.g.
every 2 hours) to prevent pressure sores. Proper
positioning and early mobilization by nurses and
physiotherapists help to prevent complications of
immobility such as joint contractures, pneumonia and
painful ‘frozen’ shoulder. Deep venous thrombosis and
pulmonary embolism can be prevented by regular passive
and active joint movement, early mobilization, graduated
compression support stockings, aspirin and subcutaneous
heparin.
• Blood glucose should be maintained within normal
limits; elevated blood glucose is an adverse prognostic
factor and may be harmful.
• Depression should be treated with psychosocial support
and antidepressants if necessary. Early socialization
may help.
• Brain edema: cytotoxic edema, which does not cause
much brain swelling (i.e. no net change in brain volume,
just a shift of fluid from extracellular to intracellular
space) is followed by vasogenic edema (which does cause
brain swelling). Specific treatments for brain edema (see
below) do not reduce the edema but shrink the
surrounding normal brain. The onset, degree and
duration of the effect of each agent on intracranial
pressure (ICP) is quite variable.
– General: restrict fluids, elevate head of bed, treat fever;
avoid hypoxia and hypercapnia; avoid hypo-osmolar fluids.
– Specific: osmotic diuretics, providing BBB intact. A bolus
of mannitol (1g/kg i.v. as a 20% solution over 1 hour),
usually decreases ICP by about 50% after about 90
minutes but returns to the pre-treatment levels after
about 210 minutes.
– Steroids: should be effective for vasogenic edema, but
have not been shown to be effective in acute stroke.
– Hyperventilation if patient is deteriorating: quick onset
of effect on ICP (within 2–30 minutes) but it lasts only
for about 30 minutes.
– Barbiturates: useful because they reduce ICP more than
they reduce BP, so cerebral perfusion pressure increases.
– CSF drainage, e.g. ventricular drain.
– Surgical decompression (hemicraniectomy): when the
ICP is rising despite the above measures, and before
signs of herniation (ipsilateral pupillary loss of reactivity
followed by dilatation, periodic breathing [even in
conscious patient], contralateral Babinski sign).
197
Specific
Acute ischemic stroke
• Aspirin 160–300 mg daily for acute ischemic stroke
reduces death and dependency from 47.0% to 45.8%, a
RRR of 3% (95% CI: 1–5%) and an ARR of 1.2%.
Therefore, treating 1000 patients prevents about 12
dying or becoming dependent. The NNT is 83. All
patients with acute ischemic stroke should be given
aspirin immediately (unless allergic/intolerant of aspirin
or entering a trial of thrombolysis).
• Intravenous thrombolysis with streptokinase or tissue
plasminogen activator (tPA) within 6 hours of ischemic
stroke reduces death and dependency from 59.6% to
55.2%, an odds reduction of 17% (95% CI: 6–27%), a
RRR of 9% (95% CI: 4–14%) and ARR of 4.4%. Treating
1000 patients prevents 44 from death or dependency.
The NNT is 23. For patients presenting within 3 hours,
i.v. tPA reduces death and dependency from 67.8% to
55.2%, an odds reduction of 42% (95% CI: 26–54%) and
ARR of 12.6%. Treating 1000 patients prevents 126
from death or dependency. The NNT is 8. However,
thrombolysis is also hazardous. The risk of early death
(within 14 days of stroke) is increased from 15.4%
(control) to 19.0% (thrombolysis), a 3.6% absolute excess
(OR: 1.3, 95% CI: 1.13–1.5). This is because of an
excess of early symptomatic intracranial hemorrhage
(2.5% [control] vs. 9.4% [thrombolysis]; OR: 3.5, 95%
CI: 2.8–4.4), and fatal intracranial hemorrhage (1.0%
[control] vs. 5.4% [thrombolysis]; OR: 4.15, 95% CI:
3.0–5.8) (see Table 27, p.199).
Thrombolytic therapy for acute ischemic stroke is
therefore very much like carotid endarterectomy for
symptomatic severe carotid stenosis (see TIA, p.186); both
are associated with an early hazard yet a greater longer term
net benefit. The burning question is no longer whether
thrombolysis (and carotid endarterectomy) is effective, but
in whom it is effective, in whom it is ineffective, and in
whom it is dangerous. At present it is not known exactly
which combination of clinical and imaging features reliably
identify patients who will benefit or be harmed by
thrombolysis. Nor is it clear what is the optimal thrombo-
lytic agent, dose, half-life, and route of administration.
Furthermore, the most effective concomitant neuro-
protective, antithrombotic and antihypertensive regime, if
any, remains to be established. What it known from current
data is that the clinical features of the patient and the
findings of early brain imaging have considerable potential
for refining patient selection for thrombolysis.
Plain CT brain scan signs of major infarction which
involves more than one-third of the middle cerebral artery
territory predicts an increased risk of symptomatic
intracranial hemorrhage after thrombolysis. However, it is
neither sensitive nor specific, and the interrater reliability
among physicians involved in acute stroke care is less than
ideal. A new CT scoring system (ASPECTS) is reported to
be a simple and reliable method of quantifying early
ischemic changes on CT scan, like an ‘ECG of the brain’,
and which accurately predicts risk of symptomatic
intracranial hemorrhage and functional outcome in ischemic
stroke patients treated with intravenous thrombolytic
therapy (Barber et al., 2000). However, its external validity
and reliability remains to be established.
198 Vascular Diseases of the Nervous System

Magnetic resonance (MR) imaging can provide a Primary intracerebral hemorrhage (PICH) (see p.238)
perfusion-weighted image (PWI) which reveals the region Surgery for PICH is associated with a non-significant increase
of brain which is underperfused and ‘at risk’, and a in odds of death and dependency at 6 months (OR: 1.23, 95%
diffusion-weighted image (DWI) which identifies the core CI: 0.77–1.98). Further evidence from ongoing trials is awaited.
of early infarction. A mismatch between the acute PWI
lesion and the (smaller) DWI lesion may represent the Subarachnoid hemorrhage (see p.249)
ischemic penumbra of potentially salvageable brain. Clinical Early aneurysm surgery is now usual practice for patients in
trials are evaluating whether patients with a PWI/DWI good clinical condition but this has not been supported by a
mismatch are likely to benefit clinically from early randomized controlled trial. Antifibrinolytic drugs prevent re-
reperfusion. If confirmed, a further challenge will be to bleeding but increase the risk of cerebral ischemia and have no
optimize the availability and feasibility of undertaking MRI net effect on overall outcome. Oral nimodipine helps to prevent
brain scans within the first few hours of stroke onset in sick, delayed cerebral ischemia and significantly reduces the risk of a
dysphasic, disorientated and claustrophobic patients with poor outcome by about 31% (RR: 0.69, 95% CI: 0.58–0.84).
acute stroke. Finally, patient selection for thrombolysis may
also be improved by proof of arterial occlusion by means of Minimizing complications
non-invasive imaging (e.g. magnetic resonance angiography, Complications after stroke (see Table 29, p.200) are common
transcranial doppler). yet preventable. The key is to anticipate them in high risk
Clearly, further studies are required, and are in progress patients, implement appropriate prevention strategies, and
(e.g. International Stroke Trial – 3) to refine patient regularly (at least daily) assess patients. Patients at particular
selection, and establish the balance of risks and benefits of risk are the elderly, those with pre-existing handicap or
thrombolysis in a broader range of patients presenting at diabetes, a total anterior circulation syndrome (TACS),
different stages, with differing types and severities of stroke, urinary incontinence and hospitalized for more than 30 days.
different risk factors, and different brain imaging findings.
Whilst awaiting the results of these studies, rt-PA has been Rehabilitation
licenced for use in the United States (1997), Canada (1999) Rehabilitation begins on day 1 as an integral part of acute
and Germany (August 2000) for patients presenting within treatment and aims to maximize survival free of handicap
3 hours of acute ischemic stroke who are similar to the by facilitating normal recovery and minimizing compli-
patients included in the trials and provided there is a stroke cations. It involves an organized, coordinated multi-
service which can ensure its safe administration. disciplinary team undertaking regular patient assessment,
rt-PA remains to be licenced for use in other parts of short and long term goal setting with the patient and
Europe and America, and in Australasia and Asia. One family/carer (including discharge planning), intervention,
lesson learnt from the North American experience is that re-assessment, and re-intervention. Failure to achieve pre-
treating patients who violate the guidelines outlined in Table specified goals usually reflects inaccurate assessment,
28 is associated with excess risk and poor patient outcome. unrealistic expectations, progression of comorbid conditions
If rt-PA is to be licenced in other countries, it is essential (e.g. angina, arthritis), or the intercurrence of a
that its use is restricted, at least initially, to dedicated stroke complication (see Table 29, p.200) or another stroke.
units which are appopriately equipped, prepared to respond
to demand and adhere strictly to current guidelines (see
Table 28), and prepared to undertake prospective, systematic
and rigorous audit as part of a national register (if not as
part of an approved randomized trial). This will ensure that
stroke patients have access to this effective (yet risky)
treatment, that stroke physicians gain experience and
expertise in its use, and that quality control and patient
selection continues to be optimized by correlation of
baseline demographic, clinical, imaging and treatment data
with early and long term patient outcome.
• Heparin and heparinoid in acute ischemic stroke have no
net effect on death or dependency (RRR: 1%, 95% CI:
–5 to 6% or (–5 – +6), despite significantly reducing the
odds of deep vein thrombosis by about 79% (OR: 0.21,
95% CI: 0.15–0.39) and pulmonary embolism by about
39% (OR: 0.61, 95% CI: 0.45–0.83).
• Trials of neuroprotective agents (e.g. selfotel, aptiganel,
chlormethiazole, tirilazad, lubeluzole) have failed to
identify a favorable treatment effect, and some have
revealed dose-limiting intolerance and systemic adverse
effects, such as excessive sedation and hypertension.
Trials of other agents (e.g. magnesium) are in progress.
• Other medical treatments such as hemodilution, corti-
costeroids, and glycerol (glycerin) have not been proven
effective.
 Stroke 199

Table 27 Risks and benefits of thrombolytic therapy for acute ischemic stroke
Outcome events Thrombolysis (%) Control (%) OR 95% CI of OR Absolute risk per 1000
patients treated (95% CI)
Within 6 hours
Early (<10 days)
• Death 16.6% 9.8% 1.85 1.48–2.32 +68 (44–93)
• Fatal
Intracranial 5.4% 1.0% 4.15 2.96–5.84 +44
hemorrhage
• Symptomatic
Intracranial 9.4% 2.5% 3.53 2.79–4.45 +70 (58–83)
hemorrhage
At final follow-up (3–6 months)*
• Death 19.0% 15.4% 1.31 1.13–1.52 +36 (17–56)
• Death or
dependency 55.2% 59.6% 0.83 0.73–0.94 - -44 (-15 to -73)
Within 3 hours
At final follow-up (3–6 months)*
• Death 22.0% 20.7% 1.11 0.84–1.47 +17 (-28 to +62)
• Death or
dependency 55.2% 67.8% 0.58 0.46–0.74 -126 (-71 to -181)
* The final follow up varied among the different studies – some completed the study after 3 months, some after 6 months

Table 28 Suggested guidelines for the use of intravenous rt-PA in ischemic stroke
• Thrombolysis with intravenous r-tPA should be considered in all patients with a definite ischemic stroke who present within 3 hours of onset.
• Thrombolytic therapy should only be administered by physicians with expertise in stroke medicine, who have access to a suitable stroke
service, with facilities for immediately identifying and managing hemorrhagic complications.
• Thrombolysis should be avoided in cases where the CT brain scan suggests early changes of major infarction (e.g. edema, sulcal effacement,
mass effect).
Other exclusion criteria
Past history:
• Any intracranial hemorrhage.
• Stroke, serious head injury or myocardial infarction in previous 3 months.
• Gastrointestinal or urinary bleeding within previous 21 days.
• Major surgery within previous 14 days.
• Arterial puncture or noncompressible site within previous 7 days.
• Heparin exposure in preceding 48 hours and partial thromboplastin time not normal.
Current (i.e. pre-treatment):
• Seizure at stroke onset.
• Neurologic deficits are mild.
• Neurologic condition is improving rapidly.
• Systolic blood pressure >24.7 kPa (185 mmHg) or diastolic blood pressure >14.7 kPa (110 mmHg).
• Oral anticoagulant use or INR >1.7.
• Platelet count <100 × 109/l.
• Prolonged partial thromboplastin time.
• Blood glucose <2.8 mmol/l (50 mg/dl) or >22 mmol/l (400 mg/dl).
• Caution in patients with severe stroke (NIH stroke scale score >22).
• Discuss potential benefits and adverse effects of treatment with patient and family before treatment.
• Recommended dose of r-tPA is 0.9 mg/kg up to a maximum of 90 mg, the first 10% of the dose as a bolus over 1 minute, the rest as an
infusion over 60 minutes.
• Perform neurologic assessments every 15 minutes during infusion of rt-PA, every 30 min for the next 6 hours, and every 60 minutes for the
next 16 hours. If severe headache, acute hypertension, or nausea and vomiting occur, discontinue the infusion and obtain an emergency CT
brain scan.
• Measure blood pressure every 15 min for 2 hours, every 30 minutes for 6 hours, and every 60 minutes for 16 hours; repeat measurements
more frequently if systolic blood pressure is >24 kPa (180 mmHg) or diastolic blood pressure is >14 kPa (105 mmHg), and administer
antihypertensive drugs as needed to maintain blood pressure at or below those levels.
200 Vascular Diseases of the Nervous System

Prevention of recurrent stroke and Cigarette smoking

other vascular events
Secondary prevention strategies should be targeted at the
cause of the stroke (e.g. steroids for arteritis, antibiotics for
infective endocarditis) and begun immediately, because the
risk of recurrent stroke is greatest immediately after stroke.
In most cases, the cause is atherothromboembolism or
cardiogenic embolism (see Pathogenesis, p.192).
Blood pressure reduction
Lowering the BP of hypertensive TIA/stroke patients by
0.7–0.8 kPa (5–6 mmHg) diastolic and 1.3–1.6 kPa
(10–12 mmHg) systolic for 2–3 years, or by 1.2 kPa
(9 mmHg) systolic and 0.5 kPa (4 mmHg) diastolic for 4
years reduces their RR of stroke by 28% (95% CI: 17–38%).
If their average annual risk of stroke is 7.0%, antihyper-
tensive therapy reduces this risk to 4.8%; a RRR of 28% and
ARR of 2.2%. Treating 1000 patients prevents about 22
strokes each year. The NNT is 45.
More intensive blood-pressure lowering (e.g. by 1.6 kPa
[12 mmHG] systolic and 0.7 kPa [5 mmHG] diastolic) for
more prolonged periods (e.g. 4 years) yields even greater
benefits (e.g. 43% [95% CI: 30–54%] reduction in relative risk
of stroke). These results irrespective of the patient’s baseline
blood pressure, type of stroke, geographic region of residence
and ethnicity, and the time since the previous stroke.
There are no randomized controlled trials (RCTs), but
observational studies suggest that stopping smoking
decreases the risk of stroke by at least 1.5 times, from 7% to
4.7%, a RRR of 33% (95% CI: 29–38%) and ARR of 2.3%.
The NNT is about 43.
Cholesterol reduction
Observational studies do not support an association between
increasing plasma cholesterol and all types of fatal stroke but
this may represent a positive association between increasing
cholesterol and ischemic stroke due to large artery athero-
thrombosis being diluted by a weaker association with
ischemic stroke due to intracranial small vessel disease, and
a possible negative association with hemorrhagic stroke. A
recent large (as yet unpublished) RCT of cholesterol-lower-
ing therapy in TIA/stroke patients, and other high vascular
risk patients (The Heart Protection Study, www.hpsinfo.org),
showed that lowering serum cholesterol by about 1 mmol/l
(37 mg/dl) over 5 years with simvastatin 40 mg/day was
associated with a reduced risk of stroke and other serious
vascular events by about 24% (SE 2.6) (p<0.0001),
irrespective of the patient’s baseline serum cholesterol. If the
annual stroke rate among TIA/stroke patients is 7% per year,
simvastatin should reduce the annual stroke rate from 7% to
5.3%, a RRR of 24%, ARR of 1.7%, and NNT of 59.

Table 29 Complications after stroke

Complication Prevention strategy
Any time after stroke
Epileptic seizures Anticipate after cortical stroke; treat after first seizure (e.g. carbamazepine, valproate, lamotrigine)
Pneumonia Assess swallowing function immediately and regularly; if risk of aspiration, feed by tube
(nasogastric, PEG, i.v.); chest physiotherapy
Fever Exclude infection (urine, chest, i.v. line, heart), infarction (chest, heart, bowel, limb), DVT, PE, drug allergy
After first few days
Urinary problems Post-void bladder ultrasound; if high residual urine volume, empty bladder by catheter, and repeat
6–8 hourly; avoid indwelling catheters
Useful appliances: absorbent pads and pants, urinals + non-spill valve for men, bedside commode,
penile sheath
Bowel problems Monitor frequency of bowel movements; maintain fluid and fiber intake
Dehydration Monitor and ensure adequate fluid intake
Pressure sores Good nursing (regular turning); natural sheepskin fleeces and bootees, padded/foam mattresses,
Roho cushions, low air loss beds
Venous thromboembolism Anticipate if immobile; mobilize early; full length graduated compression stockings; aspirin or
s/c heparin 5000 U bd if ischemic stroke
Spasticity and contractures Regular physiotherapy, and exercise at home; baclofen, diazepam; botulinum toxin (focal spasticity)
Pain Exclude treatable cause; amitriptyline or lamotrigine 200 mg/day for central post-stroke pain
Painful shoulder Recognize high risk patient (low tone, weakness, neglect, proprioceptive loss, visual field defect)
and avoid pulling on shoulder when nursing and treating the patient; physiotherapy (positioning,
mobilization, exercises); support: orthoses, sling, cuff (but may promote spasticity); medication:
analgesics (systemic, local); other physical: ultrasound, acupuncture, biofeedback,TENS; surgery:
sympathectomy, contracture relief, humeral head suspension
Falls and fractures Recognize high risk patient and environment; regularly and systematically look for signs of fracture
as patients with communication problems, sensory loss or neglect may not report injury
Low mood and anxiety Recognize high risk patient (previous depression, language problems, poor functional status, social
isolation); explain to patient nature, sequelae and prognosis of stroke; psychotherapy, antidepressants
Emotionalism Amitriptyline 25 mg nocte, or fluoxetine
PEG: percutaneous endoscopic gastrostomy; i.v.: intravenous; DVT: deep vein thrombosis; PE: pulmonary embolism;
TENS: transcutaneous electric nerve stimulation.
 Stroke
Antiplatelet drugs
Aspirin, given to TIA/ischemic stroke patients, reduces the
RR of stroke and other important vascular events by about
13% (95% CI: 4–21%), from 7.0% to 6.0% per year; an ARR
of 1.0%. The NNT is 100.
Compared with aspirin, clopidogrel reduces the risk of
stroke and other important vascular events from about 6.0%
(aspirin) to 5.4% (clopidogrel) per year, a RRR of 10% (95%
CI: 3–17%), and ARR of 0.6%. The NNT is 166 compared
with aspirin. Clopidogrel is also as safe as aspirin and, unlike
ticlopidine, does not cause an excess of neutropenia and
thrombocytopenia. Compared with aspirin, the combination
of aspirin and modified-release dipyridamole reduces the risk
of stroke from about 6.0% (aspirin) to 5.1% per year, a RRR
of 15% (95% CI: 4–26%), and ARR of 0.9%. The NNT is
111 compared with aspirin.
Anticoagulants
Long term oral anticoagulation (target INR 2.0–3.0) is
indicated for TIA/ischemic stroke patients who have a high
risk source of embolism in the heart such as recent trans-
mural anterior myocardial infarction, dilated cardio-
myopathy, valvular heart disease, and AF. Anticoagulating
TIA/ischemic stroke patients in AF reduces the annual risk
of stroke from 12.0% to 4.0%, a RRR of 67% (95% CI:
43–80%) and ARR of 8.0%. The NNT is 12. The benefit of
anticoagulation is even greater in AF patients who have a
higher absolute risk of stroke, such as the elderly (age >75
years), and those with a history of hypertension, diabetes,
or previous TIA or stroke, and echocardiographic evidence
of impaired left ventricular function.
Anticoagulation is no more effective than aspirin in
preventing recurrent stroke among patients with ischemic
stroke due to atherothrombosis (Mohr et al. [2001]).
Carotid endarterectomy for symptomatic carotid stenosis
See TIA (see p.186).
Carotid endarterectomy for asymptomatic carotid stenosis
Carotid endarterectomy is rarely indicated for asymptomatic
severe carotid stenosis because it only reduces the 3 year risk
of stroke from 9.2% (3.1% per year) to 7.4% (2.5% per year),
an RRR of 20% (odds reduction 32%, 95% CI: 10–49%), and
ARR of 1.8% (0.6% per year). The NNT is 55 to prevent one
stroke at 3 years, or 166 to prevent one stroke each year.
Carotid stenting and angioplasty
Experimental and being evaluated in clinical trials (see TIA,
p.186).
Estrogen-replacement therapy
A recent RCT showed that estrogen therapy (1 mg of
estradiol-17β per day) for post-menopausal women with
recurrent TIA/ischemic stroke did not reduce mortality or
the recurrence of stroke, and therefore should not be
prescribed primarily for the secondary prevention of
cerebrovascular disease (Viscoli et al. [2001]).
CLINICAL COURSE AND PROGNOSIS
Clinical course
Among stroke survivors, improvement begins within the
first few days and continues most rapidly in the first 3
months and more slowly over the next 6–12 months.
201
Prognosis
Death and disability
The outcome of stroke depends on the location, size and
pathology of the lesion. Within the first 30 days after stroke,
about 20–25% of patients die (10% for patients with cerebral
infarction but 50% intracerebral and subarachnoid
hemorrhage).
The prognostic clinical indicators of poor survival include:
• Depression of consciousness.
• Urinary incontinence.
• Pupillary abnormalities.
• Gaze paresis.
• Severe limb weakness.
• Bilateral extensor plantar responses.
• Cardiac failure.
• Atrial fibrillation.
At 1 year after stroke, about one-third of all stroke patients
have died, about one-third are physically or cognitively
disabled and are dependent on others for help with activities
of daily living, and about one-third are independent.
The prognostic indicators for poor functional recovery
include:
• Urinary incontinence.
• Poor postural control.
• Cognitive dysfunction.
• Poor motivation.
• Visual-spatial-perceptual dysfunction.
• Proprioceptive loss.
• Severe motor loss.
• Initially complete dependence in activities of daily living.
The patient’s chances of staying at home or returning
home from hospital depend not only on the severity of their
stroke but also on other factors such as premorbid disability,
whether they were living alone previously and their social
support and access to community services.
Stroke recurrence
The average risk of recurrent stroke in patients with a first-
ever stroke is about:
• 13% in the first year (15 times the risk in the general
population).
• 4% per year for subsequent years, so that by 5 years,
about 30% will have suffered a recurrent stroke.
Epileptic seizures
• 2% of patients with a first-ever stroke have a seizure at
stroke onset.
• 11% have a later seizure in the first 5 years of follow-up,
but nearly half of these patients have only one seizure.
• The risk of seizures is increased in survivors of intra-
cerebral and subarachnoid hemorrhage, and total
anterior circulation infarction.
• Stroke survivors who are independent at 1 month after
stroke have a very low risk of future seizures. Hence,
stroke patients who are functionally competent may
return to driving after 30 days.
202 Vascular Diseases of the Nervous System
ATHEROSCLEROTIC
ISCHEMIC STROKE
DEFINITION
Arteriosclerosis is a generic term embracing all varieties of
structural changes that result in hardening (and thickening)
of the wall of large and small, and elastic and muscular
arteries and arterioles (‘arteriolosclerosis’).
Atherosclerosis is one form of arteriosclerosis,
characterized by an intimal pool of necrotic, proteinaceous
and fatty substances in the hardened arterial wall (athere =
porridge or gruel in Greek).
Atherosclerotic ischemic stroke is cerebral infarction
caused by low blood flow to a part of the brain as a result
of the complications of atherosclerosis: acute in situ
thrombotic arterial occlusion, low flow distal to a severely
narrowed or occluded artery, or embolism of atherosclerotic
plaque or thrombus to the brain.
EPIDEMIOLOGY
• Atherosclerosis is the most common, but not the only,
cause of cerebral ischemia and infarction, accounting for
up to 75% of cases.
• Age: atherosclerosis begins in children and young adults
and is almost universal in the elderly.
• Gender: both sexes, slight excess in men during middle age.
PATHOLOGY
Cerebral infarction
Ischemic necrosis of brain tissue
Pale infarction
Devoid of blood. After 8–48 hours of ischemia, the infarcted
gray and white matter swells, the line of demarcation
between gray and white matter becomes indistinct, the white
matter loses its smooth ‘grain’, becoming uneven and
granular, and the swollen tissue feels softer. Histologically,
there is evidence of necrosis: a hematoxylin and eosin stain
reveals neurons with a brightly eosinophilic cytoplasm and
a darker nucleus, oligodendrocytes and glial cells with
homogeneously pale or dark nuclei that have serrated
borders and a collapsed or retracted nuclear membrane,
astrocytes which are swollen with fragmented processes, axis
cylinders which are fragmented and myelin sheaths which
swell and disintegrate after 8 hours (220).
After 2 days, the infarcted brain becomes mushy and
friable. Polymorphonuclear neutrophilic leukocytes, macro-
phages and other phagocytic cells infiltrate the necrotic
tissue, and are particularly prominent around small vessels,
where they phagocytose degradation products and become
transformed into fatty macrophages. After 10 days, the
swelling subsides, the necrotic tissue becomes liquefied and,
if the infarct is small, early cavitation takes place as early as
3 weeks (221).
Hemorrhagic infarction
Extravasation of blood from many small vessels in the
infarcted area. It is usually due to embolic occlusion of a
cerebral artery, which causes ischemic necrosis of the brain
tissue supplied by the artery and necrosis of the artery itself
(due to lack of blood supply to the artery via the vasa
vasorum). If the embolus lyses or fragments distally, blood
flows into the necrotic artery and penetrates that arterial
wall, resulting in hemorrhagic infarction.
Sites
• Wedge-shaped cortical/subcortical infarcts: usually due
to large or medium-sized cerebral artery occlusion (e.g.
MCA or its branches) by in situ thrombosis or embolus.
• Elongated sickle-shaped strips of infarction of variable
width from the frontal to the occipital lobes due to
infarction in the borderzone between the most distal
parts of the anterior and middle cerebral arteries, often
due to severe carotid occlusive disease.
• Small, deep lacunar infarcts, commonly in the internal
capsule, thalamus and ventral pons due to disease
affecting the small (40–800 microns diameter)
perforating arteries of the brain (222); i.e. the
lenticulostriate perforating branches of the middle
cerebral artery (MCA), the thalamoperforating branches
of the proximal posterior cerebral artery, and the
perforating branches of the basilar artery to the
brainstem. These usually manifest as a ‘lacunar’ clinical
syndrome and make up about 25% of ischemic strokes
and TIAs.
Large and medium artery atherosclerosis
• Fatty streaks: focal accumulations of subendothelial
smooth muscle cells and macrophages containing lipid
(cholesterol and cholesterol ester).
• Fibrous plaque: a central core of lipid and cell debris
surrounded by smooth muscle cells, collagen, elastic
fibers and proteoglycans. A band of fibrous tissue (the
fibrous cap) separates the lipid core (the atheroma) from
the lumen of the vessel.
• Mature atheroma: three main constituents: proliferated
cells, predominantly smooth muscle cells; lipids
(cholesterol esters) and lipid-laden macrophages (‘foam
cells’); connective tissue elements such as elastins and
glycosaminoglycans.
• Complicated lesions: mature fibrous plaque with various
types of degenerative changes such as calcification (due
to precipitation of calcium salts in the tissues),
intraplaque hemorrhage, intimal ulceration, rupture and
mural thrombosis.
Sites
• Large- and medium-sized arteries (e.g. aortic arch),
particularly at places of arterial branching (e.g. the
carotid bifurcation [223, 224]), tortuosity (e.g. the
carotid siphon), and confluence (e.g. the basilar artery
[225, 226]).
• Individuals with atheroma affecting one artery almost
always have atheroma affecting several other arteries,
either with or without clinical manifestations.
• Some sites are remarkably free of atheroma (e.g. ICA
between its origin and the siphon, and the main cerebral
arteries distal to the circle of Willis). Consequently,
occlusion of a branch of the MCA is more likely to be
due to embolism than local thrombosis on an
atheromatous plaque.
 Atherosclerotic Ischemic Stroke 203

220 221

220 Early acute ischemic necrosis of brain, hematoxylin and eosin 222
stain, showing hypoxic neurons with brightly pink (eosinophilic)
cytoplasm and darker nuclei, and oligodendrocytes (which are sensitive
to ischemia) which have homogeneously dark nuclei.

221 Microscopic section of the brain at low power showing

thrombotic occlusion of a branch of a cerebral artery and surrounding
brain infarction in the stage of organization and scar formation.

222 Microscopic section of an organized, cavitated old lacunar infarct.

223 Longitudinal section of the 223 224

common carotid artery and proximal
internal carotid artery at autopsy
showing atheroma of the origin of
the internal carotid artery.
(Reproduced with permission from
Hankey GJ,Warlow CP [1994]
Transient Ischaemic Attacks of the Brain
and Eye,WB Saunders.)

224 Autopsy specimen of a cross-

section of the internal and external
carotid arteries in the axial plane
showing a patent external carotid
artery and complete occlusion of the 225 226
internal carotid artery due to in situ
atherothrombosis.

225 CT brain scan with contrast

showing a very ectatic basilar artery
(arrows).

226 Photograph of the base of the

brain at post mortem showing
atheromatous aneurysmal dilatation
and tortuosity of the basilar artery.
(Reproduced with permission from
Hankey GJ,Warlow CP [1994]
Transient Ischaemic Attacks of the Brain
and Eye,WB Saunders.)
204 Vascular Diseases of the Nervous System

Intracranial small vessel PATHOGENESIS

lipohyalinosis/microatheroma
• Replacement of muscle and elastin in the arterial wall
with collagen.
• Subintimal hyalinization.
• Tortuosity of the vessel.
Lipohyalinosis/microatheroma may also lead to arterial
rupture and intracerebral hemorrhage, perhaps due to
microaneurysm formation (so-called Charcot–Bouchard
aneurysms), but these may be artifacts of the pathologic
specimens.
ETIOLOGY AND PATHOPHYSIOLOGY
Genetic predisposition
Genetically predisposed individuals (e.g. strong family
history of atherosclerotic disease due to presumed polygenic
inheritance) are likely to develop atheroma prematurely, or
to have particularly extensive or severe atheroma, when
exposed to causal risk factors.
Atherogenesis
Atheroma is initiated by endothelial injury and begins as
intimal fatty streaks in children. In genetically susceptible
individuals, it is then amplified and accelerated by factors such
as hypertension, cigarette smoking, diabetes and hyper-
cholesterolemia. Its distribution is determined by racial factors
(black and Oriental races tend to have more intracranial and
less extracranial atheroma) and arterial anatomy; atheroma
occurs at sites of hemodynamic shear stress and endothelial
trauma; boundary zone flow separation and blood stagnation
or turbulence, all of which might promote thrombosis which
itself may be involved in the progression of atheroma. Over
many years, arterial smooth muscle cells proliferate and the
intima is invaded by macrophages, fibrosis occurs, and intra-
and extracellular cholesterol and other lipids are deposited to
form fibrolipid plaques. These plaques invade the media,
spread around and along the arterial wall, and so the wall
thickens and the lumen narrows. Later the plaques become
necrotic and calcified.

Environmental risk factors Atherosclerotic ischemic stroke

The major risk factors for ischemic stroke and TIA are age Acute cerebral ischemia begins with the occlusion of a
(an 80 year old has about 30 times the risk of ischemic stroke cerebral blood vessel, usually by in situ thrombus or
as a 50 year old, probably due to more prolonged exposure embolism of thrombus (or other material) from a more
to causal risk factors), raised BP (definitely causal), atrial proximal source. Modern ideas about the pathogenesis of
fibrillation (AF), diabetes mellitus and cigarette smoking. vessel thrombosis began with Rudolph Virchow’s
dissertation in 1845 in which he enunciated his famous triad
Risk factors for cerebral infarction that thrombosis was due to changes in the vessel wall,
Definite changes in the pattern of blood flow and changes in the
• Age. constituents of the blood. It has since been established that
• Male sex. the most critical event in the formation of an arterial
• High blood pressure. thrombus is injury to the vascular endothelium.
• Cigarette smoking.
• Diabetes mellitus. Normal endothelium
• AF. Under resting physiologic conditions, the endothelium
• Ischemic heart disease. prevents thrombus formation. It acts as a physical barrier
• Heart failure. separating hemostatic from reactive subendothelial
• High plasma fibrinogen. components, and its negative surface charge may help to
• Carotid bruit/stenosis. repel platelets. It possesses anticoagulant properties
• TIA. attributable to constitutional expression of thrombomodulin
• Peripheral vascular disease. and heparin sulfate, endogenous synthesis of ectoenzymes
which degrade platelet agonists such as ADP, and
Possible endogenous synthesis of high local concentrations of the
• Hyperlipidemia. vasodilators prostacyclin (PGI2) and nitric oxide (NO)
• Hyperhomocystinemia. which inhibit platelet aggregation.
• High plasma factor VII coagulant activity.
• Low blood fibrinolytic activity. Injured endothelium: atherosclerosis
• Raised hematocrit. The most common cause of injury to the vascular
• Raised tissue plasminogen activity antigen. endothelium is atherosclerosis (but there are other causes
• Plasma viscosity (largely determined by plasma fibrinogen). such as arterial dissection [see p.224] and trauma). Acute
• Physical activity. coronary syndromes, and presumably many acute ischemic
• Obesity. stroke syndromes caused by arterial disease, are precipitated
• Snoring and sleep apnea. by thrombus which develops on an atherosclerotic plaque
• Recent infection. in which the overlying endothelium is eroded or, perhaps
• Family history of stroke. more commonly, the atherosclerotic plaque has ruptured.
• Diet (salt, fat). It remains uncertain exactly what triggers a ‘dormant’
• Alcohol (none, heavy drinking). atherosclerotic plaque to rupture, and become active and
• Race. symptomatic, but inflammation in the vessel wall is thought
• Social deprivation. to be a major factor (see below).
 Atherosclerotic Ischemic Stroke
The vulnerable, unstable plaque
Ruptured plaques contain a large core of eccentrically located
lipid-laden macrophages (foam cells) engorged with oxidized
low density lipoprotein (LDL) cholesterol, and a thin friable
overlying fibrous cap devoid of smooth muscle cells. The
oxidized LDL within the lipid core stimulates plaque
inflammation, which undermines the structural integrity of the
plaque and activates the endothelium to a pro-inflammatory
and procoagulant state. The oxidized LDL and other
inflammatory stimuli initiate recruitment of inflammatory cells
into the lesion, and serve as a second messenger to enhance
the synthesis of other vascular inflammatory products such as
adhesion molecules and cytokines. Cytokines and metallo-
proteinases weaken the fibrous cap. The plaque is believed to
rupture because the large lipid core redistributes the shear
stress on the thin fibrous cap and very high loads are imparted
upon localized areas of the weakened cap.
Triggers of plaque rupture
Recent epidemiologic studies suggest that plaque
inflammation (and rupture) may be triggered by exposure
(acute or chronic) to an exogenous infectious antigen.
There is a consistent significant relationship between
symptomatic coronary artery disease and moderately
elevated markers of inflammation (e.g. fibrinogen, C-
reactive protein, albumin, serum amyloid A and leukocyte
count), particularly C-reactive protein. Some studies have
identified a higher than expected incidence of chronic
infections of the teeth, gums and lungs, and with Chlamydia
pneumoniae, Heliobacter pylori, and cytomegalovirus.
Although there is emerging evidence that these associations
with chronic infections may be coincidental rather than
causal, a similar, yet less robust, body of evidence is also
mounting for the role of a systemic, low grade, inflam-
matory response being an integral part of the pathogenesis
of acute ischemic stroke due to atherosclerosis.
Sequelae of plaque rupture: atherothrombosis
Following plaque rupture or endothelial erosion, blood is
exposed to the endothelial basement membrane and
extracellular matrix. Von Willebrand factor (vWF), which is
a large, multimeric protein synthesized by the endothelium
and secreted into the subendothelium, binds to extracellular
collagen, primarily through its A3 domain. Platelets adhere
to the subendothelial collagen (particularly types I and III),
vWF and fibronectin by means of platelet-membrane
glycoprotein receptors, which are receptors for adhesive
proteins. The largest glycoprotein (Gp) is designated I, the
smallest IX. Letters a and b were added when better
techniques allowed resolution of single protein bands on
electrophoresis into two separate bands (e.g. Gp I became
Ia and Ib). The most abundant receptor is the integrin
family which are heterodimic molecules composed of a and
b subunits.
205
Under conditions of low shear stress, platelets adhere to
subendothelial collagen and fibronectin through the binding
of platelet glycoprotein Ia–IIa receptors. Under conditions
of high shear stress, platelets adhere to subendothelial vWF
by means of platelet glycoprotein Ib–V-IX (Ib/IX).
Platelets become activated when specific platelet
receptors bind to various agonists such as collagen,
thrombin, thromboxane A2, adenosine diphosphate (ADP),
adrenaline and arachidonic acid. A series of intracellular
reactions takes place. The final common pathway of platelet
activation is the assembly of the Gp IIb/IIIa receptor on
the surface of activated platelets. Under resting conditions,
the surface of a platelet contains 50 000 to 80 000 copies
of the Gp IIb-IIIa (aIIbb3) receptor. Upon platelet
activation, the platelet GPIIb-IIIa receptor undergoes a
conformational change, enabling it to bind both vWF and
fibrinogen, resulting in irreversible platelet adhesion and
aggregation, respectively. The dimeric nature of the
fibrinogen molecule allows it to bind to Gp IIb-IIIa
receptors on two separate platelets, resulting in interplatelet
bridging, platelet aggregation, and growth of the primary
platelet clot.
Platelet recruitment into the thrombus
Adherent, activated platelets recruit additional platelets into
the growing thrombus by three mechanisms which are
coordinated around the central role of thrombin.
Firstly, activated platelets release ADP from storage
granules, and the ADP binds to the ADP receptor of
adjacent platelets, which activates them.
Secondly, activated platelets generate and release
arachidonic acid, which is metabolized by the enzyme cyclo-
oxygenase to prostaglandin endoperoxides, which in turn is
converted by thromboxane synthetase to thromboxane A2,
a potent vasoconstrictor and platelet agonist. The platelets
also release other eicosanoids, such as prostaglandin F2a and
serotonin, which induce further vasoconstriction and
platelet aggregation.
Thirdly, the modified membrane of activated platelets
promotes assembly of clotting factors on the platelet surface
(V, X, VIII), thereby amplifying thrombin generation (see
below). Thrombin is central to platelet aggregation.
Coagulation
Coagulation is initiated by exposure of blood to tissue
factors located in the necrotic core of ruptured
atherosclerotic plaques, in the subendothelium of injured
vessels, and on the surface of activated leukocytes attracted
to the damaged vessel. The original cascade/waterfall
hypothesis of blood coagulation is that there are two
activating pathways: (1) the tissue factor or extrinsic
pathway; and (2) the contact or intrinsic pathway. A revised
hypothesis of blood coagulation maintains that there is a
single coagulation pathway, triggered by vessel injury and
tissue factor (TF) (the factor VIIa/TF complex). Tissue
factor binds factor VIIa and the resulting factor VIIa tissue
factor complex activates both factors IX and X (i.e. the
intrinsic and extrinsic pathways are integrated in vivo).
Factor IXa assembles on the surface of activated platelets as
part of the intrinsic tenase complex which comprises factor
IXa, factor VIIIa, and calcium.
206 Vascular Diseases of the Nervous System
Factor Xa, generated through the extrinsic (factor
VIIa/tissue factor) and the intrinsic tenase complex,
assembles on the surface of activated platelets as part of the
prothrombin-activating (prothrombinase) complex, which
consists of factor Xa, factor Va, and calcium. When
assembled in this way, the prothrombinase complex
generates a burst of thrombin activity. Thrombin (IIa)
activates platelets and factors V and VIII and also converts
fibrinogen to fibrin; thrombin then binds to fibrin where it
remains active.
As a blood clot forms at the site of vessel injury,
plasminogen, an inert circulating protein closely bound to
the deposited fibrin, is slowly activated (by tissue
plasminogen activator which has been activated by
kallikrein) to form plasmin, which digests the fibrin clot to
give fibrin degradation products. The net result is that
platelets and later fibrin accumulate at, and are limited to,
the site of vascular injury. The rest of the vasculature
remains free of platelet and fibrin deposits because, in
circulating blood, the tendency of the coagulation
mechanism to be activated is counterbalanced by inhibitory
factors in the blood such as antithrombin III (which
inactivates factors IX, X, XI and XII). However, at the point
of vessel injury, the activation of the coagulation mechanism
is so powerful that the inhibitors are overwhelmed.
The three major inhibitory systems which modulate the
coagulation pathway are the protein C anticoagulant path-
way, tissue factor pathway inhibitor (TFPI), and anti-
thrombin. Protein C is activated by the thrombin/throm-
bomodulin complex on the endothelial cell surface. When
thrombin binds to thrombomodulin (an endothelial
membrane protein) it undergoes a conformational change
at its active site that converts it from a procoagulant enzyme
to a potent activator of protein C. Activated protein C acts
as an anticoagulant in the presence of protein S by
proteolytic degradation and inactivation of factors Va and
VIIIa. TFPI binds and inactivates factors Xa and the
TFPI/factor Xa complex and then inactivates factor VIIa
within the factor VIIa/tissue factor complex. Antithrombin
inactivates free thrombin and factor Xa, but these clotting
enzymes are protected from inactivation by antithrombin
when they are bound to fibrin and activated platelets,
respectively.
Sequelae of atherothrombosis
Arterial occlusion
The atherothrombotic plaque and thrombus may grow to
obstruct the arterial lumen (224), the intraluminal
thrombus may propagate proximally or distally, or the
thrombus may be lysed by fibrinolytic mechanisms in the
vessel wall and blood.
Thromboembolism
The plaque and thrombus may also embolize, in whole or
in part, to obstruct a smaller distal artery, perhaps the same
one on several occasions. Therefore, emboli may consist of
any combination of cholesterol debris, platelet aggregates
and fibrin. Emboli are transmitted to the brain or eye via
their normal arterial supply which itself varies in distribution
between individuals. So, an embolus from the origin of the
ICA usually goes to the eye or anterior two-thirds of the
cerebral hemisphere but on occasion it may go to the
occipital cortex if the blood in the posterior communicating
artery (PCA) is flowing from the ICA to the PCA.
However, if an artery is occluded, such as the ICA,
ipsilateral MCA distribution cerebral infarction may still
occur due to an embolus travelling from the contralateral
ICA origin via the anterior communicating artery; from the
blind stump of the proximal ICA or from disease of the
ipsilateral external carotid artery (ECA) via orbital
collaterals; or from the tail of thrombus in the ICA distal to
the occlusion. Ischemic stroke ipsilateral to an ICA
occlusion may also be due to low flow in its normal territory
of supply, or within a boundary zone, particularly if the
collateral blood supply is poor. Emboli from the neck
arteries (or from the heart) seldom seem to enter the small
perforating arteries of the brain to cause lacunar infarction,
perhaps because the emboli are too large.
Dilatation and ectasia of atheromatous cerebral arteries
is unusual; such vessels often contain thrombus which may
embolize, or occlude small branch arteries of the ectatic
vessel. Cranial nerve and brainstem compression are other
occasional complications.
CLINICAL FEATURES
Atherothromboembolism is an acute on chronic disease.
Although the formation of atherothrombotic plaque is a
long and chronic process over many years, the clinical
manifestations usually occur acutely (e.g. an ischemic stroke)
and tend to cluster in time (e.g. stroke tends to occur
sooner rather than later after a TIA) as a result of the
sudden breakdown and ‘activation’ of an atherothrombotic
plaque. The clinical features depend on the site of arterial
occlusion, and the degree and duration of focal brain
ischemia; see Stroke (p.192) and Neurovascular syndromes
(p.181).
INVESTIGATIONS
As for TIA (see p.188) and Stroke (see p.194).
 Atherosclerotic Ischemic Stroke 207

227 228 229

227–229 Typical evolution of cerebral infarction on CT. Left parietal cortical infarct at 3 hours after symptom onset showing loss of the normal
basal ganglia outlines on the left (arrows) (227); same patient at 3 days after the stroke showing a well defined low density area with mass effect
(the left lateral ventricle is effaced) (228); same patient at 3 months after the stroke showing a shrunken, well defined area of CSF density (229).
This appearance will persist indefinitely.

DIAGNOSIS 230
Extracranial large artery atherothromboembolism
More likely to be the cause of ischemic stroke or TIA if
• Older patient: age >60.
• Total or partial anterior circulation infarction/ischemia
(clinical syndrome ± CT/MRI evidence) (227–229).
• Posterior cerebral artery territory infarction/ischemia.
• Border zone infarction/ischemia (clinical syndrome ±
CT/MRI evidence) (230).
• Cerebellar infarction/ischemia.
• Carotid, subclavian, or vertebral bruit; absent carotid
pulses; unequal radial pulses.
• Ultrasound or angiography shows >50% stenosis of the
symptomatic artery.
• Other clinical complications of atherothrombosis: angina,
past myocardial infarction, claudication, femoral bruits,
absent foot pulses, or vascular risk factors.

230 CT scan showing a border zone infarct in the left cerebral

hemisphere (arrows). Note the low density area (infarct) runs along
the border of the middle with anterior cerebral and middle with
posterior cerebral artery territories.
208 Vascular Diseases of the Nervous System

Less likely if 231

• Young patient: less than 40 years of age.
• Lacunar infarct/TIA (clinical syndrome ± CT/MRI
evidence) (231).
• Definite cardiac embolic source (see p.209).
• Clear evidence of alternative mechanism (eg. migrainous
stroke, high ESR and giant cell arteritis, arterial
dissection and so on).
• No vascular bruits, normal pulses.
• No arterial stenosis on duplex sonography or
angiography.
• No evidence of atherothrombosis elsewhere.

Intracranial small vessel disease

More likely to be the cause of ischemic stroke or TIA if
• Lacunar syndrome (clinically defined).
• CT/MRI shows a small deep and relevant infarct in
internal capsule/basal ganglia area, cerebral peduncle or
pons (231–234), or is normal.
• No clinical (cervical bruits) or ultrasonographic/angio-
graphic evidence of arterial stenosis >50%, or occlusion
of the symptomatic artery in the neck.
• No evidence of a cardiac embolic source.
• Vascular risk factors present, particularly hypertension,
smoking and diabetes.

TREATMENT
See Stroke (p.196). 231 T2W MRI of a lacunar infarct in the centrum semiovale (arrow).

PROGNOSIS
10% die within the first 30 days after cerebral infarction, and
death occurs usually between days 3 and 5, when mass effect 232
due to cerebral edema associated with massive cerebral
infarction is maximal.

232 Plain cranial CT scan, axial plane, showing high density (whiteness)
due to acute thrombus in the basilar artery and a wedge-shaped area
of low density in the left paramedian pons representing infarction due
to occlusion of a paramedian branch of the basilar artery.
 Cardioembolic Stroke 209

233 CARDIOEMBOLIC STROKE

DEFINITION
Embolism of material from the heart to the brain (235)
causing ischemia or infarction of a part of the brain or eye,
with or without hemorrhagic transformation of the infarct.

EPIDEMIOLOGY
Embolism from the heart probably accounts for about 20%
of ischemic stroke and TIAs.

ETIOLOGY AND PATHOPHYSIOLOGY

Cardiac sources of embolism in anatomic sequence
Right to left shunt (paradoxical emboli from the venous
system) via
• Patent foramen ovale.
• Atrial septal defect.
• Ventricular septal defect.
• Pulmonary arteriovenous malformation.

Left atrium
• Thrombus: AF*; sinoatrial disease (sick sinus syndrome);
atrial septal aneurysm.
• Myxoma and other tumors*.

*Substantial risk of embolism.

235

234

233, 234 MRI brain (233) and autopsy specimen of brainstem (234)
showing an axial section through the mid pons and floor of the fourth
ventricle, and a small area of cavitation, due to organized lacunar
infarction, in the ventral pons on the left due to occlusion of a
paramedian perforating branch of the basilar artery.The basilar artery,
containing thrombus, can be seen ventral to the pons.The patient had
a history of a previous ataxic hemiparesis.

235 Diagrammatic illustration of the pathway a left ventricular

thrombus takes as it embolizes to the brain.
210 Vascular Diseases of the Nervous System

Mitral valve Atrial fibrillation

• Rheumatic endocarditis (stenosis* or regurgitation). The most common cause of cardioembolic stroke,
• Infective endocarditis*. accounting for up to 12% of all ischemic strokes, and an
• Mitral annulus calcification. even greater proportion of ischemic strokes in the very
• Mitral valve prolapse. elderly where its frequency in the population is highest.
• Non-bacterial thrombotic (marantic) endocarditis. Atrial fibrillation is the cause of stroke in many of these
• Libmann–Sacks endocarditis. patients but it is not always the cause because:
• Antiphospholipid antibody syndrome. • Other possible causes of stroke, which may also be the cause
• Prosthetic heart valve*. of the AF, such as ischemic heart disease and hypertension
• Papillary fibroelastoma. (e.g. carotid atheroma, intracerebral hemorrhage), are
present in about 20% of fibrillating stroke patients.
Left ventricle • Some AF patients have lacunar (presumed non-embolic)
• Mural thrombus: syndromes.
– Acute myocardial infarction (within previous few weeks)* • ‘Only’ about 13% of non-rheumatic fibrillating patients have
(236, 237). detectable (by TOE) thrombus in the left atrium (although
– Left ventricular aneurysm or akinetic segment. some thrombi may have embolized or be too small to be
– Dilated cardiomyopathy*. detected) and it is unknown if these patients have a higher
– Mechanical ‘artificial’ heart*. stroke risk than those without detectable thrombi.
– Blunt chest injury (myocardial contusion). • In a few cases the AF is caused by the stroke.
• Myxoma and other tumors*.
• Hydatid cyst. The average absolute risk of stroke in unanticoagulated non-
• Primary oxalosis. rheumatic AF patients is about 5% per annum (six times greater
than in those in sinus rhythm) and about 12% per annum in
Aortic valve
• Rheumatic endocarditis (stenosis or regurgitation).
• Infective endocarditis*. 236
• Syphilis.
• Non-infective thrombotic (marantic) endocarditis.
• Libman–Sacks endocarditis.
• Antiphospholipid antibody syndrome.
• Prosthetic heart valve*.
• Calcific stenosis/sclerosis/calcification.

Congenital heart disease (particularly with right to left shunt)

Cardiac manipulation/surgery/catheterization/valvulo-
plasty/angioplasty

*Substantial risk of embolism.

Prevalence of potential cardiac sources of embolism 236 Electrocardiograph of a patient with a recent acute anteroseptal
in patients with first-ever ischemic stroke* myocardial infarction showing sinus tachycardia, and Q waves and ST
• Any AF (238): 13%. segment elevation in leads V1–V3.
– Without rheumatic heart disease: 12%.
– With rheumatic heart disease: 1%. 237
• Mitral regurgitation: 6%.
• Recent (<6 weeks) myocardial infarction: 5%.
• Prosthetic valve: 1%.
• Mitral stenosis: 1%.
• Paradoxical embolism: 1%.
• Any of the above: 20%.
• Other sources of uncertain significance: aortic
stenosis/sclerosis; mitral annulus calcification, mitral
valve prolapse and so on: 11%.

*Sandercock PAG, Warlow CP, Jones LN, Starkey IR

(1989) Predisposing factors for cerebral infarction: The
Oxfordshire Community Stroke Project. BMJ, 298: 75–80.

Note:
• Not all cardiac sources of embolism pose equal threats
(see Diagnosis).
• Not all emboli are of the same size or the same material (fibrin, 237 Cross-section of the left ventricle showing mural thrombus
platelets, calcium, infected vegetations, tumor and so on). adjacent to an area of myocardial infarction.
 Cardioembolic Stroke
unanticoagulated fibrillating TIA/stroke patients. The risk of
stroke among patients in AF is variable; some are at particularly
high risk and others at particularly low risk of embolization.
Risk factors for embolization in AF patients
Low risk: no other detectable heart disease (so-called lone AF).
High risk:
• Rheumatic mitral valve disease.
• Previous cerebral or systemic embolic event.
• Increasing age.
• Hypertension.
• Diabetes.
• Left ventricular systolic dysfunction.
• Enlarged left atrium defined by echocardiography.
• Spontaneous echo contrast in the left atrium, probably a
consequence of blood stasis.
• Left atrial thrombi, left atrial appendage size and
dysfunction, and various hemostatic variables are perhaps
adverse risk factors also.
Uncertain risk:
• Recent onset AF.
• Paroxysmal AF: probably depends on frequency and
duration of episodes of AF.
• Thyrotoxic AF.
Coronary heart disease
Coronary heart disease is common in patients with TIA and
ischemic stroke: about 20–40% have a past history of MI or
current angina. Stroke may occur in up to 5% of patients
with recent acute myocardial infarction, due to:
• Embolism of left ventricular mural thrombus.
• Systemic hypotension.
• Intracerebral hemorrhage secondary to thrombolysis,
anticoagulants or aspirin.
• Embolism of catheter thrombus during coronary
angioplasty/stenting.
• Concurrent non-cardiac cause of stroke.
After the acute period, the risk of stroke is much lower, about
1% in the first year, perhaps higher if there is persisting left
ventricular thrombus. Chronic left ventricular aneurysm after
MI often contains thrombus but embolization is uncommon.
Prosthetic heart valves
• The risk of embolism is about 2% per annum for all
prosthetic valves, provided patients with mechanical
valves are on anticoagulants.
238
211
• Mechanical valves have a higher risk of embolism than
tissue valves, but there is no difference in stroke risk
between the different types of mechanical valve.
• Some Bjork–Shiley tilting disc valves have disintegrated
and embolized pieces to the brain.
• Prosthetic mitral valves are more prone to thrombosis
than aortic valves.
• Infective endocarditis is a potential risk for any type of
prosthetic valve.
Rheumatic valvular disease
• Rheumatic mitral stenosis/regurgitation is a well
recognized cause of left atrial dilatation causing
thrombus formation and embolism to the brain.
• The valves also degenerate so even patients in sinus
rhythm who have no thrombus in the left atrium are at
risk of embolism of degenerate and sometimes calcific
fragments of valve into the circulation.
• Stroke may also occur as a result of infective endocarditis
(see p.215) and intracerebral hemorrhage due to
anticoagulation in these patients.
Non-rheumatic sclerosis/calcification of the aortic
and mitral valves
These may also be a source of embolism in some patients but
unless calcific emboli are seen in the retina or on CT it is diffi-
cult to attribute confidently the TIA or ischemic stroke to this
condition, which is very common in normal elderly people.
Mitral valve (or leaflet) prolapse
Uncomplicated mitral valve prolapse is not a cause of embolism
from the heart to the brain. It is only likely to be relevant to
the etiology of an ischemic stroke or TIA if it is complicating
infective endocarditis, AF, gross mitral regurgitation, or
thrombus in the left atrium. Prolapse may be familial and
associated with various inherited disorders of connective tissue.
Infective endocarditis (see p.215)
Non-bacterial thrombotic (marantic) endocarditis
(see Infective endocarditis, p.215)
Non-ischemic ‘primary’ cardiomyopathies
Primary cardiomyopathies are well recognized causes of
intracardiac thrombus, particularly the dilated type rather
than hypertrophic subaortic stenosis. Many are familial.
Sinoatrial disease (sick sinus syndrome)
• May be associated with intracardiac thrombus and
embolism, particularly if bradycardia alternates with
tachycardia, or the patient is in AF.
• May be familial.
Atrial septal aneurysm
• Uncommon.
• May be complicated by thrombus and embolism to the brain.
• Often associated with a patent foramen ovale and so has the
potential for paradoxical embolism from the venous system.
The presence of both atrial septal aneurysm and patent
foramen ovale increases the risk of recurrent stroke
(hazard ratio 4.2, 95% CI: 1.5–12).
238 Electrocardiograph showing atrial fibrillation.
212 Vascular Diseases of the Nervous System
Paradoxical embolism from the venous system, or
right atrium
Patent foramen ovale
• Common; present in about 10% of normal people.
• An uncommon cause of ischemic stroke; although
bubbles can be shown to move from the right to the left
side of the heart frequently, it must be rare for venous
thrombus to do so without also going to the lungs (and
causing symptoms), or at least to be able to make a
certain diagnosis of such an event during life.
• A recent study of 581 patients, aged 18–55 years, with
ischemic stroke of unknown origin in the preceding 3
months (Mas et al., 2001) has shown that after 4 years
the risk of recurrent stroke was 2.3% (95% CI: 0.3–4.3)
among patients with patent foramen ovale alone, 15.2%
(95% CI: 1.8–28.6) among patients with both a patent
foramen ovale and atrial septal aneurysm, and 4.2% (95%
CI: 1.8–6.6) among patients with neither of these cardiac
abnormalities. There were no recurrences among patients
with atrial septal aneurysm alone.
Atrial septal defect
Ventriculoseptal defect (rarely)
Pulmonary arterial venous malformation
• Occurs in isolation or as part of hereditary hemorrhagic
telangiectasia (see p.153).
• Clues are clubbing, cyanosis, hemoptysis, bruit over the
chest and a ‘coin lesion’ on the chest x-ray.
Intracardiac tumors
• Rare.
• Myxomas are the most common heart tumor and most
occur in the left atrium.
• Some are familial.
• Myxomas may cause:
– Constitutional upset: malaise, weight loss, anemia, raised
ESR and hypergammaglobulinemia.
– Cardiac symptoms: shortness of breath, palpitations, syncope.
– TIA or ischemic stroke: embolism of tumor or
complicating thrombus.
– Primary intracerebral or subarachnoid hemorrhage: myxo-
matous emboli to sites of earlier symptomatic or even
asymptomatic embolic occlusions can cause fusiform and
irregular aneurysmal dilatations at these sites which can
rupture.
• Myocardial hydatid cysts and intracardiac calcification
due to primary oxalosis are even rarer causes of embolism
to the brain, the former with the subsequent develop-
ment of intracranial cysts.
Myocardial contusion
• Blunt chest injury.
• May be associated with left ventricular thrombus and
embolization.
CLINICAL FEATURES
• Major stroke (i.e. total anterior circulation infarction)
occurs when large emboli impact permanently in the
internal carotid artery or trunk of the MCA.
• Partial anterior circulation infarction occurs when smaller
emboli impact in a distal branch of the anterior or MCA.
• Posterior circulation infarction occurs when moderate or
small sized emboli impact in the top of the basilar artery
or one of its branches.
• TIA of the brain or eye.
• Asymptomatic: some emboli do not occlude arteries
completely or, if they do, there is sufficient collateral
circulation to maintain tissue integrity.
The following strongly suggest embolism
from the heart
• Non-lacunar infarcts (i.e. TACI, PACI, POCI syndromes).
• AF.
• Recent acute MI.
• Valvular heart disease.
• Emboli, particularly calcific emboli, visible in the retina.
• Embolic infarction in other organs (e.g. kidney: hematuria).
INVESTIGATIONS
CT brain scan
• Single or multiple wedge-shaped cortical/subcortical
infarcts, with or without hemorrhagic transformation.
• High density in the middle or basilar artery on the non-
contrast CT suggestive of blood clot or calcium.
• Infarction in the territory of the top of the basilar artery
or superior cerebellar artery.
EKG (electrocardiograph): AF, IHD
Chest x-ray
Echocardiography
Indications
• Multiple cortical/subcortical cerebral infarcts in different
arterial territories.
• Wedge-shaped cortical/subcortical infarct or hemorr-
hage infarct, or striatocapsular infarct and no carotid
lesion on carotid ultrasound.
• Clinical, EKG or CXR evidence of heart disease.
• Age <45 years and no cause found for TIA or stroke.
Preferred echocardiographic technique for detecting
various cardiac disorders
Transthoracic echocardiography
• Left ventricular thrombus (239, 240).
• Left ventricular dyskinesis.
• Mitral stenosis.
• Mitral annulus calcification.
• Aortic stenosis.
Transesophageal echocardiography
• Atrial thrombus.
• Atrial appendage thrombus.
• Spontaneous echo contrast (241).
• Intracardiac tumors.
• Atrial septal defect*.
• Atrial septal aneurysm.
• Patent foramen ovale* (242, 243).
• Mitral and aortic valve vegetations.
• Prosthetic heart valve malfunction.
• Aortic arch atherothrombosis/dissection.
• Mitral leaflet prolapse?
*Transcranial doppler. Detection of intravenously injected
air bubbles is less invasive, more specific, but not quite so
sensitive; galactose particle suspension increases sensitivity.
 Cardioembolic Stroke 213

239 240

2
4

3
1

239 Transthoracic two-dimensional echocardiograph, apical four 240 Higher magnification of the left ventricular apical thrombus
chamber view, showing thrombus in the apex of the left ventricle (arrow). (239, 240 reproduced with permission from Hankey GJ,
(arrow). 1: left atrium; 2: left ventricle; 3: right atrium; 4: right ventricle. Warlow CP [1994] Transient Ischaemic Attacks of the Brain and Eye,
WB Saunders, London.)

241 242

1 3 4
2
2

3
4 1

241 Biplane transesophageal echocardiograph, longitudinal view, in a

patient with atrial fibrillation showing left atrial appendage, an enlarged
left atrium and spontaneous echo contrast. In the absence of regular
atrial contractions and the presence of a dilated left atrium, blood flow
in the left atrium is slower than normal and is seen on the real time 243
echocardiography study to be swirling around slowly in the left atrium;
slowly flowing or static blood has increased echogenicity and is called
spontaneous echo contrast (as opposed to echo contrast that is
introduced into the circulation such as agitated hemaccel). 1: mitral
valve; 2: left atrial appendage; 3: left atrium; 4: left ventricle. (Reproduced 4
with permission from Hankey GJ,Warlow CP [1994] Transient 2
Ischaemic Attacks of the Brain and Eye,WB Saunders, London.)

242, 243 Transthoracic two-dimensional echocardiograph, apical four

chamber view, using contrast (agitated hemaccel) in a patient with a
right-to-left shunt due to a patent foramen ovale. Pre-valsalva (242): 3
1
after intravenous injection of agitated hemaccel, contrast appears in
right atrium and right ventricle without passage across the patent
foramen ovale because left atrial pressure is slightly greater than right
atrial pressure. N.B. Contrast does not traverse the pulmonary
circulation to appear in the left atrium unless there is a right-to-left
shunt such as a pulmonary arteriovenous malformation.Valsalva (243):
after intravenous injection of agitated hemaccel and during valsalva maneuver (which increases right atrial pressure), contrast appears in right
atrium and simultaneously moves into the right ventricle (across the tricuspid valve) and left atrium (through the patent foramen ovale) where it is
seen here crossing the mitral valve and entering the left ventricle (arrow). 1; left atrium; 2: left ventricle; 3: right atrium; 4: right ventricle.
(Reproduced with permission from Hankey GJ,Warlow CP [1994] Transient Ischaemic Attacks of the Brain and Eye,WB Saunders, London.)
214 Vascular Diseases of the Nervous System
DIAGNOSIS
Patients may have two or more competing causes of cerebral
ischemia, such as carotid stenosis and atrial fibrillation, so
one cannot always be sure which is the cause in an individual
patient.
Embolism from the heart to the brain or eye
More likely to be the cause of ischemic stroke or TIA if
• An identified cardiac source of embolism, particularly one
with a substantial embolic risk (see Prognosis, below).
• Ischemic events in more than one arterial territory,
particularly if more than one organ is involved.
• No evidence clinically (bruits, palpation), on ultrasound
or by angiography of arterial disease (>50% stenosis) in
the neck.
• Calcific emboli in the retina (very rare).
• Calcific emboli on brain CT (even rarer).
• No vascular risk factors.
• Age <50 years.
• No other explanation for the stroke.
Less likely if
• Lacunar syndrome (clinical syndrome + CT/MRI evidence).
• Low flow infarction/ischemia (clinical syndrome +
possibly CT/MRI evidence [e.g. borderzone infarction]).
Uncertain if
• Hemorrhagic transformation of the infarct.
• Past TIA.
High risk of embolism
• Non-rheumatic or rheumatic AF.
• Infective endocarditis.
• Prosthetic heart valve.
• Recent MI.
• Dilated cardiomyopathy.
• Intracardiac tumors.
• Rheumatic mitral stenosis.
Low risk of embolism
• Mitral valve prolapse (uncomplicated).
• Mitral annulus calcification.
• Patent foramen ovale with no evidence of deep venous
thrombosis.
• Atrial septal aneurysm.
• Aortic sclerosis.
TREATMENT
Of acute ischemic stroke of suspected cardioembolic origin.
Immediate anticoagulants very likely to be
worthwhile
Start as soon as possible
TIA or ischemic stroke with complete recovery within
1–2 days + high risk of embolism (e.g. AF).
Best time to start unclear
Non-disabling ischemic stroke, no hemorrhagic transform-
ation of the infarction, and AF (?start within 3–7 days of
stroke, earlier if small infarct and normal blood pressure;
later if large infarct or high blood pressure).
Immediate anticoagulants probably worthwhile
Best time to start anticoagulants unclear
• Acute MI within past few weeks and confirmed ischemic
stroke or TIA.
• Disabling ischemic stroke and AF.
Aspirin or no antithrombotic therapy; anticoagulants
not worthwhile or contraindicated
Low risk of recurrent cardioembolic stroke without
anticoagulants
• Heart disease with a low risk of embolism.
• Other, non-cardiac lesion more likely cause of cerebral
infarct: severe ipsilateral carotid stenosis; likely disease of
intracranial small vessels (i.e. lacunar infarct).
Little to gain from long term anticoagulation
• Suspected cholesterol embolization syndrome (i.e.
ischemic stroke during cardiac catheterization, after
cerebral angiography or other vascular procedure).
• Already severely disabled before the stroke.
• Moribund or predicted to be severely disabled in the
long term.
High risk of cerebral hemorrhage on anticoagulants
• Infective endocarditis.
• Large cerebral infarct with midline shift and/or evidence
of major hemorrhagic transformation on brain CT.
• Likely to comply poorly with anticoagulation therapy and
its monitoring after discharge.
• Severe, uncontrolled hypertension.
Contraindication to anticoagulants
These depend on individual circumstances and are seldom
absolute.
• History of bleeding disorder:
– Hemophilia.
• Uncorrected major bleeding disorder:
– Thrombocytopenia.
– Hemophilia.
– Liver failure.
– Renal failure.
• Uncontrolled severe hypertension:
– Systolic pressure over 26.7 kPa (200 mmHg).
– Diastolic pressure over 16 kPa (120 mmHg).
• Potential bleeding lesions:
– Active peptic ulcer.
– Esophageal varices.
– Intracranial aneurysm.
– Proliferative retinopathy.
– Recent organ biopsy.
– Recent trauma or surgery to head, orbit, spine.
– Recent stroke, but patient has not had a brain CT scan
or MRI.
– Confirmed intracranial or intraspinal bleeding.
– History of heparin-induced thrombocytopenia or
thrombosis (if heparin planned).
• If warfarin planned:
– Homozygous protein C deficiency (risk of skin necrosis).
– History of warfarin-related skin necrosis.
– Uncooperative/or unreliable patients (long term therapy).
– Risk of falling.
– Unable to monitor INR.
 Infective Endocarditis 215

Adverse effects of heparin INFECTIVE ENDOCARDITIS

Local minor complications of subcutaneous heparin at
injection site
• Discomfort. DEFINITION
• Bruising. Direct infection of the endocardial surface of the heart
(heart valves and mural surface) by any of a wide range of
Local complications of intravenous heparin at cannula site micro-organisms.
(or elsewhere)
• Pain at cannula site. EPIDEMIOLOGY
• Infection at cannula (sometimes with severe systemic • Incidence: 2 cases per 10 000 population per year. Little
infection). change over the past 30 years.
• Reduced patient mobility because of infusion lines and • Age: adults: 50% >50 years of age; uncommon in childhood.
pump. • Gender: M=F.

Major systemic complications PATHOLOGY

• Intracranial bleeding: • Platelets and fibrin deposited on an endocardial surface
– Hemorrhagic transformation of cerebral infarct damaged by turbulent flow or instrumentation, followed
(potentially disabling or fatal). by colonization with organisms possessing appropriate
– Intracerebral hematoma. adherence properties.
– Subarachnoid hemorrhage. • Direct binding to endothelium of normal hearts by
– Subdural hematoma. organisms such as Staphylococcus aureus.
• Extracranial hemorrhages: • Mature vegetations, due to further platelet and fibrin
– Subcutaneous (can be massive). deposition, within which microbial multiplication may
– Visceral (hematemesis, melena, hematuria). proceed uninhibited.
• Thrombocytopenia:
– Type I: dose and duration related, reversible, mild, ETIOLOGY AND PATHOPHYSIOLOGY
usually asymptomatic, not serious and often resolves • Introduction of pathogens into the circulation, exposing
spontaneously. a susceptible intracardiac or intravascular lesion to
– Type II: idiosyncratic, allergic, severe (may be attachment and colonization.
complicated by arterial and venous thrombosis). Affects • The coincidence of tissue damage from turbulent blood
3–11% of patients treated with intravenous heparin and flow or a foreign body, and lesions or procedures that
less than 1% of patients treated with subcutaneous introduce pathogens.
heparin.
• Osteoporosis. Organisms
• Skin necrosis. • Streptococci: 60–80% of cases.
• Alopecia. • Staphylococci: <30%.
• Gram-negative bacteria (Salmonella, other Entero-
bacteriaceae, Pseudomonas spp.): <10% .
• Fungi (Candida albicans, Aspergillus): <4%.
• Coxiella burnetii (Q-fever).
• Chlamydia.
• Mycoplasma.
• Non-toxigenic Corynebacterium diphtheriae biovar gravis.

Risk factors
Heart abnormalities
• Rheumatic heart disease (especially mitral valve defects).
• Congenital heart disease (especially bicuspid aortic valve
in the elderly).
• Mitral valve prolapse: eightfold excess risk.
• Degenerative heart disease: calcified mitral valve annulus;
post infarct mural thrombosis.

Iatrogenic and lifestyle-associated factors

• Pre-existing dental caries.
• Intravenous drug misuse.
• Prosthetic heart valves.

Procedures involving mucosal surfaces associated with

bacteremia
• Upper airway: oral/dental procedures (15–40%).
• Gastrointestinal (10%).
• Urologic (10–30%)
• Obstetric (<10%).
216 Vascular Diseases of the Nervous System
Pediatric risk factors
• Previous cardiac surgery.
• Congenital heart defects, particularly those involving the
septum.
• Intravascular catheterization.
CLINICAL FEATURES
Infection
• Fever (90% of cases) and chills (40%): may be absent in
the elderly or following antibiotic treatment.
• Myalgia and arthralgia (40%).
• Systemic upset: anorexia, weight loss, cough, dyspnea,
hemoptysis, chest/abdominal pain (10–25%).
• Clubbing of fingers in long-standing or prolonged
infective endocarditis.
Systemic embolism
• Linear (splinter) hemorrhages may be found under the
nails (244).
• Conjunctival and oral small, red, petechial hemorrhagic
lesions with a pale center.
• Non-tender subcutaneous erythematous maculopapular
lesions (Janeway’s spots), on pulp of the fingers (245),
that may ulcerate: suggest staphylococcal infection.
• Erythematous or purple, painful, tender nodules (Osler’s
nodes) on the palms of the hands, soles of the feet, pulp
of the fingers, or other sites.
• Gangrene of fingers, toes, or larger portions of the
extremities.
• Retinal hemorrhages: small, occasionally flame-shaped
hemorrhages that may have pale centers (Roth spots).
• Pulmonary emboli (tricuspid valve).
• Ischemic stroke or TIA (about 20% of patients):
sometimes as the initial presentation but more often in
the context of someone who is already ill, perhaps in
hospital, and before the infection has been controlled;
caused by embolism of infected vegetations.
• Hemorrhagic transformation of a brain infarct: quite
common, sometimes due to the (unwise) use of
anticoagulation.
• Primary intracerebral hemorrhage, and rarely sub-
arachnoid hemorrhage: due to pyogenic vasculitis or
ruptured mycotic aneurysms, which can be single or
multiple and most often affect the distal branches of the
MCA.
• Meningitis.
• Diffuse encephalopathy, perhaps due to showers of small
emboli.
• Discitis.
• Renal emboli (hematuria).
Cardiac dysfunction
• Heart murmur: (85%); ‘changing’ or ‘new’ murmurs:
<10% of cases, usually staphylococcal infection.
• Congestive heart failure.
DIFFERENTIAL DIAGNOSIS
• Non-bacterial thrombotic (marantic) endocarditis:
– Cachectic and debilitated, often elderly, patients with
cancer (adenocarcinomas usually) and sometimes dis-
seminated intravascular coagulation, burns and septi-
cemia.
– Small, sterile, friable valve vegetations, consisting of fibrin
and platelets.
– Vegetations may embolize to cause ischemic stroke (and
sometimes global encephalopathy due to multiple emboli),
ischemia in other organs, and pulmonary embolism.
– Similar vegetations are found in systemic lupus erythe-
matosus and the antiphospholipid antibody syndrome.
• Malignancy.
• Tuberculosis.
• Connective tissue disease: systemic lupus erythematosus
associated with Osler’s nodes and Roth’s spots.
INVESTIGATIONS
No specific diagnostic tests:
• Full blood count: mild normochromic normocytic
anemia (80% of cases); neutrophil leukocytosis in acute
infective endocarditis but not in chronic infective
endocarditis.
• ESR and serum C-reactive protein: raised in 90–100% of
cases.
• Urinalysis: often abnormal, with proteinuria, hematuria,
and occasionally casts.
• Blood cultures to detect constant bacteremia: three sets
in first 24 hours: positive in 90% of cases; negative blood
cultures (10% of cases) suggest Legionella, ‘HACEK’
(Haemophilus spp., Actinobacillus actinmycetemcomitans,
Cardiobacterium hominis, Eikenella corrodens, Kingella
spp.) organisms and non-bacterial infective endocarditis.
• Serology: antistaphylococcal antibodies, antistreptolysin
O titer.
• Serial EKGs: may detect conduction defects (aortic root
abscess), pericarditis and MI (emboli).
• 2D echocardiography: valve vegetations (246), abscess
formation, and valve destruction, but can be normal.
• Doppler flow analysis and cardiac catheterization with
angiography have a role in pre-operative evaluation.
• CSF: can be normal but more than 100 poly-
morphs/mm3 in patients with stroke is said to suggest
endocarditis; however, as high or higher counts have
been described in primary intracerebral hemorrhage and
in hemorrhagic transformation of an infarct, but not in
cerebral infarction.
• Cerebral angiography to detect unruptured (mycotic)
aneurysms with a view to surgery is unnecessary, as these
aneurysms do not always rupture and tend to resolve
with time.
DIAGNOSIS
Fever, cardiac murmur, positive blood cultures and
vegetations seen on echocardiography, but these features are
not invariable. For the Duke criteria, see Heiro et al.,
(1998), Table 3, Mylonakis and Calderwood (2001),
Further reading, p.271.
TREATMENT
Medical
• Question the patient closely for a history of penicillin
‘allergy’.
• Antimicrobial chemotherapy with sustained levels of
bactericidal drugs (preferably synergistic) administered
via a central intravenous line (see Table 30).
• Because antibiotics may penetrate vegetations poorly,
prolonged treatment is required to ensure eradication
and prevent relapse.
 Infective Endocarditis 217

Table 30 Therapy for infective encarditis (also see Table 4, Mylonakis and Calderwood [2001])

Organism First line therapy Duration Alternative therapy

Streptococcus Penicillin G, 10–20 mU/day (benzylpenicillin 1.8 g 4 hourly) 4 weeks Ceftriaxone, vancomycin
viridans plus gentamicin, 3 mg/kg/day (1 mg/kg 8 hourly) 2 weeks Streptomycin
(maximum 240 mg)
Enterococci Penicillin G, 20–30 mU/day (benzylpenicillin 1.8–2.4 g 4 hourly) 6 weeks Ampicillin, vancomycin
plus gentamicin, 3 mg/kg/day (1 mg/kg 8 hourly) 4–6 weeks
(maximum 240 mg)
Staphylococcus Flucloxacillin, 12 g/day i.v. (2 g 4 hourly) 6 weeks Nafcillin, vancomycin (1 g 12 hourly)
aureus plus gentamicin, 3 mg/kg/day 3–5 days Fusidic acid
(maximum 240 mg)
Organism not identified Empirical therapy Duration Alternative therapy
Native valve Penicillin G (1 g 4 hourly) plus gentamicin (4–6 mg/kg daily) Until organism identified Ampicillin plus gentamicin
plus flucloxacillin (2 g 4 hourly)
Prosthetic valve Vancomycin (1 g 12 hourly) plus gentamicin (4–6 mg/kg daily)
Culture negative Penicillin G 6 weeks
plus gentamicin 2 weeks
(i.e. as for enterococci unless Q fever or fungus suspected)

244 245

244 Linear splinter hemorrhages under the nails, which can be difficult 245 Pulps of the fingers showing erythematous maculopapular lesions
to differentiate from traumatic lesions. (Janeway’s spots) which were non-tender.

• Close collaboration with the microbiology laboratory to 246

assess antibiotic sensitivities, including minimum inhibitory
concentrations and minimum bactericidal concentrations.
• Peak and serum levels of aminoglycosides must be
monitored.
• Anticoagulation is not advised for native valve infective
endocarditis because of the increased risk of intracranial 2
hemorrhage. If anticoagulation is required during
prosthetic valve infective endocarditis, close monitoring
of coagulation times is required.
• Fungal infection seldom responds to antifungal agents
(e.g. amphotericin B), and early surgery is often required. 1

246 Transthoracic 2D echocardiograph, parasternal long axis view,

showing vegetations (arrow) on the anterior leaflet of the mitral valve,
which is situated behind the aortic valve.This image is taken during
diastole when the mitral valve is open and the aortic valve closed. 1: left atrium; 2: left ventricle. (Reproduced with permission from Hankey GJ,
Warlow CP [1994] Transient Ischaemic Attacks of the Brain and Eye, WB Saunders, London.)
218 Vascular Diseases of the Nervous System
Surgery
Required in up to one-quarter of patients (247, 248),
particularly prosthetic valve infective endocarditis.
Indications
• Fever persisting after 2 weeks of antimicrobial therapy:
suggests antimicrobial failure, intracardiac abscess
formation, embolization, or other complications.
• Valve dysfunction.
• Arrhythmias.
• Refractory heart failure.
Surgical repair of any asymptomatic mycotic aneurysm,
which may be found after a ruptured aneurysm has been
repaired, is unnecessary because these aneurysms do not
always rupture and tend to resolve with time.
Prevention of bacterial infective endocarditis
Antibiotic prophylaxis before undergoing procedures
associated with bacteremia is indicated for adults with
conditions predisposing to infective endocarditis (see Risk
factors, p215, and Table 31).
PROGNOSIS
• Untreated: recovery is rare.
• Appropriate antibiotic treatment: >70% survival for
endogenous valve infection and >50% survival for
prosthetic valve infection.
• Poor prognostic factors: congestive heart failure, extreme
age, aortic valve or multiple valve involvement, prosthetic
valve involvement, Gram negative bacillus, fungal or
polymicrobial bacteremia, failure to identify the
infectious agent due to negative blood cultures,
antimicrobial resistance to antibiotics, and delay in
initiating therapy.
247
247, 248 Vegetations consisting of platelets, fibrin and colonizing micro-organisms removed surgically from an infected heart valve.
ANTIPHOSPHOLIPID SYNDROME
AND OTHER PROTHROMBOTIC
STATES (THROMBOPHILIAS)
Disorders of the blood that predispose to recurrent venous
and possibly arterial thrombosis.
ANTIPHOSPHOLIPID SYNDROME
DEFINITION
A heterogeneous disorder, both in terms of its clinical
manifestations and range of autoantibodies, which is
characterized by thrombosis (venous or arterial), recurrent
miscarriage, or both, in association with persistent positive
laboratory tests for antiphospholipid antibody: lupus
anticoagulant (LA), anticardiolipin antibody (ACA), or
both, on repeated studies. Thrombocytopenia is an
occasional feature.
Antiphospholipid antibodies (APAs)
• APA are a family of antibodies which are specific for
several plasma proteins, such as human prothrombin and
β2 glycoprotein (β2 GPI), which may bind to
phospholipid (PL) surfaces.
• LA and ACA are different APAs but occur together in
about 60% of patients with the phospholipid antibody
syndrome; in the remaining 40%, only one is present.
• LAs are immunoglobulins (IgG, IgM, IgA, or mixtures)
which interfere with one or more of the in vitro
phospholipid-dependent tests of coagulation (e.g.
activated partial thromboplastin time [APTT], dilute
Russell viper venom time [dRVVT], dilute prothrombin
time [dPT], and kaolin clotting time [KCT]). They
therefore slow the rate of thrombin generation and
therefore clot formation in vitro.
• ACAs are detected by immunoassay, most commonly
enzyme-linked immunosorbent assay.
248
 Antiphospholipid Syndrome and Other Prothrombotic States (Thrombophilias) 219

EPIDEMIOLOGY
• Prevalence: 1–40% or so of ischemic stroke/TIA patients
have raised circulating IgG or IgM anticardiolipin
antibodies and/or the lupus anticoagulant, depending
on the selection of patients, the timing of the blood
sample after the onset of cerebral ischemia, the
laboratory methods, and what level is deemed ‘normal’.
However, only a few of these patients have some or all of
the constellation of features known as the APA
syndrome.
• Age: any age.
• Gender: F>M.
PATHOLOGY
Thrombi are typically ‘bland’ and may be found in vessels
of any size and on heart valves, such as the mitral valve
leaflets. There is no evidence of inflammation of the vascular
wall.
PATHOPHYSIOLOGY OF THROMBOSIS (see
Atherosclerotic ischemic stroke, p.204)
The paradoxical association between the presence of auto-
antibodies with in vitro anticoagulant effects and the
occurrence of a prothrombotic state is not fully understood.
Patients with antiphospholipid syndrome have evidence of
persistent coagulation activation (increased plasma concen-
tration of markers of thrombin generation such as
fibrinopeptide A) and, as stated above, vascular occlusion is
due to thromboembolism or embolization from sterile
vegetations on heart valves, and not vasculitis.
It is unlikely that a single prothrombotic mechanism
operates. Possible mechanisms include:
• Perturbation of the protein C system: the most likely
cause of venous thrombosis: APAs interfere with activated
protein C down-regulation of factors Va and VIIIa,
resulting in an acquired activated protein C resistance.
• Alteration of the antithrombin III heparin sulfate down-
regulation of serine proteases: some APAs have specificity
for heparin sulfate found on the surface of endothelial
cells.
• Up-regulation of tissue factor expression by endothelial
cells.
ETIOLOGY
Primary
No evidence of other underlying disease.
Secondary
• Associated with rheumatic and connective tissue
disorders: systemic lupus erythematosus (SLE): about
30–40% of patients with SLE have LA; rheumatoid
arthritis; systemic sclerosis; temporal arteritis; Sjögren’s
syndrome; psoriatic arthropathy; Behçet’s syndrome;
others.
• Associated with other conditions:
– Infections: viral (e.g. HIV-1, varicella, hepatitis C);
bacterial (e.g. syphilis); parasitic (e.g. malaria).
– Drug exposure: chlorpromazine; hydralazine; quinidine;
quinine; antibiotics; phenytoin; valproate; procainamide.
– Lymphoproliferative diseases; malignant lymphoma;
paraproteinemia.
– Miscellaneous conditions: autoimmune thrombo-
cytopenia; autoimmune hemolytic anemia; sickle-cell
disease; intravenous drug abuse; livedo reticularis;
Guillain–Barré syndrome.
CLINICAL FEATURES
Any vascular site can be affected so there is a wide range of
clinical manifestations:
Dermatologic
• Sneddon’s syndrome: livedo reticularis (249), stroke-like
episodes and hypertension.
• Non-healing ulceration of the ankles and skin necrosis.
249

In some cases the APAs may represent an

epiphenomenon.

249 Livedo reticularis in a patient with antiphospholipid antibody

syndrome.

Table 31 Prophylaxis for infective endocarditis

Procedure
Dental (local anesthetic)
Adults with: prosthetic valve,
past infective endocarditis,
high-risk procedure
(e.g. genito-urinary)
Standard prophylaxis
Amoxycillin (amoxicillin), 3 g p.o. 1 hour
before, then amoxycillin, 1.5 g p.o. 6 hours later
Amoxycillin (amoxicillin), 1 g i.v. 30 min before,
plus gentamicin, 120 mg iv 30 min before
then amoxycillin, 500 mg p.o. 6 hours later
Penicillin allergy or penicillin given in last month
Clindamycin or erythromycin
Vancomycin 1g i.v. 100 min before,
plus gentamicin 120 mg i.v. 30 min before
220 Vascular Diseases of the Nervous System
Neurologic
• TIA, stroke, or multifocal encephalopathy due to arterial
or venous thrombosis in any sized vessel (250–254).
Venous thromboembolic events account for about 70%
of cases and arterial events the remaining 30%. The most
common site for arterial thrombi is the cerebral
circulation.
• Migraine-like headaches.
Obstetric
• Recurrent spontaneous miscarriage/fetal loss due to
intrauterine death in the latter part of the first trimester
or early second trimester.
• Intrauterine foetal growth retardation.
• Early-onset pre-eclampsia.
• Prematurity.
Pediatric
Post-infectious (e.g. varicella) thromboembolic events.
INVESTIGATIONS FOR ANTIPHOSPHOLIPID
SYNDROME OR ANY OTHER SUSPECTED
PROCOAGULANT STATE (THROMBOPHILIA)
Indications
• Young (<50 years) and no other cause found for TIA or
ischemic stroke.
• Past history or family history of premature arterial or
venous thrombosis, especially if unusual sites (cerebral,
mesenteric, hepatic veins).
• Past history of recurrent miscarriages.
• Abnormal full blood picture or blood film (e.g.
thrombocytopenia).
• VDRL/RPR positive: may be a false positive in the
presence of ACAs because cardiolipin is the antigen used
in the VDRL assay. However, the VDRL is positive in
only about 25% of patients with APLAb.
Thrombophilia diagnostic tests
• Full blood count and film.
• ESR.
• Prothrombin time.
Coagulation assays for lupus anticoagulant (LA)
• Activated partial thromboplastin time (APTT): lacks
sensitivity but remains the most appropriate screening
test for the LA. A prolonged APTT that fails to correct
when affected plasma is mixed with normal plasma
implies inhibition of the clotting system rather than
deficiency of a component, and is the laboratory hallmark
of LA.
• Dilute Russell’s viper venom time (dRVVT):
prolongation of the dRVVT will not correct with the
addition of normal plasma in the presence of LA (in
contrast to the clotting factor deficiency). For
confirmation, a platelet neutralization procedure, to
show the dependence of phospholipid inhibitors, should
be performed.
• Kaolin clotting time test: also detects LA, but it is not as
sensitive as the dRVVT, and sensitivity is highly reagent
dependent.
• Tissue thromboplastin inhibition test.
These are indirect coagulation assays sensitive to the
phospholipid-dependent steps of blood coagulation. At least
two assays, with sensitive reagents and techniques must be
used, most commonly the APTT with another test.
Immunologic assays
• Anticardiolipin antibody (ACA): detected by means of
solid-phase immunoassay, such as enzyme-linked
immunosorbent assay (ELISA) or radio immunoassay
(RIA), employing cardiolipin or other negatively charged
phospholipids as the antigen to measure antibody
concentration and binding avidity.
• Other phospholipids, e.g. phosphatidyl serine.
• Antibodies to β2 GPI .
Other thrombophilia diagnostic blood tests
• Antithrombin activity. (N.B. heparin reduces
antithrombin antigen and activity by 10–15%.)
• Protein C activity. (N.B. Warfarin reduces protein C and
protein S levels by 30%. These tests must be conducted
prior to, or at least 2 weeks after, cessation of warfarin.)
• Protein S antigen level.
• Factor V Leiden genetic analysis or activated protein C
resistance functional analysis.
• Prothrombin G20210A mutation.
• Antinuclear antibodies.
• Serum protein levels, serum protein electrophoresis and
plasma viscosity: indicated in patients with elevated ESR
or suspected hyperviscosity syndrome.
• Hemoglobin electrophoresis/sickle test: indicated in
appropriate racial groups (i.e. black patients) to detect
sickle cell trait or disease.
• Fibrinogen.
• Platelet aggregation.
• Fasting plasma homocysteine (before and after a
methionine load if possible).
250
250 Ocular fundus photograph showing engorged retinal veins and
multiple retinal hemorrhages due to a central retinal vein occlusion.
(Courtesy of Mr M Wade, Department of Medical Illustrations, Royal
Perth Hospital, Australia.)
 Antiphospholipid Syndrome and Other Prothrombotic States (Thrombophilias) 221

DIAGNOSIS Lupus anticoagulant (LA)

Thrombophilia
The diagnosis is usually established from routine first line
investigations (full blood count, platelet count and ESR)
and standard thrombophilia screening and diagnostic tests.
Antiphospholipid antibody syndrome
Cannot be diagnosed on the basis of a single raised titer of
ACA in the serum. The titer must be substantially raised on
several occasions and associated with not just cerebral
ischemia but also with some combination of deep venous
thrombosis, recurrent miscarriage, livedo reticularis, cardiac
valvular vegetations, thrombocytopenia and migraine.
Four sequential steps are necessary to establish the diagnosis
of LA:
1 Demonstration of an abnormal phosoholipid- (PL)
dependent coagulation test (e.g. APTT, dRVVT).
2 Proof that the abnormality in step 1 is due to an inhibitor
(synonym: anticoagulant).
3 Establishing the PL-dependence of the inhibitor.
4 Ruling out other coagulopathies.
Ischemic stroke due to a procoagulant state
It can be very difficult to attribute confidently the cause of
the ischemic stroke to the hematologic disorder if the
patient has other disease that could have caused the stroke.

251 CT brain scan showing 251 252

a triangular filling defect in the
venous sinus at the torcula
(arrow) after i.v. contrast
(‘empty delta’ sign) due to
venous sinus thrombosis.

252 MRI brain scan, proton

density weighted image,
showing hypointense (black)
flow voids in the middle and
posterior cerebral arteries
(arrowheads), and a
hyperintense (white) filling
defect (arrow) representing
loss of the flow void in the
venous sinus at the torcula
(due to the thrombus).

253 Proton density 253 254

weighted MRI of a right
thalamic infarct (arrow) at 24
hours in a young patient with
the antiphospholipid antibody
syndrome.

254 Same patient as in 253,

adjacent image shows high
signal in the right posterior
cerebral artery indicating that
it is occluded by fresh
thrombus (arrow).
222 Vascular Diseases of the Nervous System
More often than not, the hematologic disorder is one of
several factors predisposing to thrombus formation, such as
coexistent activated protein C resistance, or coexistent athero-
thrombosis, trauma or dehydration. Irrespective, the hema-
tologic disorder frequently needs treating in its own right.
TREATMENT
Uncertain; no controlled trials of aspirin, anticoagulants, or
immunosuppressive therapy have been undertaken.
Thromboembolic events
Long term anticoagulant therapy, INR: 2.5 (empirical,
controlled trials are needed), if risks considered to be
outweighed by benefits. Otherwise antiplatelet therapy.
Pregnancy
Heparin 24 000 units per day s.c. and aspirin 75 mg per day.
Low molecular weight heparin may cause less osteoporosis,
heparin-induced thrombocytopenia, and bleeding events
than standard heparin and does not require blood
monitoring.
PROGNOSIS
Uncertain, but limited studies suggest a high rate of
recurrent stroke and other vascular events in patients with
ischemic stroke and the antiphospholipid syndrome (hence
the empirical recommendation for long term anticoagu-
lation therapy).
OTHER PROCOAGULANT STATES
Quantitative abnormalities of formed blood
elements
Erythrocytes
• Polycythemia rubra vera (primary polycythemia):
– Hematocrit >0.50 in males and >0.47 in females,
provided the patient is rested, normally hydrated, and the
blood has been taken without venous occlusion.
– Raised red cell mass.
– Increased whole blood viscosity, raised platelet count,
and enhanced platelet activity, may cause TIAs, cerebral
infarction and intracranial venous thrombosis.
– Platelet function may also be defective, predisposing to
intracranial hemorrhage.
• Anemia (iron deficiency and presumably other types):
– If severe, usually causes non-specific neurologic
symptoms such as generalized weakness, poor
concentration and faintness but in the presence of severe
arterial disease, it may provoke focal cerebral ischemia.
Leukocytes
• Leukemia:
– May predispose to cerebral arterial or venous occlusion
because of increased whole blood viscosity.
– More commonly is associated with intracranial hemorr-
hage because of the hemostatic defect or CNS leukemic
infiltration. L-asparaginase (asparaginase) treatment for
leukemia can cause both cerebral ischemia and
hemorrhage.
• Malignant angioendotheliosis (intravascular lymphoma):
– Can present like a stroke but the neurologic involvement
soon becomes diffuse and progressive.
Platelets
• Essential thrombocythemia (idiopathic primary
thrombocytosis):
– Platelet count >500 × 109/l, causes arterial and venous
thrombosis.
– Headache with transient focal and non-focal neurologic
disturbances are the most common neurologic
symptoms.
– Occasionally, platelet function is defective predisposing
to bleeding.
– Other causes of thrombocytosis should be excluded:
malignancy, splenectomy or hyposplenism, surgery and
other trauma, hemorrhage, iron deficiency, infections,
polycythemia rubra vera, myelofibrosis and leukemia.
Qualitative abnormalities of formed blood elements
Erythrocytes
• Sickle cell (SC) disease:
– Ischemic stroke is common in homozygotic children and
young adults; intracranial hemorrhage may also occur
sometimes.
– Stroke is rare in heterozygotic adults, and usually in the
context of a hypoxia-provoked sickle-cell crisis.
– Small and large arteries, and veins, are occluded by
thrombi as a result of the rigid red blood cells, raised
whole blood viscosity, thrombocytosis, impaired
fibrinolytic activity, and arterial stenosis due to fibrous
proliferation of the intima; the last can be detected in the
MCA with transcranial doppler and is predictive of stroke.
• Hemoglobin SC disease:
– may also be complicated by stroke.
• Paroxysmal nocturnal hemoglobinuria:
– Very rare.
– Intracranial venous thrombosis is more common than
arterial thrombosis.
– Anemia, abdominal pain, recurrent deep venous
thrombosis, dark urine, hemolysis and a low platelet and
granulocyte count are recognized features.
Hyperviscosity
Paraproteinemias
• Waldenstrom’s macroglobulinemia, multiple myeloma
and perhaps cryoglobulinemia:
– Most commonly cause the ‘hyperviscosity syndrome’, a
global encephalopathy characterized by headache, ataxia,
diplopia, dysarthria, lethargy, poor concentration,
drowsiness and coma, visual blurring, and deafness. The
retina shows dilatation and tortuosity of the veins, venous
occlusions, papilledema and hemorrhages; similar
symptoms may also be due to uremia, hypercalcemia or
lymphoma complicating the paraproteinemia.
– Arterial or venous cerebral infarction may occur if vessels
become occluded by acidophilic material which are
probably precipitants of the abnormal plasma proteins.
– Intracranial hemorrhage also occurs due to the reduced
number and impaired reactivity of platelets, perhaps as a
result of uremia.
Coagulation disorders
Antithrombin III
• Inactivates thrombin and activated factors X, IX, XI, and
XII (but not VII).
 Antiphospholipid Syndrome and Other Prothrombotic States (Thrombophilias)
• An important mediator of the anticoagulant effect of
heparin; heparin increases the activity of antithrombin-
III by 100-fold. Indeed, heparin resistance is a clue to
low antithrombin-III activity.
• Deficiency may be inherited (as an autosomal dominant
trait with variable penetrance in about one in every
2000–5000 people), or acquired as a result of severe liver
disease (reduced synthesis), intravascular thrombosis
(consumption), the nephrotic syndrome (renal loss), or
use of medications such as L-asparaginase or the oral
contraceptive pill.
Protein C
• A vitamin K-dependent plasma protein that is synthesized
in the liver in an inactive form.
• When activated by thrombin in the presence of calcium,
it inhibits the procoagulant activity of factor Va and
factor VIIIa and inactivates plasminogen activator
inhibitor 1.
• Deficiency may be inherited as an autosomal dominant
trait, or acquired as a result of warfarin therapy or severe
liver disease (reduced synthesis), disseminated intra-
vascular coagulation and acute thrombosis. Accounts for
about 10% of cases of venous thrombosis.
• Resistance to activated protein C is commonly caused by
an autosomal dominant inherited mutation in the factor
V gene (substitution of glutamine for arginine-506),
which was discovered in Leiden, the Netherlands, in
1994; hence the inherited defect is called the Leiden
factor V mutation. Accounts for 15–50% of cases of
venous thrombosis.
Protein S
• A cofactor of protein C; free protein S increases the
affinity of protein C for phospholipid and enhances the
inactivation of factors Va and VIIIa by activated protein
C.
• Deficiency may be inherited as an autosomal dominant
trait, or acquired as a result of warfarin therapy, severe
liver disease (reduced synthesis), and the nephrotic
syndrome. Accounts for about 5% of cases of venous
thrombosis.
Hereditary deficiency of coagulation inhibitors (antithrombin
III, protein S, protein C), activated protein C resistance
(factor V Leiden mutation), and hereditary abnormalities
of fibrinolysis: plasminogen deficiency and/or abnormality
• Conditions in which spontaneous and recurrent venous
thrombosis (often in legs, occasionally in brain) and
rarely, arterial thrombosis are presenting or complicating
features.
• Usually familial (to make the diagnosis of familial
deficiency, family members must be tested).
• The relevance of low levels of these natural
anticoagulants in the etiology and prognosis (risk of
recurrent stroke) for many patients with ischemic stroke
of ‘no other cause’ is uncertain so the potential benefits
of any treatment are uncertain.
• Difficulties arise attributing the cause of the stroke to one
of these conditions:
– Familial deficiency of antithrombin III, protein C and
protein S are not uncommon in the general population
so the hypercoagulable state may be coincident and not
a sole or contributing cause of the stroke. Therefore, the
223
patient must be properly assessed and other potential
causes of ischemic stroke (e.g. arterial dissection,
paradoxical embolism from the venous system) must be
considered and excluded if possible.
– Low levels of these coagulation factors may be caused by
the acute stroke itself or its treatment (anticoagulants),
so the results must be confirmed by repeated testing on
several later occasions.
– Acute stroke is associated with activation of procoagulant
and fibrinolytic pathways, as manifest by a significant
decrease in functional antithrombin III and plasminogen
and an increase in thrombin–antithrombin complex, total
protein S, tissue plasminogen activator, plasminogen
activator inhibitor-1, and D-dimer.
Factor II (prothrombin) mutation (G20210A)
A mutation in the prothrombin gene (G20210A) results in
elevated prothrombin levels and carries a nearly threefold
increased risk of venous thrombosis, but does not appear to
be associated with an increased risk of arterial thrombosis
and ischemic stroke.
Immunologic disorders
Antiphospholipid syndrome (see p.218).
Prothrombotic states of uncertain cause
Thrombotic thrombocytopenic purpura (TTP)
• Rare.
• Microangiopathic hemolytic anemia, thrombocytopenia,
fever, and renal failure are characteristic.
• Platelet microthrombi cause infarcts in many organs,
including the brain.
• Neurologic symptoms in 90% of cases, and are the
presenting symptoms in 60%.
• Fluctuating encephalopathy (confusion, disorientation,
epileptic seizures, with or without focal features), rather
than a stroke syndrome, is the usual presentation.
• The patient is unwell with malaise, fever, skin purpura,
renal failure, proteinuria, hematuria, thrombocytopenia,
hemolytic anemia and fragmented red blood cells.
• Brain CT may be normal, or show infarcts, or
occasionally intracerebral hemorrhage, more commonly
due to heparin treatment than the disease itself.
• Non-convulsive status epilepticus is another treatable
cause of altered mental status in these patients.
Cancer
Laboratory abnormalities of coagulation or fibrinolysis are
commonly found, particularly in patients with metastases.
About 2% of patients with cancer have a TIA or stroke at
some stage.
Possible causes of ischemic stroke or TIA include:
• A coagulopathy mediated by intravascular mucinosis,
low-grade disseminated intravascular coagulation, or the
patient’s chemotherapy.
• Embolism of non-infected heart valve vegetations (non-
bacterial thrombotic, or marantic, endocarditis).
• Tumor or septic emboli, sometimes with aneurysm
formation.
• Sepsis (fungi, herpes zoster, infective endocarditis).
• Hemostatic failure (leukemia, thrombocytopenia, etc).
• Hyperviscosity syndrome (myeloma).
• Neoplastic compression or invasion of neck arteries.
• Irradiation of neck arteries.
224 Vascular Diseases of the Nervous System
Disseminated intravascular coagulation
• Manifests as an acute or subacute global encephalopathy,
rather than stroke-like episodes, in a very sick patient.
• CT brain scan reveals widespread hemorrhagic infarcts
and hemorrhages.
• Low platelet count, low plasma fibrinogen, raised fibrin
degradation products and raised D-dimer point to the
diagnosis.
Pregnancy and the puerperium
The relative risk of stroke in the pregnant woman is 13 times
the risk in the non-pregnant woman of the same age, but the
absolute risk of stroke in the last trimester of pregnancy and
the puerperium is no more than 30 per 100 000 deliveries
(i.e. about 1 in every 3000 deliveries). About three-quarters
of ischemic strokes are due to arterial occlusion and one-
quarter venous occlusion. Causes include:
• Paradoxical embolism from the venous system of the
pelvis or legs.
• Valvular heart disease.
• Cardiomyopathy of pregnancy.
• Arterial dissection during labor.
• Hematologic disorders.
Less commonly:
• Amniotic fluid embolism.
• Air or fat embolism.
• Metastatic choriocarcinoma.
Estrogens/oral contraceptives
• High estrogen dose oral contraceptive use is associated
with a threefold increased risk of TIAs and stroke. But
the absolute risk is very small.
• The risk is greater in women who are older, who smoke
and who have other vascular risk factors such as
hypertension.
• Exogenous high doses of estrogens given to elderly men
for treatment of prostatic cancer and male survivors of
MI increase their risk of vascular death.
Heparin-induced thrombocytopenia
Heparin may paradoxically lead to thrombus formation and
thrombocytopenia by two mechanisms:
• Type I consists of a transient decrease in platelet count
1–5 days after heparin is started and is thought to be due
to reversible clumping of platelets.
• Type II is a persistent depression of the platelet count
beginning 3–22 days after the introduction of heparin
which is thought to be mediated by IgG antibodies
against a heparin–platelet membrane complex.
Nephrotic syndrome
Can be complicated by ischemic stroke, perhaps due to
‘hypercoagulability’: loss of antithrombotic proteins in the
urine.
Desmopressin and intravenous immunoglobulin
May cause hypercoagulability and ischemic stroke, perhaps
by altering blood viscosity, hemorrheology, platelet
aggregability or clotting factor levels.
Snake bite
May cause ischemic stroke but is more likely to cause
defibrination and bleeding.
DISSECTION OF THE CAROTID AND
VERTEBRAL ARTERIES
DEFINITION
Tearing of the intima and/or media of arteries.
EPIDEMIOLOGY
• Incidence: symptomatic ICA dissection: >2.6 per 100 000;
probably higher as may cause transient minor symptoms
(or be asymptomatic). Vertebral artery dissection: 1–1.5
per 100 000 per year. One of the commonest causes of
stroke in young people, and 2% of all ischemic strokes.
• Age: any age; can occur in the very young.
• Gender: M=F.
PATHOLOGY
Tear in the intima or media, leading to bleeding within the
arterial wall, which tracks or dissects longitudinally and
circumferentially between the intima and media, or media
and adventitia of the arterial wall. The dissection can tear
through the intima allowing the partially coagulated
intramural blood to enter the lumen of the artery.
Site
Predominantly extracranial:
• Carotid dissections: the vast majority occur just above
the bifurcation of the common carotid artery into the
internal and external carotid arteries; common carotid
artery and intracranial carotid dissections are rare.
Multiple dissections in 25% of patients.
• Vertebrobasilar dissections: at the C2 level in more than
80% of cases, possibly reflecting increased susceptibility to
mechanical torsion and stretch at this location. Extracranial
dissections are commonly bilateral (60% of cases).
Complications
Pseudoaneurysms may form if the dissection spreads through
the media of the artery; intracranial dissections may rarely
present as a mass lesion or may rupture and present with sub-
arachnoid and intracerebral hemorrhage; extracranial pseudo-
aneurysms rarely rupture because the artery wall is much thicker.
ETIOLOGY AND PATHOPHYSIOLOGY
Spontaneous
Predisposing conditions
• Point mutation in one allele of the COL1A1 gene that
encodes the proα1(I) chains of type I procollagen,
resulting in substitution of alanine for glycine (G13A) in
about half of the α1(I) chains of type I collagen.
• Family history: 5% of cases.
• Genetic disorders of collagen.
• Marfan’s syndrome.
• Ehlers-Danlos syndrome types IV and VI.
• Cystic medial necrosis.
• Osteogenesis imperfecta.
• Pseudoxanthoma elasticum.
• Polycystic kidney disease.
• Fibromuscular dysplasia.
• Reticular fiber deficiency.
• Accumulation of mucopolysaccharides.
• Possibly atheromatous risk factors (hypertension,
diabetes, smoking, high cholesterol).
• Possibly hyperhomocystinemia.
 Dissection of the Carotid and Vertebral Arteries
Trauma
• Sports.
• Whiplash injury.
• Neck manipulation.
• Activities such as reversing the car or painting the ceiling.
• Iatrogenic: cerebral angiography.
Mechanisms of brain or ocular ischemia
• Occlusion of the dissected artery by the false lumen or
by superimposed thrombus.
• Embolism of thrombus that may have formed on the
intimal flap or in the wall.
Mechanisms of cranial nerve involvement
in ICA dissection
• Compression or stretching of the cranial nerve by the
expanded artery. This is likely for lower cranial nerves IX
to XII which lie close to the ICA below the jugular
foramen in the retrostyloid and posterior retroparotid
space and may be compressed or stretched by an
expanded or aneurysmal ICA. This is particularly so for
cranial nerves X and XII which have the longest anatomic
relationship to the ICA.
• Interruption of the blood supply to the cranial nerve via
the nutrient vessels, which are small (200–300 microns
in diameter) branches of the ICA. Mechanisms include
mechanical compromise by dissection, distal
embolization, or pressure gradient changes in collateral
supply (hemodynamic). There are three vascular systems
which play a significant role in nutrient supply to most
of the cranial nerves. Accepting that anatomic variations
are common, they basically involve:
– The inferolateral trunk: often arises from the ICA, and
supplies cranial nerves III, IV, VI, and the first division
of V.
– The middle meningeal system: derives from the external
carotid artery, and supplies the second and third division
of cranial nerve V, and also VII.
– The ascending pharyngeal system derives from the
external carotid artery and supplies cranial nerves IX
through to XII.
Mechanism of cervical spinal cord or root
disturbance in vertebrobasilar dissection
Dissection of the vertebral arteries, which lie very close to
the spinal roots, and from which arise the anterior spinal
artery, may lead to symptoms of a cervical radiculo-
myelopathy due to nerve ischemia or compression by
hematoma in vessel wall.
CLINICAL FEATURES
May be asymptomatic; a history of preceding trauma is
often present, although it may be trivial and may not be
relevant.
History
Any combination of the following symptoms, which may be
minor and transient or more persistent.
255 Horner’s syndrome (left, arrow) due to interruption of the
ascending postganglionic pupillodilator oculosympathetic fibers in the
wall of the left internal carotid artery by dissecting blood.
225
Carotid dissection
• Pain around the eye or frontal region, sometimes in the
neck, and sometimes generalized and non-specific, is
common and may be the only feature.
• Acute or delayed focal monocular or carotid territory
ischemic symptoms: ipsilateral visual loss; contralateral
hemisensori-motor deficit; difficulty speaking; onset of
ischemic symptoms usually within a few days of
dissection but can be as long as several weeks and even a
few months.
• Symptoms of single or multiple cranial nerve palsy: III,
IV, V,VI, VII,IX, X, XI, XII.
• Pulsatile tinnitus may occur.
• Dysgeusia (impaired taste sensation due to VII nerve
[chorda tympani] palsy) may occur.
Vertebrobasilar dissection
• Pain.
• Focal vertebrobasilar ischemic symptoms:
occipital/temporal lobe, brainstem, cerebellum; most
commonly a lateral medullary or cerebellar infarct.
• Upper limb peripheral motor deficits: bilateral distal
upper limb amyotrophy.
Examination
Carotid dissection
• Focal monocular or carotid territory ischemic symptoms.
• Oculosympathetic palsy (Horner’s syndrome) ipsilaterally
(255).
• Cranial nerve palsy (single or multiple): III, IV, V, VI,
VII, IX, X, XI, XII, in at least 10% of patients with
extracranial ICA dissection; may occur without
symptoms of carotid ischemia.
• Neck bruit.
Vertebrobasilar dissection
• Focal vertebrobasilar territory ischemic symptoms.
• Cervical radiculomyelopathy.
DIFFERENTIAL DIAGNOSIS
Carotid dissection
Brainstem stroke: the combination of unilateral Horner’s
syndrome and lower cranial nerve palsies with contralateral
hemisensori-motor deficit may be due to brainstem
dysfunction and draw attention to the vertebrobasilar
circulation but may also be a ‘false localizing sign’ of a
unilateral extracranial carotid artery dissection. A history of
neck trauma, and pain and a bruit over the carotid artery
may be a clue to the diagnosis of carotid dissection.
255
226 Vascular Diseases of the Nervous System

Vertebrobasilar dissection 256

• Migraine: visual symptoms and headache due to
vertebrobasilar dissection.
• Transient global amnesia: may be presenting symptom
of dissection.
• Cervical radiculopathy.

INVESTIGATIONS
Doppler/duplex ultrasound scan (2 256)
Scans most commonly show very poor flow in the artery
giving a ‘to and fro’ high resistance signal. The appearance
may suggest a stenosed or occluded ICA or CCA with a
smooth outline. Occasionally the line of the dissection and
a double lumen can be imaged. Vertebrobasilar ultrasound
is more difficult technically and not as reliable.

MRI brain and neck

T1 images through the narrowed segment of the artery may
show a narrowed arterial lumen (as a narrower flow void) 256 Color doppler ultrasound of a localized internal carotid dissection
with a rim of high signal which is the thrombus in the with a small intimal flap (arrows).
arterial wall (257). Intramural hemorrhage is almost
pathognomonic of dissection and differentiates dissection
from vasospasm in patients with subarachnoid hemorrhage. 257
Magnetic resonance angiography (MRA)
MRA may show a stenosed or occluded ICA or CCA, or
tapering of the lumen at the dissection.

CT scan
CT may image the dissected artery but experience is limited.

Contrast intra-arterial angiography

(the gold standard)
This is often not required if duplex and MR scanning are
available.
Carotid dissection may show as a smoothly stenosed ICA
or CCA with a double lumen or intimal flap (258), or a
smooth tapering occlusion. The ‘string sign’ is due to
hematoma in the wall of the artery compressing the normal
lumen to a ‘fine thread’. Sometimes the artery is completely
occluded but the occlusive stump often has a tapered shape,
suggestive of dissection. Other angiographic findings
include intraluminal clot, intimal flaps, pseudoaneurysm
formation (usually at the base of the skull), and evidence of
distal emboli obstructing smaller intracranial arteries (259). 258 257 PDW axial MRI of the
Vertebrobasilar dissection has more variable findings; the skull base showing the carotid
string sign is less consistent and there may just be an area of canals.There is a ring of high
localized narrowing, which may be difficult to differentiate signal around the left internal
from ‘spasm’ in patients who have presented with carotid artery (arrow) which is
subarachnoid hemorrhage. Other findings include suggestive of dissection (the
outpouchings, double lumens, and irregular areas of high signal is due to the
narrowing and dilatation. thrombus within the arterial
wall), though is not specific.
Skin biopsy and collagen analysis
• Point mutation in the α1(I) chain of type I collagen.
• Fibrillin defect that produces Marfan syndrome. 258 Intra-arterial angiogram
• COL3A1 gene defect (produces disorders of type III of a localized internal carotid
procollagen in Ehlers–Danlos syndrome type I, and dissection with a small intimal
associated with multiple arterial aneurysms). flap (arrows).
• Gene for lysyl hydroxylase (results in Ehlers–Danlos
syndrome type IV).
• PKD1 gene (results in polycystic kidney disease).
• Alpha1-antitrypsin.
 Central Nervous System Vasculitis 227

DIAGNOSIS CENTRAL NERVOUS

Appropriate clinical findings confirmed radiologically (with SYSTEM VASCULITIS
non-invasive doppler/duplex ultrasound and MRI/MRA,
or catheter angiography) or pathologically. Consider as a
diagnosis in all cases of young stroke, particularly if there is DEFINITION
no evidence of a source of embolism in the heart, and in the A heterogeneous group of disorders characterized by
elderly if there is no evidence of atheroma or its risk factors. histologic evidence of inflammation, and often necrosis, of
blood vessels and clinico-pathologic evidence of brain
TREATMENT ischemia or, less commonly, hemorrhage.
Uncertain as there have been no large, randomized trials:
• If symptomatic extracranial carotid dissection causing EPIDEMIOLOGY
carotid territory transient ischemic attack or mild • Incidence: rare.
ischemic stroke: immediate antithrombotic therapy with • Age: any age.
antiplatelet agent or anticoagulation (INR: 2.0–3.0) for • Gender: either sex.
4 weeks–6 months.
• If major ischemic stroke or intracranial carotid or CLASSIFICATION
vertebrobasilar dissection: no antithrombotic treatment Large arteries (aorta and its primary branches)
in view of the risk of secondary intracranial hemorrhage Takayasu’s arteritis.
and the patient has little to lose from a further ischemic
event in that arterial territory. Large and medium-sized arteries
• Surgery: uncertain role; perhaps for intracranial dis- Giant cell (temporal) arteritis.
sections which present with subarachnoid hemorrhage.
• The management of pseudoaneurysm at the base of the Medium-sized and small muscular arteries
skull remains uncertain. Primary systemic necrotizing angiitides
• Polyarteritis nodosa.
PROGNOSIS • Allergic angiitis and granulomatosis of Churg–Strauss.
• Good recovery usually if the patient presents with • Polyangiitis overlap syndrome.
headache or Horner’s syndrome. • Wegener’s granulomatosis.
• The prognosis after focal ischemic events depends on the • Lymphomatoid granulomatosis.
severity of the neurologic deficit.
• Dissections may heal in days to weeks; arterial stenosis Angiitis associated with other systemic diseases
often resolves and arterial occlusion sometimes • Sarcoidosis.
recanalizes. • Behçet’s disease.
• Pseudoaneurysms usually remain. • Relapsing polychondritis.
• Recurrent arterial dissection rate: about 1% per annum; • Inflammatory bowel disease.
about six (2–18) times greater if there is a family history • Kohlmeier–Degos disease.
of arterial dissection.
Hypersensitivity angiitis associated with connective tissue
disease
• Systemic lupus erythematosus.
259 • Mixed connective tissue disease.
• Sneddon’s syndrome.
• Rheumatoid arthritis.
• Sjögren’s syndrome.
• Scleroderma.

Primary isolated angiitis of the CNS

Isolated granulomatous angiitis of the CNS.

Other angiitis syndromes

• Eales’ disease.
• Radiation angiitis.

259 Intra-arterial DSA of an internal carotid dissection (arrow)

following a road accident. Note the occluded middle cerebral artery
(arrowhead) due to distal embolization.
228 Vascular Diseases of the Nervous System
Small vessels (arterioles, capillaries, venules)
Hypersensitivity angiitis
• Exogenous stimuli proved or suspected:
– Drug-induced angiitides.
– Henoch–Schönlein purpura.
– Serum sickness and serum sickness-like reactions.
– Angiitis associated with infectious diseases.
• Endogenous antigens likely to be involved:
– Angiitis associated with neoplasms (particularly lymphoid
malignancies).
– Angiitis associated with other underlying diseases.
– Angiitis associated with congenital deficiencies of the
complement system (hypocomplementemic angiitis).
• Mixed cryoglobulinemia.
• Cutaneous angiitides.
PATHOLOGY
Acute, subacute or chronic inflammation in the arterial
and/or venous wall with or without granuloma formation
and necrosis (260).
Vascular lesions
Granulomatous angiitis
A distinctive chronic inflammatory reaction of blood vessels
characterized by a predominance of modified macrophages
(i.e. epithelioid cells) which are aggregated into nodular
clumps referred to as granulomas and which respond to
foreign bodies by coalescing to form giant cells that often
conglomerate around the foreign body.
Necrotizing angiitis
Inflammation and necrosis (usually fibrinoid necrosis) of
vessel walls.
Brain lesions
• Focal or multi-focal cerebral infarction.
• Intracerebral hemorrhage.
• Subarachnoid hemorrhage.
ETIOLOGY
A primary manifestation of disease or a secondary
component of another disorder such as connective tissue
disease, drug abuse, neoplasia or infection (see
Classification, above).
PATHOGENESIS
Immunopathogenic
• In situ formation or deposition of immune complexes in
blood vessel wall leading to activation of the
complement-mediated inflammatory response.
• Direct antibody-mediated damage via antibodies directed
at endothelial cells or other tissue components.
• Antibody-dependent cellular cytotoxicity directed against
blood vessels.
• Cytotoxic T lymphocytes directed at blood vessel
components.
• Granuloma formation in blood vessel wall or adjacent to
blood vessel.
• Cytokine-induced (i.e. interleukin 1, TNF-alpha)
expression of adhesion vehicles for leukocytes on
endothelial cells.
Non-immunopathogenic
• Infiltration of blood vessel wall or surrounding tissue by
microbiologic agents.
• Direct invasion of blood vessel by neoplastic cells.
• Unidentified mechanisms.
Mechanisms of tissue dysfunction
• Angiitis (causing ischemia or hemorrhage).
• Coagulopathy (cf. antiphospholipid syndrome, p.218).
• Emboli (cf. non-bacterial thrombotic endocarditis, p.216).
• Compression from granulomas.
• Antineuronal antibody effects.
CLINICAL FEATURES
• Variable in onset, nature and duration.
• Features are determined partly by the size and location
of the involved vessel(s).
• Most commonly vasculitis presents as an acute or
subacute focal or diffuse encephalopathy or meningo-
encephalopathy with headache, altered mentation,
seizures and cognitive and behavioral abnormalities, with
multifocal neurologic signs.
• Less commonly, patients present with a multiple sclerosis-
like picture (i.e. relapsing and spontaneously remitting focal
neurologic dysfunction), features of a rapidly progressive
space-occupying lesion, multiple cranial neuropathies (e.g.
Wegener’s granulomatosis) and rarely, with a spinal cord
syndrome, extrapyramidal syndrome or stroke syndrome.
• Systemic symptoms and signs may be present such as
fever, headache, malaise, weight loss, joint aches and
pains, facial rash, livido reticularis.
CLINICAL HISTORY
Demographic data
• Age: young: Takayasu’s arteritis, SLE; older: GCA.
• Gender: F: Takayasu’s arteritis.
• Race: oriental: Takayasu’s arteritis.
Symptoms
• Headache: GCA.
• Scalp, face, temporal pain: GCA.
• Blindness: GCA, WG.
• Diplopia: WG.
• Syncope: Takayasu’s arteritis.
• Jaw/tongue claudication: GCA, Takayasu’s arteritis.
• Arm claudication: Takayasu’s arteritis.
• Sinus pain and drainage, nasal discharge: WG.
• Oral ulcers: SLE, Behçet’s disease.
• Dry eyes, dry mouth: SS.
• Anxiety, depression: SLE.
• Fever, headache, malaise, fatigue, weight loss, arthralgia,
sweats: non-specific.
• Skin rash: PAN, AAG, LG, sarcoid, Behçet’s disease,
SLE, Sneddon’s, hypersensitivity.
• Malar rash: SLE.
• Photosensitivity: SLE.
• Joint aches and pains (arthritis): SLE, RA.
• Stiffness/aches/pains in neck, shoulders, lower back,
hips and legs (polymyalgia): GCA.
• Chest pain (pleurisy, pericarditis): SLE, LG, Behçet’s.
• Asthma: AAG.
• Cough, shortness of breath: LG, sarcoid, Behçet’s.
• Abdominal pain: PAN, inflammatory bowel disease,
Kohlmeier–Degos disease.
 Central Nervous System Vasculitis 229

Past history • Chondritis (auricular, nasal, laryngo-tracheal): relapsing

• Allergy: AAG. polychondritis.
• Deep vein thrombosis/pulmonary emboli: SLE, APLAb, • Altered mental state, dementia, psychosis: SLE.
Behçet’s. • Blindness or altitudinal visual field defect: GCA.
• Recurrent spontaneous abortions: SLE, APLAb. • Uveitis: sarcoid, Behçet’s disease.
• Epileptic seizures: SLE. • Optic nerve head swelling (262)/pallor/hemorrhage:
• Anemia: non-specific. GCA.
• Thrombocytopenia: SLE, APLAb. • Retinal periphlebitis, hard exudates: sarcoid.
• (False) positive VDRL: APLAb. • Retinal vein occlusion: Behçet’s disease.
• Infection with toxoplasma, aspergillus, varicella-zoster, • Mononeuritis multiplex: PAN, AAG,WG, LG.
cytomegalovirus, herpes simplex virus, HIV: infectious • Temporal artery tenderness, thickening, nodularity: GCA.
arteritis. • Absent peripheral pulses: TA.
• Illicit drug abuse: amphetamine, cocaine: drug-induced • Carotid/chest bruit: TA.
arteritis. • Hypertension: TA, PAN.
• Blood pressure difficult to record or different between
Family history the arms: TA.
• Collagen vascular diseases or angiitides. • Aortic regurgitation: TA.
• Multiple spontaneous abortions: APLAb. • Pleuritic or pericardial friction rub: SLE.
• Deep venous thrombosis or pulmonary emboli: APLAb. • Chest crackles/wheeze: AAG, LG, SLE.
• Neonatal heart block in patient’s child (woman). • Arthritis: sarcoid, SLE, RA.

PHYSICAL EXAMINATION
• Malar rash: SLE.
• Skin nodules, purpura: AAG, LG, sarcoid, Abbreviations: TA:Takayasu’s arteritis; GCA: giant cell arteritis;
Kohlmeier–Degos disease, hypersensitivity. PAN: polyarteritis nodosa;AAG: allergic angiitis and
• Skin macules, papules, plaque: LG, Sneddon’s syndrome. granulomatosis of Churg–Strauss;WG:Wegener’s
• Skin infarcts (261). granulomatosis; LG: lymphomatoid granulomatosis;
• Skin fibrosis: scleroderma. SLE: systemic lupus erythematosus; RA: rheumatoid arthritis;
• Oral ulcers: SLE, Behçet’s disease. APLAb: antiphospholipid antibody syndrome; MCTD: mixed
• Ischemic necrosis of lips, palate, nasal septum: TA, WG. connective tissue disease; SS: Sjögrens syndrome
• Sinus inflammation/nasal mucosal ulceration: WG.

260 261

260 Histologic section of basal meninges showing infiltration with 262

mononuclear cells and multinucleate giant cells (arrows) in a patient
with infective arteritis of the CNS due to tuberculosis.

261 Vasculitic infarcts of the skin in a patient with polyarteritis nodosa.

262 Ocular fundus of a patient with a left optic neuropathy due to

sarcoidosis showing a swollen, congested optic disc with peripapillary
hemorrhages (papillitis).
230 Vascular Diseases of the Nervous System

DIFFERENTIAL DIAGNOSIS Causes of segmental narrowing of cerebral arteries on

Non-vascular disorders cerebral angiography
• Dementias. • Arteritis (non-infective, infective).
• Meningo-encephalitides. • Arterial dissection.
• Multiple sclerosis. • Vasospasm (drugs, subarachnoid hemorrhage, severe
hypertension, ?migraine).
Cardiac disorders • Arteriosclerosis.
• Non-bacterial thrombotic endocarditis. • Fibromuscular dysplasia.
• Cardiac tumor. • Moyamoya disease.
• Radiation.
Hematologic disorders • Leptomeningitis (infective, carcinomatous, chemical).
• Coagulopathies (paraproteinemia, thrombotic thrombo- • Multiple emboli/recanalizing embolism.
cytopenic purpura). • Intracerebral hematoma.
• Antiphospholipid antibody syndrome. • Sickle cell disease.
• Neoplasia (vascular, malignant angioendotheliosis,
Angiopathies (non-inflammatory) meningeal, glial, metastatic: atrial myxoma).
• Isolated angiopathy of the CNS. • Trauma: closed head injury.
• Arterial dissection. • Surgical manipulation.
• Vasoconstriction or due to drug use (methamphetamine • Neuroectodermal dysplasia.
or cocaine).
• Cholesterol embolization syndrome. Systemic inflammation
• Malignant angioendotheliomatosis (intravascular • Full blood count*:
lymphomatosis). – Anemia: TA, GCA, PAN, WG, SLE.
• Neurofibromatosis. – Neutrophilia: PAN, WG.
• Atherosclerosis. – Lymphocytopenia: LG, SLE.
• Fibromuscular dysplasia. – Eosinophilia: AAG, hypersensitivity.
• Moyamoya disease. – Thrombocytosis: GCA, PAN.
• Angiitis (see Classification above). – Thrombocytopenia: SLE, APLAb.
• ESR*: TA, GCA, PAN, WG, hypersensitivity.
INVESTIGATIONS • C-reactive protein*.
MRI brain* • Immunoglobulins A, G, M, E*:
For imaging brain parenchymal lesions. It may show: – Hypergammaglobulinemia: TA, WG, SLE, hypersensitivity.
• Normal brain. – Hypogammaglobulinemia: PAN.
• Areas of increased signal on T2 and PDW images typically • Complement C3, C4, C9*:
in peripheral white matter and gray matter (unlike MS – Hypocomplementemia: SLE, hypersensitivity.
where the corpus callosum is typically affected [263]). • Circulating immunocomplexes (Raji test).
There may be evidence of hemorrhage in these lesions.
Underlying connective tissue disease
Cranial CT scan may be normal or show single or Nucleic acids
multiple non-enhancing areas of low density, which may • Antinuclear antibodies*: SLE (sensitivity 95%, specificity
involve both cerebral gray and white matter. low).

Intra-arterial angiography* DNA

For imaging arterial lesions: • ds DNA: SLE (sensitivity 50–70%, specific).
• May show areas of alternate narrowing and dilatation of
intracranial arterial branches (‘beading’) (264), or areas Ribonucleoproteins
of extracranial arterial occlusion (e.g. Takayasu’s arteritis) • U1 ribonucleoprotein (RNP)*: MCTD, SLE, SS
(265). (sensitivity high, specificity low).
• In primary angiitis of the brain the small intracranial • Sm*: SLE (sensitivity 5–30%, specific).
arteries and arterioles are involved, whereas in vasculitis • Ro (SS-A)*: SS/SLE overlap (high sensitivity and
complicating meningitis, tumors or other causes the specificity for SS).
major basal intracranial arteries may be involved. • La (SS-B)*: SS/SLE overlap (high sensitivity and
However, the angiogram may be normal even in biopsy- specificity for SS).
proven vasculitis, particularly if the affected vessels are
<500 microns in diameter and too small to be seen, so DNA binding proteins
biopsy is strongly recommended (see below). • Histones: drug induced SLE.
• Magnetic resonance angiography (MRA) is not reliable • Ku: sclerodactyly.
enough to confirm or exclude vasculitis; it is too prone • PCNA: severe SLE.
to flow-related artefacts and shows insufficient detail to
image the peripheral small arteries satisfactorily. Spiral CT Cell membrane antigens
has not been widely evaluated. • Cardiolipin: APLAb, SLE (sensitivity 20–30%, specificity
low).
 Central Nervous System Vasculitis 231

Other 263
• IgM rheumatoid factor-latex fixation test*: RA
(sensitivity 80%, specificity low).
• Antineutrophil cytoplasm antibodies*: WG (sensitivity
and specificity 90%).

*Important tests.

Abbreviations: TA:Takayasu’s arteritis; GCA: giant cell arteritis;

PAN: polyarteritis nodosa;AAG: allergic angiitis and
granulomatosis of Churg–Strauss;WG:Wegener’s
granulomatosis; LG: lymphomatoid granulomatosis;
SLE: systemic lupus erythematosus; RA: rheumatoid arthritis;
APLAb: antiphospholipid antibody syndrome; MCTD: mixed
connective tissue disease; SS: Sjögrens syndrome 263 MRI (T2W image) shows areas of high signal at the gray-white
matter junction (arrows) in a patient with biopsy-proven primary
cerebral angiitis.

264 265

264 Intra-arterial angiogram shows dilatation and strictures of the

small peripheral branches of the middle and anterior cerebral arteries
(arrows). (Courtesy of Dr E Teasdale, Consultant Neuroradiologist,
Institute of Neurological Sciences, Southern General Hospital,
Glasgow, UK.)

265 An arch aortogram from a patient with Takayasu’s arteritis – note

the stricture of the left subclavian (arrow) and occlusion of the right
subclavian (arrowhead) arteries. (Courtesy of Dr A Reid, Consultant
Radiologist, Royal Infirmary, Glasgow, UK.)
232 Vascular Diseases of the Nervous System
Extent of visceral and other organ involvement
• Urine:
– Glomerular red cells: PAN, WG, LG, SLE.
– Casts*.
– Protein (if positive, 24-hour urine protein)*.
– Eosinophils.
• Creatinine: PAN, WG, LG, SLE.
• Liver function tests: transaminases*: GCA.
• Hepatitis B surface antigenemia: PAN.
• Chest x-ray* (infiltrates, nodules, cavities) (266, 267):
WG, LG, SLE, sarcoid.
• Gallium scan: sarcoid.
• Ophthalmologic examination using low dose fluorescein
angiography with slit-lamp video microscopy of the
anterior segment: slowing of flow, multifocal attenuation
of arterioles, erythrocyte aggregates, areas of small vessel
infarction, and multifocal segments of intense leakage
from post-capillary and collecting venules.
Underlying infection
• Antibodies against borreliosis*, salmonellosis, yersiniosis,
toxoplasmosis, aspergillus.
• Viral antibodies (including varicella-zoster virus,
cytomegalovirus, HIV, herpes simplex virus).
• Hepatitis screening.
• VDRL, TPHA.
• Cryoglobulins*.
• Paraproteins (serum protein electrophoresis)*.
• CSF*:
– Cell count, total protein, glucose, quantitative analysis of
immunoglobulins, oligoclonal band analysis.
– Moderate mononuclear CSF pleocytosis (usually
50–80 cells/mm3; but can be up to 800 cells/mm3).
– CSF protein usually elevated to around 1–1.5 g/l
(10–15 g/dl), but may be up to 5.8 g/l (58 g/dl).
– Xanthochromia, hypoglycorrhachia and an elevated CSF
gammaglobulin with oligoclonal banding of IgG have
been reported.
– The primary value of CSF studies is to exclude other
causes of a meningitis.
Associated coagulation abnormalities
• PT, APTT, dRVVT*: APLAb, SLE (35%).
• Anticardiolipin antibodies*: APLAb, SLE (35%).
Others
• Angiotensin converting enzyme: sarcoidosis.
• Lysozyme and beta2-microglobulin: sarcoidosis.
• Cell-mediated immunity (anergy): sarcoidosis, LG.
• Sinus x-ray/CT: WG.
• Echocardiography: atrial myxoma.
• EEG: frequently abnormal, showing generalized non-
specific slow wave activity of variable degree and location.
• Indium-labelled white-cell brain imaging: increased uptake
and accumulation in the brain of indium-labelled leukocytes.
Brain biopsy
• Cerebral or spinal cord biopsy establishes the diagnosis
in about 70% of cases.
• False-negative biopsies occur in about 30% of autopsy-
proven patients.
• The relatively low diagnostic yield from cortical biopsy
may be related to the segmental nature of the lesions and
the lack of leptomeningeal tissue in the biopsy.
• The risk of serious morbidity from brain biopsy is about
0.5–2.0%.
• The decision to biopsy is made on an individual basis; if
an extended period of treatment with potentially
hazardous immunosuppressant drugs is being
considered, then the need to establish an unequivocal
tissue diagnosis becomes of primary importance.
The results of blood and CSF laboratory tests, EEG,
brain imaging with CT and MRI, and cerebral angiography
are neither sensitive nor specific but are usually essential to
rule out infectious or malignant disease, which can mimic
CNS angiitis clinically.
DIAGNOSIS
The diagnosis is made histologically. A combined
leptomeningeal and wedge cortical tissue biopsy, preferably
of the temporal tip of the non-dominant hemisphere and
including a longitudinally-orientated surface vessel is
required. If organs other than the brain are affected, biopsy
specimens should be obtained.
TREATMENT
The decision to treat and how will depend on the clinical
condition and course of the patient and the philosophies of
the attending clinician. If the patient is well then time is
available to allow a period of observation of the natural
history of the disease. If the patient is very sick, however,
empirical immunosuppressive therapy, may be commenced
whilst awaiting biopsy confirmation (see below).
Once the histologic diagnosis is confirmed then anti-
inflammatory and immunosuppressive therapy (with corti-
costeroids and/or cyclophosphamide) should be considered,
bearing in mind that the treatment of CNS angiitis is
inferred from clinical experience with systemic angiitis or
anecdotal, lacking any controlled study. Start with oral or
intravenous glucocorticoid (e.g. prednisolone 1–2 mg/kg
per day) in divided doses every 8–12 hours. After the disease
is controlled, reduce to one morning dose, and thereafter,
taper the daily dose as rapidly as clinical disease permits.
Ideally, patients should be slowly converted to alternate-day
therapy with a single morning dosage of short acting
glucocorticoid (prednisone, prednisolone, methyl-
prednisolone) so as to minimize adverse effects; prednisone
doses of 15 mg daily (or less) given before noon usually do
not suppress the hypothalamic pituitary axis. However, the
disease may flare on the day off steroids, in which case use
the lowest single daily dosage that suppresses disease.
Strategies to minimize adverse effects of steroid include:
• Calcium (1000 mg daily) for most patients to minimize
osteoporosis.
• Vitamin D 50 000 units one to three times weekly if 24-h
urinary calcium excretion <120 mg, (monitor for
hypercalcemia).
• Estrogen replacement therapy if post-menopausal.
• Calcitonin and biphosphonates may also be useful.
• Hyperglycemia, hypertension, edema and hypokalemia
should be treated.
• Infections should be identified and treated early.
• Immunizations with influenza and pneumococcal vaccines
are safe and should be given if the disease is stable.
The addition of cyclophosphamine (1.5–2.5 mg/kg per day
orally) to prednisolone (1 mg/kg per day) may be effective.
 Central Nervous System Vasculitis
Strategies to minimize adverse effects of cyclopho-
sphamide include:
• Monitor the leukocyte count closely, keeping it above
3000 per cubic millimeter and the neutrophil count
above 1500 per microlitre.
• If severe neutropenia or bladder toxicity occurs despite
low doses of cyclophosphamide and a fluid intake of
>3 liters/day, azathioprine 1–2 mg/kg per day or
methotrexate can be used successfully with prednisone.
• A pulsed regimen of 10–15 mg/kg intravenously once
every 4 weeks has less bladder toxicity that daily oral
doses (1.5–2.5 mg/kg per day) but bone marrow
suppression can be severe.
When the disease has been controlled for a few months,
taper immunosuppressive agents and attempt to discontinue
them. The role of antiplatelet agents and anticoagulants is
uncertain. Campath-1H humanized monoclonal antibody
treatment remains experimental.
Clinical approach to the patient with
suspected CNS vasculitis
1 Is it cerebrovascular (i.e. TIA, stroke, vascular meningo-
encephalopathy) or not?
2 Where is (are) the lesion(s) neuroanatomically?
3 What is the pathologic nature of the lesion(s): ischemic
or hemorrhagic?
4 What is the etiology of the lesion(s): have more common
disorders of the arteries (atheroma, dissection), heart and
blood been excluded?
5 Are there other clinical features or investigation results
to indicate that this is part of a specific vasculitic
syndrome (i.e. sinus disease: Wegener’s granulomatosis;
jaw claudication: temporal arteritis)?
266
266 Chest x-ray, posterio-anterior view, showing bilateral hilar
lymphadenopathy in the patient in 262 with sarcoidosis.
233
6 If a syndrome is recognized and if it is associated with an
underlying disease or an offending antigen, treat the
underlying disease or remove the offending antigen
where possible.
7 Establish the histologic diagnosis of angiitis by obtaining
a tissue biopsy before committing the patient to a long
course of immunosuppressive medication.
8 Determine the extent of disease activity.
9 Start treatment with appropriate agents in disorders in
which treatment is of proven benefit and is essential (i.e.
prednisone in temporal arteritis; cyclophosphamide and
prednisone in Wegener’s granulomatosis).
10 In patients with systemic angiitis, start with glucocor-
ticoid therapy. Add a cytotoxic agent such as methotrexate
or cyclophosphamide if an adequate response does not
result of if the disorder is likely to respond only to
cytotoxic agents, such as Wegener’s granulomatosis.
11 Avoid immunosuppressive therapy (glucocorticoids or
cytotoxic agents) in disorders which rarely result in
irreversible organ system dysfunction and which usually
do not respond to such agents.
12 Closely follow patients for development of toxic adverse
effects of treatments.
13 Continually attempt to taper glucocorticoids to an
alternate-day regimen and discontinuation when possible,
and to taper and discontinue cytotoxic drugs as soon as
is feasible upon induction of remission.
14 In the event of unacceptable adverse effects or lack of
efficacy, consider alternative agents such as azathioprine.
PROGNOSIS
Variable.
267
267 Chest x-ray, posterio-anterior view, of a patient with Wegener’s
granulomatosis showing a loss of volume in the upper zones of the
lungs bilaterally and coarse interstitial infiltrate with confluence and
cavitation in the upper zones bilaterally.
234 Vascular Diseases of the Nervous System
GIANT CELL ARTERITIS (GCA)
DEFINITION
A systemic angiitis that involves a wide variety of medium
and large arteries, and tends to affect older people (over 50
years) causing two main clinical syndromes: temporal
(cranial) arteritis and polymyalgia rheumatica, which
respond rapidly to corticosteroid therapy.
EPIDEMIOLOGY
• Incidence:
– Temporal arteritis: 18 per 100 000 per annum among
people >50 years; higher incidence in northern than
southern Europe.
– Polymyalgia rheumatica: 13–68 per 100 000 population
aged over 50 years per annum.
• Prevalence: 223 per 100 000 (1 in 500) among people
over age of 50 years.
• Race: mainly white people.
• Gender: F>M; 2–3:1.
• Age: elderly; seldom under age 60 years, extraordinarily
rarely under 50 years (one case reported at age 35 years).
PATHOLOGY
Macroscopic
Any medium or large artery in the body (aorta, carotid,
vertebral, coronary, femoral and so on) may be affected, but
most commonly branches of the external carotid (superficial
temporal, facial, occipital arteries), ophthalmic, vertebral and
posterior ciliary arteries, as well as the aorta and its branches.
These are all vessels with substantial quantities of elastin in
their walls. Curiously, other vessels with lesser amounts of
elastin, such as the proximal central retinal artery, and the
petrous and cavernous portions of the internal carotid
arteries, and their branches, may also be involved, but the
cervical segment of the carotid artery is minimally involved
and there is a striking lack of arteritic involvement of the
intracranial arteries except in rare cases. Particularly
common sites of arterial stenosis in the cerebral circulation
are the internal carotid artery just before dural penetration
and the extracranial vertebral artery just before entering the
skull.
Microscopic
A panarteritis characterized by intimal proliferation and
thickening, destruction of the internal elastic lamina, and
infiltration of the media by mononuclear cells
(predominantly T lymphocytes of the helper/inducer
subset), giant cells, and occasional eosinophils with
granuloma formation (268–270). The granulomatous
changes are considered classical of GCA although the
presence of giant cells is not required for the diagnosis.
ETIOLOGY AND PATHOGENESIS
• Unknown.
• Genetic predisposition:
– Increased prevalence in Northern Europeans.
– Reports of multiple family cases.
– Frequency of human leukocyte antigen HLA-DR4 is
twice normal.
– Association with DRB1-04 variants, particularly the
second hypervariable region of DRB1-04.
• Immunopathogenic mechanisms, especially cell-mediated
immunity, are probably involved. An antigen-driven
immune response is likely to be the primary event, and
arterial damage a secondary effect. There is no direct
relationship with other connective tissue diseases.
CLINICAL FEATURES
History
Systemic
Consitutional symptoms: fever, malaise, fatigue, anorexia,
weight loss, night sweats, depression, and arthralgias.
Myalgic
Proximal, symmetric muscle pain and stiffness of
polymyalgia rheumatica:
• Intense pain and stiffness in the neck, shoulders and
buttocks.
• Worse in the morning: patients ‘roll out of bed like a log’.
Arteritic
• Headache (92% of cases):
– Due to partial occlusion of an artery.
– The site varies: may be temporal, occipital, or
generalized; severe and persistent; patients may sit up in
a chair all night.
– Often described as a new type of pain.
• Pain, swelling, erythema and tenderness over the affected
arteries (e.g. superficial temporal arteries may stand out
and be tender on brushing the hair).
• ‘Claudication-like’ symptoms of partial arterial occlusion:
– Pain on chewing (jaw and tongue claudication due to
maxillary and lingual artery occlusion): up to 65% of
cases.
– Pain and blanching of the tongue (lingual artery).
– Intermittent claudication and Raynaud’s phenomenon,
more common in arms (‘aortic arch syndrome’).
• Ischemic symptoms of total arterial occlusion:
– Visual impairment (25–50% of cases): usually sudden,
painless deterioration of vision in one eye, often on
waking in the morning. It may persist.
– Neurologic problems (31% of cases): TIA of the brain or
stroke (7%); TIA of the eye (amaurosis fugax): 10%;
deafness; peripheral neuropathy.
Examination
• Thickening, tenderness and nodularity of the temporal
arteries, sometimes with reduced or absent pulsation
(271).
• Bruits over large arteries; tenderness of arteries to
palpation occasionally.
• Visual acuity varies from 6/6 to no light perception;.
• Visual field defects; altitudinal visual field defects (loss of
either the upper or more commonly the lower half of the
field in one eye) are particularly common (in contrast to
the central scotoma usually occurring in optic neuritis
due to demyelination) and are due to occlusion of the
upper or lower division of posterior ciliary artery, which
supplies the optic nerve; inferior nasal sectorial defect;
central scotoma.
• Ophthalmoscopy: distended veins, a swollen optic disc
(may be segmental), and, occasionally, cotton-wool spots
(272) and splinter or flame-shaped hemorrhages at or
near the disc margin.
 Giant Cell Arteritis (GCA) 235

268 269

268–270 Cross-section of a temporal artery biopsy. Low power 270

magnification (268) showing the lumen is occluded by extensive
granulomatous inflammatory reaction involving the total thickness of the
vessel. Higher power (269) showing the intimal surface is replaced by a
fibroblastic proliferation, occluding the lumen; and the sub-intimal zone
has extensive fibrinoid necrosis with marked disruption of the internal
elastic lamina.There is histiocytic proliferation, and nodules of eosinophil
cells and occasional multinucleated giant cells are present. In the outer
muscle and adventitial coats there is a light infiltrate of lymphocytes and
plasma cells. High power section (270) of a temporal artery biopsy
from a patient with active giant cell arteritis showing (in the center of
the field) a multinucleate giant cell with the nuclei arranged around the
periphery of the cell in a horseshoe pattern (arrow).

271 272

272 Fundus photograph of anterior ischemic optic neuropathy due to

giant cell arteritis of the posterior ciliary artery showing a swollen
optic disc, cotton-wool spots at the disc margin, and distended veins.
(271, 272 courtesy of Mr M Wade, Department of Medical
Illustrations, Royal Perth Hospital, Australia.)

271 Lateral photograph of the forehead of a patient with giant cell

arteritis showing a visibly enlarged, tender, temporal artery.
236 Vascular Diseases of the Nervous System

50–90% of patients with the clinical syndrome of INVESTIGATIONS

temporal arteritis (constitutional symptoms, headache, Blood
temporal artery tenderness, ± jaw or tongue claudication, • ESR or plasma viscosity as measures of plasma protein
anterior ischemic optic neuropathy, and TIA or ischemic changes: the most useful supporting investigation for the
stroke) present with, or develop, the syndrome of clinical diagnosis of GCA or PMR. The ESR is elevated
polymyalgia rheumatica (constitutional symptoms and above 40 mm per hour in two-thirds of patients, and is
proximal muscle pain and stiffness). often over 100 mm per hour, but can occasionally be
normal, as can the plasma viscosity. Plasma viscosity,
DIFFERENTIAL DIAGNOSIS unlike ESR, is independent of red cell morphology and
Giant cell arteritis packed cell volume, and is only slightly influenced by age
Systemic upset and sex. Other acute phase reactants, such as C-reactive
• Infection. protein, are also raised but are no more helpful than the
• Malignancy. ESR in assessing the disease or its activity.
• Myeloma. • Full blood count: a mild to moderate normochromic,
• Depression. normocytic anemia is usually present. Thrombocytosis,
due to increased production of platelets in GCA, has
Headache been associated with the occurrence of ocular and
• Brain tumor. cerebral ischemic complications of GCA but the reason
• Cervical spondylosis. is unclear. Thrombocytosis in GCA does not necessarily
reflect a more severe degree of angiitis, nor does it
Visual loss contribute to ischemic complications unless it predisposes
• Other types of arteritis (see CNS vasculitis, p.227): to thrombosis in narrowed inflamed arteries.
immune-mediated and infectious (e.g. Lyme disease). • Liver function tests: mild dysfunction, particularly
Usually different age (younger) and distribution of increased alkaline phosphatase levels.
vascular lesions. • Thyroid function tests: if fever and weight loss.
• Non-arteritic cerebrovascular disease of the brain or eye: • Creatine kinase: to rule out inflammatory muscle disease.
atheroma, dissection. • Antinuclear antibodies, C3 complement factor,
• Leber’s hereditary optic neuropathy (mitochondrial antineutrophil cytoplasmic antibody (ANCA), immune
cytopathy) (see pp.162, 491). complexes, rheumatoid factor to exclude SLE and RA.
• Multiple sclerosis (see p.340). • Blood and urine cultures: to exclude infectious arteritis.
• Serologic tests for Borrelia burgdorferi, Q-fever,
Jaw pain salmonellosis, brucellosis, syphilis, viral hepatitis.
Dental conditions.
Radiology
Facial pain Color duplex ultrasound of the superficial temporal artery:
Trigeminal neuralgia or sinus disease. the most specific sign is a dark halo around the arterial
lumen, which may be due to edema in the artery wall.
Ear pain with or without vertigo
Otologic conditions. Surgery
Temporal artery biopsy
Polymyalgia rheumatica (PMR) • This is not necessary in a straightforward case of
Systemic upset and muscle pain/stiffness polymyalgia rheumatica with no sign of temporal arteritis
• Malignancy: myeloma, leukemia or lymphoma, because blindness is uncommon in these patients.
metastatic cancer. However, always consider, and in most cases do it, in
• Arthritis: osteoarthritis of the cervical spine, RA, patients with suspected temporal arteritis. It is
connective tissue disease. particularly important to do in patients with an atypical
• Muscle disease: polymyositis, dermatomyositis: weakness presentation to avoid later doubts about the diagnosis.
is the predominant feature rather than intense muscle • Do a biopsy as soon as possible, but do not delay steroid
pain. treatment; although treatment will reduce the chance of
• Infection: viral, bacterial; osteomyelitis; miliary a positive biopsy result, positive results after starting
tuberculosis. steroids have been reported up to 1 week, and even 3–6
• Metabolic disease: hypothyroidism, metabolic bone months in some cases. A positive biopsy gives the clinician
disease. confidence to prescribe and continue long-term steroid
• Miscellaneous: fibromyalgia syndrome; Parkinson’s treatment which may have adverse effects (and avoid
disease. possible litigation).
• Take the biopsy from the clinically abnormal side. The
biopsy is positive in 60–80% of patients with TA and
15–20% of those with PMR. The sensitivity of biopsy
depends on the quality of the biopsy, particularly biopsy
length and preparation for histologic examination. If
temporal arteries on both sides appear normal, remove a
4–5 cm (1.6–2 in) length of artery from one side and
examine histologically by serial sections because arterial
lesions can be segmental.
 Giant Cell Arteritis (GCA)
• If the biopsy is negative, and the diagnosis of GCA is still
suspected, the other superficial temporal artery should
be biopsied. If both biopsies are negative, the diagnosis
of GCA still cannot be ruled out. In these cases, the
diagnosis is clinical.
• The biopsied artery with GCA shows severe intimal
thickening and reduction in vessel lumen. The internal
elastic lamina is disrupted with fragmentation and
sometimes destruction. There is pronounced infiltration
by histiocytes, lymphocytes, epithelioid cells, and giant
cells in the artery wall, particularly the media and intima
adjacent to the internal elastic lamina (see Pathology
above, 268–270)
• Occasional complications of temporal artery biopsy
include damage to the facial nerve, skin necrosis,
drooping of the eyebrow, and stroke due to an
interruption of a collateral circulation.
Other
• MRI brain if indicated (e.g. oculomotor paresis).
• CSF if indicated (e.g. suspected infectious arteritis).
DIAGNOSIS
The diagnosis of temporal arteritis and polymyalgia
rheumatica is largely clinical, being based heavily on the
history (there are few if any clinical signs) and the clinical
response to steroids, and is largely one of exclusion.
Diagnosis can only be confirmed histologically, by biopsy
of an affected artery, usually the superficial temporal artery
(or occipital artery), and preferably one which is tender.
Temporal arteritis (TA)
American Rheumatism Association 1990 diagnostic criteria.
At least three of the five criteria:
• Age at disease onset ≥50 years.
• New onset of localized headache.
• Abnormal temporal artery clinically: tenderness or
decreased pulse.
• Elevated ESR (≥50 mm/hour).
• Abnormal temporal artery biopsy.
The triad of temporal headache, blindness, and jaw
claudication (aching of the jaw on repeated chewing caused
by involvement of the branches of the external carotid
artery), if present in an elderly person, is almost
pathognomonic for the diagnosis of temporal arteritis.
Polymyalgia rheumatica (PMR)
A clinical syndrome of middle-aged and elderly patients
characterized by:
• Pain and stiffness of the neck, shoulders and pelvic girdle.
• Constitutional symptoms: weight loss, fever, fatigue.
• Elevated ESR.
• Rapid response to small doses of corticosteroids.
Many do not have symptoms or signs of temporal
arteritis; up to one-third have a positive temporal artery
biopsy for GCA.
TREATMENT AND PROGNOSIS
Prompt treatment with corticosteroids is necessary to relieve
symptoms of TA and PMR, and to prevent blindness in
patients with TA. The use of non-steroidal anti-
inflammatory drugs has been advocated in some cases, but
237
most physicians believe steroids to be necessary to achieve
complete control of symptoms.
Initial dose
• Prednisolone 40 mg (25–50 mg)/day for TA, and
15 mg/day for PMR.
• If neurologic or neuro-ophthalmologic symptoms such
as stroke or acute visual failure are present, initial dose is
50–80 mg/day of prednisone.
• Maintain for 4 weeks.
• Reduce dose by 5 mg/day every 1–2 weeks until dose is
10 mg/day.
• Careful, frequent monitoring of symptoms remains the
best guide to management; the ESR and C-reactive
protein are not always reliable markers of disease activity
although they correlate closely with symptoms in most
patients.
• Alternatively, methotrexate 10 mg/week (for 24
months) plus corticosteroid in high initial dose, tapering
quickly to cease after 4 months, is as safe as corti-
costeroid therapy alone and more effective in controlling
disease, in one recent trial (Jover et al., 2001).
Maintenance dose
• Prednisolone 5–7.5 mg/day for about 6–12 months.
• Then, if asymptomatic and ESR is normal, reduce the
dose gradually (e.g. 1 mg/day every 2–3 months). There
is a fine line between too rapidly reducing the dose of
steroids, which leads to relapse, and too slowly reducing
the dose, which leads to adverse effects such as hyper-
tension, osteoporosis, skin fragility and diabetes mellitus.
• Adverse effects of steroids are related to the initial dose,
the total cumulative dose, and maintenance doses above
5 mg of prednisone a day. Withdrawing steroids often
proves difficult and judicious use of simple analgesia and
non-steroidal anti-inflammatory drugs may be helpful.
Despite this, most patients are still taking glucocorticoids
after 2 years and up to half of them at 4 years.
• In patients with biopsy-proven GCA in whom reduction
in corticosteroid dose is difficult, methotrexate
(7.5–20 mg per week) or azathioprine may allow a
reduction in steroid dose. Intermittent cyclical etidronate
may prevent some of the corticosteroid-induced bone
loss, if given when steroid treatment is begun.
PROGNOSIS
• Ophthalmic GCA starts as a unilateral condition but may
become bilateral after days, months, or years.
• Between one-third and one-half of patients can stop
steroids after 2 years.
• Relapses are most likely during the initial 18 months of
treatment and within 1 year of withdrawal of steroids.
Patients should be urged to report back immediately if
arteritic symptoms occur.
• Reliable predictors of relapse have yet to be identified,
although it is unusual for patients who presented with
PMR to experience an arteritic relapse, unless they have
clinical features of TA such as recent headache, jaw
claudication and abnormal temporal arteries.
238 Vascular Diseases of the Nervous System
PRIMARY INTRACEREBRAL
HEMORRHAGE (PICH)
DEFINITION
Bleeding into brain parenchyma with formation of a focal
hematoma.
EPIDEMIOLOGY
• Incidence: about 20 per 100 000 population per year;
accounting for about 10% of all strokes. Slightly more
common among US blacks and individuals of Chinese
and Japanese ancestry.
• Age: any age, incidence increases with increasing age.
• Gender: M=F.
PATHOLOGY
Site
• Putamen or internal capsule (273, 274): 30%.
• Caudate nucleus: 5%.
• Entire basal ganglia region: 5%.
• Lobar (275): 30%.
• Thalamus: 15%.
• Cerebellum: 10%.
• Pons or midbrain: 5%.
ETIOLOGY
The likely cause depends on the age of the patient:
arteriovenous malformations are the most common cause
in the young, degenerative small vessel disease in middle and
old age, and amyloid angiopathy in old age.
Raised blood pressure
• Acute arterial hypertension:
– Alcohol (also antiplatelet action, and coexistent liver
disease).
– Amphetamines (may also cause a vasculitis).
– Cocaine and other sympathomimetic drugs.
– Monoamine oxidase A inhibitors.
– Exposure to extreme cold.
– Trigeminal nerve stimulation.
– Post carotid endarterectomy.
– Post heart transplantation.
– Post correction of congenital heart lesions.
• Chronic arterial hypertension, causing lipohyalinosis and
microaneurysms (see below).
Arterial disease
• Lipohyalinosis, fibrinoid necrosis and, possibly, micro-
aneurysms in small, penetrating vessels:
– The most common cause in middle and old age.
– Hemorrhages often occur deep in putamen (40%), caudate
nucleus (8%), thalamus (15%), cerebral hemispheres (lobar)
(20%), cerebellum (8%) and brainstem (8%).
• Amyloid (congophilic) angiopathy* (276):
– The most common cause in old age, accounting for up
to a third of hematomas in the elderly.
– If young or middle aged, suspect hereditary amyloid
angiopathy (Icelandic or Dutch).
– Tend to be lobar, multiple and recurrent.
– May be preceded by episodes of transient neurologic
defects or subarachnoid bleeding.
– May be associated with dementia, due to multiple
microinfarcts or hemorrhages or Alzheimer’s disease;
mutations in the amyloid precursor protein (APP) gene
cause the Dutch variant of hereditary cerebral
hemorrhage with amyloidosis; mutations in exon 2 of
cystatin C cause the Icelandic variant of hereditary
cerebral hemorrhage with amyloidosis, but patients may
not be of Icelandic origin; apolipoprotein E (Apo E) ε4
allele may be a risk factor: present in 40% of patients.
• Vascular malformations (arteriovenous and cavernous
angiomas):
– Dural or brain, often abutting ependymal or pial surfaces
or involving choroid plexus.
– Most common cause in young normotensive people.
– Seizures and headaches commonly antedate hemorrhage.
– Cavernous angiomas tend to be multiple and familial.
• Carotico-cavernous fistula.
• Hereditary hemorrhagic telangiectasia.
• Saccular aneurysms: cause 1 in 13 intracerebral hemorr-
hages (2 in 13 of those <65 years old), usually in
conjunction with subarachnoid hemorrhage.
• Atheromatous aneurysm.
• Septic arteritis and mycotic aneurysms: most are
superficial in the cortex/subcortex.
• Necrotizing angiitis of the CNS*.
• Arterial dissection.
• Intracerebral tumors:
– Primary (glioblastoma, oligodendroglioma, medullo-
blastoma, hemangioblastoma).
– Metastases (melanoma, bronchial carcinoma, renal
carcinoma, choriocarcinoma, endometrial carcinoma).
• Intracranial venous thrombosis*.
• Moyamoya syndrome.
• Occult head injury*.
• Trauma:
– Usually multiple and abut on the basal brain surfaces,
particularly the orbital frontal and medial and inferior
temporal lobes.
– A hematoma may only become visible with CT days after
the injury (‘spät apoplexy’) due to delayed bleeding into
an area of injured blood vessels.
• Hemorrhagic brain infarction: reperfusion of infarcted
blood vessels and brain.
Bleeding diathesis*
• Anticoagulants:
– Risk of ICH is about 1% per year.
– Increased risk if elderly, previous stroke, hypertensive and
if INR >4.0.
– Usually slowly evolving lobar or cerebellar hematomas
with high fatality rates.
• Antiplatelet drugs: probably a relatively minor
contributory factor.
• Thrombolytic treatment: 0.75% of patients with MI (>2%
risk if elderly >65 years, low body weight <70 kg,
hypertensive, and given alteplase as opposed to
streptokinase; 0.3% risk if none of these risk factors).
• Thrombocytopenia.
• Hemophilia.
• Hereditary factor V deficiency: usually autosomal recessive.
• Leukemia.
• Diffuse intravascular coagulation.
• Occult head injury.
*Causes of multiple hemorrhages in the brain parenchyma.
 Primary Intracerebral Hemorrhage (PICH) 239

PATHOGENESIS CLINICAL HISTORY

Rupture of capillaries, arterioles, and small arteries leads to
extravasation of blood into brain parenchyma resulting in a
hematoma. As the local pressure increases, surrounding
capillaries are stretched and rupture so that the hematoma
enlarges on its outer circumference like a rolling snowball,
dissecting along fibers tract pathways, until it is ultimately
contained by increased pressure in the surrounding tissue,
it decompresses itself by rupturing into a ventricle or the
subarachnoid space, or the bleeding stops due to activation
of the coagulation system.
Preceding circumstances
• Neck trauma (arterial dissection).
• Physical activity: heavy exertion, defecation, lifting, sexual
intercourse.
• Administration of recreational drugs (e.g. amphetamines).
• Ischemic stroke (hemorrhagic transformation of an
infarct).
• Puerperium (choriocarcinoma, intracranial venous
thrombosis).

273 274

273 Brain, coronal section, showing a fresh putaminal hemorrhage in a 274 Brain, coronal section, showing an old putaminal hemorrhage as a
patient with severe hypertensive small vessel disease. (Courtesy of slit-like cavity, with surrounding brown hemosiderin pigmentation.
Professor BA Kakulas, Royal Perth Hospital,Western Australia.) (Courtesy of Professor BA Kakulas, Royal Perth Hospital,Western
Australia.)

275 276

275 Brain coronal section, at autopsy showing a large lobar

intracerebral hematoma that was fatal.

276 CT brain scan from a patient with pathologically-proven amyloid

angiopathy. Note multiple hemorrhages of different ages in different
parts of the brain (arrows).
240 Vascular Diseases of the Nervous System

Onset PHYSICAL EXAMINATION

• Sudden, with symptoms and signs gradually increasing
over seconds or minutes, or rarely hours.
• Often whilst physically active.
Symptoms
• Altered consciousness and/or a focal neurologic deficit
reflecting a loss of function of the site of bleeding in the
brain.
• Headache: localized (but may be generalized) at first,
often in occipital area, and may later become generalized,
spreading down the back of the neck.
• Seizures are common in patients with cortical/sub-
cortical hematomas.
Past history
• Hemophilia.
• Hemorrhage in other sites of the body (hemostatic
disorder).
• Hypertension (lipohyalinosis or microaneurysms): past
history of hypertension in about 50% of patients with
spontaneous ICH.
• Cancer (particularly melanoma, bronchial or renal
carcinoma).
• Epileptic seizures (cortical AVM, tumor, amyloid
angiopathy).
• Headache (AVM).
• Valvular heart disease (septic embolism).
Medications/drugs
• Oral anticoagulant drugs.
• Recreational drugs such as cocaine and amphetamines.
General
• Petechiae or bruising (generalized hemostatic disorder).
• Signs of malignant disease (clubbing [277], cutaneous
melanoma, hepatosplenomegaly, lung collapse).
• Needle marks (drug addict).
• Hypertension and hypertensive end organ disease
(retinopathy, cardiomegaly).
• Subhyaloid hemorrhages.
• Heart murmur (infective endocarditis).
Neurologic
• Focal neurologic deficits: determined by site and size of
hematoma. If the hematoma remains small, no other
signs develop. If the ICH becomes large, with raised
intracranial pressure, headache, vomiting and decreased
level of consciousness occur.
• Depressed conscious level: about one-third of patients;
determined by site and size of hematoma.
• Dementia.
See Table 32 Clinical features of primary intracerebral
hemorrhage.
INVESTIGATIONS
Imaging
The role of imaging is to (1) demonstrate the symptomatic
lesion (i.e. the intracerebral hemorrhage) and (2) identify
any underlying cause such as an AVM or tumor.

Family history
Intracranial hemorrhage
• Hemophilia and other inherited coagulation and platelet
disorders.
• Sickle cell disease/trait. 277
• Vascular malformations sometimes.
• Saccular aneurysm sometimes.
• Hereditary hemorrhagic telangiectasia.
• Amyloid (congophilic) angiopathy: autosomal dominant
inheritance (Iceland and Holland).
• von Hippel–Lindau syndrome.
• Ehlers–Danlos syndrome.
• Pseudoxanthoma elasticum.

Dementia
• Alzheimer’s disease.
• Vascular dementia: amyloid angiopathy.

277 Finger clubbing in a patient with hemorrhage into brain

metastases from the lung (carcinoma of the bronchus).
 Primary Intracerebral Hemorrhage (PICH) 241

Table 32 Clinical features of PICH

Clinical features Site of hemorrhage Likely causes
Hemiparesis (contralateral) Putamen and globus pallidus Hypertension
Hemisensory loss (contralateral) AVM
Conjugate eye deviation (ipsilateral) Tumor
Dysphasia (Dominant posterior putamen) Amphetamines/
Visual-spatial neglect (Non-dominant posterior putamen) cocaine
Moyamoya
Apathy Caudate nucleus Hypertension
Abulia AVM
Agitation Tumor
Forgetfulness Drugs
Conjugate deviation toward side of lesion Anticoagulants
Hemiparesis (Internal capsule) Moyamoya
Hemisensory loss (contralateral) Thalamus: ventrolateral Hypertension
Ataxia (contralateral) AVM
Small, poorly reactive pupils Thalamus: medial Tumor
Downward and inward deviation of the eyes Drugs
Upgaze paresis (supranuclear) Anticoagulants
Pseudo-VIth nerve palsies Moyamoya
Somnolence
Apathy
Anterograde amnesia
Dysphasia (dominant)
Visual-spatial neglect (non-dominant)
Behavioral and motor signs Lobar: frontal Amyloid angiopathy
Conjugate eye deviation toward side of lesion AVM
Hemisensory loss (contralateral)
Contralateral hemisensory loss, visual-spatial neglect, Lobar: parietal Hypertension
cognitive, and behavioral disturbance Anticoagulants
Dysphasia, agitation, hemianopia Lobar: temporal Trauma
Homonymous hemianopia Lobar: occipital Aneurysms
Endocarditis
Venous thrombosis
Coma Pons: large, central Hypertension
Quadriparesis AVM
Small, reactive pupils Anticoagulants
Bilateral horizontal gaze paresis Tumor
Spontaneous downward eye movements (ocular bobbing) Amyloid angiopathy
Hemiparesis (contralateral) Pons: unilateral, basal Hypertension
Ataxia (contralateral) AVM
Hemisensory loss (contralateral) Pons: lateral tegmentum Hypertension
Conjugate gaze palsy (ipsilateral) AVM
Internuclear ophthalmoplegia (ipsilateral) Tumor
Ataxia
Gait ataxia Cerebellum (dentate nucleus) Hypertension
Veering to one side Anticoagulants
Vertigo AVM
Vomiting Tumor
Miosis (ipsilateral) Amyloid angiopathy
VIth nerve or conjugate gaze palsy (ipsilateral) Drugs
Headache Intraventricular Hypertension
Vomiting AVM
Depressed consciousness Tumor
Bilateral extensor plantar responses Amyloid angiopathy
Asymmetric motor, sensory, or visual signs sometimes
242 Vascular Diseases of the Nervous System
Imaging the symptomatic parenchymal lesion
CT brain scan
Fresh blood appears denser than normal brain (whiter). This
occurs immediately, and persists for 5–10 days (278–281);
the whiteness gradually disappears to leave a low density
(black) area (often slit shaped) which is the cerebromalacic
cyst (282, 283). This process varies depending on the size
of the original hemorrhage – small hemorrhages disappear
more rapidly. Once the whiteness has disappeared it is
impossible to tell (on CT) if the original lesion was an
infarct or a hemorrhage.
MRI brain scan
On MRI the appearance of blood also changes with time (284)
and is rather complex and beyond the scope of this book.
Suffice it to say that on T2W image an area of high signal
(bright) surrounded by a dark ring is most likely to be blood.
On T1W imaging, concentric bright and dark rings around a
lesion should suggest hemorrhage. The blood breakdown
products are visible on MRI for years after the hemorrhage,
allowing late distinction of the nature of the lesion (285).
However, timely use of CT soon after the stroke is surely better
patient management than ‘salvage’ by MRI. The one caveat to
the use of MRI very early after stroke is that occasionally it may
be very difficult to distinguish hemorrhage from infarct, though
in practice this is probably not often a problem.
Identifying the underlying cause
CT and MRI brain scan
Some indication of the likely cause may come from the site and
shape of the hemorrhage. Primary hemorrhages most
commonly arise in the basal ganglia and may track into the
lateral ventricles. They are not usually closely related to any
large vessel. They can also be lobar or located in the posterior
fossa. Close inspection should be made for calcification
(suggests AVM or tumor), multiple masses elsewhere in the
brain (suggests hemorrhage into a metastasis), serpiginous
vessels visible after i.v. contrast (suggests AVM), close proximity
to a major artery such as the MCA (suggests an aneurysm).
The lack of visibility of any of these does not exclude their
presence, particularly in the early stages when the mass of blood
278 279
may compress and obscure the underlying lesion.
Amyloid angiopathy is a common cause of lobar
hemorrhage in the elderly. The features include:
• A large area of rather patchy lobar hemorrhage extending
out to the cortical surface.
• Evidence of previous hemorrhage elsewhere in the brain (on
MRI definitely identifiable as prior hemorrhage, whereas on
CT only identifiable as a prior ‘stroke’ unless recent).
• Recurrent hemorrhagic strokes in the same or other parts
of the brain, usually, but not necessarily, in an elderly
person with some degree of cerebral atrophy.
These features have been seen in pathologically-proven
cases of amyloid angiopathy, but the condition is probably
under recognized in life and many hemorrhages which are
due to amyloid are diagnosed simply as PICH.
Cerebral angiography
• Role: to detect underlying arteriovenous malformations,
saccular aneurysms and intracranial venous thrombosis
that are amenable to specific treatment.
• Indications:
– Younger than 50 years of age (provided fit for intervention).
– White matter, subcortical and superficial hematomas; i.e.
the pattern of hemorrhage is compatible with a saccular
aneurysm (in that situation the angiogram should be
performed as quickly as possible) or vascular
malformation, or MR scanning shows ‘flow void’
phenomena consistent with arteriovenous malformations.
– The patient is not hypertensive.
• Timing: angiography rarely needs to be urgent, re-
bleeding is uncommon and often after months or years,
if at all. The only important exception is when a saccular
aneurysm is suspected and, even then, MR angiography
may be sensitive enough. Repeating angiography after a
negative first study may still uncover small arteriovenous
malformations in 10–20% presumably because at the
initial study the lesion was being compressed by mass
effect from the hematoma.
• Risks: arterial dissection and contrast hypersensitivity are
among the greatest dangers.
278 Plain (non-contrast) cranial
CT scan on the day of stroke
onset showing a homogeneous
area of high attenuation,
representing an acute
hematoma, in the right posterior
putamen.The surrounding rim
of low density is mild brain
edema.
279 T2W MRI showing a
right basal ganglia hemorrhage
10 days after stroke arrest.
Note the increased (bright)
signal centrally (methemoglobin)
and the dark low signal ring
encircling this due to
hemosiderin (compare
with 285).
 Primary Intracerebral Hemorrhage (PICH) 243

280, 281 CT brain scans of a large 280 281

recent right temporal hemorrhage in
a patient on warfarin. Note the
appearance and extension into the
lateral ventricles.

282 Plain cranial CT scan in the

same patient as in 278 14 days after
stroke onset showing a residual low
density area in the right posterior
putamen, representing a resolved
hematoma.This sequence of CT
scans shows how difficult it can be
to distinguish radiologically cerebral 282 283
infarction from hemorrhage if the
CT scan is not done early.

283 CT brain scan (with contrast)

of a 2 week old frontal hematoma
(arrow).This patient had presented
with several days of headache and
confusion. Note that the ventricles
are also dilated indicating
hydrocephalus.The cause was a
subarachnoid hemorrhage due to
rupture of an anterior
communicating artery aneurysm
with a focal frontal hematoma and
secondary hydrocephalus. Note that
there is no longer any ‘whiteness’ to
identify the hematoma as blood, and
it just looks like a small mass lesion.
The contrast was given because the
initial diagnosis was of a tumor.

284 MRI (T2W) of a recent 284 285

hemorrhage in the left thalamus.The
dark central area is due to the
deoxyhemoglobin in intact red
blood cells and indicates that the
hemorrhage is only a few days old.

285 MRI (T2W) of a patient at

1 year after a severe head injury.The
black areas in the right frontal lobe
(arrow) are hemosiderin indicating
previous brain hemorrhage, in this
instance traumatic.The black areas
will persist indefinitely and are quite
specific for hemorrhage, thus MRI
can be used to identify hemorrhage
a long time after the event when CT
cannot.
244 Vascular Diseases of the Nervous System
N.B. Vascular malformations and aneurysms may still be
the cause of hemorrhages in the basal ganglia or in the
posterior fossa in patients over 65, and patients with pre-
existing hypertension.
Blood tests
• Full blood count.
• ESR.
• Coagulation studies: platelet aggregation, APTT, PT,
thrombin time (TT), INR.
• Autoantibody screen.
• Blood DNA analysis by PCR: amplification of exons 16
and 17 of the APP and exon 2 of cystatin C.
DIAGNOSIS
• Suspect when focal neurologic signs develop over a few
minutes, without preceding warning attacks, in a person
with risk factors for bleeding such as hypertension,
bleeding diathesis, and drug use.
• Confirmed by CT or MRI brain scan or at autopsy.
• Etiologic diagnosis (i.e. cause of the hemorrhage)
determined by the site of hemorrhage, age of the patient,
and other associated clinical and laboratory features.
TREATMENT
• General support (see Stroke, p.196).
• Compression stockings, if required, for prevention of
DVT and PE; the safety of heparin and aspirin is
unknown in patients with PICH.
• Cease any antihemostatic drugs.
• If anticoagulant-related hemorrhage, consider neutraliz-
ation with intravenous vitamin K 10–20 mg (no more
than 5 mg/minute) followed by infusion of a concen-
trate of coagulation factors II, VII, IX, X or fresh frozen
plasma; infusion of the factors alone restores the coagula-
tion system more rapidly than whole plasma and is safer
from the point of view of transmission of virus particles.
• If fibrinolytic-related hemorrhage, control any
hypertension and infuse cryoprecipitate; the use of
antifibrinolytic drugs is controversial.
• Other bleeding diatheses should be treated specifically
when possible.
• Blood pressure should be lowered gently when it is very
high (e.g. >26.7 kPa (200 mmHg) systolic, >16 kPa
(120 mmHg) diastolic).
• Reduce intracranial pressure if elevated: osmotic agents
such as mannitol (20–25% solution, 0.75–1 g/kg initially
then 0.25–0.5 g/kg every 3–5 hours depending on the
clinical findings, osmolality and central venous pressure).
Hyperventilation only has a role in temporarily
controlling intracranial pressure for patients in whom
surgical evacuation is planned. Corticosteroids are more
hazardous than effective.
• Ventricular drain if symptomatic hydrocephalus.
• Surgical decompression and evacuation of a superficial
lobar or cerebellar hematoma which is causing
progressive neurologic deterioration and/or impairment
of consciousness may have a role in a patient who might
otherwise recover, but more evidence is needed from
large randomized trials. Surgical intervention in the
presence of cerebral amyloid angiopathy may be
hazardous because of brittleness and lack of contractility
of the sclerotic vessels, but this remains to be confirmed.
• Intraventricular recombinant tissue plasminogen activator
for lysis of intraventricular hemorrhage (experimental).
• Prevention of recurrence:
– Diagnosis and control of hypertension.
– Surgical resection or embolization of arteriovenous
malformation.
– Surgical clipping or coiling of intracranial aneurysm.
CLINICAL COURSE
Intracerebral bleeding may continue for 24–48 hours after
onset, and appears more likely in patients who have a
bleeding diathesis (e.g. low platelet counts and low levels of
fibrinogens, liver disease) and irregularly shaped hematomas.
Early deterioration in the first week may also be due to
recurrent hemorrhage, hydrocephalus (if the hematoma
obstructs CSF outflow or blood has entered the CSF),
epileptic seizures, hypoglycemia, hypoxia (e.g. pneumonia,
PE), and electrolyte imbalance (e.g. hyponatremia).
PROGNOSIS
Death and disability
About 25% of patients die during the first day, and 50%
within the first month, usually as a consequence of
supratentorial hemorrhage large enough to cause
transtentorial herniation, or hemorrhage in the posterior
fossa causing direct brainstem compression and herniation
upwards and downwards. Amongst survivors, the outlook
for improvement in neurologic deficits is better for PICH,
which separates and disconnects normal brain tissue, than
for brain infarction of similar size, which results in tissue
destruction. About half of survivors regain independence.
Survival and functional outcome depends largely on five
factors:
• Location of the hematoma: worse outcome with
posterior fossa, thalamic and putaminal hematoma.
• Size of the hematoma: >2 cm (>0.8 in) diameter on CT
associated with raised intracranial pressure; >4 cm
(>1.6 in) diameter on CT associated with death unless
decompressed.
• Level of consciousness on admission (e.g. Glasgow coma
scale): stupor or coma is a grim prognostic sign except in
thalamic hemorrhage.
• Later progression of neurologic signs and development
of raised intracranial pressure.
• Age of the patient: worse prognosis in the elderly.
Recurrent intracerebral hemorrhage
• About 7% of 30-day survivors suffer a recurrent stroke
in the first year, of which at least 25% are hemorrhagic.
• About 70% of recurrences are fatal.
• Lobar hemorrhage at the junction of the gray and white
matter, often due to amyloid angiopathy, and poorly
controlled hypertension are risk factors for recurrence.
 Arteriovenous Malformation (AVM)
ARTERIOVENOUS MALFORMATION
(AVM)
DEFINITION
Congenital anomalies that consist of a complex tangle of
abnormal arteries and veins which lack an intervening
capillary bed but are linked by one or more fistulas.
EPIDEMIOLOGY
The most common form of vascular malformation in the
brain and spinal cord:
• Incidence: 1 per 100 000 per year.
• Point prevalence: 18 per 100 000.
• Age: symptom onset at any age, but typically before the
age of 40 years.
• Gender: M=F.
PATHOLOGY
An abnormal fistulous connection, without an intervening
capillary bed, between one or more hypertrophied feeding
arteries and dilated draining veins (286). The small arteries
have a deficient muscularis:
• Location: in the dura, surface of the brain or spinal cord,
or in brain or spinal cord.
• Size: half are small (<2.5 cm [<1 in] diameter); one-third
are medium sized (2.5–5 cm [1–2 in]) and one-fifth are
large (>5 cm [>2 in]). Most seem to grow during life but
some do not and others shrink or disappear, probably as
a result of hemorrhage.
• Blood supply: principally from parenchymal arteries,
branches of the internal carotid and vertebrobasilar
systems, but about one-quarter receive contributions
from extracranial carotid or vertebral arteries. Some
arteries that supply an AVM continue beyond the fistula
to supply adjacent brain tissue (so-called en passage
feeders). The fistulas allow high flow, rapid arterio-
venous shunting thereby inducing arterial hypotension
in vessels feeding the malformation and neighboring
areas of brain.
286
286 Histologic section of an arteriovenous malformation showing a
network of tangled thin walled blood vessels interposed between
arteries and veins and which do not have the structure of normal
arteries or veins.
245
• Atrophic changes develop in the adjacent nervous tissue,
because of direct pressure and ischemia, due to vascular
steal.
• Associated vascular anomalies:
– Saccular cerebral aneurysms coexist in about 15%
(6–58%) of patients. They may occur in vessels remote
from the lesion, proximally or distally along the course
of feeding arteries, or within the nidus of the
malformation itself. At least two-thirds of associated
aneurysms occur on the proximal feeding arteries of the
AVM or within the substance of the nidus. The
pathogenesis of related aneurysms is believed to be either
a consequence of high flow through the AVM or due to
a shared developmental abnormality that weakens the
cerebral vasculature.
– Anomalous patterns of venous drainage: kinking, ectasia,
and venous aneurysms are frequent and may compress
adjacent brain tissue, lead to venous thrombosis, or even
rupture.
Sequelae
• Intracerebral hemorrhage (about 2% per year).
• Subarachnoid hemorrhage.
• Obstructive hydrocephalus (287).
• Venous hypertension.
• Mass effect.
• Carotico-cavernous fistula.
• Epileptic seizures (about 1% per year).
ETIOLOGY
Developmental derangements occur at the embryonic stage
of vessel formation, at the fetal stage, or after birth.
287
287 Brain section, coronal plane, showing a large arteriovenous
malformation in the left medial frontal lobe and dilated lateral
ventricles. Hydrocephalus may result from involvement of the vein of
Galen, ventricular compression, or the meningeal fibrosing effect of
subarachnoid hemorrhage.
246 Vascular Diseases of the Nervous System

CLINICAL FEATURES – Meningism.

As few as 12% of AVMs are symptomatic during life. – Root pain.
Symptoms include a combination of: – Signs of acute cord compression if localized hematoma.
• Sudden focal neurologic deficit due to: • Spinal bruit.
– Intracerebral hemorrhage (see p.238): the most common
form of presentation (about half [30–82%] of cases). Diagnosis
Accounts for about 2% of all strokes. Risk factors for • Myelography (previously).
intracerebral hemorrhage: small AVM; exclusively deep • MRI (now the initial investigation of choice).
venous drainage; high intranidal pressure (high pressures • Spinal angiography.
in feeding arteries or restriction of venous outflow).
– Subarachnoid hemorrhage (see p.249). Treatment
• Epileptic seizures: partial or secondary generalized (see If AVM is causing progressive neurologic dysfunction or has
p.69): a common presentation (about one-third bled, consider:
[16–53%] of cases). • Embolization.
• Transient focal neurologic deficits, resembling transient • Surgical resection.
ischemic attacks, due to vascular steal or
microhemorrhage; more common with brainstem AVM Sturge–Weber syndrome (see p.151)
(about 10% of cases). Rarely (4–8% of cases) are the focal
neurologic symptoms progressive. Hereditary hemorrhagic telangiectasia
• Headache: a presenting symptom in about one-fifth (Osler–Rendu–Weber syndrome) (see p.153)
(7–48%) of patients. The headache is often non-specific,
and rarely ‘migrainous’ in occipital lobe AVMs. DIFFERENTIAL DIAGNOSIS
• Self-audible bruit, particularly with dural AVM. Other vascular malformations
• Progressive neurologic deficit caused by the mass effect Venous malformation
of the AVM (rare). • Consists of a collection of venous channels of various sizes.
• Hydrocephalus (obstructive, due to mass effect of the • Presents usually with small, low pressure, intracerebral or
AVM; or communicating, due to subarachnoid intraventricular hemorrhage that carries little morbidity.
hemorrhage).
• Intracranial hypertension, with headache or visual Cavernous malformation
symptoms, due to drainage of the malformation into the • Sharply circumscribed lesions, consisting of thin-walled
superior sagittal sinus, causing venous hypertension. sinusoidal vessels, that are of varying size and are often
• Orbital tumor (mass lesion in orbit). multiple (288).
• Carotico-cavernous fistula (ruptured dural AVM): • May be familial.
sudden onset of unilateral pulsating exophthalmos, often • Present usually with epileptic seizures (partial or
with monocular visual loss, a self-audible orbital bruit, secondary generalized) and rarely with small, low
orbital pain, chemosis, and involvement of cranial nerves pressure, intracerebral or intraventricular hemorrhage.
III, IV, VI, and the first (and sometimes second) division
of cranial nerve V. Telangiectases
Collections of dilated capillaries which usually have no
SPECIAL FORMS clinical significance unless as part of hereditary hemorrhagic
Spinal arteriovenous malformation telangiectasia (289).
Epidemiology
• May present at any age. Arteriovenous fistulas
• M>F (2:1). • Trauma.
• Occlusion of venous sinus or sinuses with formation of
Pathology neovascular collaterals.
• Extramedullary more common than intramedullary • Occlusion of branch arteries with formation of arterial
location. collaterals.
• Complications of AVM: spinal cord compression; venous
infarction; vascular ‘steal’ from the cord to the AVM; low INVESTIGATIONS
pressure intramedullary hemorrhage; subarachnoid CT brain scan
hemorrhage. Non-contrast scan may show calcification or hemorrhage or
occasionally enlarged vessels; contrast-enhanced scan may
Clinical features reveal enhancement of the AVM and serpiginous vessels.
• Spinal cord syndrome:
– Gradual onset and progressive course is common but MRI brain scan
onset may be acute. MRI is more sensitive; it can demonstrate flow voids of
– Back pain is common. multiple serpiginous arteries and large draining veins (290).
– Myelopathy, signs may indicate a rather long cord lesion The size of the AVM (i.e. small) and site of venous drainage
over several levels. (i.e. deep), as detected by MRI, increase the risk of a first
– Neurologic deficit may be exacerbated by physical (incident) hemorrhage.
exercise.
• Spinal subarachnoid hemorrhage: Intra-arterial angiography
– Sudden back or neck pain. The gold standard for demonstrating AVMs and their
 Arteriovenous Malformation (AVM) 247

supply arteries and draining veins (291, 292). Typically 288

early venous drainage is seen due to the rapid flow through
the abnormal arteries. There are multiple, closely meshed
tortuous arteries which may arise from several major arteries.
AVMs may be very small or very large.
Dural AVMs are supplied by the external carotid artery
or dural branches of the vertebral artery and may
anastomose with the intracranial supply. They typically lie
on the surface of the brain.
Angiography should be delayed (if possible) after a
hemorrhage as there is more chance of seeing the full extent
of the AVM once the hematoma has resolved and is no
longer compressing and obliterating the AVM (though
obviously if emergency surgery is necessary an angiogram
should be done before that).
A high intranidal pressure is a risk factor for incident
hemorrhage. The pressure of the feeding arteries can be
measured directly only during microcatheter (superselective)
angiography. It can crudely be estimated during routine
angiography by assessing the size of the feeding arteries or
by determining how long it takes for contrast medium to
pass through the AVM.

288 T2W MRI of a right 289 290

temporal cavernous
hemangioma (arrow). Note
the areas of bright and dark
signal which are characteristic
of old hemorrhage. Flow
voids are not usually seen
because the vessels are too
small.

289 CT scan with contrast

of a right parietal capillary
hemangioma. Note the
slight calcification (arrow)
and peripheral site.The
appearance was similar
pre-contrast.

290 MRI scan, PDW

image, in an 18 year old
female with a first ever
partial motor seizure
involving the left face and
arm. Note the black flow 291 292
voids (arrows) in the small
arteriovenous malformation
in the right frontal lobe
cortex.

291, 292 Intra-arterial

digital subtraction
angiogram of an AVM. Early
film (291), late film (292).
Note the enlarged tortuous
mesh of arteries (arrow)
and early draining vein
(arrowhead).
248 Vascular Diseases of the Nervous System

MRA and spiral CT may show the AVM but usually the
lesion is visible on MRI (293, 294) or contrast CT and neither
angiographic technique supplies enough information to replace
conventional angiography, so are probably not of much help.
N.B. All forms of imaging may fail to show small,
compressed or obliterated vascular malformations.
DIAGNOSIS
Clinical clues to the diagnosis
• Known hereditary hemorrhagic telangiectasia or
Sturge–Weber syndrome.
• Subarachnoid hemorrhage with a past history of seizures.
• Carotid, orbital or skull bruit in a patient presenting with
headache, seizures or intracranial hemorrhage.
Diagnosis is established by MRI or angiography
TREATMENT
Treatment decisions are based on the risk of bleeding for
each individual AVM and the risks of the proposed
treatment. Advances in anesthetic and microsurgical
techniques have resulted in substantial reductions in
operative morbidity. Operative mortality is now less than 1%
in carefully selected patients.
Conservative
• AVMs discovered incidentally in the elderly.
• Large or critically located AVMs:
– Control hypertension.
– Avoid antithrombotic agents, including aspirin.
– Anti-epileptic drugs for symptomatic seizures.
– Elective cesarean section at 38 weeks gestation for
pregnant women with AVM.

PROGNOSIS Surgical excision

• The course is difficult to predict: the AVM may remain Superficial (and thus surgically accessible), small AVMs that
static, grow, or even regress. link a single cortical arterial branch through a shunt to a
• The long term crude annual case fatality is 1–1.5%. cortical vein are the best surgical candidates.
• The annual risk of first (incident) bleeding is about 2–3%
and is similar in patients with or without a previous Spetzler and Martin (1986) classification for evaluating the
hemorrhage. risk of surgery in patients with AVMs:
• The case fatality for a first bleed is about 10–15%, and Graded feature Points assigned
the overall morbidity is about 50%. Size of AVM:
• The annual risk of future re-bleeding is probably higher, Small (maximal diameter <3 cm [<1.2 in]) 1
particularly in the first year after initial hemorrhage, and Medium (maximal diameter 3–6 cm [>1.2–2.4 in]) 2
one study has suggested that the risk is as high as about (maximal diameter >6 cm [>2.4 in]) 3
18% per year (among patients who have had a hemorrhage
Location:
at initial presentation). The risk of re-hemorrhage appears
Non-eloquent area of brain 0
to be greater in patients over 60 years, if there is an
Eloquent area of brain* 1
associated saccular aneurysm (the risk is about 7% per year),
if there is only a single draining vein, or if venous drainage Pattern of venous drainage:
is impaired or confined to the deep venous system. Superficial only 0
• For untreated AVMs, the annual risk of developing de Any deep 1
novo seizures is 1%.
*Sensorimotor, language, or visual cortex; hypothalamus or thalamus;
internal capsule; brain stem; cerebellar peduncles; or cerebellar nuclei.

293 294 293 T2W MRI of an AVM

in the left occipital lobe.
Note the dark areas
(arrows) which are ‘flow
voids’ marking the
abnormal arteries.

294 PDW MRI of a left

temporal AVM. Again note
the serpiginous dark
structures which are flow
voids in abnormal arteries
(arrows).
 Subarachnoid Hemorrhage (SAH) 249

The assigned grade of the AVM (1–5) corresponds
numerically to the cumulative score. A score of 4 or 5 is
associated with the highest risk of persistent neurologic
deficits after surgery.
Stereotactic radiosurgery (radiotherapy)
Used for small (<3 cm [<1.2 in] diameter), deep AVMs
<2.5–3 cm (1–1.2 in] in diameter. Radiotherapy is effective
in obliterating about 80–90% of these AVMs within a latency
interval of 2–3 years.
A stereotactic frame is screwed into the skull vault.
Cranial CT scan and cerebral angiogram are undertaken
with the frame in place. Using the frame and coordinates
the location of the nidus can be plotted. It may involve the
use of a gamma knife, proton beam, or linear accelerator. A
single session therapeutic radiation dose is applied to the
nidus and a little of the penumbra, via multiple focused
beams to cause vascular injury, subsequent thrombosis, and
delayed obliteration of the AVM. This may cause some
necrosis of underlying normal brain tissue; the amount
depends on how large the penumbra is. The fact that
radiotherapy takes months to years to have an effect is unlike
other treatments. As a result, the major disadvantage is that
patients remain at risk for hemorrhage during the latency
interval until the AVM obliterates.
Endovascular embolization with rapidly
polymerizing liquid glues
Preferable for deep and large (>3.5 cm [1.4 in]) lesions,
often in combination with open surgery.
SUBARACHNOID HEMORRHAGE (SAH)
DEFINITION
The spontaneous extravasation of blood into the
subarachnoid space when a blood vessel near the surface of
the brain leaks. It is a condition, not a disease, that can be
produced by many causes.
EPIDEMIOLOGY
• Incidence: 6–8 per 100 000 person years outside
Finland; almost three times higher in Finland.
• Age: typically over 40 years of age.
• Gender: F>M = 1.6 (1.1–2.3):1.
PATHOLOGY
Blood in the subarachnoid space, which may be diffuse or
localized and may have extended into the brain parenchyma.
Most commonly, subarachnoid blood is maximal adjacent
to a ruptured saccular aneurysm at the base of the brain
(295–297). In 10% of cases, the center of the hemorrhage
is around the midbrain (perimesencephalic), usually ventral
to it, but there is no other pathology; the angiogram is
295

295 Section of a saccular aneurysm at the base of the brain, taken at

autopsy, showing disruption of the internl elastic lamina and
hemorrhage.

296 Section of the brain in the axial plane showing subarachnoid

hemorrhage in the anterior interhemispheric fissure and intraventricular
extension of the
hemorrhage due to a 296 297
ruptured anterior
communicating artery
aneurysm. (Courtesy of
Professor BA Kakulas, Royal
Perth Hospital,Western
Australia.)

297 Photograph of the

base of the brain at
autopsy, with the right
temporal lobe resected,
showing a ruptured
aneurysm of the right
middle cerebral artery
(arrow) and blood
in the Sylvian fissure.
(Courtesy of Professor
BA Kakulas, Royal Perth
Hospital,Western
Australia.)
250 Vascular Diseases of the Nervous System
normal, showing no evidence of an aneurysm and the
patients do not come to autopsy: they recover and go on to
live a normal life. Rarely, other vascular pathologies, such as
arterial dissection, are identified.
Saccular aneurysms, or berry aneurysms:
• Small, thin-walled blisters protruding from the arteries
of the circle of Willis or its major branches (298).
• Located at bifurcations and branchings:
– Anterior communicating artery complex: 41%.
– Internal carotid artery: 31%; origin of the posterior
communicating artery from the stem of the ICA;
terminal bifurcation of the ICA, into the middle and
anterior cerebral arteries.
– Middle cerebral artery: first major bifurcation: 18%.
– Posterior circulation: tip of basilar artery: 10%.
• Vary in size from 0.2–3 cm (0.1–1.2 in) in diameter;
mean 7.5 mm (0.3 in).
• Vary in form: round with a narrow stalk, broad based
without a stalk; narrow cylinders.
• Aneurysms are multiple in about 25% of cases.
• Usually rupture through the dome of the aneurysm.
• The risk factors for the formation and the rupture of
aneurysms probably differ. The formation of aneurysms
if probably due to a developmental or acquired (possibly
due to hypertension, smoking and atheroma) defect in
the media and elastica of the arterial wall; perhaps focal
destruction of internal elastic membrane by hemo-
dynamic forces at the apices of the bifurcations.
• The rupture of an aneurysm may be due to acute rises in
blood pressure, such as with heavy physical exertion and
sexual intercourse, but this remains to be established.
ETIOLOGY AND PATHOPHYSIOLOGY
Saccular aneurysms (85% of cases)
Conditions associated with saccular aneurysms
• Disorders of connective tissue:
– Marfan’s syndrome.
– Ehlers–Danlos syndrome type IV.
– Pseudoxanthoma elasticum.
– Alpha1-antitrypsin deficiency.
– Neurofibromatosis.
• Disorders of angiogenesis: hereditary hemorrhagic
telangiectasia.
• Associated hypertension:
– Coarctation of the aorta.
– Polycystic kidney disease: hypertension and develop-
mental factors contribute to the development of intra-
cranial aneurysms.
• Hemodynamic stress:
– Anomalies of the circle of Willis.
– Arteriovenous malformations.
– Moyamoya syndrome.
Non-aneurysmal perimesencephalic hemorrhage
(10% of cases)
Arterial dissection
Rare conditions
• Cerebral arteriovenous malformation: very few rupture
only into the subarachnoid space; most form an
intracerebral hematoma with or without extension into
the subarachnoid space.
• Dural arteriovenous fistula.
• Spinal arteriovenous malformation.
• Saccular aneurysm of a spinal artery.
• Head trauma: may cause SAH and may also be a
consequence of SAH.
• Mycotic aneurysms.
• Metastasis of cardiac myxoma.
• Cocaine abuse.
• Sickle cell disease.
• Coagulation disorders.
• Pituitary apoplexy.
• Spinal meningioma.
• Rupture of circumferential artery of the brain stem.
CLINICAL FEATURES
Symptoms
• Sudden loss of consciousness (one-half of patients).
• Headache (two-thirds of patients): may be the only symptom.
– Onset: sudden, in a split second, like a ‘blow’ or
‘explosion’ on/in the head: gradual over minutes rather
than seconds in about 10–15%; maximal in seconds.
– Location: diffuse and poorly localized, but may be
occipital or retro-orbital.
– Severity: unusually severe, ‘the worst headache in my life’.
– Precipitants: uncommon; weight lifting, sexual intercourse.
– Duration: hours (possibly minutes) to weeks, may be
biphasic in SAH due to vertebral artery dissection.
– It is not clear how frequently patients with aneurysmal
SAH have had preceding and unrecognized ‘warning
leaks’.
• Nausea.
• Vomiting.
• Neck stiffness: takes about 3–12 hours after onset to
develop, in response to blood in the subarachnoid space
which acts as a meningeal irritant.
• Pain and stiffness in the back and legs, hours to days after
onset: blood irritating lumbosacral nerve roots.
• Photophobia.
• Epileptic seizures: uncommon.
• Family history of SAH: 6–9% of patients. In first-degree
relatives of patients with SAH, the risk of SAH is three
to seven times higher than in second-degree relatives or
in the general population.
Signs
• None (very often).
• Meningism (but absence of neck stiffness does not
exclude SAH).
• Focal neurologic signs:
– IIIrd nerve palsy: aneurysm of internal carotid artery, at
the origin of the posterior communicating artery; rarely
aneurysm of the basilar artery or superior cerebellar
artery.
– VIth nerve palsy: non-specific rise of CSF pressure.
– IX–XIIth nerve palsy: compression by subadventitial
vertebral artery dissection.
– Hemiparesis: large subarachnoid clot in Sylvian fissure
(MCA aneurysm).
– Paraparesis: aneurysm of anterior communicating artery.
– Cerebellar ataxia, Wallenberg’s syndrome, or both:
vertebral artery dissection.
– N.B. Intraparenchymal hematomas may give rise to other
deficits, depending on their site.
• Subhyaloid hemorrhages in optic fundi (299) (20%).
 Subarachnoid Hemorrhage (SAH) 251

• Fever ( if due to blood in subarachnoid space, the heart rate
is normal; if due to infection, the heart rate is increased).
• Raised blood pressure.
• Kernig’s sign: passive extension of the knee with the hip
flexed elicits pain in the back and leg and resistance to
hamstring stretch.
• Brudzinki’s sign: forward flexion of the neck elicits
flexion at the hip and knee.
• Altered consciousness.
• Carotid or vertebral artery dissection.
• Intracranial venous thrombosis.
• Occipital neuralgia.
• Acute obstructive hydrocephalus.
Primary intraventricular hemorrhage: causes
Uncommon aneurysms
• Posterior inferior cerebellar artery.
• Anterior inferior cerebellar artery.

DIFFERENTIAL DIAGNOSIS Arteriovenous malformations

With neck rigidity • Ependymal lining.
• Acute painful neck conditions: bony and ligamentous • Choroid plexus.
injury, extrapyramidal rigidity, cervical lymphadenitis. • Dural fistula of the superior sagittal sinus.
• Meningitis/encephalitis.
• Stroke: ischemic or hemorrhagic; cerebellar or Occlusive arterial disease
intraventricular (see below). • Moyamoya syndrome: idiopathic, atherosclerotic, or with
• Recent head injury. associated aneurysm.
• Lacunar infarction.
Without neck rigidity
If acute severe headache (1 minute–1 hour) is the only Tumors
symptom, the chance of SAH is about 12% and of a Pituitary tumor; ependymoma; meningioma.
ruptured aneurysm is about 6%. Other diagnoses include:
• Migraine. Infectious diseases
• Thunderclap headache. Brain abscess; parasitic granuloma.
• Pressor responses.
• Benign orgasmic cephalgia. Drugs
• Benign exertional headache. Cocaine; amphetamine.
• Reaction while on monoamine oxidase inhibitors.
• Pheochromocytoma. Wernicke’s encephalopathy
• Expanding intracranial aneurysm.

298 299

299 Ocular fundus of a patient with subhyaloid hemorrhage,

appearing as sharply demarcated linear streaks of brick red-colored
blood or flame-shaped hemorrhage in the preretinal layer, adjacent
to the optic discs and spreading out from the optic disc. (Courtesy of
Mr M Wade, Department of Medical Illustrations, Royal Perth Hospital,
Western Australia.)

298 Dissection of the arteries on the surface of the base of the brain
showing the circle of Willis and bilateral aneurysms of the middle
cerebral arteries (arrows). (Courtesy of Professor BA Kakulas, Royal
Perth Hospital,Western Australia.)
252 Vascular Diseases of the Nervous System
INVESTIGATIONS
Subarachnoid hemorrhage or not?
CT brain scan
The primary imaging modality to diagnose SAH. It may show:
• High density (whiteness) due to blood in the CSF spaces
in 95–97% of cases of SAH (300).
• The subarachnoid blood can be very subtle. Look in the
occipital poles of the lateral ventricles for sediment and
for ‘fissures which have disappeared’ (because they
contain just enough blood to raise their density from the
black of CSF to the gray of normal brain, but not enough
to make the fissure look white with blood) (301).
• The distribution of blood may help to localize the site of
hemorrhage (e.g. if in the anterior interhemispheric fissure,
rupture of an anterior communicating artery aneurysm is
likely [296], and if in the sylvian fissure, rupture of a
middle cerebral artery aneurysm is likely) (302).
Spontaneous subdural and subarachnoid blood suggests
rupture of a posterior communicating artery aneurysm.
• The actual aneurysm may occasionally be seen if large.
• Complications such as hydrocephalus (with dilatation of
the ventricles) (300) or cerebral ischemia (with low
density areas in an arterial territory) (303) may be seen.
• Perimesencephalic hemorrhage typically results in blood
around the brain stem, not usually a heavy load, and
hydrocephalus occurs but is unusual.
There are several important caveats:
• A normal CT scan does not exclude SAH. A lumbar
puncture must be performed if the CT is normal (about
3–5% of cases of SAH) but SAH is still suspected.
• Blood can disappear very quickly from the CT scan: if
the headache started more than 3 days ago, the chances
of seeing blood decline rapidly and lumbar puncture
becomes more important (after CT has excluded
hydrocephalus) to look for xanthochromia.
MRI brain scan
MRI is not useful to diagnose SAH: the blood is difficult to
see and it is less easy to use the technique with acutely ill
confused patients.
300 301
Lumbar puncture
Performed if a CT brain scan is negative for subarachnoid
blood (about 3–5% of cases).
If the onset of sudden headache was less than 12 hours ago
• Wait for at least 12 hours to have elapsed since the onset
of symptoms before doing a lumbar puncture (unless
meningitis is suspected).
If the onset of sudden headache was more than 12 hours ago
• Do a lumbar puncture immediately (after brain CT).
• If the CSF is unequivocally xanthochromic (with or
without red cells), no further CSF tests are necessary: the
diagnosis of SAH is confirmed.
• If the CSF is blood-stained:
– Spin down the CSF immediately (if it contains red blood
cells from a traumatic tap and is allowed to stand,
oxyhemoglobin will be formed in vitro, bilirubin will
not, but its absence cannot exclude SAH).
– Perform spectrophotometric analysis of the supernatant
for xanthochromia, (unless the yellow color is evident to
the naked eye). Distinction between a traumatic tap and
SAH is not possible with the naked eye. If spectro-
photometry has to be deferred for practical reasons, store
the CSF wrapped in tin foil, because daylight may induce
breakdown of bilirubin.
• If the CSF is clear, colorless and acellular, still do
spectrophotometry: the presence of pigment may not be
visible with the naked eye.
If the onset of sudden headache was more than 2 weeks ago
Consider doing a lumbar puncture if <4 weeks ago because
xanthochromia may still be detectable up until 4 weeks, but nor-
mal spectrophotometric testing cannot exclude SAH.
Imaging the underlying cause of SAH
Intra-arterial angiography
Indicated if CT brain scan shows subarachnoid hemorrhage
(95–97% of cases) or lumbar puncture performed more than
12 hours (and up to 2–4 weeks) after headache onset reveals
xanthochromia (yellow color) of the CSF supernatant fol-
lowing centrifugation and spectrophotometry. Performed with
300 CT brain scan showing
obvious recent SAH with
blood (white) in the basal
cisterns (arrows). Note there
is also secondary
hydrocephalus (dilatation of
temporal horns of lateral
ventricles).
301 Subtle SAH: blood is
visible in the Sylvian fissures
but is less obvious than in
300.The sulci are ‘missing’, i.e.
they would normally be filled
with black material.
 Subarachnoid Hemorrhage (SAH) 253

multiple views of each major artery to identify the sympto-
matic aneurysm (304–306) and any incidental ones (306):
• The gold standard and most surgeons require this prior
to operation.
• Most aneurysms arise from the arteries near or on the
circle of Willis, or at the major bifurcation points.
• Aneurysms arising elsewhere should suggest unusual
etiologies such as mycotic or traumatic.
• A negative angiogram should be repeated after a few
weeks as some aneurysms do not show up on the initial
one, except where the CT scan shows typical
perimesencephalic hemorrhage. Indeed, CT angiography
only is the best diagnostic strategy for patients with
perimesencephalic hemorrhage.

302 Cranial CT 302

scans showing
hemorrhage into the
left Sylvian fissure;
left posterior
inferior frontal lobe;
left anterior
temporal lobe;
subarachnoid space
(interpeduncular
cistern, ambient
cisterns, inter-
hemispheric fissure);
third and lateral
ventricles; and
cerebral aqueduct,
together with
hydrocephalus in a patient 303 304
with a ruptured left middle
cerebral artery aneurysm.

303 CT brain scan of a

patient presenting 2 weeks
after symptom onset.The
subarachnoid blood is no
longer visible, but there is
some low density in the left
parieto-occipital cortex
(arrow) which is ischemic
brain secondary to ‘vasospasm’
complicating
the SAH.

304 Intra-arterial angiogram of

the left internal carotid artery
showing an aneurysm at the
trifurcation of the middle 306
cerebral artery (arrow).
305
305 Catheter cerebral
angiogram, coronal plane,
showing the left middle
cerebral artery aneurysm
(arrow).

306 Intra-arterial angiogram

of the internal carotid artery
showing three aneurysms: a
large internal carotid tip
(arrow); a small pericallosal
(arrowhead) and a small
middle cerebral (short arrow).
Multiple aneurysms are not
uncommon. Usually the largest
one is the symptomatic one.
254 Vascular Diseases of the Nervous System
Others
• MRI, MRA and dynamic spiral CT angiography are still
undergoing evaluation for use in the diagnosis of
aneurysms (307, 308), though may be useful when
there are localizing signs such as a IIIrd nerve palsy and
when there is a perimesencephalic pattern of
hemorrhage. Their use in screening for asymptomatic
aneurysms is controversial and still under evaluation.
• Angiography may show other features such as narrowed
arteries due to vasospasm in the acute phase after SAH.
• Transcranial doppler ultrasound (TCD) is widely used in
some countries to identify patients with vasospasm (as
evidenced by raised arterial blood velocities) after SAH.
Complications of SAH
Electrocardiography (EKG) changes
• ST segment and T wave changes, U-wave abnormalities,
QT prolongation and sinus arrhythmias are common
after SAH.
• Life-threatening arrhythmias such as ventricular
fibrillation or ‘torsade de pointe’ are rare.
• Mechanism is unexplained but thought to be sustained
sympathetic stimulation, perhaps caused by dysfunction
of the insular cortex.
Urea and electrolytes
Hyponatremia is a sign of hypovolemia, due to excessive
natriuresis (salt wasting), rather than inappropriate secretion
of antidiuretic hormone.
DIAGNOSIS
Clinical plus CT or CSF evidence of subarachnoid blood.
Grading system for patients with SAH, according to the
World Federation of Neurological Surgeons (WFNS):
WFNS grade Glasgow Focal deficit
coma scale
I 15 Absent
II 14–13 Absent
III 14–13 Present
IV 12–7 Present or absent
V 6–3 Present or absent
It is preferable to record the patient’s condition in
descriptive terms (e.g. level of consciousness and any focal
neurologic deficits) rather than in codified terms. In
addition, the cause of any neurologic deficit should be
identified (e.g. acute hydrocephalus, intracerebral hema-
toma, cardiorespiratory difficulties).
TREATMENT
Indications for immediate operation
• Large intracerebral hematoma associated with
deterioration in conscious level.
• Symptomatic hydrocephalus: gradual obtundation within
24 hours of SAH, downward deviation of the eyes, and
slow pupillary responses.
• Prevent re-bleeding (see below).
General care
Nursing
Continuous observation (Glasgow coma scale, pupils, any
focal deficits).
Nutrition
• Oral route:
– Only if intact cough and swallowing reflexes.
– Keep stools soft by adequate fluid intake and restricting
milk content; if necessary add laxatives.
• Nasogastric tube:
– Deflate endotracheal cuff (if present) on insertion.
– Confirm proper placement by x-ray.
– Begin with small test feeds of 5% dextrose.
– Feed in sitting position and check gastric residue hourly
(to prevent aspiration).
– Crush tablets and flush down (if needed, phenytoin levels
won’t be adequate in conventional doses).
• Total parenteral nutrition: use only as a last resort.
Blood pressure
Do not treat hypertension unless there is clinical or
laboratory evidence of progressive hypertensive end-organ
damage. Existing antihypertensive drugs can be continued.
Fluids and electrolytes
• Give at least 3 l per day (normal saline) to compensate
for ‘cerebral salt wasting’ and to prevent hypovolemia,
because this predisposes to cerebral ischemia.
• Compensate for negative fluid balance and for fever.
• Empty bladder by catheter every 6–8 hours if post-void
residual >100 ml (see p.197)
Pain: headache
• Start with paracetamol (acetaminophen) 1 g every 3–4
hours and/or dextropropoxyphene (propoxyphene);
avoid aspirin.
• Midazolam if the pain is accompanied by anxiety (5 mg
i.m. or infusion pump).
• For severe pain, add codeine 20 mg orally, piritramide
2 mg subcutaneously, then, as a last resort, morphine
2 mg intravenously, with 1–2 mg increments.
Prevention of deep venous thrombosis and
pulmonary embolism
Apply compression stockings or intermittent compression
by pneumatic devices.
Prevention of re-bleeding
• Re-bleeding of a ruptured aneurysm cannot be predicted
reliably.
• Surgical clipping of the aneurysm as early as possible
(within 3 days) is usual practice but it is not supported
by evidence from randomized trials.
• Antifibrinolytic drugs (e.g. tranexamic acid) reduces re-
bleeding by two-thirds but the increased risk of cerebral
infarction negates any beneficial effect.
• Endovascular application of coils into the aneurysm
causing occlusion of the remaining lumen of the
aneurysm by reactive thrombosis: currently being
evaluated in clinical trials.
 Subarachnoid Hemorrhage (SAH) 255

Prevention of delayed cerebral ischemia Management

• Avoidance of antihypertensive drugs.
• Adequate intake of fluid and sodium.
• Calcium antagonists routinely: oral nimodipine reduces
the risk of a poor outcome by about one-third.
• Fludrocortisone to limit sodium loss.
• Free radical scavengers: tirilazad mesylate: no consistent
improvement of outcome in four trials of tirilazad
involving more than 3500 patients.
• Aspirin and other antiplatelet agents, after clipping the
aneurysm: unknown benefit; currently being trialed.
• Intrathecal thrombolytics: unknown benefit.
CLINICAL COURSE AND COMPLICATIONS
Sudden deterioration
• Re-bleeding (two-thirds).
• Epileptic seizure.
• Delayed cerebral ischemia, with atypical, sudden onset.
• Ventricular fibrillation.
• Undetermined.
Subacute deterioration
• Edema surrounding intracranial hematoma.
• Cerebral ischemia.
• Hydrocephalus.
• Unsuspected re-bleeding.
• Systemic complications (hyponatremia, arrhythmia,
hypotension, infection, neurogenic pulmonary edema).
• If respiratory arrest: resuscitate and ventilate; within
hours either spontaneous respiration will return or all
other brainstem functions will be lost.
• Repeat CT scan.
• Consider emergency clipping or coiling of aneurysm after
recovery, as the majority will re-bleed again, with high
case fatality; any intracerebral hematoma can be removed
at the same time.
Acute hydrocephalus
• Anticipate if intraventricular hemorrhage or extensive
hemorrhage in perimesencephalic cisterns is present.
• Conscious level gradually deteriorates, particularly on the
first day after the bleed.
• Pupils become small and unreactive, and eyes deviate
downwards (upgaze paresis) due to pressure on rostral
midbrain.
307

Re-bleeding
• Risk of re-bleeding after rupture of an intracranial
aneurysm, without medical or surgical intervention:
about 50% in the first month; about 20% on the first day,
and about 40% in the first month for survivors of the first
day.
• Sudden apnea, in a patient with SAH, usually signifies re-
bleeding.

307 MRI brain scan, proton density image, axial plane, showing
hypodense flow voids in the middle cerebral arteries and a left middle
cerebral artery aneurysm (arrow).

308 MR angiography, coronal plane, showing the left middle cerebral

artery aneurysm (arrow).

308
256 Vascular Diseases of the Nervous System

Management • Treatment with antihypertensive drugs.

• Repeat the CT scan and compare the bicaudate index
with that on any previous scan.
• Spontaneous improvement occurs within 24 hours in half
the patients (except those with massive intraventricular
hemorrhage); take action if patient further deteriorates
or fails to improve within 24 hours.
• Lumbar punctures are reasonably safe if there is no brain
shift, and effective in about half the patients who have
obstruction in the subarachnoid space and not in the
ventricular system.
• External drainage of the ventricles is very effective in
restoring the level of consciousness but carries a high risk
of re-bleeding (consider emergency clipping or coiling
of the aneurysm at the same time), and of infection (this
may to some degree be prevented by prophylactic
antibiotics or subcutaneous tunnelling).
Hyponatremia
• Almost invariably caused by sodium depletion, not by
sodium dilution (SIADH).
• Associated hypovolemia increases risk of delayed cerebral
ischemia.
• Treatment with antifibrinolytic drugs.
Management
• Establish diagnosis: clinical and serial brain CT or MRI
scans (rule out other causes of deterioration).
• Stop nimodipine.
• Immediately administer a plasma volume expander: 500 ml
of a colloid solution such a hetastarch or hemaccel.
• Insert a subclavian vein catheter or pulmonary arterial
balloon catheter; maintain central venous pressure
between 1.1–1.3 kPa (8–12 mmHg), or pulmonary
wedge pressure between 1.9–2.2 kPa (14–18 mmHg).
• Maintain fluid intake with at least 3 l of normal saline
(0.9%) per 24 hours.
• Correct hyponatremia.
• Keep hematocrit around 40%.
• Keep arterial pressure 2.7–5.3 kPa (20–40 mmHg)
above baseline values; may need inotropic support in
intensive care unit.
Cardiac arrhythmias
Rarely need to be treated.

Management PROGNOSIS
• Give isotonic saline (with or without albumin to expand • Half of patients die; sudden death occurs in about 15%
plasma volume) or a mixture of glucose and saline; no of patients: usually ruptured posterior circulation
free water. aneurysms and intraventricular hemorrhage.
• If necessary add fludrocortisone acetate, 400 µg/day in • Half of survivors remain severely disabled.
two doses, orally or intravenously. • Delayed ischemia is a major cause of death and disability.
• Keep central venous pressure between 1.1–1.3 kPa • Outcome in patients with familial SAH is worse than in
(8–10 mmHg), or pulmonary capillary wedge pressure patients with sporadic SAH.
between 1.1–1.6 kPa (8–12 mmHg). • Non-aneurysmal perimesencephalic SAH: excellent
prognosis; re-bleeding and ischemia do not occur.
Delayed cerebral ischemia
Up to one-third of patients with a ruptured aneurysm Adverse prognostic factors
develop cerebral ischemia, mainly between day 5 and day Decreased level of consciousness on admission ++++
14 after the initial bleed. Cerebral ischemia or infarction is Large amount of blood in subarachnoid space on +++
not confined to the territory of a single cerebral artery or CT scan
one of its branches. The pathogenesis is complex. Increasing age ++
Vasospasm is often implicated because its peak frequency Loss of consciousness at onset +
from days 5–14 coincides with that of delayed ischemia and High blood pressure on admission +
because it is often generalized, like the clinical and Pre-existing medical condition +
radiologic findings, but it is not the only factor in the Aneurysm in posterior rather than anterior circulation +
pathogenesis of cerebral ischemia. Use of anticoagulants +
Angiographic evidence of vasospasm occurs in up to 70% Intravenous drug abuse +
of patients with aneurysmal SAH, but neurologic Associated intracranial hematoma +
deterioration secondary to vasospasm occurs in about one- Level of creatinine kinase BB in CSF +
third of all patients, and about half of these patients with
symptomatic vasospasm die or suffer neurologic disability
as a direct result of the ischemia.

Determinants of delayed cerebral ischemia

• SAH caused by a ruptured aneurysm.
• Arterial narrowing.
• Depressed level of consciousness for more than 1 hour
after the onset.
• Amount of subarachnoid blood on early CT scanning,
not the distribution.
• Acute hydrocephalus.
• Hyponatremia and hypovolemia.
• Detection of emboli on transcranial Doppler monitoring,
after surgical clipping.
 Cerebral Venous Thrombosis 257

CEREBRAL VENOUS THROMBOSIS Cerebral veins

DEFINITION
Occlusion of cortical cerebral veins or dural venous sinuses,
or both, by thrombus (phlebothrombosis).
EPIDEMIOLOGY
• Incidence: unknown (previous studies have relied on
autopsy data, and more recently cerebral angiography)
but uncommon.
• Low prevalence in autopsy series; 0.1–0.9% of autopsies.
• Age: any age, but young and middle-aged women at
greatest risk: mean age 40 years.
• Gender: higher incidence in females (1.3:1).
Three groups of veins drain the blood supply from the
brain: superficial cerebral veins (or cortical veins), deep
cerebral veins and posterior fossa veins.
PATHOLOGY
• Isolated cortical venous thrombosis is rare, most patients
have dural sinus thrombosis with or without cortical vein
involvement (310, 311).
• The thrombus itself is like other venous thrombi
elsewhere in the body. When it is fresh, it is a red
thrombus rich in red blood cells and fibrin but poor in
platelets; when it is old, it is replaced by fibrous tissue
sometimes showing recanalization.
• Hemorrhagic infarction of the brain is common.

RELEVANT VENOUS ANATOMY

Blood from the brain is drained by cerebral veins which
empty into dural sinuses that drain mostly into the internal
jugular veins. There is extensive collateral circulation in the
cerebral venous system.

Dural sinuses 309

The most commonly affected by thrombosis are the
superior sagittal sinus, lateral sinus, cavernous sinus and
straight sinus (309).

309 MR venogram, left postero-lateral view, showing the normal

appearance of the venous sinuses in the head.

310, 311 Autopsy specimen of brain, vertex of the brain (310), and
coronal section through the frontal lobes (311), showing bilateral
parasagittal hemorrhagic infarction due to superior sagittal sinus
thrombosis.

310

311
258 Vascular Diseases of the Nervous System
ETIOLOGY
Predisposing factors can be identified in up to 80% of
patients.
Local conditions directly affecting the veins and
sinuses
Non-infective
• Head trauma (open or closed, with or without fracture).
• Intracranial surgery.
• Brain infarction or hemorrhage.
• Tumor invasion of dural sinuses (meningioma, meta-
stases, glomus tumor).
• Catheterization of, and infusions into, the internal
jugular veins (e.g. for parenteral nutrition).
Infective
• Direct septic trauma.
• Local regional infection (scalp, sinuses, ears, mastoids,
nasopharynx).
• Intracranial infection:
– Bacterial meningitis.
– Meningovascular syphilis.
– Subdural empyema.
– Bacterial or fungal brain abscess.
Systemic conditions
Non-infective
• Surgery: any surgical procedure, with or without deep
venous thrombosis.
• Hormonal:
– Pregnancy or more commonly the puerperium.
– Oral contraceptives (estrogens or progestogens
[progestins]) (OCP): age-adjusted odds ratio of 13 for
OCP use and risk of CVST; age-adjusted odds ratio of
30 for OCP use combined with prothrombin G20210A
gene mutation and risk of CVST.
• Medical:
– Severe dehydration of any cause (including angiography
or myelography).
– Hyperviscosity syndrome: multiple myeloma;
Waldenstrom’s macroglobulinemia.
– Hypercoagulable state:
Red blood cell disorders: polycythemia; post-hemorr-
hagic anemia; sickle cell disease/trait; paroxysmal
nocturnal hemoglobinuria.
Platelet disorders: essential thrombocythemia.
– Coagulation disorders (see p.222): deficiency of anti-
thrombin III, protein C, or protein S; circulating lupus
anticoagulant; activated protein C resistance (factor V
Leiden gene mutation); prothrombin G20210A gene
mutation (see p.223); disseminated intravascular coagu-
lation; heparin- or heparinoid-induced thrombo-
cytopenia; antifibrinolytic treatment.
– Extracranial malignancy (non-metastatic effect): any
visceral carcinoma, carcinoid, lymphoma, leukemia, L-
asparaginase therapy.
– Connective tissue disease: SLE; Wegener’s granuloma-
tosis; giant cell arteritis.
– Cardiac: congenital heart disease; congestive heart failure;
pacemaker.
– Gastrointestinal: inflammatory bowel disease; cirrhosis.
– Various others: Behçet’s disease (312–314); sarcoidosis;
nephrotic syndrome; androgen therapy; diabetes mellitus;
parenteral injections; hyperhomocystinemia.
Infective
• Bacterial: septicemia, endocarditis, typhoid, tuberculosis.
• Viral: measles, hepatitis, encephalitis, herpes, HIV, CMV.
• Parasitic: malaria, trichinosis.
• Fungal: aspergillosis.
Uncertain etiology (20–25%)
PATHOGENESIS
Thrombus formation due to venous stasis, increased clotting
tendency, changes in the vessel wall, and less frequently,
embolization.
CLINICAL SYNDROMES
Occur in isolation or combination.
Sagittal and/or transverse sinus thrombosis
Syndrome of progressive idiopathic intracranial hypertension
• Headache.
• Obscurations of vision.
• Papilloedema.
Cortical venous thrombosis
Syndrome of subacute or chronic focal or generalized
encephalopathy
Evolution over a few days, weeks or months of headache,
confusion, drowsiness, epileptic seizures (partial and
secondary generalized), raised intracranial pressure, and
coma with or without focal neurologic signs.
Stroke-like syndrome (frequently with seizures)
A cortical stroke syndrome (i.e. non-lacunar) occurring in
patients suffering from any one of the etiologic conditions
should suggest venous thrombosis, particularly if the
evolution of the focal neurologic deficit is rather slow, if
seizures occur, and if there is hemorrhagic infarction or
frank hemorrhage in the territory of drainage of a cortical
vein in the cortex/subcortex.
Thunderclap headache
Abrupt onset of very severe pain in the head, perhaps caused
by intraparenchymal hemorrhage, venous hemorrhagic
infarction, or venous subarachnoid hemorrhage.
Cavernous sinus thrombosis
Syndrome of chemosis, proptosis and painful ophthalmoplegia
Usually due to suppuration spreading from face, orbit or
paranasal sinuses (staphylococcal, streptococcal, mucormy-
cosis), causing:
• Pain around the eye and face.
• Conjunctival and eyelid edema, episcleral congestion.
• Proptosis.
• Blindness and papilledema.
• Cranial nerve III, IV, VI, V1 and perhaps V2 palsies.
Thrombosis may spread to the contralateral cavernous
sinus and other dural sinuses. Suppuration may spread to
cause subdural empyema, bacterial meningitis, or infective
arteritis and thrombosis of the terminal carotid and middle
cerebral artery origin.
 Cerebral Venous Thrombosis 259

Deep cerebral vein thrombosis 312

Variable clinical features. May have an ‘encephalitic’
presentation characterized by the gradual onset of headache,
confusion, obtundation and vomiting with or without the
development of focal neurologic signs such as amnesia or
long tract signs due to bilateral thalamic infarction or
unilateral temporoparietal infarction (that may become
hemorrhagic) depending on the collateral venous circulation
and whether the thrombus propagated from the lateral sinus
into the vein of Labbé.

DIFFERENTIAL DIAGNOSIS
• Subdural empyema.
• Bacterial meningitis.
• SAH.
• Encephalitis.
• Brain abscess.
• Stroke: arterial occlusion or dissection, SAH. 313
• Benign thunderclap headache, ‘crash’ migraine.

INVESTIGATIONS
Cranial CT and MRI imaging
The appearance of the brain in cerebral venous thrombosis
depends on whether the venous sinuses or cortical veins (or
both) are involved. Thrombosis of the cortical veins usually
results in venous infarction (315), whereas isolated venous

312–314 Tongue (312) and and genital (scrotal) (313, 314) ulcers
in a young man with Behçet’s disease who presented with cerebral
venous thrombosis.

315 CT scan without contrast of a 6 hour old venous infarct

(compare with the arterial infarct of similar age in 227). Note the well
defined edges, marked swelling, central hemorrhage.There was no sinus
involvement.
315
314
260 Vascular Diseases of the Nervous System
sinus thrombosis may not cause infarction but results in
generalized brain swelling and raised ICP (316, 317). The
imaging of venous thrombosis is therefore directed at:
• Recognizing correctly the venous origin of any
parenchymal lesion.
• Diagnosing the extent of any sinus involvement.
• Identifying any predisposing factors (such as tumors
pressing on the sinus or local infection).
Venous sinus thrombosis
This may be imaged by CT and MRI and appear as:
• A high density (or altered signal and loss of flow void on
MRI) in the sinus (due to the thrombus) (316–319).
• A triangular filling defect in the sinus after i.v. contrast
(‘empty delta’ sign (251, 252). High splitting of the
superior sagittal sinus can mimic a delta sign, as can an
adjacent epidural abscess.
• Generalized brain swelling (cerebral edema);
• Local infection such as mastoiditis or sinusitis as a
precipitating cause.
Venous infarction
• May be single or multiple.
• Typically more clearly demarcated and of lower density
than arterial infarction of the same age (315).
• More frequently hemorrhagic than arterial infarcts.
• The hemorrhage typically starts in the center and extends
towards the periphery, (whereas in arterial infarcts the
hemorrhage is typically around the edge).
• Infarction occupies territories which are not typically
arterial, or involve adjacent areas of brain (e.g. occipital
lobe and cerebellum) which is difficult to explain from
the arterial anatomy.
• More swollen than an arterial infarct of the same age.
• The brain beyond the visible boundaries of the infarct
also may appear swollen.
• The cord sign refers to a thrombosed vein, present on
pre-contrast views.
Normal scans are more likely when the thrombotic
process has been confined to the deep venous system,
including the vein of Galen and the straight sinus; and when
the patient has presented with signs of intracranial
hypertension alone.
MRI of the brain is now the diagnostic procedure of
choice because it is non-invasive, sensitive to blood flow, and
readily visualizes the thrombus itself.
Four vessel conventional or digitalized intra-arterial
cerebral angiography
This technique, which visualizes the entire venous phase on
at least two projections (frontal and lateral), has been the
gold standard for diagnosis, revealing the partial or
complete lack of filling of veins or venous sinuses.
CSF
• Pressure is usually increased.
• May be normal or contain a modest excess of red blood
cells, lymphocytes, neutrophils and protein.
• It is usually not necessary to perform a lumbar puncture
and CSF examination in patients with suspected cerebral
venous sinus thrombosis.
Other investigations
All other investigations are directed towards demonstrating
the underlying cause (see Etiology, above).
Coagulation studies (see p.220)
Indicated in all patients, and particularly if family or past
history of thrombotic episodes, or unexplained infarction:
• Protein C and S.
• Antithrombin III.
• Prothrombin G20210A gene mutation.
• Factor V Leiden mutation.
• Antiphospholipid antibodies.
• Fibrinogen.
• Plasminogen.
Chest x-ray
Chest x-ray or other imaging, inflammatory markers,
autoantibodies, and tissue biopsy if suspected malignancy or
connective tissue disease.
DIAGNOSIS
Angiography remains the gold standard for diagnosis but
MRI with MR venography allows accurate diagnosis in most
cases.
TREATMENT
• Any underlying cause (e.g. infection) should be identified
and treated.
• The risks and benefits of anticoagulant therapy with
intravenous heparin followed by oral anticoagulation for
3–6 months remain uncertain, based on a systematic
review of the only two randomized controlled trials in a
total of 70 patients. Anticoagulants may be useful in
patients with dural sinus and even cortical venous
thrombosis and may not necessarily be harmful, even in
the presence of hemorrhagic infarction.
• If patients deteriorate, local thrombolysis with intrasinus
urokinase may also have a role but this remains to be
evaluated in controlled trials.
PROGNOSIS
Mortality rate <10%. If patients survive, the prognosis for
recovery of function is generally favorable and much better
than in arterial occlusion.
Prognostic factors
• Topography of thrombosis: deep cerebral vein and
cerebellar vein thrombosis carry a much higher risk than
cortical vein thrombosis.
• Underlying cause: septic cerebral venous sinus
thrombosis still has a mortality rate of 30% in cavernous
sinus thrombosis and up to 78% in SSS thrombosis.
 Vascular Dementia 261

VASCULAR DEMENTIA EPIDEMIOLOGY

DEFINITION
An acquired syndrome of cognitive impairment (dementia)
that is characterized by the abrupt onset and stepwise
progression of deficits of memory and at least two other
cognitive functions (e.g. abstract thinking), sufficient to
interfere with the person’s usual social activities, and caused
by vascular diseases of the brain.
• Incidence: 2.5 per 1000 undemented individuals per year.
• Prevalence: about 22 per 1000 population (up to 40% of
cases of dementia: the second most common cause of
dementia after Alzheimer’s disease); about 62 per 1000
people over the age of 59 years. Estimates of the
prevalence of vascular dementia may be unreliable because
of different diagnostic and pathologic criteria used in
different studies.
• Age: elderly.
• Gender: M=F.

316 317

317 Same patient as 316,T1W midline sagittal MRI shows the

thrombus in the sagittal sinus (arrows).There should normally be a flow
void in the sagittal sinus.

316 CT scan without contrast shows thrombosed sagittal and straight

sinuses (arrows) without any actual infarction complicating
meningococcal meningitis.

318, 319 MRI brain scans 318 319

showing an hypointense
(dark) (318), and
hyperintense (white) (319)
defect in the venous sinus at
the torcula (arrows) due to
loss of the flow void as a
result of venous sinus
thrombosis.
262 Vascular Diseases of the Nervous System

PATHOLOGY AND PATHOGENESIS of the periventricular white matter, rather than any atheroma
Parenchymal pathology of the large arteries which is variable in extent and severity.
The site of brain tissue loss is a more important determinant White matter lesions are found in about 80% of patients with
of cognitive function than the volume of tissue lost. vascular dementia, about 15% of patients with early-onset
Alzheimer’s disease and about 75% of patients with late-onset
Single strategically placed infarcts or hemorrhages Alzheimer’s disease. They are associated with hypertension
A single infarct or hemorrhage, if located in a strategically and, in some studies, with heart disease and diabetes. They
important part of the brain, such as the circuits involving the are thought to cause dementia by disconnecting the
dorsolateral frontal convexity-caudate nucleus-globus pathways between the cortical and subcortical areas.
pallidus-thalamus, can produce a vascular dementia.
Examples include infarction or hemorrhage of the: Diffuse laminar necrosis (global cerebral ischemia)
• Dominant angular gyrus, situated in the inferior parietal
lobule, usually by embolic occlusion of the angular branch Vascular pathology
of the inferior division of the MCA, and characterized by Hypoxic-ischemic lesions
the acute onset of fluent dysphasia, dysgraphia, memory • Large artery atherosclerosis.
loss and visuospatial disorientation. • Small vessel hyaline wall thickening (arteriolosclerosis),
• Thalamus, particularly the dominant dorsomedial microatheroma and lipohyalinosis.
thalamus, by occlusion of the paramedian thalamic • Embolism from the heart.
(thalamoperforate) branches of the posterior cerebral • Non-atheromatous angiopathies.
artery, causing memory loss, slowness, apathy, ocular – Granular degeneration of the media of small arteries
palsies, and drowsiness. (CADASIL).
• Caudate nucleus and globus pallidus, usually by – Cerebral vasculitis
thrombotic or embolic occlusion of the penetrating lateral – Neoplastic angioendotheliomatosis (malignant lymphoma
lenticulostriate branches of the middle cerebral artery. of blood vessels).
• Basal forebrain and dorsolateral pre-frontal cortex. – Mural dissections.
• Hippocampus, usually by embolic occlusion of the – Dural arteriovenous malformation.
cortical branches of the posterior cerebral artery, or • Hematologic disease (thrombophilia).
diffuse cerebral ischemia.
Hemorrhagic lesions
Multiple infarcts or hemorrhages • Subdural hematoma.
Cortical/subcortical infarcts or hemorrhages may cause a • SAH: anterior communicating artery aneurysm.
‘cortical’ type dementia with signs of amnesia, aphasia, • Intracerebral hemorrhage (see p.238):
apraxia, and agnosia. The infarcts are commonly the result – Amyloid angiopathy.
of thromboembolism from the heart or a large artery (aortic – Hypertensive small vessel disease.
arch, carotid and vertebrobasilar) to the anterior, middle, or
posterior cerebral arteries or their branches, but can also be RISK FACTORS FOR VASCULAR DEMENTIA
caused by large vessel disease causing hypoperfusion and Age and stroke are the most important risk factors for
infarcts in the borderzones between major arterial territories, developing dementia:
and small vessel disease such as microatheroma/lipo- • Increasing age;
hyalinosis and vasculitis. Multiple cortical/subcortical • Past history of stroke (symptomatic stroke increases the
hemorrhages are most commonly due to amyloid angiopathy risk of dementia more than ninefold) or myocardial
but can also be seen with vasculitis, bleeding diatheses, infarction (one-third of patients).
metastases, hemorrhagic infarction and trauma.
Small deep (‘lacunar’) infarcts may cause a ‘subcortical’ Other putatitive risk factors include:
dementia characterized by signs of psychomotor slowing, • Hypertension (60% of patients).
poor concentration, indecision and mental apathy. Other • Smoking (35%).
features, besides cognitive impairment, include hemiparesis, • Diabetes (20% of patients).
small stepping gait (marche á petits pas), dysarthria, and • Hyperlipidemia (20%).
dysphagia. Typical patients are elderly, ex- or current • Alcohol abuse.
smokers, with hypertension and diabetes. Rarely, they are • Family history (CADASIL).
part of the syndrome of cerebral autosomal dominant • Lower education level.
arteriopathy with subcortical infarcts and leuko- • Residing in a rural area.
encephalopathy (CADASIL), which is a hereditary disease • Living in an institution.
with linkage to chromosome 19, and features of a subcortical • Brain atrophy.
dementia, recurrent stroke-like events and visible white • Cortical infarcts.
matter lesions on brain imaging. • Brain white matter lesions.
• Left hemisphere stroke.
Diffuse white matter infarction • Early urinary incontinence.
(Subcortical arteriosclerotic leukocencephalopathy, • Falls.
Binswanger’s disease). Diffuse or multifocal, often • Abnormal EKG (80% of patients compared with 30% of
periventricular, areas of demyelination, axonal loss, and people with Alzheimer’s disease).
reactive gliosis in the white matter probably due to anoxia as
a result of arteriosclerotic changes (hyalinization, fibrosis and
thickening) in the long penetrating end arteries and arterioles
 Vascular Dementia
CLINICAL FEATURES
Slowly progressive intellectual impairment, with recurrent
stroke-like events.
History
• Presenting symptoms: sudden onset and stepwise course
of cognitive decline with history of transient ischemic
attacks, strokes, or both. Epileptic seizures occur in 10%
of patients. Incontinence of urine and feces is not
uncommon.
• Past history of vascular risk factors: hypertension,
diabetes, heart disease, smoking.
• Family history: CADASIL.
Neurologic examination
• Focal neurologic deficits such as pyramidal tract signs
(hemiparesis, extensor plantar response, pseudobulbar
palsy), extrapyramidal signs, hemisensory loss,
hemianopia, and dysarthria.
• Gait abnormality: start and turn hesitation, shuffling,
reduced arm swing.
• Grasp reflexes
• Hypertension and hypertensive retinopathy.
• A source of thromboembolism such as AF, valvular heart
disease, heart failure, carotid artery disease.
Neuropsychologic examination
• Essential to ascertain the presence or absence of a
cognitive deficit, the nature of the deficit (i.e. in what
domains) and the degree of the deficit.
• Concentration and executive function: poor learning
strategies, impaired word list generation, emotional
blunting and lability, poor insight and judgement.
• Memory: impaired learning of verbal and visual
information, reduced recall following a delay.
• Verbal output: dysarthria, reduced grammatical
complexity of spontaneous speech.
• Depression: present in 25% of patients; depressive
symptoms in 60%.
• Anxiety: common.
• Delusions: present in up to one-half of patients.
• Personality alterations: apathetic, listless, lifeless, quiet
and labile.
DIFFERENTIAL DIAGNOSIS
Vascular dementia and Alzheimer’s disease (mixed or
‘double dementia’)
Clinical course may be slowly progressive and it may be
difficult to interpret the relevance of brain lesions, consistent
with infarction, seen on neuroimaging (e.g. white matter
lesions).
Alzheimer’s disease (see p.407)
• More likely to have retrieval errors and irrelevant
intrusions on memory tests and to perform more poorly
on a story recall test.
• Less likely to have a history of previous strokes,
hypertension, and alcohol abuse, depression, or an
abnormal EKG (30% of cases).
263
Lewy body type dementia (see p.430)
• Marked fluctuations of symptoms.
• Prominent extrapyramidal signs, particularly rigidity and
bradykinesia.
• Early and florid visual hallucinations and delusions.
• Poor tolerance of neuroleptic drugs.
Parkinson’s disease dementia (see p.420)
• Possibly affects 10–20% of patients with Parkinson’s
disease.
• Dementia is subcortical (apathy, poor concentration,
indecision, slowness of central processing).
• Dementia is usually preceded by parkinsonian features.
• Gait changes of vascular dementia and Parkinson’s
disease closely resemble each other.
• Dopaminergic medication usually improves the
parkinsonian features.
Progressive supranuclear palsy (see p.432)
• Subcortical dementia.
• Preceding parkinsonian features.
• Paralysis of vertical gaze.
• Truncal ataxia.
• Parkinsonian features do not respond to dopaminergic
medication.
Multiple systems atrophy (see p.435)
• Dementia is slowly progressive.
• Accompanying signs of dysfunction of any or all of the:
– Pyramidal tract.
– Extrapyramidal system.
– Autonomic system.
– Cerebellum.
Frontal lobe tumors
Early symptoms may be behavioral disturbance (disinhibited
and irrational) or mental apathy and indecision. Later signs
may be those of raised intracranial pressure (see p.477).
Uncommon but treatable causes of dementia
• Hypothyroidism.
• Vitamin B12 deficiency.
• Neurosyphilis.
• Normal pressure hydrocephalus.
• Frontal lobe tumors.
• Cerebral ischemia due to cerebral vasculitis,
hyperviscosity syndrome and severe bilateral carotid
stenosis.
• HIV dementia (see p.301).
INVESTIGATIONS
CT or MR imaging of the brain
Excludes other causes of dementia (e.g. frontal tumor,
hydrocephalus) and almost always identifies one or more
vascular lesions. CT brain scan reveals more or less
symmetric periventricular and subcortical hypodensity in the
cerebral white matter, with or without ventricular dilatation
and focal hypodensities and thought to be due to ‘small
vessel’ ischemia and infarction.
264 Vascular Diseases of the Nervous System

MR T2W or proton density imaging demonstrates the Hachinski ischemia scale

same features even better as high signal areas (320, 321). Item Score value
These radiologic appearances (leukoaraiosis [leuko=white, Abrupt onset* 2
araiosis=rarefaction]) are rather non-specific and can be Stepwise course* 1
found in apparently normal elderly people. However, they Fluctuating course 2
are more commonly associated with gradual dementia, Preservation of personality 1
unsteadiness of gait, and recurrent ischemic, particularly Nocturnal confusion 1
lacunar, or occasionally hemorrhagic strokes, and are more Depression 1
frequent in patients with hypertension, other vascular risk Somatic complaints* 1
factors, atherosclerosis and cerebral atrophy. Emotional incontinence* 1
Additional features may include multiple small ‘holes’ in History of hypertension* 1
the basal ganglia and pons, and cortical infarcts may also be Evidence of associated atherosclerosis 1
present. History of stroke* 2
Focal neurologic symptoms* 2
Blood tests Focal neurologic signs* 2
• Full blood count and ESR.
• Plasma viscosity. *Discriminating items after validation at post mortem examination.
• Serum urea and electrolytes.
• Plasma glucose. A score of 7 or higher is said to be diagnostic of vascular dementia but
• Serum cholesterol and triglycerides. this scale has poor interrater reliability.
• Liver function tests.
• Serum protein electrophoresis. NINDS–AIREN CRITERIA FOR VASCULAR
• Antinuclear antibodies. DEMENTIA
• Thyroid function tests. Definite vascular dementia
• Syphilis serology. • Clinical criteria for probable vascular dementia.
• Vitamin B12. • Autopsy demonstration of appropriate ischemic brain
• Coagulation studies (younger patients) (see p.220): injury and no other cause of the dementia.
– Antiphospholipid antibodies.
– Proteins C and S. Probable vascular dementia
– Antithrombin III. Dementia
– Factor V Leiden mutation. • Decline from a previous higher level of cognitive
functioning.
Other • Impairment of two or more cognitive domains.
• EKG. • Deficits severe enough to interfere with activities of daily
• Echocardiography: if prosthetic heart valves, rheumatic living and are not due to physical effects of stroke alone.
valvular heart disease, or suspected left atrial myxoma. • Patients must not be delirious; must not have psychosis,
• Doppler ultrasonography of the carotid arteries. aphasia or sensory-motor impairment that precludes
• Single photon emission computed tomography (SPECT): neuropsychologic testing; and the patient must not have
asymmetric patchy areas of reduced cerebral blood flow. any other disorder capable of producing a dementia
• Positron emission tomography (PET): fluorodeoxyglucose syndrome.
PET reveals multifocal regions of reduced cerebral
metabolism (due to local infarction or a distant effect of Cerebrovascular disease
diaschisis) in contrast to symmetric biparietal • Focal neurologic signs consistent with stroke.
hypometabolism typically observed in Alzheimer’s disease. • Neuroimaging evidence of extensive vascular lesions.

DIAGNOSIS Relationship between the dementia and the

The purpose of the clinical and laboratory assessment is to
establish the diagnosis of vascular dementia, the cause of the
cerebrovascular disease, and other factors that may be
contributing to the cognitive compromise.
The diagnosis of vascular dementia is based on a decline
in cognitive function (dementia) that correlates with a clear
history of strokes. However, the association between
declining cognitive function (dementia) and cerebrovascular
disease may not be causal; it may be merely contributory or
even coincidental. Various diagnostic criteria exist to aid the
diagnosis but many have not been validated.
cerebrovascular disease
As evidenced by one or more of the following:
• Onset of dementia within 3 months of a recognized stroke.
• Abrupt deterioration, or fluctuating or stepwise
progression of the cognitive deficit.
Possible vascular dementia
• Dementia with focal neurologic signs but without
neuroimaging confirmation of definite cerebrovascular
disease.
• Dementia with focal neurologic signs but without a clear
temporal relationship between dementia and stroke.
• Dementia with focal neurologic signs but with a subtle
onset and variable course of cognitive deficits.
 Hypertensive Encephalopathy 265

TREATMENT HYPERTENSIVE ENCEPHALOPATHY

• Treat any underlying causes and risk factors that may be
remediable:
– Cerebral vasculitis: corticosteroids and cyclophosphamide.
– Hyperviscosity syndrome.
– Neoplastic angioendotheliomatosis: chemotherapy.
• Control vascular risk factors such as hypertension,
smoking, hypercholesterolemia and diabetes.
• Long term antiplatelet therapy such as low dose aspirin.
• Physiotherapy: gait, spasticity.
• Speech therapy: dysarthria, dysphasia, dysphagia.
• Psychologic therapy: visual-spatial neglect.
No benefit is obtained with hemorrheologic agents
(pentoxifylline), nootropic compounds (oxiracetam),
calcium channel blockers (nimodipine) or neuroprotective
agents.
CLINICAL COURSE AND PROGNOSIS
• Characteristically, a progressive stepwise course of
cognitive decline but in up to half of patients it can
follow a slow progressive course.
• 50% survival: 6.7 years (cf. 8.1 years for Alzheimer’s
disease).
• Cause of death: heart disease or recurrent stroke.
DEFINITION
A relatively rapidly evolving clinicoradiologic syndrome
caused by capillary leakage related to abrupt hypertension,
and characterized by confusion, cognitive changes, seizures
and sometimes cortical blindness; and MRI evidence of
diffuse or posterior (parieto-occipital) white matter changes.
EPIDEMIOLOGY
• Incidence: rare.
• Age: any age, mean age: 40 years.
• Gender: M=F.
PATHOLOGY
Macroscopic
The brain appears normal or shows evidence of cerebral
swelling or hemorrhages in various sizes. Brain hemorrhage
is not a sequela of the encephalopathy but is due to the
primary disease causing the encephalopathy or one of the
complications of the disease; so it is a complication of
uncontrolled hypertension, eclampsia and potential bleeding
disorders.
Microscopic
Widespread minute infarcts, with a predilection for the basis
pontis, due to fibrinoid necrosis of the walls of arterioles and
capillaries, and occlusion of their lumens by fibrin thrombi.
Similar vascular changes are found in other organs,
particularly the retinae and kidneys.

320 T2W MRI in a 78 year 320 321

old female with vascular
dementia due to
Binswanger’s disease. Note
the cerebral atrophy and the
diffuse hyperintense areas
adjacent to the frontal and
posterior horns of the lateral
ventricles, representing
subcortical ischemic
leukoencephalopathy due to
‘small vessel disease’.

321 T2W MRI at the level

of the lateral ventricles in a
75 year old female with
cognitive impairment due to
multi-infarct dementia. Note
the atrophy and multiple
hyperintense areas in the
periventricular white matter
in keeping with ‘small vessel
disease’.
266 Vascular Diseases of the Nervous System
ETIOLOGY
• Abrupt increase in blood pressure usually in patients with
known hypertension (most common). Encephalopathy
is rare in chronic hypertension unless the diastolic blood
pressure exceeds 20 kPa (150 mmHg) because the upper
limit of anticoagulation is ‘set’ higher.
• Renovascular hypertension.
• Parenchymal renal disease.
• Acute glomerulonephritis.
• Scleroderma and other connective tissue diseases.
• Vasculitis.
• Drugs: sympathomimetic agents (amphetamines,
cocaine, phencyclidine hydrochloride, lysergic acid
diethylamide, diet pills), tricyclic antidepressants.
• Ingestion of tyramine in conjunction with a monamine
oxidase inhibitor.
• Withdrawal of antihypertensive drugs (centrally acting
agents and beta-antagonists).
• Pre-eclampsia, eclampsia.
• Pheochromocytoma.
• Renin-secreting tumor.
• Head injury.
• Autonomic hyperactivity in Guillain–Barré or spinal cord
syndromes.
• Bilateral carotid endarterectomy (baroreceptor reflex
failure).
PATHOPHYSIOLOGY
Increases in circulating levels of vasoconstrictor substances,
such as norepinephrine, angiotensin II, or antinatriuretic
hormone lead to an abrupt increase in systemic vascular
resistance and blood pressure. Severely elevated blood
pressure precipitates endothelial damage, platelet and fibrin
deposition, arteriolar fibrinoid necrosis and loss of
autoregulatory function with resultant end-organ (brain,
retina, kidney, heart) ischemia. Ischemia, in turn, triggers
the further release of vasoactive substances, thus initiating
a vicious cycle of further vasoconstriction and myointimal
proliferation.
Failure of autoregulation of cerebral blood flow leads to
a breakdown of the blood–brain barrier with transudation
of fluid, causing widespread cerebral edema, and petechial
hemorrhages, sometimes culminating in frank, fatal
intracranial hemorrhage.
Encephalopathy may occur with a diastolic blood
pressure of 13.3 kPa (100 mmHg) or less if autoregulation
is normal and easily exceeded by a rapid rise in blood
pressure from a normally low level.
RISK FACTORS
• High blood pressure (e.g. poor antihypertensive drug
compliance or blood pressure control).
• Pre-existing dysfunction of the vascular endothelium, as
may occur in pre-eclampsia and eclampsia or with
immunosuppressive therapy, may predispose patients to
failure of autoregulation and encephalopathy after
relatively slight increases in blood pressure.
CLINICAL HISTORY
• Subacute onset:
– Headache: severe.
– Nausea, vomiting.
– Confusion.
– Declining conscious state.
– Blurred vision or blindness.
– Seizures: partial or generalized.
– Weakness: focal or generalized.
• Past history of hypertension: duration, severity and level
of control.
• Extent of pre-existing end-organ damage (heart, brain,
retina, kidneys).
• Coexisting acute or chronic illnesses.
• Family history of hypertension.
• Medications: prescription, over-the-counter, illicit;
antihypertensive drug compliance.
EXAMINATION
• Disorientation.
• Obtundation.
• Focal neurologic signs (e.g. cortical blindness due to
bilateral occipital lobe dysfunction).
• Seizures: generalized or focal.
• Hypertensive retinopathy (including papilledema) (322,
323).
• Pulses (if unequal, suspect aortic dissection).
• Blood pressure supine and erect: can be apparently
normal, particularly in young or pregnant patients in
whom the base-line pressures are normally low. A single
blood pressure reading may be deceptive. Blood pressure
should be measured frequently and compared with base-
line values.
• Cardiac and chest auscultation (suspect congestive heart
failure).
DIFFERENTIAL DIAGNOSIS
• Stroke: there may be doubt about the onset of symptoms
(i.e. if the patient is confused or obtunded), the blood
pressure may be only moderately elevated, and focal or
lateralizing neurologic signs may accompany the
symptoms of more diffuse brain disturbance (headache,
confusion, visual disturbances, and seizures). Even a
severely elevated blood pressure is not specific because it
can be a consequence of stroke and a cause of stroke.
• SAH.
• Epilepsy.
• Encephalitis.
• Vasculitis of the CNS.
• Brain tumor.
• Reversible posterior multifocal leukoencephalopathy:
– Puerperal eclampsia.
– Renal failure.
– Immunosuppressive agent treatment: cyclosporin: has
direct toxic effects on vascular endothelial cells;
interferon-alfa; tacrolimus; levamisole; fluorouracil.
• Multiple sclerosis.
• Progressive multifocal leukoencephalopathy.
 Hypertensive Encephalopathy
INVESTIGATIONS
Imaging
CT or MRI brain scan
Scans may show:
• Areas of infarction/ischemia in the distribution of an
arterial territory.
• Typical areas of involvement are the posterior parieto-
occipital lobes bilaterally.
• The abnormalities may resolve as the patient recovers.
• MRI is more sensitive than CT to these changes, but
confused patients tolerate MRI less well than CT.
Causes and consequences of hypertension
• FBP.
• ESR: ?arteritis.
• Serum urea and electrolytes: ?hypernatremia,
?hypokalemia, ?renal impairment.
• Urinalysis: blood, protein, casts, glomerular red blood
cells, 24 hour urinary catecholamines.
• EKG: left ventricular hypertrophy.
• Chest x-ray: cardiomegaly, coarctation of the aorta.
• Renal ultrasound.
• Antinuclear antibodies.
DIAGNOSIS
A diagnosis of exclusion, requiring that the differential
diagnoses (above) be ruled out.
TREATMENT
The goal of therapy is to reduce systemic vascular resistance
and thus reduce the mean arterial pressure gradually by no
more than 20–25% or to a diastolic blood pressure of
13.3 kPa (100 mmHg), whichever value is higher, during
the first hour. The reason for the cautious reduction is
because the lower limit of cerebral bloodflow autoregulation
is reached when blood pressure is reduced by about one-
quarter and rapid reductions of blood pressure by more
than a half can precipitate cerebral ischemia or infarction.
The patient should be placed on a cardiac monitor and
intravenous access established.
322
322 Optic fundus showing papilledema, narrow arterioles, and a
macular star in a patient with hypertensive encephalopathy.
267
Hospital admission, preferably to an intensive care unit,
should be arranged. An arterial line should be placed as
soon as possible to confirm the cuff readings and to guide
therapy (along with the clinical response).
Sodium nitroprusside is the drug of choice. It is
administered by continuous infusion (0.5–10 μg/kg/min)
and therefore the blood pressure demands constant
surveillance, preferably intra-arterially. Adverse effects
include hypotension, nausea, vomiting, and apprehension.
Effective alternatives include labetalol (20–80 mg i.v.
bolus every 5–10 min, up to 300 mg; onset in 5–10 min,
duration of action 3–6 hours), diazoxide (50–100 mg i.v.
bolus every 5–10 min up to 600 mg; onset in 1–5 min,
duration of action 6–12 hours), and nifedipine sublingually,
but the latter can cause precipitous falls in blood pressure.
Clonidine and methyldopa should be avoided because they
depress the CNS, making it difficult to distinguish further
CNS deterioration.
Diuretics and fluid restriction should not be prescribed
routinely because most patients are volume depleted,
presumably due to a pressure-related diuresis.
If neurologic function deteriorates after blood pressure
reduction, antihypertensive therapy should be suspended
and the blood pressure allowed to increase. Subsequent
blood pressure reductions should be effected more slowly.
Magnesium sulfate intravenously is effective for eclampsia.
A loading dose of phenytoin 15–18 mg/kg (no faster than
50 mg/min) may be required if seizures occur.
PROGNOSIS
Usually reversible within hours of controlling the blood
pressure, but the course can be prolonged for days to weeks.
If the hypertension cannot be controlled, the outcome is
usually fatal.
323
323 Optic fundus showing features of grade IV hypertensive
retinopathy (malignant hypertension): superficial flame-shaped retinal
hemorrhages near the optic disc, soft exudates, retinal edema and
papilledema. (Courtesy of Mr M Wade, Department of Medical
Illustrations, Royal Perth Hospital,Western Australia.)
268 Vascular Diseases of the Nervous System

PITUITARY APOPLEXY 324

DEFINITION
Acute massive infarction or hemorrhage of the pituitary
gland.

EPIDEMIOLOGY
• Incidence: rare but probably underestimated because of
incomplete non-fatal pituitary infarction. Infarction of
more than 25% of the pituitary gland is reported to be
present in 1–3% of patients in large unselected autopsy
series.
• Age: evenly distributed between 20 and 70 years of age;
range 6–83 years. 324 Facial appearance of a patient with Cushing’s disease due to an
• Gender: M>F (2:1). ACTH-producing pituitary adenoma (which bled) featuring obesity,
hirsutism (a fine ‘downy’ coat), plethora and ecchymoses (due to
ANATOMY weakening and rupture of collagenous fibers in the dermis, exposing
Arterial blood supply to the pituitary: internal carotid artery heavily vascularized subcutaneous tissues).
via the superior and inferior hypophyseal arteries bilaterally.

PATHOLOGY VI; sympathetic chain; internal carotid and branches;

• Pituitary infarction (sometimes hemorrhagic) or hemorr- hypothalamus), leakage of blood or necrotic tissue into the
hage, most often in an enlarging pituitary adenoma. subarachnoid space and compromise of neurologic function.
• The pituitary may or may not have a pre-existing tumor, The initial event in post partum pituitary necrosis is
and if present, the tumor may be primary or metastatic. probably occlusive arterial spasm of the arteries to the anterior
• Primary pituitary tumors are most commonly a pituitary lobe and stalk. After a period of total ischemia, attempts at re-
adenoma. establishment of circulation subsequently lead to vascular
• Chromophobe adenomas predominate over eosinophilic congestion and thrombosis of the anterior lobe. The inferior
adenomas, merely reflecting the relative prevalence of hypophyseal arterial flow is relatively spared accounting for the
these tumors. Rarely, basophilic adenomas, cranio- preservation of the infundibular process in most circumstances.
pharyngiomas, and primary pituitary carcinoma occur.
• Metastatic pituitary tumors are most commonly breast CLINICAL FEATURES
and lung cancers, in patients with widespread disease. There are three main clinical syndromes.
• Most pituitary tumors are endocrinologically silent; a
minority are hormone-secreting: acromegaly, Cushing’s Acute apoplexy
disease. • Sudden severe retro-orbital headache.
• Cranial nerve dysfunction:
ETIOLOGY – II: impaired visual acuity; visual field defects (chiasmal
Predisposing factors compression).
• Pituitary tumor of any type. – III, IV, VI: ophthalmoplegia, diplopia.
• Pregnancy. – V1: facial pain.
• Diabetes. • Proptosis.
• Following obstetric hemorrhage: infarction of non- • Eyelid edema.
tumorous pituitary. • Horner’s syndrome.
• Raised intracranial pressure. • Nausea and vomiting.
• Bleeding disorders. • Altered consciousness, progressing to coma.
• Anticoagulants. • Focal hemispheric dysfunction: hemiparesis, seizures
• Upper respiratory infections. (carotid sinus compression, vasospasm due to SAH).
• Radiation therapy of pituitary tumors. • Fever.
• Trauma.
• Carotid angiography. Subacute meningeal irritation (blood/necrotic tumor
• Atherosclerosis. in subarachnoid space)
• Sickle cell trait. • Fever.
• Acromegaly. • Neck stiffness.
• Cushing’s disease (324). • Encephalopathy.
• Adrenalectomy.
• Mechanical ventilation. Subacute or chronic pituitary insufficiency months or
years after the event
PATHOPHYSIOLOGY • Diabetes insipidus (uncommon).
Infarction of the pituitary with secondary hemorrhage and • Syndrome of inappropriate antidiuretic hormone secretion.
edema destroys the pituitary and causes rapid expansion of the • Anterior hypopituitarism:
pituitary lesion, acute compression of adjacent structures (optic – Absence of lactation.
chiasm and tracts; cavernous sinus; cranial nerves III, IV, V, – Persistent amenorrhea.

– Lethargy.
– Acute or delayed adrenal failure.
DIFFERENTIAL DIAGNOSIS
• Meningitis: viral, bacterial.
• Meningoencephalitis: viral, bacterial.
• Brain abscess.
• Cavernous sinus thrombosis.
• Carotid aneurysm.
• SAH: the association of SAH with ocular motor palsies in
pituitary apoplexy can be distinguished from SAH due to
rupture of an aneurysm by the presence of mixed, and
usually, bilateral ophthalmoplegias, multiple cranial nerve
palsies, and the presence of an afferent pupillary defect or
chiasmal pattern of field loss with pituitary apoplexy,
although the latter goes unnoticed in obtunded patients.
• Intracerebral hemorrhage.
• Transtentorial uncal herniation.
• Mesencephalic infarction.
• Parasellar tumor (meningioma or nasopharyngeal tumor).
• Metastatic pituitary tumors.
INVESTIGATIONS
Cranial CT or MRI brain scan
Plain scans often show a midline, hyperdense mass in the
pituitary fossa and an expanded sella due to hemorrhagic
infarction of the pituitary gland. The mass may compress
the cavernous sinus and optic chiasm. Subarachnoid blood
may be evident. The CT scan may be normal initially
however, in patients with small pituitary tumors in whom
radiographs of the pituitary fossa are also normal.
Hypothalamic and pituitary function tests
• Luteinizing hormone.
• Follicle stimulating hormone.
• Thyrotrophin (thyroid stimulating hormone).
• Growth hormone.
• Prolactin: low prolactin is very characteristic.
• Adrenocorticotropin.
• Cortisol.
• Thyroid-releasing and gonadotrophin-releasing hormone
stimulation tests.
FURTHER READING
NEUROVASCULAR SYNDROMES
Bamford J, Sandercock P, Dennis M, Burn J, Warlow
C (1991) Classification and natural history of
clinically identifiable subtypes of cerebral infarction.
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Tatu L, Moulin T, Bogousslavsky J, Duvernoy H
(1996) Arterial territories of the human brain:
Brainstem and cerebellum. Neurology, 47:
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Tatu L, Moulin T, Bogousslavsky J, Duvernoy H
(1998) Arterial territories of the human brain.
Cerebral hemispheres. Neurology, 50: 1699–1708.
TRANSIENT ISCHEMIC ATTACKS (TIA) OF THE
BRAIN AND EYE
General
Albers GW, Hart RG, Lutsep HL, et al. (1999)
Supplement to the guidelines for the management
of transient ischemic attacks. A statement from the
Ad Hoc Committee on Guidelines for the manage-
ment of transient ischemic attacks, Stroke Council,
American Heart Association. Stroke, 30:
2502–2511.
Further Reading 269
CSF
• Cells: may contain red and/or white blood cells, and
necrotic tumor cells.
• Protein: mildly elevated.
• Gram stain, microscopy for organisms, and culture: negative.
Cerebral angiography
Used if an intracavernous carotid aneurysm needs to be
excluded.
TREATMENT
Vigorous support
• Careful evaluation and monitoring of hormonal status.
• Immediate corticosteroid therapy in ‘stress dosages’
(hydrocortisone 100 mg i.v. every 6–8 hours) due to the
high incidence of acute adrenal insufficiency, and other
hormone replacement as appropriate.
• Fluid and electrolyte balance (cf. adrenal insufficiency,
diabetes insipidus).
• Conservative management if consciousness, vision and
endocrine function are maintained.
Surgery
Early transphenoidal neurosurgical decompression of tissues
compromised by the rapidly expanding intrasellar mass is
indicated if symptoms progress such as deteriorating visual
acuity, declining consciousness, or evidence of hypothalamic
damage.
PROGNOSIS
• Highly variable and unpredictable clinical course.
• Potentially fatal.
• Ophthalmoplegia often resolves spontaneously but
recovery of vision is optimized by early decompression.
• Multiple pituitary hormone deficiencies occur in most
patients after pituitary apoplexy and if unrecognized may
contribute to morbidity and mortality.
Hankey GJ (2001) Management of the first-time TIA.
Emergency Medicine, 13: 72–84.
Antiplatelet therapy
Algra A, van Gijn J (1996) Aspirin at any dose above
Hankey GJ, Warlow CP (1994) Transient ischaemic 30 mg offers only modest protection after cerebral
attacks of the brain and eye. WB Saunders/Ballière ischaemia. J. Neurol. Neurosurg. Psychiatry, 60:
Tindall, London. 197–199.
Wolf PA, Clagett P, Easton JD, et al. (1999) Algra A, van Gijn J, Koudstaal PJ (1999) Secondary
Preventing ischemic stroke in patients with prior prevention after cerebral ischaemia of presumed
stroke and transient ischemic attack. A statement arterial origin: is aspirin still the touchstone? J.
for healthcare professionals from the Stroke Council Neurol. Neurosurg. Psychiatry, 66: 557–559.
of the American Heart Association. Stroke, 30: Antiplatelet Trialists' Collaboration (1994) Collaborative
1991–1994. overview of randomised trials of antiplatelet therapy-I:
Prevention of death, myocardial infarction, and stroke by
Epidemiology prolonged antiplatelet therapy in various categories of
Brown RD, Petty GW, O’Fallon WM, et al. (1998) patients. BMJ, 308: 81–106.
Incidence of transient ischemic attack in Rochester, Derry S, Loke YK (2000) Risk of gastrointestinal
Minnesota, 1985–1989. Stroke, 29: 2109–2113. haemorrhage with long term use of aspirin: meta-
analysis. BMJ, 321: 1183–1187.
Diagnosis De Schryver ELLM, on behalf of the European/ Australian
Gunatilake S (1998) Rapid resolution of symptoms Stroke Prevention in Reversible Ischaemia Trial
and signs of intracerebral haemorrhage: case (ESPRIT) Group (2000) Design of ESPRIT: An
reports. BMJ, 316: 1495–1496. international randomised trial for secondary prevention
Prognosis after non-disabling cerebral ischaemia of arterial origin.
Johnston SC, Gress DR, Browner WS, Sidney S Cerebrovasc. Dis., 10: 147–150.
(2000) Short-term prognosis after emergency Hankey GJ, Sudlow CLM, Dunbabin DW (2000)
department diagnosis of TIA. JAMA, 284: Thienopyridines or aspirin to prevent stroke and
2901–2906. other serious vascular events in patients at high risk
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270 Vascular Diseases of the Nervous System
Mohr JP, Thompson JLP, Lazar RM, et al. (2001) A
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The Stroke Prevention in Reversible Ischemia Trial
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of anticoagulants versus aspirin after cerebral is-
chemia of presumed arterial origin. Ann. Neurol.,
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Wilterdink JL, Easton JD (1999) Dipyridamole plus
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Carotid revascularization
Alamowitch S, Eliasziw M, Algra A, et al. (2001) Risk,
causes, and prevention of ischaemic stroke in elderly
patients with symptomatic internal-carotid-artery
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Barnett HJM, Taylor DW, Eliasziw M, et al. for the North
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Benavente O, Moher D, Pham B (1998) Carotid
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Biller J, Feinberg WM, Castaldo JE, et al. (1998)
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Pritz MB (1997) Timing of carotid endarterectomy
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Rothwell PM, Warlow CP (1995) Is self-audit reliable?
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Rothwell PM, Warlow CP (1999) Prediction of benefit from
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STROKE
General
Hankey GJ, Warlow CP (1999) Treatment and
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Hankey GJ (2002) Stroke: Your Questions Answered.
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Epidemiology
Chang CL, Donaghy M, Poulter N, et al. (1999)
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Gillum LA, Mamidipudi SK, Johnston SC (2000)
Ischemic stroke risk with oral contraceptives. A meta-
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Sudlow CLM, Warlow CP, for the International Stroke
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Pathophysiology
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Kristián T, Siesjö BK (1998) Calcium in ischemic cell
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Imaging
Culebras A, Kase CS, Masdeu JC, et al. (1997) Practice
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Keir SL, Wardlaw JM (2000) Systematic review of
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Markus HS (1999) Transcranial Doppler ultrasound. J.
Neurol. Neurosurg. Psychiatry, 67: 135–7.
Wardlaw JM (2001) Radiology of stroke. J. Neurol.
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Barber PA, Demchuk AM, Zhang J, Buchan AM (2000)
Validity and reliability of a quantitative computed
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Brott T, Bogousslavsky J (2000) Treatment of acute
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Chen Z, Sandercock P, Pan H, et al. (2000) Indications
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Davenport R, Dennis M (2000) Neurological emergencies:
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European Stroke Initiative (2000) European Stroke
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Gorelick P (2000) Neuroprotection in acute ischaemic
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Gubitz G, Counsell C, Sandercock P, Signorini D
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Stroke Unit Trialists’ Collaboration (2001) Organised
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Kim JS (2001) Delayed onset mixed involuntary
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O’Connell JE, Gray CS (1994) Treating hypertension
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Smith Hammond CA, Goldstein LB, Zajac DJ, et al.
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Rehabilitation
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three doses of botulinum toxin type A (Dysport) with
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Kwakkel G, Wagenaar C, Koelman TW, et al. (1997)
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Community care
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Mant J, Carter J, Wade DT, Winner S (2000) Family
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Prognosis and prognostic factors
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of raised plasma osmolality on clinical outcome after acute
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Hajat C, Hajat S, Sharma P (2000) Effects of poststroke
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Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill
PW, Anderson CS, Stewart-Wynne EG (1998) Long-
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Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill
PW, Anderson CS, Stewart-Wynne EG (2000) Five-
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Langhorne P, Tong BLP, Stott DJ (2000) Association
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Secondary prevention
Blood Pressure Lowering Trialists’ Collaboration (2000)
Effects of ACE inhibitors, calcium antagonists, and other-
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Bucher HC, Griffith LE, Guyatt GH (1998) Effect of HMG
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The Heart Outcomes Prevention Evaluation Study
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The INDANA (Individual Data Analysis of
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See TIA (above) for further reading about antiplatelet
therapy and carotid revascularization, and
Cardioembolic stroke (below) for further reading about
anticoagulation.
Miscellaneous
Yonehawa Y, Taub E (1999) Moyamoya disease: status
1998. The Neurologist, 5: 13–23.
ATHEROSCLEROTIC ISCHEMIC STROKE
The French Study of Aortic Plaques in Stroke Group
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Atherosclerotic plaque
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Inflammation
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Davies P (1998) Chlamydia pneumoniae antibody
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DeGraba TJ (1997) Expression of inflammatory mediators
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bacterial and viral infection is a risk factor for
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Koenig W (2000) Heart disease and the inflammatory
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Markus HS, Mendall MA (1998) Helicobacter pylori
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Further Reading
Ross R (1999) Atherosclerosis – an inflammatory disease.
N. Engl. J. Med., 340: 115–126.
Rothwell PM, Villagra R, Gibson R, Donders RCJM,
Warlow CP (2000) Evidence of a chronic systemic
cause of instability of atherosclerotic plaques. Lancet,
355: 19–24.
Wald NJ, Law MR, Morris JK, Zhou X, Wong Y, Ward
ME (2000) Chlamydia pneumoniae infection and
mortality from ischaemic heart disease: large
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Thrombosis
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Haematol., 29(3): 159–69.
Coller BS (1997) Platelet GPIIb/IIIa antagonists: the first
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of blood coagulation. N. Engl. J. Med., 326: 800–806.
Hirsh J, Weitz JI (1999) New antithrombotic agents.
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Rosenberg RD, Rosenberg JS (1984) Natural
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Topol EJ, Byzova TV, Plow EF (1999) Platelet GPIIb-
IIIa blockers. Lancet, 353: 223–227.
van Kooten F, Ciabattoni G, Patrono C, Dippel DW,
Koudstaal PJ (1997) Platelet activation and lipid
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Stroke, 28: 1557–1563.
Clinical
Min WK, Park KK, Kim YS, et al. (2000)
Atherothrombotic middle cerebral artery territory
infarction. Topographic diversity with common
occurrence of concomitant small cortical and
subcortical infarcts. Stroke, 31: 2055–2061.
CARDIOEMBOLIC STROKE
General
Oppenheimer SM, Lima J (1998) Neurology and the
heart. J. Neurol. Neurosurg. Psychiatry, 64: 289–97.
Atrial fibrillation
Yamanouchi H, Nagura H, Mizutani T, et al. (1997)
Embolic infarction in nonrheumatic atrial fibrillation:
A clinicopathologic study in the elderly. Neurology,
48: 1593–1597.
Other embolic sources
De Castro S, Cartoni D, Fiorelli M, et al. (2000)
Morphological and functional characteristics of
patent foramen ovale and their embolic implications.
Stroke, 31: 2407–2413.
Freed LA, Levy D, Levine RA, et al. (1999) Prevalence
and clinical outcome of mitral-valve prolapse. N.
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Gilon D, Buonanno FS, Joffe MM, et al. (1999) Lack
of evidence of an association between mitral-valve
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Med., 341: 8–13.
Libman R, Wein T (1999) ‘Newer’ cardiac sources of
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Mas J-L, Arquizan C, Lamy C, et al. (2001) Recur-
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Imaging
Blackshear JL, Brott TG (1999) Transesophageal
echocardiography in source-of-embolism evaluation:
the search for a better therapeutic rationale. Mayo Clin.
Proc., 74: 941–945.
Channon KM, Banning AP (1999) Echocardiography in
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Acute treatment
Berge E, Abdelnoor M, Nakstad PH, et al. (2000)
Low molecular-weight heparin versus aspirin in
patients with acute ischaemic stroke and atrial
fibrillation: a double-blind randomised study.
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Secondary prevention
Cromheecke ME, Levi M, Colly LP (2000) Oral
anticoagulation self-management and management by a
specialist anticoagulation clinic: a randomised cross-over
comparison. Lancet, 356: 97–102.
EAFT (European Atrial Fibrillation Trial) Study Group
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271
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Lip GYH (1999) Thromboprophylaxis for atrial fibrillation.
Lancet, 353: 4–6.
Thomson R, Parkin D, Eccles M, et al. (2000) Decision
analysis and guidelines for anticoagulant therapy to
prevent stroke in patients with atrial fibrillation. Lancet,
355: 956–962.
INFECTIVE ENDOCARDITIS
Dajani AS, Bisno AL, Chung KJ, et al. (1990) Prevention
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1318–1330.
ANTIPHOSPHOLIPID SYNDROME AND OTHER
PROTHROMBOTIC STATES
Bushnell CD, Goldstein LB (2000) Diagnostic testing
for coagulopathies in patients with ischemic stroke.
Stroke, 31: 3067–3078.
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CENTRAL NERVOUS SYSTEM VASCULITIS
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Interferon alfa-2b, colchicine, and benzathine penicillin
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PRIMARY INTRACEREBRAL HEMORRHAGE
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ARTERIOVENOUS MALFORMATION
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The Arteriovenous Malformation Study Group (1999)
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SUBARACHNOID HEMORRHAGE
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UNRUPTURED ANEURYSMS HYPERTENSIVE ENCEPHALOPATHY
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CEREBRAL VENOUS THROMBOSIS
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VASCULAR DEMENTIA
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Pathogenesis
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 Chapter Eleven 273

Infections of the
Nervous System
BACTERIAL INFECTIONS

ACUTE PYOGENIC (BACTERIAL) • Incidence rates are influenced by country, ethnic group,
MENINGITIS social class and deprivation, and immunization
programmes.
• Lifetime prevalence: 1(95% CI: 0.8–2) per 1000.
DEFINITION • Age: any age (see Table 33); most common in the first
Inflammation of the leptomeninges (pia and arachnoid month of life.
membranes) caused by bacterial infection.

EPIDEMIOLOGY
• Annual incidence: 1.9 per 100 000 for Neisseria menin-
gitidis; 1.6 per 100 000 for Haemophilus influenzae; 1.0
per 100 000 for Streptococcus pneumoniae.

Table 33 Empirical therapy for suspected bacterial meningitis*

Age Likely bacterial pathogens Empirical therapy**

0–4 weeks Escherichia coli (50%) Amoxycillin + cefotaxime, or amoxycillin + aminoglycoside
Group B Streptococci(30%)
Listeria monocytogenes (10%)
Klebsiella pneumoniae
4–12 weeks Escherichia coli Amoxycillin + a third generation cephalosporin
Group B Streptococci (S. agalactiae) (cefotaxime or ceftriaxone)
Listeria monocytogenes
Haemophilus influenzae
Streptococcus pneumoniae
Neisseria meningitidis
3 months–18 years Haemophilus influenzae Third generation cephalosporin (cefotaxime or ceftriaxone)
Neisseria meningitidis ± amoxycillin***, or amoxycillin + chloramphenicol
Streptococcus pneumoniae
18–50 years Streptococcus pneumoniae (40%) Third generation cephalosporin (cefotaxime or ceftriaxone)
Neisseria meningitidis (30%) ± amoxycillin**
>50 years Streptococcus pneumoniae Amoxycillin + a third generation cephalosporin
Neisseria meningitidis (cefotaxime or ceftriaxone)
Aerobic Gram-negative bacilli
Listeria monocytogenes
*Applies only to the immunocompetent patient
**Add vancomycin to empirical regime when pneumococcal meningitis highly resistant to penicillin or cephalosporin is suspected
***Add if L. monocytogenes meningitis suspected (i.e. deficiencies in cell-mediated immunity)
274 Infections of the Nervous System: Bacterial
PATHOLOGY
The fundamental process is inflammation of the lepto-
meninges (325, 326). Complications include vasculitis,
cerebral infarction, hydrocephalus (327), brain abscesses,
and cerebral edema.
ETIOLOGY
The most common organisms causing meningitis are:
• Haemophilus influenzae: 45% of cases.
• Streptococcus pneumoniae (pneumococcus): 18%.
• Neisseria meningitidis (meningococcus): 14%.
However, there are important differences in the patterns
of organisms encountered in different age groups (see Table
33). Listeria monocytogenes, although uncommon, occurs
especially during pregnancy and the neonatal period.
Among neonates (<1 month of age), group B streptococci
(S. agalactiae) and coliforms (particularly Escherichia coli,
but also Proteus and Pseudomonas) predominate.
In the 1980s, H. influenzae was the most common cause
of meningitis in children 1 month–4 years of age, N.
325
325 Base of the brain of a patient who died from acute pyogenic
meningitis showing purulent meningeal exudate. (Courtesy of
Professor BA Kakulas, Royal Perth Hospital,Western Australia.)
326 Histologic section of the meninges and cerebral cortex of a
patient who died of acute pyogenic meningitis showing neutrophilic
infiltration of the subarachnoid space, pia, arachnoid and
Virchow–Robin spaces of the outer part of the brain. Bacteria are
numerous, lying free in the subarachnoid space and inside neutrophilic
leukocytes (phagocytosis).
327 CT brain scan showing early hydrocephalus in a patient with
pneumococcal meningitis.Their symptoms had started 18 hours
previously.
meningitidis predominated in older children and young
adults (5–29 years old) and S. pneumoniae in older adults.
During the 1990s widespread use of conjugate H.
influenzae type b (Hib) vaccines, consisting of protein
combined with the Hib polysaccharide capsule, has virtually
eliminated Hib disease from several developed countries
(and is now being introduced in developing countries). This
reduction means that S. pneumoniae and N. meningitidis
have become the predominant causes of meningitis in
children. There are at least 13 known groups of
meningococcal disease, but the most important are group
B (which is the most common, accounting for about 60%
of cases) and group C (which accounts for about 40% of
cases and causes most deaths). Meningitis due to
meningococcus group C is most common in babies, and
next most common in adolescents (15–17 years old). A
second epidemiologic trend is the worldwide increase in
infection with strains of S. pneumoniae that are resistant to
penicillin and other β-lactam antibiotics, mediated by
alterations in the penicillin-binding proteins involved in the
synthesis of bacterial cell walls.
326
327
 Acute Pyogenic (Bacterial) Meningitis
Risk factors
CSF leak due to:
• Recent craniotomy: risk of staphylococcal meningitis.
• Recent open skull fracture: risk of pneumococcal meningitis,
and Gram-negative bacillary (coliform) pathogens, such as
Klebsiella spp., E. coli and Pseudomonas spp.
PATHOGENESIS
Organisms may reach the meninges by direct spread from
adjacent structures in the skull and spine (middle ear,
paranasal sinuses, skull fractures) and via the blood stream.
Bacterial cell wall materials and bacterial products such
as endotoxin stimulate the local release of proinflammatory
cytokines such as tumor necrosis factor alpha, interleukin 1
and interleukin 6 from host cells and thereby initiate the
inflammatory response. Hyperemia of the meninges is
followed by migration of neutrophils into the walls of blood
vessels and into the subarachnoid space where the
inflammatory infiltrate extends along cranial and spinal
nerves. Foci of necrosis develop in vessel walls, sometimes
with thrombosis sufficient to cause cerebral infarction and
seizures. Fibrino-purulent exudate accumulates in the
subarachnoid space and may block the flow of CSF at the
328, 329 328
Purpuric skin rash.
Rash in an
unconscious child
(328) and adult
(329) with
meningococcal
meningitis and
septicemia.
(Courtesy of Dr
AM Chancellor,
Tauranga, New
Zealand.)
329
275
base of the brain or in the arachnoid granulations causing
hydrocephalus. Infection may become loculated to form
abscesses. Cerebral edema may develop also and raise
intracranial pressure.
CLINICAL FEATURES
Meningeal inflammation
Fever, headache, meningismus (neck stiffness), and signs of
cerebral dysfunction (confusion, delirium, vomiting or
declining consciousness) are found in about 85% of patients
at presentation. Meningismus is accompanied by Kernig’s
and/or Brudzinski signs in about half of adults.
Complications
• Cranial nerve palsies, particularly nerves III, IV, VI and
VII (30% of cases).
• Deafness due to cochlear damage either by a direct effect of
bacterial toxins or by an indirect cytokine-mediated effect.
• Epileptic seizures (30%) or focal neurologic signs
(10–20% of cases), due to inflammation and thrombosis
of cortical arteries and veins and venous sinuses (causing
cerebral infarction), or subdural effusion.
• Signs of increased intracranial pressure (coma, cranial nerve
III palsy, hypertension, bradycardia) due to hydrocephalus
or cerebral edema, or subdural effusion. Papilledema is
unusual at presentation (<1% of cases), and should suggest
an alternative diagnosis at that time, but is more common
among acutely ill patients who are deteriorating.
ETIOLOGIC CLUES
• Sources of infection: evidence of suppuration may be
present in the ears (otitis media), paranasal sinuses, skin,
lungs, and heart (infective endocarditis).
• Skin rash: primarily on the limbs, that is typically
erythematous and macular early in the infection, but may
quickly evolve into a petechial phase with further
coalescence into a purpuric form, is present in about 50%
of patients with meningococcemia, with or without
meningitis (328, 329).
• Features of a rhombencephalitis, such as ataxia, cranial
nerve palsies, and nystagmus early in the clinical course
may indicate Listeria monocytogenes meningitis.
Atypical presentations
Neonates and infants
Change in affect or state of alertness, irritability, lethargy,
listlessness, feeding difficulties, weak suck, high-pitched
crying, fretfulness, vomiting, diarrhea, respiratory distress,
temperature instability (fever or hypothermia), or jaundice.
Neck stiffness may be absent. A bulging fontanelle is found
in one-third of cases and usually occurs late in the course of
the illness.
Elderly patients (particularly with diabetes or
cardiopulmonary disease)
May present insidiously with lethargy or obtundation, no
fever, and variable signs of meningeal inflammation.
Neutropenic patients
Symptoms and signs may be subtle because of the impaired
ability to mount an inflammatory response in the
subarachnoid space.
276 Infections of the Nervous System: Bacterial

DIFFERENTIAL DIAGNOSIS Other

Meningitis due to non-bacterial causes
Aseptic meningitis (see p.291)
The physical signs are not so marked and the illness is not
as severe and prolonged as bacterial meningitis. A CSF
finding of >2000 white cells/mm3, >1180 neutro-
phils/mm3, protein >22 g/l (>220 mg/dl), glucose
<1.9 mmol/l (<34 mg/dl), or a glucose ratio below 0.23
are individual CSF predictors of bacterial, rather than viral
meningitis, with 99% certainty or better.
Tuberculous meningitis
CSF white cell count predominantly lymphocytic and seldom
>1000/mm3; CSF protein can be very high (>10 g/l
[1000 mg/dl]).
Fungal meningitis (Cryptococcus neoformans, Candida,
aspergillus, histoplasma)
Insidious onset, often immunosuppressed (HIV infection,
lymphoma, leukemia, other malignancies), with capsular
antigen present in serum and CSF.
Protozoal meningitis
Toxoplasmosis causes meningo-encephalitis and brain
abscesses in people who are usually immunosuppressed with
HIV infection, malignancy or immunosuppressive therapy.
• Subarachnoid hemorrhage (see p.249).
• Acute prolapsed cervical disc (see pp.545, 550).
• Brain abscess and subdural empyema (see p.284).
• Migraine (see p.95).
• Acute tonsillitis, parotitis, cervical lymphadenitis and
pneumonia: may cause neck pain in children but
meningism is uncommon.
INVESTIGATIONS
Brain imaging
The imaging modality of choice is either CT or MRI; typically
neither will show any abnormality in the early stages of uncom-
plicated meningitis. The main reason for imaging in suspected
meningitis is to exclude other causes of headache, focal
neurologic signs or papilledema (such as a mass lesion), and to
ensure that it is safe to do a lumbar puncture (LP).
In cases presenting later, or with proven bacterial
meningitis, the following features may be seen:
• Hydrocephalus (dilated ventricles) (327), enlarged CSF
spaces (basal cisterns and interhemispheric fissure).
• Sediment in the posterior horns of the lateral ventricles
(pus) (330).
• Absence of the basal cisterns (due to inflamed meninges
and pus).
• Areas of altered density in the brain parenchyma
representing infarction (secondary to vasculitis) or
cerebritis (these areas may enhance).

Table 34 Cerebrospinal fluid profiles in various forms of meningo-encephalitis

Infection Cells/mm3 Protein Glucose Bacteriology
(g/l [mg/dl]) (mmol/l [mg/dl])
Normal 0–4 mononuclears 0.15–0.45 (15–45) 2.9–4.6 (52–83) Negative
Bacterial meningitis: acute 103 polymorphs Increased Markedly decreased Bacteria +ve
Bacterial meningitis: 102–103 mononuclears or Normal or increased Normal or decreased Bacteria +ve or -ve
partially treated polymorphs
Aseptic meningitis* 10–102 mononuclears Normal or increased Normal** Viruses
Meningoencephalitis 10–102 mononuclears Normal or increased Normal** Viruses or -ve
Tuberculous meningitis 10–102 mononuclears Increased Decreased Acid-fast bacilli +ve
Fungal meningitis 10–102 mononuclears Increased Decreased Organism +ve
Carcinomatous meningitis 10–102 mononuclears Increased Normal or decreased Malignant cells
Syphilitic meningitis 10–102 mononuclears Increased Normal** Serologic tests +ve
Raised gamma globulins
Subacute sclerosing Normal Increased Normal Measles antibody titer
panencephalitis Raised gamma globulins very high
Creutzfeldt–Jakob disease Normal Normal Normal Normal
Progressive multifocal Normal Normal Normal Normal
leukoencephalopathy
* Polymorphonuclear leukocytes may predominate early
** CSF glucose may be low in mumps and herpes simplex virus infections and acute syphilitic meningitis
 Acute Pyogenic (Bacterial) Meningitis
• After i.v. contrast, periventricular enhancement
(indicating ventriculitis) or enhancement in the basal
cisterns (from inflamed meninges).
• MRI is more sensitive to the enhancement following
contrast than CT.
• Evidence of local infection such as sinusitis or mastoiditis
should be sought (opacified sinuses).
• Late complications include generalized atrophy,
infarction, subdural empyema, mycotic aneurysms and
loculated CSF collections.
• In cases of recurrent meningitis, a connection between
the nasal or middle ear spaces and the CSF should be
suspected and a contrast CT cisternogram performed to
identify a leak when the patient is well.
CSF (and simultaneous blood glucose) (see Table 34)
If no focal neurologic signs are present, LP should be
performed immediately and the CSF examined for cell
count, protein, glucose, polymerase chain reaction (PCR),
and cultured:
• White cell count: usually 1000–5000/mm3 with a
neutrophil predominance; lymphocyte predominance in
10%, particularly L. monocytogenes meningitis and newborns
with Gram-negative bacillary meningitis. A very low CSF
white cell count (0–20/mm3) in conjunction with high
CSF bacterial concentrations indicates a poor prognosis.
• Gram stain: positive in 60–90% of untreated cases and
40–60% of partially treated patients. Specificity nearly 100%.
• Protein: raised (1–5 g/l [100–500 mg/dl]) in virtually
all patients.
• Glucose: low (below 2.22 mmol/l [40 mg/dl]) in 60%
of patients. The CSF: serum glucose ratio is below 0.31
in 70% of cases.
• Culture: positive in 70–85% of untreated and <50% of
partially treated meningitis.
Latex agglutination test for bacterial antigen (H. influenzae
type b, S. pneumoniae, N. meningitidis, Escherichia coli K1,
and S. agalactiae)
• Indicated if clinical features and CSF profile are
consistent with bacterial meningitis but CSF gram stain
is negative.
• Sensitivity: 50–100%, specificity: high.
Polymerase chain reaction
The most sensitive method but frequently false positive
results are obtained. Further refinements of this technique
are required to confirm its usefulness in patients with
bacterial meningitis in whom the CSF Gram stain, bacterial
antigen tests and culture are negative.
Reagent strips
If no facilities for laboratory examination of CSF are available,
the CSF can be tested with reagent strips that measure protein
and glucose concentrations and leukocyte counts in the urine.
Blood
• Full blood count and ESR: a neutrophil leukocytosis and
raised ESR are typical but not invariable nor specific:
severe viral infections can cause similar changes.
• Blood cultures are essential because bacteria are often
easier to isolate from the blood than the CSF.
• Acute and convalescent viral serology in blood and CSF,
including HIV serum antibody in at-risk individuals.
277
• Serology for borrelia, brucellosis, legionella, leptospirosis,
and toxoplasmosis.
Other
• Culture (bacterial and viral) from septic sites, biopsy
material, throat swab and feces.
• Chest x-ray may show signs of infection by pneumococci,
mycoplasma, legionella and tuberculosis (TB).
• Skin scrapings may identify meningococci that are
present in the skin rash. The lesion is scraped with the
point of a sterile needle until blood just starts to appear.
The blood is then blotted on to microscope slides,
allowed to dry, and examined for Gram-negative
diplococci. This can provide results rapidly and, unlike
examination of blood and CSF, is not greatly affected by
prior antibiotic treatment.
DIAGNOSIS
The diagnosis is based on the finding of an increased
number of white cells in the CSF (CSF pleocytosis) and
demonstration of bacteria in the CSF whether by Gram
stain, CIE, culture or PCR, in a patient with consistent
clinical features.
MANAGEMENT
Antibacterial chemotherapy
Principles
• The need to commence antibiotic treatment as soon as
the diagnosis is suspected, even before admission to
hospital or performing a lumbar puncture.
• The need for bactericidal activity in CSF.
• Factors influencing bactericidal activity in CSF:
– Permeability of the blood–brain barrier.
Continued overleaf
330
330 CT brain scan from an elderly lady who had been unwell for
several days with headache and confusion.There is debris in the
occipital horns of the lateral ventricle (arrows) which is pus due to
pyogenic meningitis.
278 Infections of the Nervous System: Bacterial
Principles (continued)
– Characteristics of the antibiotic (molecular size, protein
binding, lipid solubility, degree of ionization).
– CSF pH, protein concentration, temperature.
• Potential hazards of bactericidal activity in CSF: release
of biologically active cell-wall products, increasing the
production of cytokines in CSF, exacerbating inflam-
mation and damaging the blood–brain barrier.
See management algorithm (331).
Types of therapy
• Empirical (see Table 33).
• Specific (see Table 35): an important epidemiologic trend
is the worldwide increase in infection with strains of
S. pneumoniae that are resistant to penicillin and other
β-lactam antibiotics, mediated by alterations in the
penicillin-binding proteins involved in the synthesis of
bacterial cell walls.
Supportive measures
• General nursing care.
• Attention to the airway.
• Maintenance of adequate hydration: fluids should be
replaced and maintained, and not restricted.
• Antipyretic measures.
Adjunctive therapy
Dexamethasone
Insufficient evidence exists to support the routine use of
dexamethasone as an adjunct treatment in adults with
bacterial meningitis. Selective use may be considered in
patients at high risk with severely impaired mental status,
cerebral edema or substantially raised intracranial pressure.
Lowering intracranial pressure
• Elevate the head of the bed to 30° to maximize venous
drainage with minimal compromise of cerebral perfusion.
• Hyperosmolar agents, such as mannitol and oral glycerol
(glycerin), increase the osmolality of the intravascular
space with respect to the brain and facilitate diffusion of
water from the brain to the intravascular space.
331 Algorithm for the initial
management of patients with
acute bacterial meningitis.
Absent
Obtain blood cultures and do lumbar
puncture immediately
CSF consistent with bacterial meningitis
Gram stain or bacterial antigen test positive
No
Empirical antimicrobial therapy (Table 33) Specific antimicrobial therapy (Table 35)
• Hyperventilation, to maintain arterial pCO2 between 3.6
and 4 kPa (27 and 30 mmHg), but this may lead to a
reduction in cerebral blood flow below ischemic thresholds.
• Barbiturate therapy (pentobarbitone [pentobarbital]), in high-
dose titrated to development of a burst-suppression pattern on
the EEG, may help to protect the brain from ischemic insult
(by causing vasoconstriction in normal tissues, thus shunting
blood to ischemic tissue) and decrease metabolic demands of
the brain. This is of unproven benefit in bacterial meningitis.
Treatment of complications
Specific treatment is indicated for specific complications
such as seizures and hydrocephalus.
Prophylactic treatment
Prophylaxis prevents secondary cases by eradicating
nasopharyngeal carriage in the short term
Meningococcal infections
• Rifampicin (rifampin) 10 mg/kg/day for 4 days is recom-
mended for close contacts (usually household) and the patient.
• The meningococcal C vaccine is a conjugate vaccine
administered to infants, children and young adults. It
overcomes the problems of the existing polysaccharide
vaccine which offers limited protection against groups B
and C, and does not protect infants <2 years old (but is
75–90% effective in older children and adults).
Haemophilus infections
Rifampicin (rifampin) 20 mg/kg/day for 4 days is recom-
mended for families and other close contacts with children
<4 years of age (i.e. at high risk) and for the patient.
PROGNOSIS
• Overall case fatality rate is 25%.
• Case fatality rate varies according to the patient’s age and
the type of bacteria: 31% for S. pneumoniae meningitis in
adults over 60 years of age compared with 3% for
children younger than 5 years of age. Overall case fatality
is higher for S. pneumoniae (19%) than for either N.
meningitidis (13%) or H. influenzae (3%).
331
Bacterial meningitis suspected
N.B.There is an increasing trend to
administer antibiotics immediately after
suspecting bacterial meningitis (i.e. before
Consider empirical antibiotic therapy
performing a lumbar puncture, and even
before referral to hospital.)
Focal neurologic signs or papilledema Present
Obtain blood cultures
Empirical antimicrobial therapy (Table 33)
Cranial CT scan
Yes
No mass lesion Mass lesion present
 Subacute and Chronic Meningitis and/or Encephalitis 279

SUBACUTE AND CHRONIC Bacterial meningitis (see p.273): inadequately treated

MENINGITIS AND/OR ENCEPHALITIS
Chronic bacterial infection following:
• Head injury.
DEFINITION • Intracranial surgery.
A syndrome characterized by various combinations of fever, • Use of intracranial shunts.
headache, lethargy, stiff neck, confusion, nausea, and
vomiting with accompanying CSF pleocytosis, of greater Parameningeal foci
than 4 weeks duration. • Otitis.
• Mastoiditis.
EPIDEMIOLOGY • Sinusitis.
• Incidence: uncommon. • Brain abscess.
• Age: any age. • Subdural empyema.

ETIOLOGY AND PATHOPHYSIOLOGY Non-infectious

Infection Connective tissue/granulomatous diseases
De novo infection • Systemic lupus erythematosus.
• Bacterial: • Behçet’s syndrome (oral and genital ulcers, iritis,
– Actinomycosis. meningitis).
– Brucellosis. • Sjögren’s syndrome.
– Listeria. • Sarcoidosis (see p.350).
– Nocardia. • Systemic vasculitis.
– Whipple’s disease (see p.289). • Isolated granulomatous angiitis of the nervous system
• Mycobacterial: TB. (see p.227).
• Spirochete: • Vogt–Koyanagi–Harada disease (uveitis, alopecia, vitiligo,
– Borrelia burgdorferi (see p.316). dysacousis, tinnitus).
– Leptospirosis.
– Syphilis (see p.312) (332). Malignant meningitis
• Viral: • Carcinoma: seeding of tumor cells in the CSF with, or
– HIV (see p.301). more often without, a solid intracranial or spinal primary
– Mumps. or secondary tumor. The common primary tumors are
– Cytomegalovirus. carcinoma of the breast, bronchus and nasopharynx;
– Lymphocytic choriomeningitis (LCM). leukemia, lymphoma and melanoma; primary intracranial
• Fungal: tumors rarely seed through the CSF.
– Cryptococcus. • Lymphoma (including intravascular lymphoma [neo-
– Coccidioides. plastic angioendotheliosis]).
– Histoplasma. • Leukemia.
– Candida. • Glioma.
– Aspergillus. • Melanoma.
– Blastomyces.
• Protozoal: toxoplasmosis. Chemical meningitis (see p.291)
• Helminthic (cestode worms): cysticercosis. Craniopharyngioma (see p.377), epidermoid cyst, drugs, dye.

Mollaret’s meningitis (see p.291)

Steroid-responsive chronic meningitis
Table 35 Antimicrobial therapy for bacterial meningitis Chronic benign lymphocytic meningitis
based on pathogen identification by positive Gram stain
and/or bacterial antigen test
Bacterial pathogen Therapy
Haemophilus Third generation cephalosporin 332
influenzae type B (cefotaxime or ceftriaxone): for 7 days
Neisseria meningitidis Penicillin or amoxycillin (amoxicillin) or
third generation cephalosporin: for 7 days
Streptococcus Vancomycin + third generation cephalosporin•:
pneumoniae for 10–14 days
Listeria Amoxycillin (amoxicillin) or penicillin G**:
monocytogenes for 14–21 days
Group B streptococci Amoxycillin (amoxicillin) or penicillin G**:
(S. agalactiae) for 14–21 days
Escherichia coli Third generation cephalosporin
(cefotaxime or ceftriaxone): for 21 days
*Consider addition of rifampicin (rifampin)
**Consider addition of aminoglycoside
332 Skin rash on the sole of the foot of a patient with syphilitic
meningitis.
280 Infections of the Nervous System: Bacterial

CLINICAL FEATURES clinically and radiologically involved leptomeninges and

Indolent onset and course. brain.

Meningitis DIFFERENTIAL DIAGNOSIS

• Headache. Chronic recurrent meningitis (vs. chronic persistent
• Fever. meningitis)
• Malaise. • Mollaret’s meningitis.
• Confusion. • Anatomic defects (e.g. skull fractures, post-operative).
• Weight loss. • Congenital defects (e.g. meningomyelocele, dermal sinus).
• Meningism. • Parameningeal focus (e.g. otitis, mastoiditis, sinusitis,
brain abscess, subdural empyema).
Associated syndromes • Immunosuppression.
• Seizures. • Tumors (e.g. craniopharyngioma, epidermoid, ependymoma).
• Hydrocephalus (obstructive or communicating). • SLE.
• Confusion, dementia.
• Papilledema. Chronic persistent meningitis (see Etiology, above)
• Syndrome of inappropriate antidiuretic hormone (SIADH). CSF cell count: <50 cells/mm3
• Migraine with CSF pleocytosis. • Behçet’s syndrome.
• Cranial neuropathies. • Benign lymphocytic meningitis.
• Radiculopathies. • Carcinoma.
• Spinal root pain, weakness, sensory loss. • Sarcoidosis.
• Myelopathy. • Vasculitis.

332)
Other manifestations of the underlying cause (3 CSF cell type
• Neutrophils:
INVESTIGATIONS – Bacterial meningitis.
Blood – Chemical (e.g. craniopharyngioma).
• Full blood count. – Fungal meningitis.
• ESR. – SLE.
• Serum biochemistry (e.g. urea and electrolyies, liver • Eosinophils:
function tests). – Chemical (e.g. intrathecal drugs).
• Antinuclear antibodies, anti-DNA antibody. – Coccidioides.
• Rheumatoid factor. – Lymphoma.
• Serum protein electrophoresis. – Parasites.
• Serum immunoglobulins. • Lymphocytes: all other causes.
• Serum complements.
• Serum angiotensin-converting enzyme. CSF glucose: low
• Serology should be repeated for borrelia, brucellosis, • Bacterial meningitis.
fungal antibodies, HIV, and leptospirosis. • Carcinoma.
• Fungi.
CSF • Syphilis.
Testing should be repeated on several occasions: • Sarcoid.
• Microscopy, cell count, Gram stain, culture, protein, • Subarachnoid hemorrhage.
glucose, VDRL, TPHA, oligoclonal bands, IgG/albumin • Viral (mumps, herpes, LCM).
ratio, cytology for inflammatory and malignant cells, • Mollaret’s meningitis.
cryptococcal antigen and other antigens and antibodies • Benign lymphocytic meningitis.
as appropriate from the list above (see Etiology, above). • Epidermoid cyst.
• Malignant cells are more likely to be seen if the CSF is
fresh and collected on several occasions. TREATMENT
• Lymphocytes usually predominate but occasionally • Specific treatment of underlying cause.
neutrophils do. • Empirical:
• CSF lymphocytes should be typed if there is any – Anti-TB (see p.282) and antifungal (see p.320) therapy:
suspicion of lymphoma. if no definite cause identified, and if the patient is unwell
and deteriorating.
Other – Corticosteroids: indicated if there is no favorable response
• Urine, sputum, and gastric washings for TB, fungi. clinically to empirical anti-TB and fungal therapy, and if
• Chest x-ray: if suspected TB, sarcoidosis or neoplasm. fungi have not been identified, because some patients have
• Ultrasound abdomen and pelvis: suspected hepatic a steroid-responsive chronic meningitis.
metastases or pelvic infection. – Relapse may occur when treatment is withdrawn.
• Cranial CT or MRI scan, or spinal MRI scan to exclude a • Malignant meningitis and the primary tumor are seldom
focal parameningeal collection of pus such as an treatable, and death occurs in weeks or months.
intracranial or spinal subdural empyema, or hydrocephalus.
• Biopsy with microscopy, cytology and culture of clinically PROGNOSIS
involved extraneural sites (e.g. lymph nodes, liver) or Depends on the underlying cause and response to treatment.
 Tuberculous Meningo-encephalitis 281

TUBERCULOUS • The basal cisterns become blocked, resulting in a

MENINGO-ENCEPHALITIS meningeal obstructive type of hydrocephalus.
• The CSF in the aqueduct, or fourth ventricle more rarely,
becomes blocked by marked ependymitis, leading to
DEFINITION obstructive hydrocephalus.
Infection of the meninges and underlying brain by the acid-
fast organism Mycobacterium tuberculosis and exceptionally ETIOLOGY
by Mycobacterium bovis. Mycobacterium tuberculosis and exceptionally by
Mycobacterium bovis.
EPIDEMIOLOGY
• Incidence: increasing, concurrent with the HIV Risk factors
epidemic. Higher in developing countries, particularly • HIV infection: 500 times higher incidence of TB meningitis
the Indian subcontinent and sub-Saharan Africa, with than in the general population; HIV increases the lifetime
higher prevalence of HIV infection. risk of developing TB to one in three.
• Age: any age. • Alcohol abuse.
• Gender: either sex. • Diabetes mellitus.
• Malignancy.
PATHOLOGY • Recent corticosteroid use.
Macroscopic • Populations with a high prevalence of pulmonary
• Discrete, small, white tubercles scattered over the convexi- tuberculosis (i.e. poorer backgrounds, India, Africa).
ties and base of the brain. The ependyma and choroid
plexus are also studded with minute glistening tubercles. PATHOGENESIS
• Thick, gelatinous exudate over the basal meninges, Meningitis may occur as part of generalized TB with a single
obliterating the pontine and interpeduncular cisterns and focus (tuberculoma) in the brain or as a terminal event in
extending to the meninges in the floor of the third ventricle miliary TB. Two stages:
and subthalamic area, the optic chiasm, the under-surfaces • Bacterial seeding of the meninges and subpial regions of
of the temporal lobes, and around the medulla and spinal the brain, forming tubercles.
cord. The convexities are relatively spared. • Rupture of one or more of the foci (tuberculomas) with
discharge of bacteria into the subarachnoid space.
Microscopic
• Meningeal tubercles: a central zone of caseation CLINICAL FEATURES
surrounded by epithelioid cells and some giant cells, Subacute or chronic onset over weeks.
lymphocytes, plasma cells, and connective tissue.
• Exudate: composed of fibrin, lymphocytes, plasma cells, and Syndromes
other mononuclear cells, some polymorphonuclear leuko- • Meningo-encephalitis:
cytes and areas of caseation necrosis. The exudate is not – Headache, lethargy, confusion, drowsiness, fever, stiff
confined to the subarachnoid space (as is the case with the neck, Kernig and Brudzinski signs.
pyogenic meningitides) but frequently spreads along the pial – Cranial neuropathies: usually oculomotor palsies, less
vessels and invades the underlying brain, leading to a pure often facial palsies and deafness:
meningoencephalitis. The inflammatory exudate involves the • Focal neurologic deficit: due to brain infarction caused
cranial nerves as they traverse the subarachnoid space (333). by infectious arteritis.
• Arteries become inflamed and occluded, leading to focal • Raised intracranial pressure: due to hydrocephalus.
brain infarction.
Associated conditions
Systemic tuberculosis (two-thirds of patients): pulmonary,
333 bone or renal.

OTHER FORMS
Tuberculous serous meningitis
• Due to a meningeal reaction to an adjacent tuberculous
focus.
• Asymptomatic, or headache, lethargy and confusion with
mild meningeal signs.
• CSF: modest pleocytosis in some, normal or elevated
protein, normal glucose.
• Self-limiting usually, but may progress to fatal generalized
TB meningitis.

333 Microscopic examination of the mononuclear inflammatory cell
exudate involving the trigeminal nerve root as it traverses the
subarachnoid space of a patient with tuberculous meningitis. An artery
in the lower part of the field has become inflamed and occluded.
Tuberculoma
• Tumor-like masses of tuberculous granulation tissue in
the brain parenchyma.
• Asymptomatic or symptoms of a space-occupying lesion.
• CSF: mild pleocytosis and raised protein; normal glucose.
282 Infections of the Nervous System: Bacterial
Myeloradiculitis
• Spinal cord or nerve root compression by an epidural
mass of granulation tissue or angulation of the vertebral
column (see Spinal epidural abscess, p.555).
• May accompany vertebral body disease (Pott’s paraplegia).
DIFFERENTIAL DIAGNOSIS
• Meningitis: fungal (e.g. cryptococcal, see p.318; see
Chronic meningitis, p.279); pyogenic.
• Meningeal carcinomatosis (malignant meningitis).
• Brain tumor (e.g. brainstem glioma).
INVESTIGATIONS
Blood
Hyponatremia is common due to the syndrome of inap-
propriate ADH secretion (SIADH) or TB of the adrenals.
Brain imaging
Similar features will be seen on CT or MRI, though MRI is
more sensitive:
• Tuberculomas may be single or multiple, usually small
(2–3 mm diameter) and can coalesce to form a larger lesion
(334, 335). They may be low or high density on CT, may
adhere to the dura, cause hyperostosis (mimicking a
meningioma), and may calcify (<20%). They may produce
symptoms from intracranial mass effect and edema.
• Tuberculous meningitis causes basal pachymeningitis and
hydrocephalus, usually of the meningeal obstructive
variety (336, 337). The basal cisterns are difficult to see
as they are filled with exudate. They enhance intensely
(particularly on MRI) with contrast. On MRI the basal
cisterns may appear brighter than normal on T1W image
because of the protein content of the exudate. The
cisterns may calcify (best seen on CT).
• Tuberculoma and tuberculous meningoencephalo-
vasculitis can simulate an infiltrating brainstem glioma
radiologically.
• With treatment the tuberculomas may shrink and disappear
(or calcify) but the hydrocephalus does not change.
CSF (lumbar puncture)
• Pressure: increased.
• Cells: 50–500 white cells/mm3; initially polymorpho-
nuclear leukocytes and lymphocytes in equal numbers
but after several days, lymphocytes predominate.
• Organisms: Ziehl–Neelsen stain of smears of CSF sedi-
ment reveals acid-fast tubercle bacilli in about 10–20% of
patients; culture requires 3–4 weeks to become manifest
(so treatment must be instituted on suspicion).
• Protein: 1.0–2.0 g/l (100–200 mg/dl); higher if CSF
flow is blocked around the spinal cord.
• Glucose: <2.22 mmol/l (<40 mg/dl), but the glucose
falls slowly over several days and rarely falls to the
extremely low levels seen in pyogenic meningitis.
Mantoux test
10 tuberculin units are given intradermally on the flexor
surface of the forearm. An area of induration measuring
5 mm or more read at 48–72 hours following the injection
is a positive Mantoux. This indicates previous or recent
exposure to M. tuberculosis and does not prove active TB;
i.e. it may also indicate previous TB, healed infection, or
BCG vaccination. The test may also be negative in active
TB, if the test is done within 6 weeks of the patient
acquiring the infection, or where the infection is over-
whelming or the patient is immunosuppressed.
Other
• Sputum smears and cultures for acid-fast bacilli.
• Chest x-ray.
• Gastric washings.
• Urine examination.
DIAGNOSIS
Clinical and microbiologic: demonstration of acid-fast
bacilli, either on microscopy of smears of CSF sediment
stained by the Ziehl–Neelsen method or by culture, in a
patient with clinical evidence of meningo-encephalitis.
TREATMENT
Initial anti-TB chemotherapy treatment
1 Rifampicin (rifampin) 600 mg daily as a single oral dose
(15–20 mg/kg/day in children); plus
2 Pyrazinamide 30–50 mg/kg as a single oral dose
(10 mg/kg/day in children); plus
3 Isoniazid 400 mg/day (5 mg/kg in adults; 10 mg/kg in
children) as a single oral dose; plus
4 Pyridoxine 20–50 mg daily, oral should always be given
with isoniazid to prevent peripheral neuropathy.
Alternative initial treatments
• Streptomycin 1 g i.m. daily (20–40 mg/kg/day in
children) can be used instead of rifampicin (rifampin) if
rifampicin causes intolerable adverse effects.
• Ethambutol may be substituted for pyrazinamide. The
dose is 25 mg/kg/day as a single oral dose for the first
month, then 15 mg/kg/day. Ethambutol should be
avoided in children, and patients with renal failure. It is
given in divided doses, after meals, because of its
tendency to produce gastric irritation. Visual acuity and
red-green color discrimination are regularly checked
because of the risk of optic neuropathy.
Additional treatments
Dexamethasone (adults 12 mg/day; children <25 kg,
8 mg/day) given for 3 weeks (in conjunction with anti-TB
therapy) then tapered over a further 3 weeks may reduce the
incidence of sequelae in patients who are culture-positive,
particularly those who have a decreased conscious level at
presentation. Prednisolone, 60–80 mg/day tapering after
2 weeks to finish at 4–6 weeks, is an alternative.
Treatment after 2 months
If the mycobacterium is shown to be sensitive to all three
antibiotics (rifampicin [rifampin], pyrazinamide and
isoniazid) in vitro, pyrazinamide can be discontinued, but
rifampicin and isoniazid (and pyridoxine) should be
continued together for about another 7 months; the dose
of isoniazid can be reduced to 300 mg once daily. The
duration of treatment depends on many factors, including
the degree of supervision and compliance.
N.B. Intracranial tuberculomas require a similar course
of chemotherapy as outlined above. The tuberculomas may
transiently increase in size despite clinical improvement soon
after the start of antimicrobial treatment, or disappear and
calcify. If they persist, particularly exerting ‘mass effect’,
surgical excision may be required.
 Tuberculous Meningo-encephalitis 283

Adverse effects – Serum levels of streptomycin should be monitored and

• Rifampicin (rifampin):
– Fever, skin rash, nausea, vomiting, diarrhea, thrombo-
cytopenia, hepatitis.
– Saliva and urine turn orange-red and soft contact lenses
may discolor.
– An early transient rise in liver enzymes is common.
• Pyrazinamide: fever, urticaria, flushing, nausea, vomiting,
arthralgia, hepatitis, hyperuricemia.
• Isoniazid:
– Skin rash, nausea, vomiting, arthralgia, peripheral
neuropathy, confusional and psychotic states, seizures,
hepatitis, pellagra.
– If symptoms of hepatitis or abnormal liver function tests
occur, stop the isoniazid.
• Streptomycin:
– Skin rash, deafness, tinnitus, vertigo, ataxia, nephro-
toxicity, and exacerbation of myasthenia gravis.
if renal impairment occurs, the dose should be reduced.
• Ethambutol: blurred vision, optic atrophy, peripheral
neuropathy, hepatitis.
CLINICAL COURSE AND PROGNOSIS:
• Untreated, the course is progressive and invariably fatal
within weeks to months.
• Overall mortality: about 10%; higher in infants, the
elderly and HIV-infected patients.
• Survival is enhanced by early diagnosis.
• Neurologic impairments persist in 20–30% of survivors,
most commonly cognitive dysfunction, epileptic seizures,
visual and oculomotor disorders, deafness and hemiparesis.
• Focal weakness, Glasgow coma scale, and somatosensory
evoked potentials are the best predictors of outcome at
6 months (in one recent study).

334, 335 CT brain scans with 334 335

contrast showing calcified
nodules (arrows) in the
parenchyma (tuberculomas) and
a degree of hydrocephalus.The
white linear structure in the
anterior horn of the right lateral
ventricle is a shunt (335).

336, 337 CT brain scans 336 337

showing hydrocephalus due to
tuberculous meningitis in a
person from the Indian
subcontinent. Note the dilated
ventricles right down to the
fourth where there is good
communication with the basal
cisterns, i.e. this is a
communicating hydrocephalus.
284 Infections of the Nervous System: Bacterial
INTRACRANIAL ABSCESS
(BRAIN ABSCESS AND
SUBDURAL EMPYEMA)
DEFINITION
• Brain abscess: a localized collection of pus within the
brain, and usually supratentorial.
• Subdural empyema: a thin layer of pus between the dura
and arachnoid membranes over the surface of one side
of the brain, frequently spreading into the inter-
hemispheric fissure (parafalcine) and over to the surface
of the other side of the brain.
EPIDEMIOLOGY
• Incidence: uncommon.
• Point prevalence 2 per 100 000.
• Age: any age.
• Gender: M=F.
PATHOLOGY
Bacterial infection of a part of the brain causes inflammation
and edema around the periphery of the infected brain
parenchyma (so-called ‘cerebritis’), which is followed by
necrosis in the center of the lesion, with the formation of
pus in the abscess cavity.
PATHOPHYSIOLOGY
Local spread of infection/complications
• Trauma: penetrating head wounds with CSF leak.
• Suppurative middle ear, mastoid, paranasal sinus or
dental infections (the most common local events leading
to brain abscess formation).
• Bacterial meningitis.
• Orbital cellulitis.
Local spread of infection usually causes a subdural
empyema or a single/solitary intracerebral abscess.
Hematogenous spread
• Septicemia.
• Right to left shunt:
– Intracardiac: cyanotic congenital heart disease.
– Intrapulmonary: pulmonary arteriovenous malformation.
• Infective endocarditis.
• Suppurative chest infection (abscess, bronchiectasis,
empyema).
Hematogenous spread of infection usually causes
multiple intracerebral abscesses.
Other predisposing factors
Immune system compromise (e.g. HIV infection).
ETIOLOGY
Brain abscesses are often polymicrobial, particularly if they
arise from a dental source.
Aerobic organisms
• Streptococcus milleri (causes suppurative dental and sinus
infection in the middle-aged and elderly): up to 80% of
cases of brain abscess are caused by a streptococcus.
• Streptococcus pneumoniae (pneumococcus): carried in the
nasopharynx from where it can spread by droplets to
cause sinusitis, otitis media and pneumonia. Severe
infection tends to occur in patients who have had a
splenectomy or have hypogammaglobulinemia, comple-
ment deficiencies or sickle cell disease.
• Enterobacter/coliforms: increasing incidence (10–30% of
cases).
• Staphylococcus aureus (head injury, neurosurgical
procedure, ventricular shunt, CSF fistula): decreasing as
a cause (10–30% of cases).
• Fusobacterium spp.: (<10% of cases).
• Haemophilus spp.: (<1%).
• Fungi (Aspergillus and Candida spp.): (especially if
immunocompromised).
• Mycobacterium tuberculosis.
• Protozoa: Toxoplasma gondii, helminths (e.g. Strongyloides
stercoralis) (especially if immunocompromised).
• Ameba.
Anaerobic organisms
• Gram-negative rods: Bacteroides, Prevotella, Porphyomonas
spp.: increasing incidence: comprise 20–50% of cases.
• Peptostreptococcus spp., particularly P. micros: (10–40% of
cases).
Several bacterial strains are frequently present in a single
abscess but sometimes nothing is seen on Gram stain or
grown in aerobic or anaerobic culture.
CLINICAL FEATURES
Brain abscess
The usual presenting features are the subacute onset and
progressive evolution of:
• Fever.
• Headache.
• Lethargy and malaise.
• Seizures.
• Focal neurologic signs.
• Symptoms and signs of raised intracranial pressure, such
as papilledema, may follow as the abscess acts as an
expanding space-occupying lesion.
• Meningism and systemic evidence of bacterial infection
may be present.
• Features of the underlying source (e.g. dental or ear
infection) may be present.
Subdural empyema
Supratentorial
• Severe headache, often unilateral.
• Dysfunction of, and focal seizures referable to, the
underlying hemisphere.
• Cranial nerve III and VI palsies due to compression.
Infratentorial (rare)
• Severe headache.
• Meningism.
• Cerebellar and brainstem signs.
• Features of raised intracranial pressure.
 Intracranial Abscess (Brain Abscess and Subdural Empyema)
DIFFERENTIAL DIAGNOSIS
• Bacterial meningitis.
• Tuberculous meningitis.
• Encephalitis.
• Intracranial tumor: both abscess and tumor frequently
appear as ring-enhancing lesions on neuroimaging
studies. A raised C-reactive protein and increased uptake
of tracer on 99mTc-HMPAO leukocyte scintigraphy
raises the likelihood of abscess; steroid therapy should be
discontinued for 48 hours prior to leukocyte scintigraphy.
• Cerebral infarction.
INVESTIGATIONS
Full blood count and other blood tests
In general, laboratory tests are of little value in the diagnosis
of brain abscess. Only 30% of patients have peripheral
leukocyte counts greater than 11 000 cells/ml. However,
blood tests can be helpful in identifying the underlying
cause or predisposing condition (e.g. HIV serology,
toxoplasma serology, serum immunoglobulins, serum
complement).
Cranial CT or MRI scan without and with contrast
Chronic sinusitis, mastoiditis, osteomyelitis, fracture.
Abscess
• CT or MR can be used, though MR is probably more
sensitive particularly in the very early ‘cerebritis’ stage.
• CT shows a low density area (sometimes multiple)
usually at the gray/white matter junction, and which
may lie adjacent to an infected (opacified) nasal sinus or
338
338 CT brain scan with contrast showing a rounded area in the left
temporal region with ring enhancement (arrows) and some
surrounding edema typical of an abscess. Note that the only certain
way of establishing the diagnosis is by biopsy, as many tumors can have
a similar appearance.
285
mastoid. It has some mass effect and surrounding white
matter edema, and shows enhancement in a thin walled
ring after i.v. contrast (338, 339).
• MRI, T1W, reveals a central region of marked low
intensity surrounded by a discrete ring that is isointense
to mildly hyperintense. This area is surrounded by a
region of mild hypointensity. These regions correlate
with the necrotic center, the abscess capsule, and
surrounding edema respectively. N.B. Some tumors can
look very much like abscesses and vice versa, and
abscesses do not always cause pyrexia. The only sure way
of differentiating an abscess from a tumor is by biopsy
which may be necessary prior to starting steroids.
(Steroids may be acceptable for a brain tumor but not so
good for abscesses!)
Subdural empyema
On CT or MRI:
• A collection in the subdural space which may be very
difficult to see on the unenhanced scan as it is often
isodense with brain or so thin that it is not visible.
• Often adjacent to an infected nasal sinus or mastoid.
• Swelling (edema) of the adjacent underlying cerebral
hemisphere is usually present, sometimes with effacement
of cortical sulci, compression of horns of lateral
ventricles, and midline shift. The appearance may be
extremely subtle, for example only slight widening of the
interhemispheric fissure as the only clue (if in doubt give
contrast and preferably do an MRI).
(Continued overleaf)
339
339 CT brain scan of a more established abscess containing an
air–fluid interface (arrows) due to the presence of gas-forming
organisms. Note the considerable mass effect with midline shift.
286 Infections of the Nervous System: Bacterial
On CT or MRI (continued):
• After intravenous contrast injection, a thin rim of intense
contrast enhancement over the cerebral hemisphere may
become evident (340), and enhancement in the brain if
the infection has spread to cause cerebritis.
• Magnetic resonance imaging without and with
gadolinium enhancement is superior to CT due to the
absence of bone artefact; increased contrast between
bone, CSF and brain parenchyma; and the ability to
produce images in multiple planes. Furthermore, MRI
can better characterize subdural collections, allowing
differentiation of sterile, bloody and infected collections.
• Complications include meningitis (see above), cerebral
infarction, cerebral abscess, venous thrombosis.
Radionuclide scan
Increased uptake by the collection of pus on 99mTc-
HMPAO leukocyte scintigraphy.
Carotid angiography
Rarely required, but may be useful if a subdural empyema
is suspected but not imaged on CT or MRI, to show the
avascular gap between the skull and underlying cerebral
hemisphere, or in the interhemispheric fissure.
Exploratory burr holes
These may be necessary when a subdural empyema is
strongly suspected but not imaged by serial application of
the above techniques.
Chest x-ray
• Heart abnormality (e.g. cyanotic congenital heart disease).
• Pulmonary arteriovenous malformation.
• Lung infection (e.g. abscess, bronchiectasis, empyema).
Blood cultures
340
340 CT brain scan with contrast shows a frontal subdural empyema
(arrowheads) secondary to frontal sinusitis. Note the enhancing
membrane on its inner edge.
Culture (aerobic and anaerobic) of pus
Pus is cultured from the abscess, sputum, sinuses and blood.
Prolonged incubation of specimens under a wide range of
cultural conditions is necessary to ensure isolation and
identification of all organisms.
Lumbar puncture
LP is contraindicated when a brain abscess is suspected. If
done inadvertently, the CSF may be normal or show no
organisms, a mild CSF pleocytosis, mild elevation of CSF
protein, and a normal glucose. Cultures of CSF are usually
negative (i.e. similar to acute viral encephalitis, and viral or
tuberculous meningitis).
DIAGNOSIS
The diagnosis of brain abscess is suggested but not confirmed
by the presence of a suggestive clinical picture, and imaging
evidence of an asymmetric capsule, multiple lesions, the
location of the lesion at the corticomedullary junction, and
associated leptomeningeal enhancement. Ultimately, aspiration
and biopsy are often necessary to confirm the diagnosis of
brain abscess. Isolation and identification of all organisms is
vital to allow rational decision-making about optimal therapy.
TREATMENT
Small abscesses (<2.5 cm [<1 in])
Antibiotics
Antibiotics that enter the brain at high concentrations include
chloramphenicol, selected third-generation cephalosporins,
metronidazole, methicillin, nafcillin, penicillin, trimethoprim
plus sulfamethoxazole, and vancomycin.
Despite bacteriocidal concentrations of these antibiotics,
bacteria may still be cultured from abscess aspirates,
probably because of the acidic environment favoring
bacterial growth and inhibiting antibiotic action.
Initial empirical antibiotic therapy
• Penicillin G 200 mg/kg/day intravenously (i.v.) in 4
hourly boluses (about 33 mg/kg every 4 hours); plus
• Chloramphenicol 3 g daily i.v. in 8 hourly doses (i.e. 1 g
every 8 hours) (75 mg/kg/day in children); plus
• Metronidazole 2 g daily i.v. in 6 hourly boluses (i.e.
500 mg infused over 1 hour every 6 hours) (7.5 mg/kg
6 hourly in children).
If staphylococcal infection is suspected (i.e. post-
neurosurgery, ventricular shunts, and so on), replace
penicillin G in the above regime with:
• Flucloxacillin 6 g daily i.v. in 4 hourly doses (i.e. 1 g
every 4 hours) (children 50 mg/kg/day); or
• Fusidic acid, 1.5 g daily i.v. (i.e. 500 mg infused over 6
hours, every 8 hours), particularly if osteomyelitis is present.
Alternatives
• Cefotaxime + metronidazole (+ penicillin G).
• Ampicillin + gentamicin + metronidazole.
Specific antibiotic therapy
Specific antibiotic therapy (choice of antibiotics and dose)
will depend on bacterial culture, sensitivities and serum
levels. Intravenous antibiotic therapy should be continued
until the patient is at least neurologically stable, and
preferably fully recovered. It should then be possible to
change to oral therapy for several weeks.
 Tetanus
Large abscesses (>2.5 cm [>1 in])
Rarely cured by antibiotics alone; indeed long-term
combined use of several antibiotics may allow for the
uncontrolled growth of resistant organisms or may lead to
greater toxicity to the patient. Furthermore, because the
clinical and radiologic diagnosis of brain abscess is not
always certain, be aware that antibiotic therapy may be given
for a brain tumor that is mistaken as an abscess.
Neurosurgery
With the advent of image-guided stereotactic techniques,
aspiration of a brain abscess can be performed quickly and
safely under local anesthesia.
Aspiration provides diagnostic material, immediate
decompression, and removes acidic and hypoxic necrotic
material, providing a more favorable environment for
antibiotic therapy. Aspiration is indicated in the stages of
cerebritis, multiple lesions, deep seated lesions, and lesions
in eloquent areas of the brain.
Open surgical excision is limited to large superficial lesions
at risk of causing herniation and which are well encapsulated
and in non-eloquent lesions, fungal abscesses, multiloculated
abscesses, and post-traumatic abscesses which often contain
contaminated foreign bodies.
Pre-operative antibiotics are not given because they
increase the risk of sterile cultures. Antibiotic therapy as
directed by culture and sensitivity is given for 6 weeks.
Neuroimaging studies are obtained at weekly intervals during
therapy and monthly thereafter until the abscess has resolved.
Subdural empyema
At some stage it is usually necessary to drain surgically the
purulent loculation, but the decision of when and whether
to undertake burr hole drainage or a formal craniotomy
should be made in conjunction with the neurosurgeon. The
method of drainage probably matters less than its timing
and adequacy.
The local instillation of antibiotics (e.g. amphotericin B)
as an adjunct to the treatment of otherwise intractable brain
abscess and subdural empyema appears to be promising.
Orbital, ear, mastoid and sinus infection
These must be treated accordingly.
Antiepileptic therapy
Institute if recurrent seizures.
PROGNOSIS
Brain abscess
• Case fatality rate:
– Pre-CT era: up to 30%, together with a high morbidity
rate among survivors.
– Post-CT era: <6%, due to: improvements in
microbiologic isolation techniques, more effective
antibiotics, availability of CT and MRI that have resulted
in earlier diagnosis and more effective treatment at stages
when patients are relatively well neurologically.
• Predictors of a poor outcome in terms of morbidity and
mortality:
– Severely impaired mental status and neurologic
impairment on admission.
– Brain abscess in infants, particularly those that are large
(>5 cm [>2 in]) or multiple.
• Epilepsy is a complication in more than 50% of survivors.
287
TETANUS
DEFINITION
A serious preventable disease caused by infection of the skin
and deep and necrotic wounds by Clostridium tetani, a
Gram-positive bacillus, which secretes a neurotoxin.
EPIDEMIOLOGY
• Incidence: 1 million cases annually world-wide. Rare in
developed countries because of immunization; only 36
cases were reported (of an estimated 170 cases) in the
United States in 1994.
• Age: more than half of cases occur in people 60 years of
age or older.
ETIOLOGY AND PATHOPHYSIOLOGY
The source of infection is usually a wound (about 65%), often
a minor one such as a thorn, splinter of wood, or a piece of
metal. Chronic skin ulcers account for about 5% of cases, and
there is no obvious source in the remainder.
Clostridium tetani are Gram-positive, spore-forming bacilli
that exist primarily in soil. Their prevalence in soil samples
ranges from 2–23%.
Under anaerobic conditions, the spores germinate and
produce two toxins: tetanolysis (a hemolysin with recognized
pathologic activity) and tetanospasmin, which is responsible
for tetanus. Tetanospasmin is synthesized as a single 151-kd
chain and cleaved to two chains joined by a single disulfide
bond. The heavy chain (100 kd) is responsible for specific
binding to neuronal cells and transport proteins. The light
chain (50 kd) is a zinc endopeptidase that cleaves an integral
membrane protein of small synaptic vesicles, synaptobrevin,
at a single site and blocks the release of neurotransmitters.
Once the toxin is synthesized it moves from the
contaminated site to the spinal cord or brainstem. The toxin
reaches the CNS by intra-axonal transport, moving at a rate
of 75–250 mm (3–10 in) per day. So, the process takes 2–14
days. With facial injuries the interval is short. Once the toxin
reaches the CNS, local or cephalic tetanus may occur initially,
followed by generalized tetanus. The toxin produces
presynaptic blockade of the synapses of inhibitory Renshaw
cells and 1a fibers of alpha motor neurons that handle the
transmission of γ-aminobutyric acid and glycine, but not of
the synapses of Renshaw cells that handle acetylcholine
transmission. Instability of the autonomic nervous system also
occurs. The toxin binding appears to be irreversible; recovery
depends on the sprouting of new axonal terminals.
CLINICAL FEATURES
As described by Gowers (1888):
‘Tetanus is ... characterized by persistent tonic spasm with
violent brief exacerbations. The spasm almost always
commences in the muscles of the neck and jaw, causing
closure of the jaws (trismus, lockjaw) and involves muscles
of the trunk more than those of the limbs.’
Initially, within days or weeks of the injury, the patient
complains of stiffness, pain and rigidity in the voluntary
muscles of the jaw, face and abdomen. The disease may be
mild and progress no further or the muscle stiffness, pain and
rigidity may spread to involve the neck, pharynx, back and
sometimes limbs. Involuntary spasms of the affected muscles
288 Infections of the Nervous System: Bacterial
may occur and be painful, frightening and cause difficulty
opening the jaw (trismus), a grimacing facial appearance ‘risus
sardonicus’ due to contraction of the facial muscles (341),
and difficulty swallowing, sometimes prompting the patient
to complain of a ‘sore throat’. The patient is usually afebrile
unless there is concurrent local infection.
With severe tetanus, all muscles contract, with the stronger
overpowering the weaker. There is opisthotonos, flexion of the
arms, extension of the legs, periods of apnea due to spasm of
the intercostal muscles and diaphragm, and rigidity of the
abdominal wall. Spasms are precipitated by startle, cough,
touch, and a full bladder. Laryngeal spasm can be precipitated
by swallow or the passage of a nasogastric tube. Late in the
disease autonomic dysfunction develops with tachycardia and
hypertension alternating with bradycardia and hypotension,
cardiac arrhythmias, sweating, fever, salivation and gastric stasis.
Ophthalmoplegia and facial weakness are rare.
DIFFERENTIAL DIAGNOSIS
• Dystonic reactions to neuroleptic drugs (which typically in-
volve lateral turning of the head, often with protrusion of the
tongue [symptoms that are rarely, if ever, seen in tetanus]).
• Strychnine poisoning.
• Local infection in the pterygomandibular space (e.g. dental
or in the masseter muscle) with trismus.
• Dislocation of the mandible leading to ‘lockjaw’.
• Facial or jaw trauma.
• Rabies.
• Hysteria.
INVESTIGATIONS
• Laboratory tests are of virtually no value except to
exclude strychnine poisoning.
• Blood counts and blood biochemistry findings are
unremarkable.
• Imaging studies of the head and spine reveal no
abnormalities.
• A LP is not necessary; the CSF is normal except for a
raised opening pressure, particularly during spasms.
DIAGNOSIS
Clinical.
TREATMENT
• Nurse in quiet surroundings.
• Excise and debride any wound.
• Control muscle spasms: benzodiazepines are the main-
stay of treatment; intravenous diazepam 10–40 mg every
1–8 hours may be required to prevent spasms that last
more than 5–10 seconds. At high doses, lactic acidosis
can occur, possibly as a result of the solvent vehicle,
propylene glycol. There are γ-aminobutyric acid agonists
that indirectly antagonize the toxin, but they do not
restore glycinergic function.
• Maintain ventilation and oxygenation and prevent
pulmonary aspiration of gastric contents:
– Control the muscle spasms.
– Tracheostomy is indicated if rigidity and spasms cannot
be controlled and interfere with swallowing or breathing.
341 Facial photograph of a patient with facial muscle stiffness and
grimacing (risus sardonicus) and difficulty opening the jaw (trismus) due
to tetanus.
– Paralysis and ventilation are required if spasms become
severe.
• Maintain nutrition and fluid balance with oral feeds if
mild, or i.v. line or nasogastric tube if spasms are
moderate but not severe. If severe, the patient must be
intubated and ventilated.
• Human antitetanus immunoglobulin (500 units) is
recommended, although its efficacy is controversial.
• Antitetanus toxin.
• Antimicrobial chemotherapy: metronidazole (0.5 g every
6 hours or 1.0 g every 12 hours intravenously) is as good
as, or better than, penicillin G which is no longer the
drug of choice. Also, penicillin is an antagonist of
γ–aminobutyric acid, just as is tetanus toxin.
• Prevent gastric stress ulcers: H2 receptor antagonists.
• Prevent deep vein thrombosis: low dose heparin
5000 units subcutaneously twice daily.
• Control autonomic dysfunction: beta-blockade or
combined alpha and beta-blockade as necessary for labile
blood pressure and heart rate.
PROGNOSIS
• The disease progresses over about a week, stabilizes for
another week, and then recovers over several weeks.
• The severity is very variable.
• Case fatality ranges from 10 to >50% worldwide. At least
half of deaths from tetanus worldwide occur in neonates.
These deaths are preventable through antepartum
maternal immunization.
• In the USA, 75% of deaths occur in people who are 60 years
of age or older (who make up 59% of all cases of tetanus).
PREVENTION
Tetanus is a serious preventable disease that remains a threat
even in developed countries, particularly in older people. A
case of tetanus reflects the failure of our health care delivery
system to provide immunization. Routine boosters every
10 years should be emphasized in older people.
About 70% of a random sample of Americans aged 6 or
more years had protective levels of tetanus antibodies. The
prevalence of protective antibodies is less than 50% in people
aged 60–69 years, and about 30% in people aged 70 years
and older.
341
 Whipple’s Disease
WHIPPLE’S DISEASE
DEFINITION
A rare, chronic, relapsing, multisystem granulomatous
disorder that is caused by infection by Tropheryma whippelii,
a Gram-positive bacillus; it primarily involves the intestine
causing chronic diarrhea, together with fever and migratory
polyarthralgias. About 5% of patients present with
neurologic manifestations and 6–43% eventually develop
symptomatic CNS involvement.
HISTORY
Described in 1907 by George Whipple. The patient was a
missionary who had weight loss, diarrhea, and abdominal pain
associated with polyarthralgia and lymphadenopathy. At
autopsy, numerous argyrophilic rod-shaped organisms were
present in mesenteric lymph nodes. In 1949 Black-Schaffer
showed that the bacilli gave a strongly positive result when
stained with periodic acid Schiff reagent. In 1991 and 1992
specific DNA sequences were amplified from affected tissue.
The nucleotide sequence had phylogenetic similarities to the
actinomyces group, and the organism was named T. whippelii.
EPIDEMIOLOGY
• Incidence: rare; fewer than 800 cases have been reported
(<10 cases per year).
• Age and gender: usually presents in middle-aged men.
PATHOLOGY
• Symptomatic neurologic involvement occurs in at least
10% (6–43%) of patients at some stage in their illness.
Autopsy more frequently reveals brain involvement, even
in the absence of neurologic symptoms.
• Sites of predilection are the basal ganglia, insular cortex,
midbrain, pons and cerebellum.
• Microscopic examination of the brain reveals widespread
inflammation (encephalitis) throughout the cerebral
hemispheres and brainstem (particularly the striatum,
other basal nuclei and pons) characterized by
mononuclear cell perivascular cuffing and infiltration of
white and gray matter, marked astrocytosis, proliferation
of microglia, and focal necrosis of many nerve cells.
• With hematoxylin and eosin (H&E) stain some nerve
cells appear swollen and the cytoplasm has a very fine,
granular, bluish-purple staining appearance.
• Fat stains demonstrate nerve cells containing numerous,
rather coarse, varying-sized pale granules and globules of fat.
• PAS stain shows that the cytoplasm of neurons, astrocytes
and perivascular inflammatory cells contain abundant
foamy macrophages filled with masses of coalescent PAS-
staining granules.
• Electron microscopy shows numerous bacilli in the
distended macrophages and in the intercellular spaces.
The bacilli measure 1.5–3.0 μm in length and 200 nm in
diameter. The bacilli are lined by a thin surface membrane
and a thick (20 nm) cell wall. Whipple’s bacteria are most
frequently found in microglial and ependymal cells in the
brain but they are also found within astrocytes, pericytes,
and choroid plexus cells. The internal layers of the retina
also show many large, pale, granule-containing cells.
289
ETIOLOGY AND PATHOPHYSIOLOGY
Infection by T. whippelii, a Gram-positive bacillus.
CLINICAL FEATURES
The most common clinical presentation is the insidious
onset of a malabsorption syndrome (e.g. diarrhea),
sometimes preceded by migratory polyarthralgia and fever.
Cardiac (pericarditis, myocarditis, marantic endocarditis)
and CNS involvement is also common, and a few present
with primarily neurologic manifestations.
Neurologic triad
• Dementia, apathy and personality change: progressive.
• Myoclonus (facial) and tonic-clonic seizures; oculomastica-
tory myorhythmia (facial myoclonus) is pathognomonic:
the eyes converge synchronously (convergent nystagmus)
with involuntary jaw, palatal and tongue movements.
Rhythmic spinal myoclonus has also been described.
• Supranuclear ophthalmoplegia (voluntary vertical and, less
so, horizontal gaze palsy; not caused by cranial nerve
involvement but by lesions in the brainstem).
Other features
• Ataxic gait.
• Hypothalamic dysfunction (sleep [hypersomnolence],
drinking [polydipsia], and eating [hyperphagia] disorders).
• Coma.
• Chronic meningitis.
• Blurred vision or visual loss due to vitritis, uveitis, retinitis,
retinal hemorrhage, choroiditis, papilledema, optic atrophy
or keratitis.
• Progressive peripheral neuropathy and myopathy are rare.
DIFFERENTIAL DIAGNOSIS
Depends on the clinical features:
• Progressive supranuclear palsy.
• Pituitary tumor.
• Alzheimer’s disease.
• Vascular dementia.
• Cerebral tumor: primary or metastatic.
• Sarcoidosis.
• Syphilis.
INVESTIGATIONS
Full blood count, ESR and other blood tests
Minimal neutrophil pleocytosis; ESR and serum ACE may
be raised.
Molecular DNA analysis
Amplification of sequences of bacterial 16S ribosomal RNA
(rRNA) specific for Whipple bacillus (T. whippelii) from
peripheral blood mononuclear cells using PCR.
Cranial CT scan
May be normal, show cortical atrophy, areas of low attenuation
with or without contrast enhancement, areas of mixed density
with multifocal enhancement and regions of vasogenic edema.
MRI brain
May be normal in the early stages or show diffuse abnor-
malities on T2W images. Areas of increased T2W signal inten-
sity on MRI scans are a sensitive indicator of disease activity
and the lesions may enhance intensely with contrast medium.
290 Infections of the Nervous System: Bacterial
The lesions may be seen in the hypothalamus, midbrain and
basal ganglia and may have slight mass effect (342, 343).
CSF
CSF is normal or more commonly contains excess white cells
and protein, oligoclonal banding and increased IgG. It may
reveal sickle-particle-containing cells. Staining of the CSF with
periodic acid Schiff reagent may give a positive result. PCR can
be used to amplify sequences of bacterial 16S rRNA specific
for Whipple bacillus (T. whippelii) in the CSF.
Other
• EEG: non-specific.
• Biopsy of jejunal mucosa, lymph nodes, vitreous or brain.
DIAGNOSIS
Definite CNS Whipple’s disease
Must have any one of the following three criteria:
• Oculomasticatory myorhythmia (OMM: pendular
vergence oscillations of the eyes that are synchronous
with masticatory myorhythmia) and oculo-facial-skeletal
myorhythmia (OFSM: similar to OMM, also involves
myorhythmia of non-facial skeletal muscle).
• Positive tissue biopsy: ultrastructural findings of
distinctive periodic acid Schiff-positive bacillary rods and
sickle-shaped inclusion bodies in macrophages in the
CSF, vitreous or in a jejunal or brain biopsy.
• Positive PCR amplification of sequences of bacterial 16S
rRNA gene corresponding to the Whipple’s disease
bacillus (T. whippelii) in infected tissues.
• If histologic or PCR analysis is not performed on CNS
tissue, then the patient must also demonstrate neurologic
signs. If histologic or PCR analysis is performed on CNS
tissue, then the patient need not demonstrate neurologic
signs (i.e. asymptomatic CNS infection).
Possible CNS Whipple’s disease
Must have any one of four systemic symptoms, not due to
another known etiology:
• Fever of unknown etiology.
• Gastrointestinal symptoms (steatorrhea, chronic diarrhea,
abdominal distension, or pain).
342 343
• Chronic migratory arthralgias or polyarthralgias.
• Unexplained lymphadenopathy, night sweats, or malaise.
• Also must have any one of four neurologic signs, not due
to another etiology:
– Supranuclear vertical gaze palsy.
– Rhythmic myoclonus.
– Dementia with psychiatric symptoms.
– Hypothalamic manifestations.
• A favorable response to trimethoprim-sulfamethoxazole
or chloramphenicol therapy helps to confirm the diagnosis.
TREATMENT
Antimicrobial treatment
• Oral trimethoprim (160 mg) and sulfamethoxazole
(800 mg) twice daily for 1 year plus folate (folic acid)
supplementation.
• If allergic: intravenous penicillin G (2 million units,
4 hourly) and oral doxycycline (100 mg bd).
The choice of antimicrobial treatment is based mainly on
taxonomy, which has been known for only the past few years.
The organism has not been cultured, and therefore in vitro
susceptibilities are not available. There are no data on compari-
son of antibiotics. However, empirical clinical experience sug-
gests that patients initially treated with drugs that do not pene-
trate the blood–brain barrier are at risk of neurologic relapse.
Myoclonus (see p.124)
• Valproate 500 mg bd.
• Clonazepam 0.5 mg nocte, increasing up to 8 mg per
day (or tolerance).
PROGNOSIS
• The clinical course is usually one of progression to death
within 6–12 months but can be fulminant, leading to
death within weeks, in spite of treatment with appro-
priate antibiotics.
• Involvement of the neuraxis carries a poor prognosis,
even when the intestinal disease has been eradicated.
• Relapses are most common with CNS Whipple’s disease
and are often resistant to antibiotics.
342, 343 T2W axial
(342) and T1W axial (343)
post contrast MRI in a
patient with biopsy-proven
Whipple’s disease. Note
the areas of increased signal
with mass effect and some
enhancement in the basal
ganglia.The lesion was
initially mistaken for an
infarct but, because it
involves the carotid and
basilar territory, this would
be distinctly unusual.
 Acute Aseptic Meningitis
VIRAL INFECTIONS
ACUTE ASEPTIC MENINGITIS
DEFINITION
Acute meningeal irritation, benign and self-limiting, with
sterile pleocytic CSF and complete recovery.
EPIDEMIOLOGY
• Incidence: 2–27 cases per 100 000 per year are reported.
The incidence is probably higher by several multiples
because of under-reporting.
• Lifetime prevalence: 0.9 (95% CI: 0.6–1.0) per 1000.
• Infections occur throughout the year, with a preponderance
in summer and autumn in temperate climates.
• Age: mostly in children and young adults.
ETIOLOGY AND PATHOPHYSIOLOGY
Virus infection: at least 70% of cases
• Enteroviruses (over half cases of viral meningitis):
– Coxsackie-B.
– Echovirus.
• Herpes simplex virus (HSV) type 1 and type 2.
• Varicella-zoster.
• Mumps.
• Lymphocytic choriomeningitis.
• HIV.
Other causes
• Chemical and physical agents:
– Myelography with oil-based contrast media.
– Intrathecal drug administration.
– Craniopharyngiomas.
– Cholesterol crystals discharged from cholesteatoma.
– Pituitary apoplexy.
• Parasites.
• Granulomatous inflammation: sarcoidosis.
• Connective tissue disease.
• Malignant infiltration.
• Drugs:
– Cytotoxic drugs.
– Non-steroidal anti-inflammatory drugs such as ibuprofen.
– Immunoglobulins.
– Antibiotics such as penicillin, isoniazid, ciprofloxacin,
trimethoprim-sulfamethoxazole.
PATHOPHYSIOLOGY
Viral infections of the CNS are complications of systemic viral
infections. The virus gains access to the brain by the bloodstream
or, less commonly, by travelling along peripheral nerves. In order
for viruses to enter the CNS from the blood they must cross the
endothelial cell junctions of the blood–brain barrier (the ability
to do this is dependent on surface adhesion molecules on the
cells, and surface charges and cellular receptor of the virus).
Certain viruses preferentially infect the meninges, choroid
plexus, and ependyma rather than cerebral parenchyma, causing
meningitis; others infect neurons and glia to cause encephalitis.
There is, however, considerable overlap, and some viruses may
cause meningo-encephalitis. Drug-induced meningitis is either
a direct chemical irritation or a hypersensitivity reaction.
344 Herpes zoster skin rash in a patient with aseptic meningitis.
291
CLINICAL FEATURES
Usually a rapid onset over hours of fever, headache, malaise,
neck stiffness, photophobia, lethargy, myalgia and irritability.
The patient usually remains coherent and can be roused
easily. The occurrence of depressed consciousness, focal
neurologic signs, or epileptic seizures usually implies
encephalitis. The physical signs are not so marked and the
illness is not as severe and prolonged as bacterial meningitis.
The pathogen is seldom identified clinically:
• Myalgia and myocarditis point to coxsackie.
• Skin rash to enteroviruses, or herpes zoster virus (344).
• Parotitis and orchitis to mumps.
• Arthralgia and lymphadenopathy to HIV.
SPECIAL FORMS
Mollaret’s meningitis
A benign recurrent ‘non-infectious’ meningitis of hitherto
unknown cause characterized by fever, malaise and CSF pleo-
cytosis (lymphocytes, neutrophils and endothelial cells), which
may respond to corticosteroids, colchicine or phenylbutazone.
New diagnostic techniques, such as the PCR for detecting viral
DNA in CSF have shown HSV, predominantly type 2, to be
a major cause of benign recurrent lymphocytic meningitis.
DIFFERENTIAL DIAGNOSIS
• Meningitis:
– Early bacterial meningitis (see p.273).
– Partially treated bacterial meningitis.
– Meningitis caused by fastidious bacteria.
– Fungal and parasitic meningitis (fungi and parasites do
not grow readily in routine culture).
– Parameningeal inflammation, infection or neoplasia.
• Subarachnoid hemorrhage (see p.249).
INVESTIGATIONS
Blood
Serologic studies of acute and convalescent serum samples (e.g.
coxsackie, echovirus, HSV, varicella-zoster, mumps, HIV, measles,
adenovirus, Epstein–Barr virus [EBV], cytomegalovirus [CMV]).
CT or MRI brain scan
Typically neither scan will show any abnormality. The main
reason for imaging is to exclude other causes of headache,
such as a space-occupying lesion or raised intracranial
pressure, and ensure that it is safe to do an LP.
344
292 Infections of the Nervous System: Viral
CSF
• Pressure: normal or raised slightly.
• Appearance: clear to the naked eye.
• Microscopy: up to 500–1000 white cells/mm3, mainly
lymphocytes; polymorphs may predominate in some cases
early. In such cases it is prudent to re-examine the CSF
12–24 hours later to identify a lymphocytosis and exclude
a bacterial cause.
• Protein: raised slightly.
• Glucose: normal or reduced a little; CSF glucose can be
low in antibiotic-induced meningitis.
• Viral antigen and IgM antibody.
• Culture: negative.
• PCR: may detect viral DNA.
Many laboratory tests have been applied to CSF (i.e.
creatine kinase, lactate, lysozyme, and C-reactive protein) to
try and differentiate a viral from a bacterial cause but none is
sufficiently discriminating to be useful; nor is the blood count,
blood biochemistry and EEG.
DIAGNOSIS
• Appropriate clinical features and a raised white cell count
in sterile CSF.
• Provided other similar treatable diseases have been excluded
(see Differential diagnosis), it is not necessary in most cases
to establish an exact etiologic diagnosis for treatment pur-
poses because the disease is usually benign and self-limiting.
TREATMENT
Symptomatic treatment with analgesics and antiemetics is all
that is required. Antibiotics should not be given.
CLINICAL COURSE AND PROGNOSIS
Determined by the underlying cause. Most cases do not
progress; resolution begins within a few days and is complete
within 2 weeks in most patients. A few will have persistent
malaise and myalgia for some weeks.
345
345 T2W MRI brain scan of the temporal regions in a patient with
herpes simplex encephalitis. Note the increased signal in the medial
temporal gray and white matter, more on the right (arrows), associated
with some swelling.These features are typical of HSV encephalitis though
are not specific, and a normal MRI does not exclude encephalitis.
VIRAL ENCEPHALITIS
DEFINITION
Inflammation of the brain caused by a virus, often accompanied
by inflammation of the meninges (meningo-encephalitis).
EPIDEMIOLOGY
The most common cause of encephalitis world-wide but in
certain locations and seasons other organisms such as
malaria and other protozoans, rickettsiae and fungi may be
more common causes of encephalitis.
• Incidence: 1 in 20 000 per year.
• Lifetime prevalence: 0.4 (95% CI: 0.2–0.7)/1000.
• Age: most common in the first decade of life, with a peak
incidence of 1 in 500–1000 infants in the first 6 months
of life, but any age may be affected.
• Gender: M=F.
PATHOLOGY
Acute viral encephalitis
• Cortical vessels in the gray matter and at the junction of
gray and white matter: striking endothelial and capillary
inflammation. Perivascular lymphocyte infiltration results
from either the passive transfer of virus across the
endothelium at pinocytic junctions of the choroid plexus
or active replication of virus in capillary endothelial cells.
• Gray matter: lymphocytic infiltration and neuronophagia
may occur; astrocytosis and gliosis if progressive disease.
Specific cell types infected by specific virus and their pathologies
• Poliovirus (motor neurons), rabies (limbic system), and
togavirus infect neurons and cause necrosis.
• Lymphocytic choriomeningitis virus infects choroid plexus,
meninges, and ependyma and causes fatal choriomeningitis.
• Mumps virus can infect the ependymal cells of newborns.
• Papovavirus infects oligodendrocytes and causes
demyelination.
• Parvovirus infects endothelial cells and produces a
hemorrhagic encephalopathy.
• Varicella-zoster virus infects multiple cell types, including
blood vessels causing a vasculopathy leading to
ischemic/hemorrhagic infarction and oligodendrocytes
causing demyelination.
• HSV infects neurons of the temporal and inferior frontal
lobes (345).
Unique histopathologic features
• Cowdry type A inclusion bodies: herpes virus.
• Negri bodies: rabies.
Postinfectious encephalomyelitis
Perivascular inflammation and demyelination.
ETIOLOGY
Most cases are sporadic accompaniments of common
infections such as mumps, measles, herpes simplex and
varicella-zoster, and less commonly EBV, but in as many as
one-third of all cases no specific etiology can be established.
Acute viral encephalitis
Endemic
• HSV: 10% of cases (see p.295).
• Rabies.
 Viral Encephalitis
Epidemic or sporadic
• Japanese B encephalitis: probably the most common
epidemic infection outside North America.
• Arthropod-borne viruses (arboviruses – viruses transmit-
ted by insects):
– St Louis encephalitis.
– Eastern equine encephalitis.
– Venezuelan equine encephalitis.
– La Crosse virus, the most important mosquito-borne
virus in the USA; found in all 13 states east of the Missis-
sippi river. Encephalitis caused by La Crosse virus is
transmitted by mosquitos and most commonly affects
children and young adults. There is no therapy but most
patients recover (death occurs in <1%). The primary
reservoirs of the virus are small forest mammals.
• Enteroviruses: coxsackie virus, echovirus and poliovirus
(usually cause aseptic meningitis).
• Paramyxoviruses: measles, mumps, respiratory syncytial
virus, parainfluenza.
• CMV.
• EBV.
• Rubella.
• Influenza.
• Adenovirus.
• Yellow fever.
Postinfectious encephalomyelitis
• Influenza A.
• Measles (1 in 1000 cases; in countries where vaccination
is not routine).
• Varicella-zoster virus.
• EBV.
• Mumps.
• Rubella.
• Vaccination (vaccinia, rabies).
• No recognizable preceding illness sometimes.
PATHOGENESIS
The rare occurrence of encephalitis after viral infection
depends on the nature and virulence of the organism and
the host immune response.
Access routes to the brain
Viruses generally gain access to the CNS by the
hematogenous or peripheral intraneuronal routes.
Haematogenous
Viruses may enter the body through the skin following an
insect bite (as with arbovirus infection) or via the respiratory
or gastrointestinal route where they replicate locally.
Transient viremia may ensue if the inoculum spills into the
blood, where it is transported to the reticuloendothelial
system (particularly the liver, spleen, lymph nodes and
sometimes muscle) whence, following further replication,
secondary viremia may occur and the organism spreads to
other sites including the CNS.
Neuronal
Organisms, such as herpes simplex virus and rabies may
ascend neurons centripetally and directly invade brain
parenchyma. Clinical manifestations are caused by cell
dysfunction from viral invasion and associated inflammatory
change.
293
Preferential sites of involvement
Certain viruses preferentially infect neurons and glia, and
some exhibit tropism towards specific neuronal cell types:
• Frontal and temporal lobes: HSV.
• Cerebellum: varicella-zoster and EBV.
• Limbic system: rabies.
Direct virus-induced cellular damage, secondary
immunologically mediated events, or both?
Serum IgG and IgM antineuronal antibodies in patients
with encephalitis suggest a role for autoimmune mechan-
isms; e.g. in EBV encephalitis either EBV-transformed B
cells secrete antineuronal antibodies or antibodies against
EBV proteins cross-react with neuronal antigens.
Postinfectious encephalomyelitis
An autoimmune phenomenon, initiated by the viral
pathogen and characterized by immunoregulatory failure
rather than immunosuppression. There is an apparent latent
phase between the acute illness and the onset of neuro-
logical symptoms due to demyelination.
CLINICAL FEATURES
• Can be enormously variable.
• Onset is usually insidious but may occasionally be
cataclysmic.
• Prodrome of fever, malaise, myalgia, irritability, mild
upper respiratory tract infection, rash or parotitis lasts
4–10 days.
• Fever (not invariable).
• Headache.
• Stiff neck (meningismus).
• Photophobia.
• Disorientation.
• Behavioral disturbances.
• Focal neurologic signs such as dysphasia and hemiparesis
(frontal lobes), epileptic seizures (cerebral cortex), ataxia
(cerebellum), and memory disturbance (temporal
lobes/limbic system) depending on which part of the
brain is involved. It is vital to distinguish between
generalized and focal neurologic dysfunction, and to
determine whether focal neurologic signs could be
explained by the tropism of certain viruses to infect
certain CNS cell types (see Pathology and pathogenesis).
• Depressed consciousness.
• Raised intracranial pressure.
Other possible features
• Season of the year and climate:
– Summer and damp climates: mosquito propagation (cf.
arthropod-borne virus infection).
– Late summer/early autumn in temperate climate:
enteroviral infections.
• Travel to or from an area that harbors known vectors (i.e.
arboviruses).
• Insect bite: tick or mosquito (cf. arbovirus).
• Animal bite: potentially rabid (cf. rabies).
• Skin rash: varicella or measles.
• Parotitis: mumps.
• Hepatosplenomegaly: EBV, CMV.
• Immunocompromised (neonates, organ transplant
recipients, HIV infection): CMV.
294 Infections of the Nervous System: Viral
The disease may be more severe in the very young, very
old and immunocompromised.
SPECIFIC FORMS
• Herpes simplex encephalitis (see p.295).
• Varicella-zoster encephalitis (see p.299).
DIFFERENTIAL DIAGNOSIS
Other intracranial infections
• Viral meningitis: usually only fever, headache, neck
rigidity and photophobia without signs of brain
dysfunction such as mental change and focal neurologic
signs.
• Bacterial meningitis.
• Mycoplasma pneumoniae encephalitis.
• Malaria and other protozoal and fungal infections.
• Cerebral abscess.
Non-infectious conditions
• Cerebral tumor or metastases.
• Connective tissue disease.
• Drug abuse.
• Reye’s syndrome
• Hypoxic-ischemic encephalopathy
• Hemorrhagic shock and encephalopathy
• Metabolic/toxic encephalopathy
• Mitochondrial encephalomyopathy, lactic acidosis, and
stroke-like episodes (MELAS).
• Deep cerebral venous thrombosis.
INVESTIGATIONS
Blood
• Full blood count.
• Urea and electrolytes: hyponatremia secondary to
SIADH.
• Blood film: malarial parasites.
• Blood cultures.
• Viral culture of samples of respiratory secretions, blood,
CSF, urine and stool, taken within 4 days of onset of the
illness if possible; throat swab in viral transport medium.
• Blood viral serology (paired acute and convalescent
samples to demonstrate seroconversion or seroboosting)
and PCR (detection of viral antigen by amplification of
nucleic acid sequences): herpes simplex, measles, mumps,
rubella, influenza, parainfluenza, adenovirus, varicella-
zoster, CMV, EBV.
Cranial CT scan
Normal, or diffuse or focal areas of low attenuation, with or
without space effect. The findings are non-specific and can
look just like an infarct. Changes may not become apparent
for 5 or 6 days, if ever. CT is useful to exclude other possible
causes of headache and drowsiness but will not give positive
confirmatory evidence of encephalitis.
MRI brain
More sensitive than CT, particularly early in the illness, and
may help identify other pathologies in the differential
diagnosis, such as tumors and abscesses.
EEG
Abnormal, most often non-specific diffuse slow wave
activity, sometimes with epileptiform activity.
CSF
Abnormal in 95% of patients:
• Pressure: increased.
• Microscopy: cell count: raised; 10– several hundred white
cells/mm3.
• Cell type: lymphocytes; polymorphs may predominate
early, red cells may be present if there is a necrotizing
component, as in herpes simplex encephalitis.
• Organisms: not seen.
• Protein: raised.
• Glucose: normal.
• Viral antigen or IgM antibody.
• IgG index and oligoclonal bands.
• PCR: a positive result increases the likelihood of a
definite diagnosis of viral meningo-encephalitis by 88
times (95% CI: 21–378) compared with a negative PCR
result.
• Culture: of little value for virus isolation.
• Interferon alpha in the CSF: only moderately sensitive
but highly specific for virus infection of the CNS; not
widely available.
Brain biopsy
• No role in confirming the diagnosis of viral encephalitis
(neither sensitive nor safe).
• Biopsy has a role in clarifying the differential diagnosis
of a mass lesion that could be an abscess, granuloma,
tumor or inflammatory mass, particularly if no response
to acyclovir.
DIAGNOSIS
Blood viral serology demonstrating seroconversion or
seroboosting in paired acute and convalescent serum is still
the mainstay of diagnosis, but PCR of infected tissue
(blood, CSF) is soon likely to provide rapid and accurate
diagnosis.
TREATMENT
Antiviral chemotherapy
Acyclovir must be commenced immediately if there is any
possibility of HSE (see p.295).
Symptomatic
Supportive care: adequate oxygenation, hydration and
nutrition; maintain fluid and electrolyte balance, control the
temperature and seizures, and treat dysfunction of other
organs.
Steroids
In severe cases of acute post infectious encephalomyelitis,
corticosteroids are given empirically (prednisolone 20 mg
four times daily).
Complications
• Cerebral edema and raised intracranial pressure:
dexamethasone, mannitol, glycerol (glycerin), and
intubation and hyperventilation may be required.
Dexamethasone is often used despite the theoretical
disadvantage that interferon synthesis may be inhibited.
There is no consensus on the correct treatment.
• Epileptic seizures: anti-epileptic drugs such as sodium
valproate or carbamazepine, if seizures occur.
• Secondary infections: treat as necessary.
 Herpes Simplex Virus Encephalitis (HSE)
PROGNOSIS
• Mortality: about 3%.
• Serious morbidity: about 7%.
• At 10 year follow-up: almost half the survivors have
motor dysfunction and educational dysfunction; well
over a third have neurologic dysfunction, and almost a
fifth have behavioral, self-care and sensory dysfunction.
Adverse prognostic factors
• Young age: children younger than 3 years of age: 34%
case fatality.
• Low conscious level.
• Abnormal oculocephalic responses.
• High ratio of albumin in CSF to that in serum.
• Laboratory evidence of infection of the CSF.
• Organism:
– Herpes simplex virus encephalitis: 12-fold excess
mortality.
– M. pneumoniae encephalitis: sevenfold excess mortality.
– Measles encephalitis: 15% mortality, most survivors
disabled.
– Varicella-zoster encephalitis: 10% mortality with diffuse
form.
– EBV and mumps encephalitis: excellent prognosis.
PREVENTION
Immunization of the whole child population is necessary for
effective prevention.
295
HERPES SIMPLEX VIRUS
ENCEPHALITIS (HSE)
DEFINITION
An acute asymmetric necrotizing infection of the brain
parenchyma, primarily the frontal and temporal lobes and
the limbic system, by HSV, usually type 1.
EPIDEMIOLOGY
The most common cause of sporadic, non-epidemic, acute
focal encephalitis in immunocompetent adults in developed
countries; comprising about 10% of cases of encephalitis in
the United States.
• Incidence: 1 per 500 000 people per year (an
underestimate; milder cases go unrecognized). The
incidence is higher in immunocompromised individuals
(e.g. those with HIV infection) but most patients are
immunocompetent.
• It occurs throughout the year.
• Age: any age; one-third <20 years of age, and one-half
>50 years.
• Gender: M=F.
PATHOLOGY
Acute focal hemorrhagic necrotizing inflammation
predominantly in the temporal and inferior frontal lobes
(orbital surface) but adjacent frontal, parietal, and occipital
lobes and cingulate gyri may also be involved.
Pathologic findings are due to the direct cytopathic
effects of viral infection and include neuronal necrosis,
reactive astrocytosis, perivascular lymphocyte cuffing and
characteristic Cowdry type A intranuclear inclusion bodies.
ETIOLOGY AND PATHOGENESIS
HSV type 1 (HSV-1, >90% of cases) and type 2 (HSV-2, up
to 10% of cases):
• Both viruses are widespread in the adult population, with
a rate of seropositivity of 60–100% for HSV-1 and
10–80% for HSV-2. Levels of seropositivity are related
to socio-economic status and geographic area.
• Primary HSV infection occurs relatively early in life and
is usually asymptomatic.
• Pathogenesis of HSE is only partly understood, and
includes primary HSV infection, re-infection and
reactivation of latent virus infection.
Neonatal HSE
• HSV-1 or HSV-2.
• HSE caused by HSV-2 in neonates with multiple organ
disseminated disease is probably blood-borne and is
associated with a diffuse encephalitis, resulting in
generalized encephalomalacia.
• Isolated HSE in neonates (without systemic disease) is
transmitted by the peripheral intraneuronal route; tends to
infect one temporal lobe and then the other as the disease
progresses, as is also the case in older children and adults.
296 Infections of the Nervous System: Viral
Childhood (>2 years) and adult HSE
• HSV-1 in the vast majority (>90%) of cases; HSV-2 in
<10% (HSV-2 tends to cause viral meningitis in adults,
particularly in association with primary genital infection).
• HSV-1 enters the nervous system by way of the olfactory
bulb, or reactivation of a latent infection in the trigeminal
and other cranial nerve ganglia, with centripetal spread
of virus to the frontal or temporal lobes of the brain
through its branches that innervate the meninges. The
virus causes encephalitis by direct invasion of brain
parenchyma but the mechanism of reactivation in HSE
is poorly understood.
CLINICAL FEATURES
• Onset is commonly quite abrupt but may be insidious.
• Concurrent cold sores or genital herpes are uncommon.
• Prodrome of fever, headache, lethargy and nausea over a
few days.
• Behavioral change.
• Disorientation.
• Altered conscious level.
• Focal neurologic signs such as anosmia or altered
olfactory perception, dysphasia, hemiparesis, memory
loss, olfactory or gustatory hallucinations, bizarre
behavior and complex partial seizures.
Other, unusual presentations of HSV infections of the
nervous system include:
• Mild/subacute encephalitis.
• Psychiatric syndromes.
• Brainstem encephalitis.
• Benign recurrent meningitis.
• Myelitis.
DIFFERENTIAL DIAGNOSIS
• Meningitis: bacterial, fungal and mycobacterial.
• Brain abscess.
• Subdural empyema.
• Stroke: frontotemporal infarction, hemorrhagic infarction
or hemorrhage.
• Subdural hematoma.
346 347
• Brain tumor.
• Granuloma.
• Other forms of viral encephalitis: e.g. arbovirus
(appropriate travel history), mumps, enterovirus.
• Deep cerebral venous thrombosis.
• MELAS.
INVESTIGATIONS
Cranial CT scan
CT is useful to exclude other possible causes of headache
and drowsiness. It may be normal initially but commonly
(although not always) it eventually shows low density lesions
due to edema and necrosis, sometimes with hemorrhagic
change, in the inferior frontal and medial temporal lobe, and
which may demonstrate enhancement after injection of
intravenous contrast. The changes may not become
apparent however for 5 or 6 days and can look just like an
infarct (346, 347). Herpes encephalitis is therefore a
diagnosis which needs a low index of suspicion as there is
an effective treatment.
MRI brain scan
Hypointense lesions on T1W images and hyperintense
lesions on proton density and T2W images (T2WI) at an
earlier stage than by CT. The T2WI typically shows
increased signal in the temporal and inferior frontal lobes
(more ‘whiteness’ on T2WI) accompanied by swelling of
the affected cortex, and possibly evidence of hemorrhage
(black bits on the T2WI). The appearance can be quite
asymmetric (348, 349).
MRI brain is more sensitive than CT to the abnormalities
of encephalitis particularly early in the illness and is the
imaging investigation of choice. MRI also may show more
extensive involvement than CT (350, 351) and help
identify other pathologies such as cerebral tumors or
abscesses.
EEG
EEG may be normal early in disease but usually is abnormal
and shows non-specific slow wave activity in the first few
days. Later, more characteristic periodic lateralized
346, 347 Cranial CT scan in
the axial plane of a patient
with herpes simplex
encephalitis involving the
right inferior frontal and
antero-medial temporal lobe.
The lesion extends to involve
the external capsular region
and the associated mass
effect is seen to compress
the frontal horn of the right
lateral ventricle.These scans
(with 348, 349) highlight the
difficulty of distinguishing focal
encephalitis from infarction
sometimes.
 Herpes Simplex Virus Encephalitis (HSE) 297

epileptiform discharges (PLEDs) which consist of 50–100 mV, occurring every 1 to several seconds (352).
paroxysmal, high voltage, sharp waves, sharp and slow The PLEDs are maximal over the affected temporal region
waves, spikes, or multiple spikes with amplitude of and, if bilateral, suggest HSE.

348, 349 MRI brain scan, 348 349

T2W images in the axial
plane of a patient with
herpes simplex encephalitis
involving the right inferior
frontal and antero-medial
temporal lobe.The lesion
extends to involve the
external capsular region and
the associated mass effect is
seen to compress the frontal
horn of the right lateral
ventricle.

350, 351 MRI brain scan, 350

T2W images in the axial 351
(350) and coronal (351)
planes showing extensive
high density due to cystic
gliotic change in the anterior
three-quarters of the right
temporal lobe, the medial left
temporal lobe, the inferior
and lateral right frontal lobe,
the right insular cortex, and
the right cingular gyrus of a
patient with severe amnesia
due to bilateral herpes
simplex encephalitis several
years previously.The right
cerebral peduncle has
atrophied.

352 Electroencephalogram of a patient with herpes simplex 352

encephalitis showing complex discharges composed of spiky
elements mixed with slower waveforms diffusely over the left
hemisphere and recurring at not quite regular intervals.
Periodic lateralized epileptiform discharges (PLEDs) usually
indicate an acute or rapidly progressive focal brain lesion such
as infarction, hemorrhage, glioblastoma, abscess or encephalitis.
Rarely, a severe metabolic disturbance may be present.
Occasionally, PLEDs may be bilateral, such as in patients with
severe brain injury due to hypoxia, encephalitis, and status
epilepticus. PLEDs are usually short lived and disappear within
a few weeks, irrespective of etiology and intervention, but a
chronic seizure disorder may remain.
298 Infections of the Nervous System: Viral
CSF
• May be normal in about 5% of cases.
• Pressure: increased.
• Microscopy: cell count raised; 5–1000 (typically 5–100)
white cells per mm3.
• Cell type: lymphocytes; polymorphs may predominate
early, red cells may be present.
• Organisms: not seen.
• Protein: normal or raised up to 2 g/l.
• Glucose: normal.
• IgG index and oligoclonal bands: raised IgG; oligoclonal
bands may be present.
• HSV antibody titers: an increased CSF:serum quotient
for the HSV antibody titer, adjusted for CSF-blood
barrier integrity, indicates a specific intrathecal antibody
response.
• HSV antigen: virus isolated in less than 5% of cases.
• PCR for detection of HSV DNA in CSF: sensitive but
not 100% reliable. If positive, it remains positive for at
least 5 days after initiation of acyclovir therapy; the
method of choice for diagnosis of HSE.
• Viral culture: low sensitivity in detecting HSV in adults
but HSV can be retrieved from CSF in about half of
babies with encephalitis or disseminated disease.
Blood viral serology
Acute and convalescent serum samples to demonstrate
seroconversion or seroboosting.
Brain biopsy
The definitive diagnostic technique (characteristic histologic
changes, immunofluorescence for HSV antigens, culture of
HSV, and detection of viral DNA by in situ hybridization),
but has little role because it is neither sensitive or specific
(or safe), and in many cases it is appropriate to treat on the
basis of clinical, EEG and radiologic findings and observe
the clinical response to acyclovir. It does have a role in
clarifying the differential diagnosis of a mass lesion that
could be an abscess, granuloma, tumor or inflammatory
mass, particularly if no response to acyclovir.
DIAGNOSIS
The diagnosis is suggested by neurologic, electrophysiologic
and neuroimaging signs of fronto-temporal lobe necrosis
with serologic evidence of seroconversion or seroboosting
in paired acute and convalescent serum. However, a specific
diagnosis can only be achieved by virologic studies of the
CSF, PCR of the CSF, or by examination of brain tissue
obtained by biopsy or at post mortem. Nested PCR
amplification is a rapid, sensitive, inexpensive, and relatively
non-invasive method for establishing the initial diagnosis of
HSE and for monitoring the response to therapy. Although
nested PCR is more susceptible to contamination artefact
(false positive) than traditional methods such as virus
isolation or serology, diagnostic PCR has been successfully
incorporated into many laboratories and is likely to become
the gold standard. HSV sequences can be detected for up
to 5 days after commencing acyclovir and can differentiate
between HSE due to HSV-1 and HSV-2.
TREATMENT
Prompt antiviral chemotherapy
Acyclovir must be commenced immediately in any patient
with suspected HSE. The dose is 10 mg/kg given by
intravenous infusion over 1 hour, every 8 hours for
10–14 days. Acyclovir is extremely well tolerated with few
adverse effects in patients with normal renal function, and
so it is often appropriate to treat patients with suspected
HSE presumptively pending the results of further
investigations. New anti-HSV agents with enhanced
bioavailability, such as famciclovir are also available.
Symptomatic
Adequate oxygenation with assisted ventilation if necessary,
optimal fluid and electrolyte balance and hydration,
nutrition and analgesia.
Complications
• Cerebral edema and raised intracranial pressure:
dexamethasone (4 mg 6 hourly i.v. or orally), mannitol
(1 g/kg i.v. as a 20% solution over 1 hour), glycerol
(glycerin) and intubation and hyperventilation may be
required but remain controversial. Dexamethasone is
often used despite the theoretical disadvantage that
interferon synthesis may be inhibited. There is no
consensus on the correct treatment.
• Epileptic seizures: anti-epileptic drugs such as sodium
valproate or carbamazepine, if seizures occur.
• Secondary infections: treat as necessary.
CLINICAL COURSE AND PROGNOSIS
Untreated, HSE is rapidly progressive, typically leading to
brain edema and death after 7–14 days; the 1 month
mortality rate exceeds 70%, and only about 2.5% regain
normal function.
Early aggressive antiviral therapy with acyclovir reduces
mortality to 28% at 18 months, and is superior to that of
vidarabine which reduces mortality to 28% at 1 month and
44% at 6 months. At 2 years after treatment with acyclovir
about 38% are normal or have mild impairment, 9% have
moderate sequelae, and 53% have died or are severely
impaired. Among vidarabine recipients, only 15–20% are
judged to be normal on long term follow-up.
Outcome is influenced by:
• Age.
• Level of consciousness (if Glasgow coma score is <6,
outcome is uniformly poor).
• Duration of untreated disease (if treatment is com-
menced within 4 days of onset of symptoms, the chance
of survival increases from 72% to 92% at 1 month).
• Infants with HSV-1 encephalitis have a significantly
better neurologic outcome than those with HSV-2
infection of the CNS.
Relapse
Relapse of HSE after acyclovir or vidarabine therapy can
occur in up to 5% of cases. In the few cases in which HSV
isolates were tested for resistance to acyclovir, they remained
sensitive. Re-institution of treatment with a higher dose of
acyclovir (15 mg/kg every 8 hours) for a longer course
(21 days) or in combination with vidarabine has been tried
in a few patients but the results are inconclusive.
 Varicella-Zoster Virus Encephalomyelitis 299

VARICELLA-ZOSTER VIRUS • Arteritis: involves small vessels with fibrinoid necrosis and
ENCEPHALOMYELITIS granulomatous inflammatory infiltrates causing throm-
bosis and multifocal deep white matter lesions
(demyelination or infarction). In purely ischemic lesions,
DEFINITION characteristic Cowdry A inclusions may be scant or
Inflammation of the brain or spinal cord caused by infection absent. Rarely, mycotic aneurysms may form and
with the varicella-zoster virus (VZV), an α-herpes virus. rupture, causing hemorrhage.

EPIDEMIOLOGY Brain infarction does not usually occur until weeks to

• Incidence: rare, about 1 case per million population per
year.
• Prevalence: about 0.1% of VZV infections involve the
nervous system and 90% of these are in the form of
encephalitis. VZV encephalitis has become more
prevalent in the era of acquired immunodeficiency
syndrome and other immunosuppressive diseases.
• Age: in immunocompetent individuals, herpes zoster is
predominantly a disease of the elderly.
• Gender: M=F.
PATHOLOGY
A combination of ischemic and demyelinative features.
Multifocal demyelinating leukoencephalomyelitis
Infection of oligodendrocytes causes demyelinative lesions
in the deep white matter which are smaller and less
coalescent than those seen in PML. Target-like lesions with
central necrosis and surrounding myelin pallor, and Cowdry
type A intranuclear inclusions in surrounding glia and
neurons are the pathologic hallmarks of varicella-zoster
multifocal leukoencephalitis. Cowdry type A inclusions are
virtually specific for herpes viruses but their absence does
not rule out subtle infections.
months after trigeminal nerve distribution herpes zoster rash
(shingles).
ETIOLOGY AND PATHOPHYSIOLOGY
Chickenpox
Primary VZV infection causes the typical rash of
chickenpox. During chickenpox, VZV establishes latency in
multiple dorsal root ganglia.
Shingles
After a variable, but usually long period, the VZV reactivates
to cause shingles (herpes zoster), which is a disease of the
peripheral nervous system causing severe radicular pain,
herpetic vesicles on the skin usually in the distribution of one
to three dermatomes (353–355), and pain after the vesicles
have healed (post herpetic neuralgia). Focal muscle weakness
353

Angiopathy causing cerebral infarction and

hemorrhage
• Non-inflammatory angiopathy: involves mainly large
cerebral arteries with non-inflammatory hyperplasia of
intima and media, sometimes resulting in thrombosis and
multifocal large ischemic and hemorrhagic infarcts in the
cerebral cortex and subcortical white matter.

354

355

353–355 Herpes zoster infection (shingles) in the distribution of the

ophthalmic division of the trigeminal nerve.
300 Infections of the Nervous System: Viral
(zoster paresis) occurs in about 5% of cases, of whom about
60% recover completely, 25% incompletely, and 15% do not
improve. Encephalitis may rarely follow shingles.
Post herpetic pain probably occurs because reactivation
of VZV in the dorsal root ganglia appears to cause structural
damage which results in chronic stimulation of the CNS.
This re-sets the homeostatic mechanisms controlling pain,
so that the patient perceives chronic pain, severe pain from
minor stimuli, and allodynia (abnormal sensations).
Encephalomyelitis
Caused by reactivation of the VZV, latent in sensory ganglia
after primary infection. Several mechanisms have been
proposed, including hematogenous, transaxonal
(transneural) and/or vascular spread to the CNS, and an
immune-mediated effect. VZV may enter the CNS via
transaxonal spread from ocular or dermatomal zoster and
directly invade and infect small blood vessels, ultimately
leading to ischemic infarction and necrosis of brain or spinal
cord, or directly infect oligodendrocytes, leading to
demyelination. The finding of an active ‘centrifuge wave’ of
infection at the periphery of lesions and their random
distribution in the brain however, suggests hematogenous
spread during viremia.
Risk factors
Immunocompromised: elderly, acquired immunodeficiency
syndrome (AIDS), immunosuppressive therapy.
CLINICAL FEATURES
In about half of cases, usually young people with chicken
pox, the encephalitis predominantly affects the cerebellum,
causing cerebellar ataxia, dysarthria, headache and
drowsiness. The skin rash often precedes the neurologic
symptoms by about a week but occasionally the rash of
chicken pox may follow.
In immunocompromised and older individuals zoster
encephalomyelitis and granulomatous arteritis (the latter after
zoster ophthalmicus) usually develops concurrent with rash
or weeks to months after acute herpes zoster rash (353–355)
and is characterized by fever, seizures, mental status changes
and multifocal or isolated focal neurologic deficits.
DIFFERENTIAL DIAGNOSIS
• Other forms of viral encephalitis (see p.292): CMV,
HIV-1 related encephalitis, HSE (see p.295).
• Hemorrhagic multifocal leukoencephalopathy secondary
to angiopathy caused by toxoplasmosis, aspergillus,
CMV, HSV, ameba, HIV-1 (see p.301).
• Isolated angiitis of the CNS (see p.227).
• Stroke: ischemic (see p.202) or hemorrhagic (see p.238).
• Progressive multifocal leukoencephalopathy: typically
causes hemiparesis, aphasia, visual-field defects and
confusional states; MRI reveals larger and more
coalescent zones of demyelination than VZV
encephalitis; and CSF PCR detects JC virus DNA.
INVESTIGATIONS
Blood viral serology
Acute and convalescent serum samples to demonstrate
seroconversion or seroboosting.
Cranial CT scan
CT shows focal or multifocal areas of low attenuation and
swelling, and sometimes petechial or frank hemorrhage.
Intracranial calcification may occur as a sequelae to zoster
encephalitis.
MRI brain
MR may reveal a spectrum of lesions from multifocal ischemic
and hemorrhagic infarction of varying size, depending on the
caliber of the vessel involved, to a leukoencephalopathy
characterized by multifocal small ovoid lesions involving white
matter more than gray matter, and often more concentrated
at gray-white matter junctions, due to both demyelination
and necrosis caused by a small vessel vasculopathy. There are
no specific distinguishing features however.
CSF
Findings are similar to viral encephalitis (see p.292).
Enzyme immunoassay for antibody to VZV and PCR for
detection of VZV DNA.
EEG
Abnormal, most often non-specific focal or diffuse slow
wave activity, occasionally with epileptiform activity.
Cerebral angiography
May reveal segmental narrowing of large and medium-sized
arteries in cases of angiopathy.
Brain biopsy
Necrosis and gliosis consistent with infarction;
immunohistochemical localization of viral antigens and in
situ hybridization or PCR detection of VZV DNA.
DIAGNOSIS
• The finding of brain infarction (ischemic or hemorr-
hagic) and/or demyelination lesions in an immuno-
compromised patient with or without a history of zoster
rash, and with a fever and encephalopathy, should
suggest the diagnosis of VZV encephalitis.
• Serologic evidence of seroconversion or seroboosting in
paired acute and convalescent serum or the detection of
antiviral antibody and VZV DNA in CSF can confirm the
diagnosis.
• Brain biopsy or autopsy evidence of immunohistochemical
localization of viral antigens and in situ hybridization or
PCR detection of VZV DNA are required for the
unequivocal demonstration of virus-specific antigens or
nucleic acids.
TREATMENT
Encephalomyelitis
• General management is as for viral encephalitis (see
p.292).
• Specific antiviral therapy with intravenous acyclovir
10 mg/kg every 8 hours for 10–14 days, or alternatively
famciclovir.
PROGNOSIS
Patients with the cerebellar form usually recover completely
but at least 10% of those with the general form die.
 HIV-Associated Cognitive/Motor Complex (HIV-CMC)
HUMAN IMMUNODEFICIENCY
VIRUS (HIV)-ASSOCIATED
COGNITIVE/MOTOR COMPLEX
(HIV-CMC)
DEFINITION
A distinct neurologic syndrome of subcortical dementia
characterized by slowness and imprecision of cognition and
motor control, and called the AIDS dementia complex or
HIV-1-associated cognitive/motor complex. It is the most
important ‘primary’ neurologic complication of HIV infection.
EPIDEMIOLOGY
HIV dementia usually occurs late in the course of HIV
disease, when CD4 lymphocyte counts are less than
200 cells/mm3, but in 3–10% of patients it is the first
manifestation of AIDS.
• Incidence:
– 2 (95% CI: 0.8–5) per 100 000 per year.
– 7% annual incidence during the first 2 years after AIDS
diagnosis.
– 7.3 cases per 100 person years for people with CD4
counts of ≤100.
– 3.0 cases per 100 person years if CD4 count 101–200.
– 1.3 to 1.7 cases per 100 person years if CD4 count
201–500.
– 0.5 cases per 100 person years if CD4 count >500.
• Prevalence: 0.4% during the asymptomatic phase,
7.5–27% during the late stages of HIV disease; at least
15% of AIDS patients develop moderate to severe
dementia, and up to another 20–25% have less severe
cognitive dysfunction.
PATHOLOGY
Key features
• Multiple foci of microglia, macrophages, and
multinucleate giant cells or the presence of HIV-infected
cells in the CNS (356).
• Other abnormalities: inflammatory cell infiltrate, multi-
nucleate giant cells (HIV encephalitis), reactive gliosis and
diffuse white matter pallor (HIV leukoencephalopathy).
The pathologic changes are often less prominent than the
clinical symptoms.
PATHOGENESIS
Complex and obscure but determined by :
• The effectiveness of the immune defences and their
capacity to suppress viral replication within the brain.
• The genetic variance of the virus and its macrophage
tropism (i.e. capacity to replicate well in macrophages
and related cells but not well in lymphocyte-derived
chronic cell lines).
• The genetic predisposition of the individual.
Probably due to indirect effects of HIV infection on the
CNS. Infected and activated macrophages and microglia
produce increased intracerebral cytokines and neurotoxins
leading to secondary neuronal damage, principally in the
subcortical and basal ganglia regions, but also in neocortical
areas. White matter pallor may be due to demyelination or
changes in the blood–brain barrier that are mediated by
cytokines and contribute to extravasation of serum proteins
301
into the brain and viral entry into the brain. Certain strains
of HIV-1, characterized by specific sequences in the
envelope region, may have a predilection for infecting the
brain and causing dementia.
CLINICAL FEATURES
Subtle early in the course, and may only be identified by
formal neuropsychologic evaluation.
Three main categories:
• Cognitive: initially a predominantly subcortical dementia
characterized by forgetfulness and slowed mental and
motor abilities.
• Motor: loss of balance and occurrence of spastic leg
weakness.
• Behavioral: apathy and social withdrawal (often mistaken
as depression); sometimes organic psychosis, such as
acute mania.
The disease stages have been classified from normal
(stage 0) to profoundly impaired (stage 4).
Examination findings
• Cognitive: psychomotor slowing, and abnormalities of
reaction time, memory, executive function and complex
attention.
• Eye movements: abnormal: saccadic pursuit and
hypometric saccades.
• Limbs: bradykinesia; impairment of rapid alternating and
repetitive movements and tandem (heel-to-toe) gait.
• Reflexes: brisk and symmetric; primitive reflexes may
manifest in later stage disease.
Concurrent illness
Subclinical HIV-associated dementia may be ‘unmasked’ by
intercurrent illnesses, such as depression, metabolic derange-
ments, systemic and cerebral opportunistic infections (e.g.
toxoplasmosis, PML, cryptococcal meningitis), and lym-
phoma, which are important to look for (and treat).
356
356 Histologic section of the brain of a patient who died with the
HIV-associated cognitive/motor complex showing an inflammatory
cell infiltrate with multiple foci of macrophages and multinucleate
giant cells. (H&E stain, magnification ×16.) (Courtesy of Professor
BA Kakulas, Royal Perth Hospital,Western Australia.)
302 Infections of the Nervous System: Viral
DIFFERENTIAL DIAGNOSIS
Other causes of subcortical dementia:
• Vascular dementia.
• Hydrocephalus.
• Subcortical tumor.
• Huntington’s disease.
• Parkinson’s disease.
• Syphilis (see p.312).
• Hypothyroidism.
• Vitamin B12 deficiency.
• Non-convulsive status epilepticus.
• Progressive multifocal leukoencephalopathy.
• Subacute/chronic meningitis (see p.279).
• Cryptococcal meningitis (see p.318).
INVESTIGATIONS
Neuropsychologic assessment
Characteristically reveals impairment in cognitive domains
of memory, complex attention and executive function.
Blood
• Full blood count and ESR.
• Thyroid function tests.
• Vitamin B12 level.
• VDRL/RPR, TPHA.
• HIV serology.
• Cryptococcal antigen.
• CD4 cell count: usually around or less than 100/µl at
time of diagnosis.
• Plasma HIV RNA viral load.
Cranial CT and MRI scan
Scans are rarely normal. Both often show various degrees of
cortical atrophy, ventricular enlargement, widened sulci, and
diffuse or multifocal white matter abnormalities (357, 358).
The amount of atrophy on brain MRI tends to correlate
with the severity of HIV dementia. MRI may also reveal
areas of high signal in the white matter on T2 and PDWI.
The white matter changes may be focal or diffuse,
symmetric or not, and not associated with mass effect or
enhancement. MRI is more sensitive in detecting
confounding illnesses such as PML.
CSF
• Cells: mild pleocytosis in 25%.
• Protein: elevated in 55% (common CSF findings in non-
demented patients also).
• Glucose: normal.
• Cryptococcal antigen: negative.
• VDRL, TPHA: negative.
• Total immunoglobulin fraction: increased.
• Immunoglobulin: anti-HIV IgG.
• Oligoclonal bands: may be present.
• β2 microglobulin, neopterin and quinolinate levels:
markers of immune activation. β2 microglobulin is a low
molecular weight protein expressed on the surface of
nucleated cells (particularly lymphocytes and macro-
phages) and is elevated in the CSF of patients with HIV
dementia, independent of serum level. CSF β2 micro-
globulin and neopterin levels correlate with severity of
dementia.
• Culture.
DIAGNOSIS
A diagnosis of exclusion(359); there are no specific
laboratory or imaging results.
Blood and CSF studies are helpful to screen for systemic
infections (VDRL, cryptococcal antigen). The diagnosis is
likely if the patient has a subcortical dementia, positive HIV
serology and typical neuroimaging and CSF findings.
MANAGEMENT
Highly active antiretroviral therapy (HAART)
• Simultaneous treatment with at least three combination
antiretroviral medications, including various com-
binations of nucleoside reverse transcriptase (RT)
inhibitors, non-nucleoside RT inhibitors, and at least one
protease inhibitor (PI).
• About 30% of patients with HIV-CMC show
improvement in neurocognitive function after 3 months
of HAART, and improvement on psychomotor speed
over the course of 1 year.
• May reduce plasma and CSF HIV RNA viral loads to
undetectable levels, but viral suppression is often
incomplete and drug resistance may develop
concomitantly. Another problem is that the newer
antiretroviral medications, such as the majority of the PIs,
do not cross the blood–brain barrier readily.
• Adverse effects of antiretroviral therapy include mito-
chondrial toxicity, hypersensitivity, lipodystrophy and
more drug-specific adverse effects (Carr and Cooper,
2000).
Clinical and laboratory follow-up
Repeat clinical, neurologic and neuropsychologic assessment
every 4–6 weeks to ascertain any treatment benefit. Involve
physiotherapist, occupational therapist and social worker
early.
Counselling
Frequently required for patient and carers early in the illness.
Medical power-of-attorney
Recommend to patient early in the illness.
Respite and palliative care
Regular respite care can be helpful for the patient and carers
during the illness. Palliative care facilities are usually required
to manage late complications of dementia.
CLINICAL COURSE
Progressive, may be insidious or rapid.
PROGNOSIS
Until recently there was about a 67% cumulative mortality
over 6 months for moderate/severe (stages 2–4: motor
abnormalities in addition to psychomotor retardation)
patients. This is three times the rate for Pneumocystic carinii
pneumonia. However, HAART has substantially improved
survival. In addition to clinical status, both viral load (which
reflects the amount of viral replication occuring in an
infected person) and CD4 cell count (depletion reflects
ongoing viral replication and immune compromise) are
useful prognostic markers.
 HIV-Associated Cognitive/Motor Complex (HIV-CMC) 303

357 358

357 CT brain scan of a patient with HIV-associated 358 T2W MRI scan from a 25 year old HIV positive
cognitive/motor complex showing widened cortical sulci, patient. Note the atrophy, which in a young person
enlargement of the lateral ventricles, and diffuse low should raise the possibility of AIDS, and the subtle
attenuation in the periventricular deep white matter. white matter hyperintensities (arrows).

359
359 Algorithm for the management CNS abnormalities1 and HIV infection
of brain lesions in patients with HIV
infection. CT or MRI without and with contrast

Focal enhancing lesions

Focal non-enhancing
Normal or atrophy white matter lesion(s)

Single lesion Multiple lesions Large lesion with mass

Further studies: Consider stereotactic effect and impending
bloods, LP, etc biopsy herniation

Toxoplasma serology Toxoplasma serology

Cryptococcal Decompression
HIV dementia2 PML3 Negative Positive Open biopsy
meningitis,
neurosyphilis

Stereotactic biopsy
Anti-toxo therapy5

Others: Improvement in
Lymphoma4 toxoplasmosis, 2–3 weeks?
cryptococcosis,
tuberculosis
No Yes

1Headache, altered mental state, focal neurologic signs Toxoplasmosis:

2Highly Stereotactic biopsy
active antiretroviral therapy (HAART), clinical trial continue therapy
3Antiretroviral, Ara-C (intravenous, intrathecal), clinical trial
4Radiation therapy
5Pyrimethamine + sulfadiazine or pyrimethamine + clindamycin
Follow-up MRI or
CT scan
CNS = central nervous system PML = progressive multifocal leukocencephalopathy
CT = computed tomography LP = lumbar puncture
MRI = magnetic resonance imaging HIV = human immunodeficiency virus
304 Infections of the Nervous System: Viral

SUBACUTE SCLEROSING • Mutations of the measles virus, resulting in a lack of

PANENCEPHALITIS (SSPE) production of an M (matrix) protein in the measles virus,
which allows the virus to remain relatively protected in
an intracellular form and environment, away from the
DEFINITION extracellular host defence mechanisms, and spread by
A rare slowly progressive disease of the CNS in children and cell-to-cell contact.
young adults that is probably caused by chronic infection
by defective measles virus not expressing its M protein. CLINICAL FEATURES
• History of primary measles infection at a very early age;
EPIDEMIOLOGY often before 2 years.
• Incidence: extremely rare, about 1 case per million • Latent interval of 6–8 years after measles infection, or in
children per year; measles vaccination has greatly reduced rare cases live measles vaccination.
the incidence. Many ethnic groups are affected. • First stage:
• Age: affects children and adolescents; mean age of onset – Cognitive decline: less proficient at school, language
of 7–8 years; rarely beyond 18 years. difficulties.
– Behavioral changes: temper outbursts, loss of interest in
PATHOLOGY usual activities, and other changes in personality.
• Cerebral cortex and white matter of the cerebral • Second stage:
hemispheres and brainstem (360): – Intellectual deterioration: severe and progressive.
– Nerve cell destruction, neuronophagia, and perivenous – Myoclonic jerks; widespread.
cuffing by lymphocytes (361) reflect the viral nature of – Seizures: focal or generalized.
the infection. – Visual disturbance sometimes: due to progressive
– Degeneration of medullated fibers (myelin and axis chorioretinitis.
cylinders) of the white matter, accompanied by • Third stage: neuromotor retardation with spasticity,
perivascular cuffing with mononuclear cells and fibrous rigidity, autonomic dysfunction and unresponsiveness.
gliosis (sclerosing encephalitis). • Final stage: insensate, virtually ‘decorticated’.
– Eosinophilic inclusions in the cytoplasm and nuclei of
neurons and glial cells are the hallmark of the disease DIFFERENTIAL DIAGNOSIS
(362–364). • Lipid storage diseases.
– Virions, thought to be measles nucleocapsids, may be • Schilder disease.
seen with electron microscopy in inclusion-bearing cells. • HIV infection.
• Immunohistochemical studies reveal measles virus • Neurosyphilis.
antigen (365). • Creutzfeldt–Jakob disease (CJD).
• Paired helical filament-tau immunohistochemistry and
electron microscopy reveal early stages of neurofibrillary INVESTIGATIONS
tangle formation in hippocampal neurons. Serum
High titers of measles virus specific IgG antibody; negative
ETIOLOGY AND PATHOPHYSIOLOGY syphilis and HIV serology.
• Measles virus infection acquired pre-natally or in infancy
or early childhood: measles virus infection below 1 year
of age is a risk factor.
• Persistent measles virus infection of the brain.

360 361

360 Section of the brain at autopsy, coronal plane, showing severe 361 Histologic section of brain showing perivenous cuffing by
generalized atrophy of the brain due to subacute sclerosing lymphocytes and destruction of neurons.
panencephalitis.
 Subacute Sclerosing Panencephalitis (SSPE) 305

EEG CSF
Characteristic periodic bursts (every 3–10 seconds) of • Cell count: normal.
symmetrically bisynchronous slow and sharp wave • Protein: normal or raised.
complexes (Rodermacker complexes), with an amplitude • Immunoglobulin levels: high.
around 500 μV, and often associated with myoclonic jerks, • Oligoclonal bands of IgG: present (measles virus-specific
appear early in the clinical disease process and may be antibody).
diagnostic (366). The periodic discharges are more • Measles virus antibody titer: extremely high titers of
complicated in outline and separated by longer intervals measles specific IgG.
than in CJD. Unlike other types of periodic phenomena,
they may occur on a fairly normal background in SSPE.

362 363

364 365

362–364 The histologic hallmark of subacute sclerosing 366

panencephalitis: eosinophilic inclusions in the cytoplasm and nuclei of
neurons and glial cells.

365 Brain immunohistocytochemistry showing measles virus antigen.

366 Electroencephalograph, sensitivity 30 μV, of a 6 year old girl with

subacute sclerosing panencephalitis showing periodic discharges taking
the form of double or triple sine waves separated by long intervals and
a rather flat, abnormal background.
306 Infections of the Nervous System: Viral

CT brain scan doses, is said to prolong survival by 1–2 years.

May be normal in the early stages, and at all stages in rapidly
progressive disease; may show generalized brain swelling and
ventricular compression (367). In slowly progressive cases,
CT may show marked generalized cerebral atrophy with
widened cortical sulci and a slightly dilated ventricular
system, and low density areas in the basal ganglia and
periventricular white matter (367, 368).
• Intraventricular α-interferon, 100 000 U/m2 with daily
increments up to 106 U/m2 on the fifth day, to a total
dose of 30 × 106 U/m2 over a 6 week period,
administered via an Ommaya reservoir located under the
scalp, into the frontal horn of the right lateral ventricle,
in combination with oral inosiplex (isoprinosine) may
prolong survival.

MRI brain PROGNOSIS

• T2W images are frequently abnormal, unlike CT. • Evolves over some months; steadily progressive.
• Lesions of high signal intensity (bright) are seen on • Death usually occurs within 1–3 years.
T2WI and PDWI in the basal ganglia, periventricular • In about 10% of cases the course is fulminating leading
regions, cerebellum and pons. The periventricular and to death within 3 months, and in another 10% the course
subcortical white matter lesions are most common is quite prolonged, with one or more remissions.
(369). They tend to start in the cortex-subcortical white • Occasional patients recover and may return to school or
matter (370) and progress to involve the periventricular work, but usually with some neurologic deficit.
white matter and lead to diffuse cerebral atrophy.
• Other findings include glial and parenchymal contrast
enhancement, local mass effect of parenchymal lesions, 367 367 CT brain scan
and involvement of the splenic portion of the corpus in a patient with
callosum. biopsy-proven
• Cortical and subcortical lesions have some correlation subacute sclerosing
with the clinical findings but the extent and location of panencephalitis.
the periventricular white matter lesions and cerebral Note the
atrophy do not reflect the neurologic status of many generalized brain
patients. swelling (the
ventricles are small
DIAGNOSIS with effacement of
History of exposure to measles at a very young age, cortical sulci) and
appropriate clinical findings and course, periodic complexes low density area in
on EEG, elevated gamma globulin in CSF and elevated the right frontal
measles antibody titers in serum and CSF are sufficient to region.
make the diagnosis.

TREATMENT
• No specific treatment.
• Inosiplex (isoprinosine) (an antiviral or immuno-
modulator drug): 100 mg/kg/day orally, in 4 hourly

368 369 370

368, 369 CT (368) and MRI (369) brain scans,T2W image, axial plane showing bifrontal and 370 T2W MRI from the same patient as in
right occipital signal abnormality in a patient with subacute sclerosing panencephalitis. 367 a few weeks later.The brain appears
swollen, particularly the gray matter, with loss
of clarity of the gray-white matter junctions.
 Progressive Multifocal Leukoencephalopathy (PML) 307

PROGRESSIVE MULTIFOCAL • The occurrence of PML in the absence of cellular

LEUKOENCEPHALOPATHY (PML)
DEFINITION
A demyelinating disease of the CNS that results from infection
of oligodendrocytes with JC virus (JCV), a papovavirus.
EPIDEMIOLOGY
• Prevalence: PML is uncommon; even among AIDS
patients it only develops in 2–5% of patients.
• Seropositivity for IgG antibodies against JCV is very
common, being present in about 10% of children aged 1–5
years, 50% of children aged 10 years, and 80–90% of middle-
aged adults. Acute infection appears to be asymptomatic.
• Age and gender: before the AIDS epidemic, PML chiefly
affected elderly individuals and men and women equally.
Since then, PML has become a disease of the young and
middle-aged populations affected by AIDS and the male
to female ratio is now about 5:1. However, it is likely that
the changing pattern of HIV infection with increasing
numbers of women affected by AIDS as opposed to
homosexual men will return this ratio towards parity.
PATHOLOGY
Macroscopic
• The cardinal feature is demyelination.
• Multiple areas of pronounced demyelination in the white
matter of the cerebral hemispheres (371), brainstem and
spinal cord, with frequent involvement of the gray–white
matter junction and cortical gray matter in the most
severe cases.
• A higher incidence of large confluent lesions and marked
perivascular inflammatory infiltrates have been described
in patients with AIDS.
immunodeficiency is quite extraordinary. Indeed, only a
small minority of people with impaired cellular immunity
ultimately develop PML suggesting that something more
than the presence of JCV and cellular immunodeficiency
are required for PML to develop.
CLINICAL FEATURES
Subacute onset over weeks.
Focal neurologic deficit
• Mono- or hemiparesis (30–50%).
• Visual deficits such as homonymous hemianopia or
quadrantanopia, cortical blindness and visual agnosia
(20–30%).
• Speech defects (20–30%).
• Limb incoordination (10–30%).
• Gait disturbances.
• Rapid cognitive decline in conjunction with other focal
neurologic deficits (30%).
• Headache (10%).
• Preserved consciousness and without fever.
The clinical features in patients with AIDS are not
significantly different from those who have other immuno-
suppressive disorders.
371

Microscopic
The histopathologic hallmarks are a triad of:
• Multifocal demyelination.
• Hyperchromatic, enlarged oligodendroglial nuclei.
• Enlarged bizarre astrocytes with lobulated hyperchromatic 371 Microscopic low power section of cerebral cortex and
nuclei. subcortical white matter, myelin stain, showing multiple foci of
demyelination (i.e. lack of staining) in a patient with progressive
Large ‘ballooned’ oligodendroglial cells are seen, with multifocal leukoencephalopathy.
nuclear inclusions containing many virions (372). In situ
hybridization techniques for JCV antigen is more sensitive
than light microscopy for detecting virion in infected 372
oligodendrocytes. Electron microscopy reveals the JCV in
the nucleus of oligodendroglial cells.

ETIOLOGY AND PATHOPHYSIOLOGY

• Infection with JCV, a human papillomavirus, in patients
with cellular immunodeficiency, and perhaps some other
unknown factor.
• It is unclear whether PML results from reactivation of
latent JCV within the brain or from transport of virus to
the CNS from other infected organ systems; JCV DNA
has been detected in peripheral blood lymphocytes in the
vast majority of patients with AIDS-associated PML.
• AIDS is the underlying cause of immunodeficiency in about
75% of patients with PML (PML is the initial manifestation
of AIDS in about one-third of these cases); the remainder 372 Histologic section of cerebral white matter showing large
have other disorders such as Hodgkin’s disease, chronic ‘ballooned’ oligodendroglial cells with hyperchromatic, enlarged nuclei
lymphocytic leukemia and lymphosarcoma. and nuclear inclusions which contain many virions.
308 Infections of the Nervous System: Viral
DIFFERENTIAL DIAGNOSIS
• HIV dementia: the demyelination of PML may be
radiographically indistinguishable from that of HIV
dementia but PML is clinically associated with focal
neurologic signs, dementia is uncommon, and the clinical
course is usually rapid over weeks. Radiographically a
greater proportion of PML lesions involve the subcortical
white matter, the T1W images are hypointense (isointense
in HIV dementia), faint and peripheral enhancement
occurs rarely, and infratentorial lesions occur more
frequently (30% of cases).
• Multiple infarcts: systemic lupus erythematosus or HIV-
associated granulomatous angiitis.
• Multiple sclerosis.
• Cerebral toxoplasmosis.
• Neurosyphilis.
• CMV ventriculoencephalitis and other viral opportunistic
infections: typically CMV lesions are located in the
periventricular white matter and centrum semiovale, and
subependymal enhancement is observed.
• CNS lymphoma.
• Multifocal necrotizing leukoencephalopathy with a
predilection for the pons.
• Immunosuppression-induced leukoencephalopathy:
tacrolimus (FK506), cyclosporin, fluorouracil, levamisole.
• Metachromatic leukodystrophy.
INVESTIGATIONS
Cranial CT and MRI scan
Single or multiple confluent, non-contrast-enhancing areas of
hypodensity without mass effect, predominantly located in the
parieto-occipital white matter, but also in the basal ganglia,
external capsule and posterior fossa (brainstem and cerebellum),
and without mass effect (373–375). The lesions may have a
‘scalloped’ appearance as a result of the subcortical arcuate
fibers lying directly beneath the cortex. In about 5–10% of cases
however, PML is confined to the posterior fossa.
373 374
373, 374 T2W axial (373) and T1W coronal (374) MRI with contrast showing a
non-enhancing area on T1W image, high intensity on T2W image in the parietal region
typical of PML. (Courtesy of Professor J Best, Department of Medical Radiology, Royal
Infirmary, Edinburgh, UK.)
MRI brain
T2W spin-echo MRI scan is the preferred imaging
technique as it demonstrates more lesions and the lesions
are seen more prominently.
MRI
• A focal region of low intensity on T1WI and high
intensity on T2WI anywhere in the brain, but most
commonly involving the parieto-occipital region.
• Usually involves white matter but may involve gray matter.
• May be single or multiple, patchy or confluent.
• May have mass effect.
• Usually without enhancement; about 5–10% of cases
show contrast-enhancement which is typically faint and
peripheral.
CSF
CSF is usually normal in the absence of HIV infection but
there may be a mild lymphocytic pleocytosis, slight elevation
of CSF protein and the presence of myelin basic protein.
JCV may be detected in CSF by PCR.
Other
• EEG: may show focal slowing but is non-diagnostic.
• Serum antibodies to JCV: not helpful in establishing the
diagnosis because more than 80% of the population show
seropositivity to antibodies against JCV by adulthood.
• Plasma levels of HIV RNA (‘virus load’): critical to assess
the effectiveness of antiretroviral therapy.
DIAGNOSIS
Despite the characteristic radiologic findings, the only
definitive method of diagnosis is brain biopsy, but the
causative virus, the JCV, may be detected in CSF by PCR.
375
375 T2W MRI of the brain showing
biopsy-proven progressive multifocal
leukoencephalopathy in an HIV-infected
patient. Note the T2W high signal
abnormalities involving the parietal subcortical
white matter and sparing the cerebral cortex.
 Poliomyelitis (Infantile Paralysis)
TREATMENT
HAART, with its use of multiple antiretroviral drugs
including various combinations of nucleoside RT inhibitors,
non-nucleoside RT inhibitors, and PI antiretrovirals has
become the standard practice for HIV treatment.
The HAART regimen is guided by viral load
measurements, with the goal of achieving non-detectable
HIV RNA viral loads in the patient’s plasma.
These practices have resulted in dramatic improvement
in life expectancy of HIV patients. Intravenous and
intrathecal cytarabine (Ara-C) therapy does not appear to
offer any survival advantage over best antiretroviral therapy.
CLINICAL COURSE AND PROGNOSIS
HIV-associated PML: median survival of 2–4 months
previously. However, cohorts treated with HAART have
experienced a median survival of more than 46 weeks.
About 10% of patients have a more benign course, with
remission and prolonged survival, or even spontaneous
recovery on rare occasions.
309
POLIOMYELITIS (INFANTILE
PARALYSIS)
DEFINITION
Infection of the spinal cord and brain by the poliovirus.
EPIDEMIOLOGY
Distribution and incidence: polio had a worldwide
distribution prior to vaccination. Epidemics occurred during
the summer months and were more frequent in temperate
climates. The incidence was greater in areas of poor sanitation.
Following the development of the Salk trivalent inactivated
vaccine (1955) and the Sabin trivalent oral live attenuated
vaccine (1961) and introduction of mass vaccination
programmes in the late 1950s and early 1960s, the incidence
of paralytic poliomyelitis has declined dramatically in countries
with these programmes. In England and Wales there were 21
cases of paralytic poliomyelitis between 1985–91. The
majority (13) were vaccine-associated, of whom nine occurred
in the recipient; three occurred in previously healthy
unimmunized adolescent or adult contacts of infants who had
received their first vaccination, two cases were infants with
unsuspected immune deficiency and five were imported and
the source of infection was unknown.
The remaining principal reservoirs of the wild poliovirus
are West and Central Africa and South Asia, which result in
nearly 100 000 new paralytic cases per year.
• Prevalence: the World Health Organization (WHO)
estimates there are 12 million people worldwide with
some degree of disability caused by poliomyelitis.
• Lifetime prevalence: 0.7 (0.4–1.0) per 1000.
• Age: any age.
• Gender: either sex.
PATHOLOGY
Site
• Neurons in the anterior, intermediate, intermediolateral
and posterior horns of the spinal cord are most
commonly affected.
• The precentral gyrus, globus pallidus, thalamus,
hypothalamus, brainstem nuclei (particularly the nucleus
ambiguus, V, VII, XII and vestibular nuclei) and
brainstem reticular formation, cerebellar vermis, and
dorsal root ganglia may also be affected.
Microscopic findings
• Early: neuronal chromatolysis, particularly affecting the
cytoplasmic Nissl substance, and a perivascular
inflammatory cell infiltrate.
• Later: the nucleus disintegrates, followed by necrosis and
lysis of the whole cell.
ETIOLOGY AND PATHOPHYSIOLOGY
Poliovirus infection
A neurotrophic enterovirus of high infectivity:
• Three subtypes; prior to vaccination, type I caused 85%
of cases of paralytic polio.
• Route of infection: oral–oral and fecal–oral.
• Viruses multiply in the pharynx and intestine during the
1–3 week incubation period before blood-borne dis-
semination occurs. The virus continues to be excreted in
saliva for 2–3 days, and in feces for a further 2–3 weeks.
(Continued overleaf)
310 Infections of the Nervous System: Viral

Poliovirus infection (continued) Chronic poliomyelitis

• In countries with mass vaccination programmes, about
half of cases are caused by the live vaccine virus in adult
contacts of vaccinated infants, one-quarter occur in the
vaccine recipient, and the remaining quarter are thought
to be due to wild virus infection in non-immunized
people.
Possible risk factors for development of
paralytic disease
Physical activity and intramuscular injections during the
prodrome.
CLINICAL FEATURES
Non-paralytic or pre-paralytic poliomyelitis
Asymptomatic or a self-limited ‘flu-like’ illness characterized
by fever, pharyngitis, myalgia, nausea, anorexia, vomiting,
headache and neck stiffness due to meningitis, which
subsides within 1 or 2 weeks: 95% of all infections.
Acute anterior horn cell poliomyelitis
Spinal form (>60% of cases)
• Severe muscle pain and spasms.
• Fasciculations and asymmetric weakness of lower limbs
more than upper limbs, maximal within 48 hours,
particularly in children. Further weakness may occur after
a short period of stability if fever is still present, but
generally paralysis stops progressing within 5–7 days.
• Muscle tone: flaccid.
• Reflexes initially brisk, then become absent.
• No objective sensory loss, but paresthesiae are common.
Bulbar form (20% of cases)
• May occur in children, adults tend to have spinal as well
as bulbar involvement.
• Most commonly the lower cranial nerve nuclei are
affected.
• Dysphagia.
• Dysphonia.
• Tongue wasting and fasciculation (376).
• Respiratory failure.
• Vasomotor disturbances (hypo- and hypertension,
circulatory collapse).
• Motor neuron disease.
• Spinal muscular atrophy.
INVESTIGATIONS
Swabs
• Nasopharynx swab: virus may be isolated for 5 days after
onset of symptoms.
• Stool swab: virus may be isolated for 5 weeks after onset
of symptoms.
Blood viral serology
Following type 1 poliovirus there is an acute rise in serum IgM
titer with IgG antibody developing over about 3 months.
CSF
Pleocytosis (neutrophils in the first few days then
lymphocytes), increased protein, normal glucose, virus rarely
isolated by PCR. If the virus is isolated, it is serotyped using
stain-specific antisera, to differentiate wild-type from
vaccine-induced disease.
EMG
• Early: reduced recruitment and interference pattern with
voluntary muscle activation.
• Later: at rest: electrically silent, fibrillations develop in
2–4 weeks and persist indefinitely; fasciculations may also
be seen during voluntary activation: motor unit action
potentials are reduced in number but return during
recovery and then become abnormally large in amplitude
and of increased duration and polyphasic, due to
reinnervation.
• Motor conduction velocities: remain normal.
DIAGNOSIS
Asymmetric purely motor flaccid paralysis with an aseptic
meningitis; virus isolation from nasopharynx or stool.

Encephalitic form (rare)

• Agitation, confusion, stupor and coma.
• Autonomic dysfunction is common. 376
• High mortality rate.

DIFFERENTIAL DIAGNOSIS
Acute poliomyelitis
• Other enterovirus infection:
– Coxsackie A and B.
– Echovirus.
– Enterovirus 70 and 71.
• Guillain–Barré syndrome: acellular CSF, prolonged nerve
conduction velocities.
• Acute intermittent porphyria.
• HIV.
• Diphtheria.
• Lyme disease.
• Triorthocresylphosphate poisoning.
• Botulism. 376 Tongue wasting and fasciculation due to necrosis of neurons in
the hypoglossal (XIIth cranial) nerve nucleus.
 Poliomyelitis (Infantile Paralysis)
TREATMENT
Acute attack
• Nurse in isolation; cases are most infectious 7–10 days
before and after the onset of symptoms.
• Observe vital capacity, cardiovascular responses and other
bulbar functions.
• Relieve pain.
• Prevent joint contractures and ankylosis: frequent passive
movements, physiotherapy.
• Negative pressure ventilation (iron lung) which allows
concurrent physiotherapy and postural drainage.
• Tracheostomy in severe bulbar weakness to protect the
airway; under these circumstances intermittent positive
pressure ventilation is preferable during the acute illness.
Prevention
Vaccination
• Salk trivalent inactivated polio vaccine is administered by
injection and stimulates serum IgM, IgG, and IgA but
not secretory IgA, immunity being induced by antibody
transuding into the oropharynx. It is highly effective and
remains indicated in pregnant, immunosuppressed and
unvaccinated individuals over the age of 50 years.
• Sabin trivalent oral live attenuated polio vaccine is taken
orally and causes an active attenuated infection of the
oropharynx and intestinal endothelium leading to local
secretory IgA in addition to serum antibody production.
Furthermore, the attenuated virus is excreted in the feces
producing herd immunity.
• Individuals born before 1958 may not have been
immunized and should be.
• Oral polio vaccine is recommended for infants from
2 months of age. The primary course consists of three
separate doses with intervals of 1 month between doses.
• Unimmunized contacts of recently immunized infants
are at particular risk of infection when changing nappies
and must be vaccinated.
In 1988, the WHO declared its commitment to the
complete eradication of acute paralytic poliomyelitis by the
year 2000. This has been achieved in most Western
countries using strategies relying on:
• Mass vaccination campaigns using live attenuated oral
polio vaccine in all children under the age of 5 years.
• Enhanced surveillance.
• Targeting immunization to areas and populations where
poliovirus transmission is likely to persist.
However, wild-type poliomyelitis continues to occur in
regions with high rates of endemic poliomyelitis and, rarely,
in outbreaks in areas believed to be free of disease.
311
PROGNOSIS
Clinical course
• After the initial insult, paralysis remains stable for several
days or weeks before a slow recovery occurs over several
months or years, caused by sprouting and re-innervation
of muscle by surviving motor neurons, before stabilizing.
• About 10% of patients with bulbar paralysis die, usually
from vasomotor disturbances or respiratory failure.
Post-polio progressive muscular atrophy
Slowly progressive, painless, weakness and wasting of
muscles that were often severely affected by the original
disease, after at least 10–15 years, is a rare, late complication
of polio.
Post-polio syndrome
Progressive muscle pain, weakness, wasting and fatigue
occur in about 60% of polio survivors but they are non-
specific symptoms, particularly in an elderly population, and
are not due to progressive neuromuscular failure. In two-
thirds of symptomatic patients, an underlying cause that is
unrelated to earlier polio can be readily identified, most
commonly degenerative joint disease, but also diabetes,
excessive weight gain, alcoholism, depression, acute lumbar
disc herniation and radiculopathy and motor vehicle trauma.
In the other one-third, in whom a ready explanation is not
apparent, the cause remains unknown but the symptoms are
similar to patients with chronic fatigue syndrome (a disorder
often associated with depression) and tension myalgia/fibro-
myalgia (a disorder that is common in middle-aged,
deconditioned people that is not usually associated with
depression but in which muscle pain, usually at tendon
insertion, is worsened with, and may persist after, use or
overuse). In neither is there any evidence of intrinsic nerve
or muscle disease.
The chronic use of weak muscles or muscles acting in a
compensatory fashion may well predispose people to this
type of problem, If this is the cause of the post-polio
syndrome, it leads directly to therapeutic strategies. Patients
with fibromyalgia can be effectively treated with
conditioning, physical medicine/rehabilitation approaches,
and tricyclic antidepressants. There is no basis for the use of
drugs designed to improve neuromuscular function because
there is no evidence of progressive neuromuscular
deterioration.
312 Infections of the Nervous System: Other

OTHER INFECTIONS: SPIROCHETAL, FUNGAL,

PROTOZOAN, WORM AND PRION

NEUROSYPHILIS • General paralysis of the insane develops about

DEFINITION
Syphilis is an infectious disease caused by Treponema
pallidum, which is a natural pathogen only in humans. Four
stages can be distinguished in the natural history of syphilis:
primary, secondary or disseminated, latent and tertiary
syphilis. Neurosyphilis is one of the tertiary forms of syphilis.
15–20 years after the primary infection. It is due to
widespread spirochetal invasion of the brain and chronic
meningovascular syphilis.
CLINICAL FEATURES
Clinically, neurosyphilis can be classified into well defined
syndromes, representing different clinical expressions of the
same disease.

EPIDEMIOLOGY Asymptomatic neurosyphilis

• Incidence: the incidence of syphilis is rising in the United
States, mainly due to an increase in the number of cases
of cocaine/crack addiction.
• Prevalence: in Florida, USA, the prevalence of syphilis in
1987 was 66 per 100 000 persons, particularly among
homosexual men. Neurosyphilis occurs in less than 3%
of all syphilis cases due to administration of antibiotics in
the first stages of the disease.
• Age: adults of any age.
• Gender: M>F.
• The manifestations of primary or secondary syphilis (e.g.
skin rash [379–382]) have resolved, and there are no
neurologic gray signs.
• The CSF is abnormal, such as positive serology, an
increased cell count and, occasionally, an increased
protein content.
377

PATHOLOGY
Meningovascular syphilis
• Diffuse thickening and lymphocytic infiltration of the
leptomeninges and perivascular spaces.
• Vasculitis (endarteritis obliterans) of terminal arterioles,
which show concentric proliferative thickening of the
endothelium as well as appearance of fibroblasts (377).
The most commonly involved artery is the MCA.

Tabes dorsalis
Degeneration with neuronal loss in the dorsal root entry
zones of the spinal cord and fibers in the dorsal columns
(378).
377 Cross section of a branch of the middle cerebral artery showing
ETIOLOGY AND PATHOPHYSIOLOGY Intimal hyperplasia due to meningovascular syphilis.
• Acquired infection, mainly by sexual intercourse with an
infected individual but also by vertical transmission at 378
delivery, by laboratory accidents or blood transfusions.
• If the CNS is to be invaded, this usually occurs within
2 years after primary infection.

Stages of neurosyphilis
• Acute syphilitic meningitis usually occurs within the first
2 years of the primary infection. May involve the brain
or the spinal cord.
• Meningovascular syphilis may occur any time from the
onset of the secondary syphilis rash to 10 years after the
primary infection but generally does not occur until
4–7 years after the primary infection. It is due to
granulomatous syphilitic infiltration and vasculitis around
the brainstem, spinal cord and spinal roots.
• Tabes dorsalis develops 20 years or so after the primary
infection. Degeneration of dorsal roots and fibers in 378 Transverse section of the spinal cord in a patient with tabes
dorsal columns interrupt the stretch reflex arc to cause dorsalis showing degeneration of the posterior columns (arrows)
hypotonia and loss of reflexes, and lightning (stabbing) secondary to Treponema pallidum infection and inflammation along the
pains mainly in the legs. dorsal roots. (Courtesy of Professor BA Kakulas, Royal Perth Hospital,
Western Australia.)
 Neurosyphilis 313

Acute syphilitic meningitis Meningovascular syphilis

• Symptoms include headache, nausea and vomiting, neck
stiffness, seizures and changes in mental status; patients
are often afebrile.
• Ocular or cranial nerve abnormalities, especially VII and
VIII, may occur due to involvement at the base of the
brain.
• Some patients can develop leptomeningeal granulomas,
hydrocephalus or neuritis.
Generally presents with a prodromic phase, weeks or
months before the onset of identifiable vascular syndromes.
Specific clinical features include:
• TIA or stroke-like syndrome (if focal inflammation of
intracranial arteries).
• Slowly progressive cognitive decline and personality changes
(if multifocal involvement of small intracranial arteries).
• Epileptic seizures.
• Argyll Robertson pupils.
(Continued overleaf)

379, 380 Skin rash on the 379 380

axilla and trunk of a patient in
the initial stages of secondary
syphilis.The lesions are
bilaterally symmetric, pale
red/pink, non-pruritic,
discrete, round macules,
about 5–10 mm (0.2–0.4 in)
in diameter, distributed on
the trunk and proximal
extremities. After 1–2
months, red, papular lesions
3–10 mm (0.1–0.4 in) in
diameter also appear on the
palms, soles, face and scalp.

381, 382 Skin rash on the 381 382

legs and foot soles of a
patient in the later stages of
secondary syphilis.The lesions
are red/copper-colored,
papular and papulosquamous,
about 3–10 mm (0.1–0.4 in)
in diameter and were also
present on the palms, face
and scalp.
314 Infections of the Nervous System: Spirochete
Meningovascular syphilis (continued)
• Optic neuritis, optic atrophy and chorioretinitis.
• Deafness: acute and subacute, unilateral at first.
• Other cranial neuropathies: acute and subacute.
• Meningitis: acute, subacute and chronic.
• Spinal cord and/or nerve root syndromes (spinal cord
compression, infarction and transverse myelitis): acute
and subacute.
Usually there is no fever.
Tabes dorsalis
Symptoms
• Lightning (stabbing) pains mainly in the legs and back.
• Abdominal pains and vomiting.
• Loss of deep pain sensation in the legs.
• Patch loss of superficial pain sensation in the face and
limbs.
Signs
• Ptosis.
• Argyll Robertson pupils in about 90% of cases.
• Optic atrophy.
• Sensorineural deafness.
• Hypotonia and loss of deep tendon reflexes in the legs,
and sometimes arms.
• Flexor plantar responses, but sometimes extensor plantar
responses.
• There is no primary motor involvement.
• Patchy loss of sensation to pain over the bridge of the
nose, sternum, and tibial prominences.
• Impaired position and vibration sense.
• Painless destruction of weight-bearing joints (Charcot
joints) in the lower limbs in about 10% of patients due
to loss of deep pain sensation.
• Trophic foot ulcers.
• High stepping unsteady gait due to proprioceptive loss
in the lower limbs
• Painless urinary retention/incontinence is common.
• Impotence.
• Postural hypotension.
General paralysis of the insane
Clinical features reflect widespread and diffuse parenchymal
damage and include:
• Personality and affect changes.
• Progressive dementia: impaired recent memory,
disorientation, dyscalculia, impaired judgement.
• Sensorium abnormalities including illusions, delusions
and hallucinations.
• Dysarthria.
• Tremor.
• Epileptic seizures.
• Pyramidal tract signs.
• Argyll Robertson pupils.
DIFFERENTIAL DIAGNOSIS
Charcot joints
May be seen in other neurologic conditions in which central
or peripheral pain pathways are damaged: syringomyelia,
diabetes, hereditary sensory neuropathy.
Argyll Robertson (AR) pupils
AR pupils are small, irregular, unequal pupils that constrict
to accommodation but not to light and dilate poorly with
a mydriatic. Iris atrophy may be present. They were
described by Douglas Argyll Robertson, an Edinburgh
physician, and are probably due to a lesion in the pretectal
periaqueductal gray matter or ciliary ganglia. They are
almost pathognomonic of meningovascular syphilis, tabes
dorsalis and general paralysis of the insane.
Other causes of AR pupils include:
• Diabetic autonomic neuropathy.
• Amyloid neuropathy.
• Hereditary motor and sensory (hypertrophic)
polyneuropathy type III.
• Late Holmes–Adie pupil.
• Upper dorsal mid-brain lesions, usually a pineal region
tumor, causing Parinaud’s syndrome (failure of upward
gaze, bilateral pupil dilatation with a poor response to
light and often to accommodation as well, sometimes
accompanied by convergence-retraction nystagmus on
attempted upgaze) give rise to pseudo-AR pupils, which
do not react to light but are neither small nor irregular.
• Iris trauma.
Positive non-specific or specific syphilis serology
(VDRL, RPR, TPHA and FTA)
• Yaws.
• Mycoplasma pneumoniae.
• Malaria.
• Acute bacterial and viral infections.
• Smallpox vaccination.
• Addiction: e.g. narcotics.
• Autoimmune disease: e.g. systemic lupus erythematosus,
anticardiolipin antibody syndrome.
• Ageing.
INVESTIGATIONS
Blood serology
Non-treponemal antibody
Rapid plasma reagin (RPR) and Venereal Disease Research
Laboratory slide flocculation test (VDRL): subject to false
negative reactions (e.g. VDRL in early infection, RPR in late
disease and both in HIV infection; sensitivity varies from
30–70%) and false-positive reactions in certain clinical
situations (e.g. pregnancy, autoimmune disease, i.v. drug use
and HIV infection).
Specific treponemal antibody
• Treponema pallidum hemagglutination test (TPHA).
• Fluorescent treponemal antibody test (FTA).
• Treponema pallidum immobilization test (TPI).
• Enzyme immunoassay for treponemal antibodies.
Syphilis cannot be differentiated serologically from yaws,
a spirochetal disease which is endemic in the Caribbean.
CT/MRI brain scan
• Multifocal areas of low density are seen on CT and
increased signal on T2W MRI in the brain parenchyma,
consistent with infarction, due to meningovascular
syphilis.
• Widespread thickening of the meninges or extra-axial
enhancement suggestive of meningitis.
• Various enhancing parenchymal nodules (cerebral
gumma).
 Neurosyphilis
CSF
In active neurosyphilis, the CSF is characterized by:
• Lymphocytosis: up to 1000 cells/mm3.
• Protein: increased moderately.
• Glucose: normal or reduced.
• Specific antibody serology (FTA, TPHA): positive.
• Non-specific VDRL/RPR: negative in up to 50% of
cases.
• Oligoclonal bands: commonly present.
• PCR: amplifies specific T. pallidum DNA in the CSF or
the blood, which is then detected by agarose gel
electrophoresis or by hybridization with probes. It
detects the actual presence of the organism rather than
the immune response of the host to the organism.
If the CSF cell count and protein are normal, then the
patient’s disease is ‘burnt out’ or the diagnosis of
neurosyphilis is incorrect.
It is unnecessary to examine the CSF if:
• The clinical picture is not compatible with neurosyphilis
and is clearly due to a non-syphilitic cause.
• The patient has had effective treatment for syphilis in the
past.
• The blood serologic titers are low.
Cerebral angiography
Concentric or asymmetric constriction and occlusion of the
intracranial portion of the internal carotid, proximal middle
and anterior cerebral and basilar arteries, and narrowing
with aneurysmal dilatation of small vessels are seen in
meningovascular syphilis.
DIAGNOSIS
• Suggestive clinical picture.
• Positive treponemal serology: fluorescent treponemal
antibody absorption (FTA-ABS) (serologic evidence of
exposure to T. pallidum).
• One of the following CSF abnormalities:
– White blood cell pleocytosis of >5 leukocytes/mm3.
– CSF protein >0.45 g/l (at least 450 mg/dl protein).
– Positive CSF VDRL/RPR.
• Positive PCR: blood or CSF.
TREATMENT
Since neurologic deficits, once established, may only slightly
improve with treatment, the goal of therapy is to halt the
progression of the disease.
Active disease (raised CSF lymphocytes or protein)
• Aqueous crystalline penicillin G (benzylpenicillin)
12–24 million units (600 mg), i.v. daily for 10–14 days
followed by either further penicillin G, i.v. or daily
procaine penicillin, i.m. or weekly benzathine penicillin
2.4 million units, i.m. for a total of 4 weeks; or, if
hospital admission undesired: procaine penicillin, 600 mg
once daily, i.m., for 21 days.
• If minor penicillin allergy occurs, cefotaxime or
ceftriaxone can be prescribed.
• If more severe penicillin sensitivity occurs: tetracycline
(500 mg oral 6-hourly for 30 days) or erythromycin
(500 mg oral 6-hourly for 30 days) can be given.
315
Herxheimer reaction prophylaxis
Oral prednisolone, 40 mg daily, for 1 day before and 3 days
after beginning treatment.
Lightning pains
Carbamazepine may be helpful.
FOLLOW-UP
• The CSF must be re-examined at 3 months, 6 months,
1 year and 2 years after treatment is commenced. If the
cell count remains elevated, then treatment should be
repeated until it returns to normal.
• The CSF protein level may not return to normal until
1–2 years after successful treatment.
• The blood and CSF serology often remains positive for
life, although the VDRL titers should fall.
PROGNOSIS
Antimicrobial therapy can cure meningovascular syphilis and
arrest tabes dorsalis and GPI, but lightning pains and fixed
neurologic deficits are likely to remain.
SPECIAL FORMS
Concurrent HIV infection
• Neurosyphilis may present at any time during the course
of HIV infection. Considerable overlap is present
between the spectrum of neurologic diseases caused by
HIV and Treponema pallidum. Both may result in
dementia, cerebrovascular disease, chronic meningitis,
myelopathy and cranial and peripheral neuropathies; and
both may produce similar CSF abnormalities, particularly
persistent pleocytosis. In addition, atypical presentations
may occur with concurrent HIV infection.
• Patients without clear documentation of adequate
therapy for past syphilis should be assessed for
neurosyphilis by LP. A positive CSF VDRL test is
diagnostic of neurosyphilis but this assay has a sensitivity
of only 30–70%.
• Concurrent HIV infection may alter the natural history of
syphilis (e.g. fulminant, necrotizing encephalitis may occur),
the yield of tests (serologic tests are less sensitive in
diagnosing late syphilis in HIV infection) and response to
conventional therapy (e.g. neurosyphilis may relapse in HIV-
infected patients after therapy with benzathine penicillin).
Consequently, neurosyphilis should be treated aggressively
in patients with HIV infection and closely followed-up.
• Penicillin-based regimens are preferred; procaine
penicillin 1.5 g daily i.m. plus probenecid (to increase
serum and CSF levels of penicillin) 500 mg four times a
day by mouth for 21 days, or penicillin G 2.4 g every
4 hours by i.v. injection plus probenecid 500 mg four
times a day by mouth for 10 days. Ceftriaxone (1–2 g for
14 days) is an alternative regimen, although experience
is limited.
• Serum and CSF should be followed for at least 2 years to
monitor response to therapy. The goal is normalization
of CSF values and VDRL titers but the presence of
concurrent HIV infection may cause persistent CSF
abnormalities.
• If a patient with HIV infection has symptoms consistent
with neurosyphilis, a positive serum VDRL, and a
reactive CSF profile, even in the absence of a positive
CSF VDRL, then treatment with intravenous high-dose
penicillin is probably indicated.
316 Infections of the Nervous System: Spirochete

LYME DISEASE • Mononeuritis multiplex.

(NEUROBORRELIOSIS) • Neuralgic amyotrophy (see p.595).
• Myositis.

DEFINITION Stage 3: Chronic stage

A multisystem non-venereal treponemal disease caused by a
spirochete of the genus Borrelia, called Borrelia burdorferi,
and named after the town of Lyme, Connecticut, where a
cluster of cases was first recognized in 1975.
EPIDEMIOLOGY
A worldwide zoonosis and currently the most common
vector-borne illness in the United States.
• Incidence: 3.9 per 100 000 in 1992 in the United States
(a 19-fold increase since 1982). Reforestation and an
increasing deer population are believed to contribute to
the increasing number of cases. The disease usually
appears in the summer in endemic areas: in the USA
where it is known as Lyme disease, and in Europe where
it is called Bannwarth’s syndrome.
• Age and gender: any.
ETIOLOGY
Caused by B. burgdorferi, a spirochete carried primarily by
the hard-shelled deer ticks: Ixodes dammini, I. pacificus, and
I.ricinus in the Eastern United States, Western United
States, and Europe respectively. The ticks infest deer and
small mammals, and are transmitted to man by tick bite.
Many months, and even a year or more, after the initial
infection, other neurologic complications may occur:
• Encephalopathy can present as severe encephalomyelitis
complicated by seizures or can be more mild, with mild
memory and mood disturbances, word letter reversals,
and spatial disorientation. Major depression, anxiety,
panic attacks and catatonia have been reported.
• Peripheral neuropathy is primarily axonal in nature,
includes both motor and sensory fibers, and can present
as a radiculopathy, plexopathy, distal neuropathy, or
mononeuritis multiplex.
• Arthritis may not occur until 6 months after the onset of
Lyme disease.
• Post borrelia syndrome: some patients treated for Lyme
disease continue to experience symptoms of fatigue,
fibromyalgia, insomnia, or psychiatric disorder. The
etiology is uncertain.
DIFFERENTIAL DIAGNOSIS
• Viral encephalitis (see p. 292).
• Bell’s palsy.
• Chronic meningitis (see p.279).
• Guillain–Barré syndrome (no CSF pleocytosis).

PATHOPHYSIOLOGY
Following intradermal inoculation, B. burgdorferi
proliferates within the dermis and then invades the blood
stream to cause a spirochetemia. After a few weeks it directly
invades the meninges to cause a basilar meningitis. It may
also cause an encephalopathy by invading the brain
parenchyma or by stimulating an immune response with the
production of quinolinic acid, a CNS excitotoxin.

CLINICAL FEATURES
Stage 1: Early, localized disease stage 383
Within a few days of tick bite, an erythematous papule
appears at the site of the bite and this expands into an
annular lesion with a partially clearing center (erythema
chronicum migrans), sometimes with multiple secondary
skin lesions and often accompanied by headache, myalgia,
general malaise, and lymphadenopathy. Sometimes the
illness is more indolent; some patients do not recall an insect
bite, and there may be no preceding skin lesion nor very
much systemic upset initially.

Stage 2: Early disseminated disease stage

A few weeks to a few months after infection there is often
resolution of earlier symptoms and evolution of arthritis
and/or the subacute onset of a chronic basilar lymphocytic
meningitis with or without encephalopathy, cranial neuritis and
radiculoneuropathy. The neurologic complications include:
• Meningitis (headache, nausea, photophobia).
• Subacute or chronic facial palsy: usually bilateral and
complete but may be unilateral and incomplete (383).
• Other cranial nerve palsies (II, V).
• Encephalitis: mild, subacute or chronic.
• Transverse myelitis.
• Polyradiculopathy with severe root pain, sensory and 383 Right lower motor neuron facial nerve palsy in a patient with
motor loss. neuroborreliosis.
 Lyme Disease (Neuroborreliosis) 317

INVESTIGATIONS • Other tests, such as the immunocytochemical antigen

Blood
• Peripheral white cell count: normal or lymphopenic.
• ESR: may be raised.
• Serology: serum titers of IgG antibodies to B.
burgdorferi: elevated. However, a raised serum IgG does
not necessarily indicate active infection and the serum
IgM may no longer be raised at the time that neurologic
complications occur (see below).
Imaging
The following imaging findings may occur:
• A normal CT and MRI brain scan.
• Areas of increased signal on T2WI/PDWI varying in size
from small punctate to large mass lesions, with a
predilection for the frontal and parietal lobes.
• Contrast-enhancing parenchymal lesions, meninges and
cranial nerves.
• Lyme disease should be considered in the imaging
differential diagnosis of multiple sclerosis, ADEM and
vasculitis.
CSF
• Cell count: raised, lymphocytic (in acute Lyme disease
but uncommonly in chronic Lyme disease).
• Protein: raised.
• Glucose: normal glucose.
• IgG/albumin ratio: raised.
• Oligoclonal bands: present.
• Cytology: a lymphoplasmacytic pleocytosis with frequent
mitotic figures may occur, simulating leptomeningeal
lymphoma.
• Serology: borrelia antigens are sometimes, albeit rarely,
detected in CSF when serum tests are negative and when
CSF is otherwise normal. So, the diagnosis should not
be excluded solely on the basis of normal routine CSF or
negative CSF antibody analyses. Exceptionally, the CSF
is normal in neuroborreliosis.
binding test and the cell-mediated immunity response
test, are available but not recommended for laboratory
diagnosis.
• In patients with neurologic complications that occur very
early in the course of infection, before a strong immune
response develops (e.g. facial nerve palsy), an ELISA is
obtained at the time of presentation and if positive, the
CSF is examined for confirmation of the diagnosis. If the
ELISA is negative, the ELISA is repeated in 1 month and
the CSF is repeated if seroconversion occurs. If the CSF
findings support the diagnosis, intravenous antibiotics
are commenced, and if the CSF is normal, oral
doxycycline therapy is started (see below).
PCR
PCR is now available as a diagnostic test. The test amplifies
specific B. burgdorferi DNA in the blood or CSF, which is
then detected by agarose gel electrophoresis or by
hybridization with probes. It detects the actual presence of
an organism rather than the host’s immune response to the
organism. However, it has a high false negative rate of
30–50%, perhaps because the organism prefers tissue over
body fluids.
TREATMENT
Treat early and promptly.
Cranial neuropathy (usually VIIth) with normal CSF
Doxycycline and amoxycillin (amoxicillin) (especially in
children) with or without probenecid, orally, for 2–4 weeks.
Other neurologic complications
• Penicillin G, i.v. 200 mg/kg/day in 6-hourly doses for
14 days.
• Tetracycline, oral, 500 mg four times daily for 30 days.
• Alternatives to penicillin include intravenous ceftriaxone,
cefotaxime, or doxycycline; or oral chloramphenicol.

DIAGNOSIS
Prompt and precise diagnosis is difficult because basic
microbiologic tests such as staining and culture of this
fastidious organism remain low yield procedures.

Serologic testing
• Detection of specific antibodies to B. burgdorferi in
blood and CSF by means of ELISA and the indirect
fluorescent antibody test, is commonly used to support
or refute the diagnosis but the tests are not well
standardized, false positive results are not uncommon
(particularly in patients with other infectious and
inflammatory diseases), a true positive result is evidence
of exposure and not necessarily active infection, a (false)
negative result may be present initially in cases with
eventually proven neuroborreliosis, and the test may
remain positive for years, despite clinical resolution after
therapy.
• A positive ELISA or indirect immunofluorescent
antibody result should be confirmed with the Western
blot assay but this test is laborious, expensive, and its
criteria for positivity have not been adequately
standardized. Quantitative criteria using a gel
densitometric approach have been recently devised to
help standardize this procedure.
318 Infections of the Nervous System: Fungal
CRYPTOCOCCAL MENINGITIS
DEFINITION
Infection of the leptomeninges caused by the yeast
Cryptococcus neoformans.
EPIDEMIOLOGY
Cryptococcosis (formerly called torulosis) is one of the most
common fungal infections of the CNS and cause of
meningitis, particularly in patients with HIV infection,
affecting about 10% of AIDS patients, usually late in the
course. It is most common in Thailand and Central Africa.
PATHOLOGY
• Granulomatous meningitis.
• Small granulomas and cysts within the cerebral cortex.
The cortical cysts contain large numbers of organisms in
a gelatinous material. The solid granulomatous nodules
are composed of fibroblasts, giant cells, organisms, and
regions of necrosis.
• Large granulomas and cystic nodules sometimes form
deep in the brain.
ETIOLOGY AND PATHOPHYSIOLOGY
• Cryptococcus neoformans is the etiologic agent. It is a
common soil fungus found in the roosting sites of birds,
particularly pigeons. The portal of entry is usually the
respiratory tract, and less often skin and mucous
membranes.
• It is usually acquired in the community.
• It may cause minimal inflammation in people with AIDS
and impaired immune responses.
Risk factors
A debilitating disease that alters T lymphocyte-mediated
immune responses:
• AIDS due to HIV infection.
• Transplantation recipients.
• Lymphoma.
• Hodgkin’s disease.
• Leukemia.
• Carcinoma.
• Tuberculosis.
CLINICAL FEATURES
• Cryptococcosis is a respiratory infection in patients who
usually present with disseminated disease, most
commonly as meningitis.
• Presenting features are often subacute in onset, subtle
and non-specific; indeed, in the setting of HIV infection,
cryptococcal meningitis can be truly cryptic with little or
no neurologic dysfunction. The classic symptoms signs
of meningitis such as neck stiffness and photophobia, are
often absent.
• Fever, headache, malaise, nausea and vomiting, and
mental changes are common but can be mild.
• Some patients do not have fever, headache and stiff neck,
but present with symptoms of gradually increasing
intracranial pressure due to hydrocephalus, or with a
confusional state, dementia, cerebellar ataxia or spastic
paraparesis.
• Cranial nerve palsies, psychiatric abnormalities, speech
disturbances and seizures are not common.
• Seizures and focal neurologic signs suggest the presence
of complications such as a granulomatous mass lesion in
one part of the brain (a cryptococcoma), granulomatous
meningovasculitis, or venous sinus thrombophlebitis.
• Confusion and impaired consciousness tend to develop
late and in severe cases.
• Extraneural manifestations, which may occur with or
without meningitis, include pulmonary infiltrates, skin
lesions (abscesses, ulcers, or molluscum contagiosum-like
lesions), prostatic abscess, hepatitis and lytic bone lesions.
DIFFERENTIAL DIAGNOSIS
Meningitis
• Aseptic (normal CSF glucose levels; early HIV).
• Syphilis (see p.312).
• Listeria.
• Tuberculosis (distinguished by fever, pulmonary lesions,
hyponatremia due to SIADH, and organisms in the CSF;
late HIV; see p.281).
• CNS vasculitis (normal CSF glucose levels, see p.227).
• Malignant meningitis (carcinomatous, lymphomatous;
see Metastases to the CNS, p.396).
• Other causes of subacute or chronic meningitis (see
p.279).
Other uncommon CNS infections in AIDS
• Candida albicans infection.
• Coccidioidomycosis.
• Histoplasmosis.
• Mycobacterium tuberculosis infection.
• Herpes zoster infection.
• Herpes simplex infection.
• JC papovavirus infection (progressive multifocal
leukoencephalopathy).
• Aspergillosis.
• Amebiasis.
• Trypanosoma cruzi infection.
• Nocardia.
CNS mass lesion
• Brain tumor.
• Brain abscess.
• Brain granuloma.
INVESTIGATIONS
CT or, preferably, MRI of the brain
Findings include:
• Normal scan.
• Dilated Virchow–Robin spaces which may enhance (in a
young immunosuppressed patient this should raise the
possibility of cryptococcus infection).
• Hydrocephalus (rare) (384–387).
• Multiple miliary enhancing nodules in the parenchyma
and leptomeninges involving the choroid plexus of the
trigone, cranial nerves and spinal nerve roots. Contrast
is required to demonstrate the miliary nodules.
• Diffuse meningeal enhancement rarely (differentiating it
from tuberculous and bacterial meningitis) (388–390).
• Multiple small areas of increased signal in the basal
ganglia that do not enhance are characteristic, but not
pathognomonic, of cryptococcus, and occur in
coccidioidomycosis and candidiasis.
 Cryptococcal Meningitis 319

384 385 386

387 388

389

384–387 Plain CT brain scan showing dilatation of all ventricles and

low density, due to edema, in the subependymal and periventricular
regions of a patient with communicating hydrocephalus due to
cryptococcal meningitis.

390

388–390 Cranial CT scan with contrast showing diffuse enhancement

of the basal meninges, particularly those surrounding the upper cervical
spinal cord at the level of the foramen magnum (390, arrows), and also
within the fourth ventricle and its lateral recesses (389, arrows).
320 Infections of the Nervous System: Fungal

CSF Mild case

• Gram stain: spherical cells, 5–15 μm in diameter, which • Fluconazole 800 mg loading dose by mouth, then
retain the Gram stain and are surrounded by a thick 400 mg daily by mouth.
refractile capsule. • Itraconazole may be used instead of fluconazole but
• India ink stain for cryptococcal antigen. The carbon experience with itraconazole is limited.
particles fail to penetrate the capsule, producing a white
halo around the double refractile wall of the yeast. Most patients respond clinically within 1–2 weeks, with
• Latex agglutination test or ELISA for the cryptococcal an early mortality of 5–10%. Continue therapy for
polysaccharide antigen. 4–6 weeks or until the CSF is sterile.
• Cryptococcal antigen titer (more than 1 : 8 is diagnostic).
• Culture: positive in 4–12 days. Isolation of yeast confirms Management of raised intracranial pressure
the diagnosis and allows for sensitivity tests in vitro. • Mechanical drainage (repeated LPs, intraventricular
• Opening pressure should be measured because elevated shunt).
intracranial pressure may have important prognostic • Acetazolamide treatment.
implications, particularly for visual impairment. • Corticosteroids are being studied in a controlled trial.
• White cell count: may be normal or only mildly elevated.
• Protein: normal or elevated. Maintenance therapy to prevent relapses
• Glucose: normal or decreased. Triazole antifungal agents (fluconazole 200–400 mg daily
by mouth, and itraconazole) have a more favorable toxicity
N.B. It is essential to test the CSF for cryptococcal profile and may be preferable for long term suppressive
organisms and antigen in patients with suspected cryptococcal treatment necessary to avoid the high incidence of relapse
meningitis because the CSF cell count, protein and glucose (more than 50%) in patients with AIDS. With maintenance
can all be normal, particularly in AIDS patients. Large volumes therapy, relapses are uncommon and usually related to non-
of CSF (20–40 ml) may be needed to find the organism. compliance with treatment, but may also occur because of
development of drug resistance and drug interactions which
Other lower fluconazole levels. Monitoring serum cryptococcal
• Serum cryptococcal antigen: positive. AIDS patients have antigen titers is not useful in predicting relapse.
higher antigen titers in blood than in CSF.
• Blood and urine cultures are often positive. CLINICAL COURSE/PROGNOSIS
A steadily progressive course occurs over several weeks or
DIAGNOSIS months. In a few patients, the course may be remarkably
Serum cryptococcal antigen is almost always positive in indolent with periods of clinical improvement and
cryptococcosis, but meningitis should be confirmed by CSF normalization of the CSF. In others, it may be fatal within
examination. Positive India ink staining or CSF cryptococcal a few weeks if untreated.
antigen titer will provide rapid diagnosis, which is confirmed Unfavorable prognostic factors are:
subsequently by CSF culture. • Altered mental status.
• High CSF cryptococcal antigen titer.
TREATMENT • Low CSF leukocyte count.
Treatment is determined by the severity of the illness. • Positive extrameningeal culture for cryptococcus, hypo-
natremia, and raised intracranial pressure (for vision).
Primary therapy (treatment of acute infection)
Severe case
Altered consciousness, CSF white blood cell count
>20/mm3, CSF antigen titer >1 : 1024 and a positive blood
culture:
• Amphotericin B 0.5–0.7 mg/kg body weight per day by
intravenous injection. Amphotericin is limited by
frequent adverse effects, such as fever, renal dysfunction
with renal tubular acidosis and, rarely, leukoencepha-
lopathy. A liposomal form of amphotericin B may have
less adverse effects.
• +5-flucytosine (100–150 mg/kg/day by mouth or
intravenously) for 2–3 weeks (the value of adding
flucytosine remains undetermined). Flucytosine adverse
effects include myelosuppression and gastrointestinal
toxicity.
• Followed by fluconazole (an oral triazole antifungal
agent) 400 mg/day by mouth, for an additional
8–10 weeks; fluconazole is as effective as amphotericin B
but fluconazole causes delayed clearance of cryptococcus
from the CSF.
 Mucormycosis of the Nervous System 321

MUCORMYCOSIS OF THE RISK FACTORS/PREDISPOSING CONDITIONS

NERVOUS SYSTEM • Diabetes mellitus:
– Present in about three-quarters of cases.
– A risk factor for cutaneous and localized paranasal
DEFINITION infection.
An opportunistic, malignant infection of the brain vessels – The fungus thrives in an environment rich in glucose and
caused by zygomycete fungi, including those of the genera acid pH.
Absidia, Rhizomucor and Rhizopus. – Poor glycemic control and ketoacidosis impair phagocytic
activity of neutrophils.
EPIDEMIOLOGY – Diabetic ketoacidosis is associated with increased serum
• Incidence: rare. free-iron levels, which facilitates growth of rhizopus, an
• Age: often adolescents and young adults. iron-requiring organism.
• Gender: M=F. • Burns (for skin invasion).
• Neutropenia (for widespread mucor infection).
PATHOLOGY • Leukemia.
Several forms • Lymphoma.
• Orbital. • Cytotoxic drug treatment.
• Rhino-orbital. • Corticosteroid treatment.
• Rhino-orbito-cerebral. • Post organ transplant.
• Cutaneous. • Renal failure.
• Pulmonary. • AIDS.
• Gastrointestinal. • Amebiasis.
• Disseminated. • Malnutrition.
• Kwashiorkor.
Rhino-orbito-cerebral form • Intravenous drug abuse.
• Mucosal thickening of the paranasal sinuses on one or
both sides. CLINICAL FEATURES
• Soft tissue retro-orbital mass. Retro-orbital mucormycosis
• Numerous broad, irregular non-septate fungal hyphae History
with non-parallel margins, within the arterial wall and • Headache (75%).
often extending into the surrounding brain parenchyma. • Eye pain.
• Secondary intraluminal arterial thrombosis. • Facial swelling.
• Secondary hemorrhagic infarction of the brain. • Dark, blood-stained nasal discharge (45%).
• Intracranial granuloma from hematogenous spread are
unusual. Examination
• Cavernous sinus thrombosis following invasion of orbital • Sick (i.e. looks unwell).
apex. • Altered sensorium (30%)
• Brain abscess following direct intracranial extension. • Fever (55%)
• Orbito-fascio- cellulitis (35%): swelling, mucopurulent
ETIOLOGY AND PATHOPHYSIOLOGY discharge from the eye.
The fungi are acquired from the environment and infect the • Proptosis.
lungs, paranasal sinuses and, less commonly, the skin. • Edema of the eyelids.
The brain infection begins in the nasal turbinates and • Reduced visual acuity and direct light reflex.
paranasal sinuses and spreads along infected vessels through • Relative afferent pupillary defect.
the orbital apex to the retro-orbital tissues and through the • Retinal edema.
cribriform plate to the brain, where it may cause a cerebral • Rapid reduction in visual acuity, resulting in blindness in
vasculitis with secondary arterial and venous thrombosis and one eye.
hemorrhagic infarction. • Ophthalmoplegia (35%).
• Hemiparesis (30%).

Cerebral mucormycosis
Carotid territory hemorrhagic infarction of the brain (e.g.
hemiparesis, dysphasia).

DIFFERENTIAL DIAGNOSIS
• Cavernous sinus syndrome such as cavernous sinus
thrombophlebitis (see p.258).
• Retro-orbital tumor.
322 Infections of the Nervous System: Fungal

INVESTIGATIONS DIAGNOSIS
CT or MRI brain scan (391–393) The diagnosis of fungal infection due to mucormycosis is
• Typically starts as a rim of soft tissue thickness along the strongly suggested by painful proptosis and redness of the
walls of the paranasal sinuses. eye with blood-stained nasal discharge in the setting of
• Fluid levels, obliteration of the nasopharyngeal tissue diabetes mellitus and poor glycemic control. Although
planes, bone destruction. demonstration of non-septate hyphae on histopathologic
• Orbital extension causes proptosis, superior orbital vein examination further supports the clinical diagnosis, the
thrombosis. definitive diagnosis depends on growth of zygomycetes in
• Extension through the orbital apex causes cavernous fungal culture of the purulent discharge, lesion scrapings or
sinus thrombosis. biopsy material.
• Further intracranial extension causes brain parenchymal
low density on CT with mass effect and enhancement in
the anterior and temporal fossae.
• Intracranial abscesses are also seen. 391
• CT is best for demonstrating soft tissue invasion, necrosis
and early bone erosion.
• MRI, with or without gadolinium, is best for evaluating
intracranial extension including carotid artery thrombosis
and cavernous sinus thrombosis.

Carotid angiography
May show features of vasculitis, pseudoaneurysm formation,
arterial occlusion.

Blood
• Full blood count: leukocytosis (white cell count may be
used to monitor response to treatment).
• Glucose: hyperglycemia.
• Arterial blood gases: acidosis.
• Serology has no place in the diagnosis of mucormycosis.

Other
• Swab of purulent discharge from the eye and nose:
culture fungus on Sabouraud medium.
• External ethmoidectomy: scrapings or biopsy of the nasal
lesion to look for broad, irregular non-septate hyphae on
microscopy.
391 CT scan showing extensive muco-periosteal disease involving the
maxillary antra (arrows) in a patient with non insulin-dependent
diabetes mellitus, chronic renal failure, and cavernous sinus thrombosis
due to mucormycosis.The sphenoid and frontal sinuses were also
involved.

392 393 392, 393 CT brain scans

with contrast same patient
as 391). Coronal (392) and
axial (393) views of an
enhancing mass extending
from the paranasal sinuses
into frontal fossa (arrows)
due to mucormycosis.
 Toxoplasmic Encephalitis
TREATMENT
• Control diabetes (e.g. correct hyperglycemia and
acidosis) with fluids and insulin.
• Amphotericin B: rapid infusion of 0.5–1 mg/kg/day
dissolved in 5% dextrose solution to a total cumulative
dose of 1.5–4 g over a prolonged period of 8 weeks
because of the fungistatic rather than fungicidal nature of
the drug. Cessation of treatment is guided by clinical
symptoms and signs, including resolution of fever, wound
healing, decreasing white cell count, and negative cultures.
Limitations are nephrotoxicity, bone marrow depression,
cardiotoxicity and hypokalemic weakness. Liposomal
amphotericin can be used in much higher doses without
any significant risk of the above adverse effects.
N.B. Azole group of antifungals, such as
ketoconazole, are not recommended.
• Surgical debridement: in early cases without necrosis,
simple nasal, transantral or ethmoidal biopsy and
curettage should be undertaken. Extensive necrosis
requires more radical debridement. A blind eye should
not be removed as routine because there are no data to
suggest that orbital exenteration improves survival.
• Hyperbaric oxygen: reported to inhibit the growth of
Zygomycetes in vitro.
PROGNOSIS
• Orbital mucormycosis: amphotericin B has considerably
reduced mortality from 90% in the untreated state to
40%.
• Rhino-orbito-cerebral mucormycosis: infection of the
brain and cerebral vessels is usually rapidly fatal but a
minority recover with appropriate emergent treatment.
Adverse prognostic factors for survival
• Delayed diagnosis and treatment.
• Leukemia.
• Renal disease.
• Treatment with desferrioxamine.
• Bilateral sinus involvement.
• Facial necrosis.
• Nasal deformity.
• Hemiparesis.
323
TOXOPLASMIC ENCEPHALITIS
DEFINITION
Infection of the brain by Toxoplasma gondii, which is a
protozoan intracellular parasite that reproduces sexually only
in cats and differentiates into encysted forms.
EPIDEMIOLOGY
Prevalence
Toxoplasma infection
Toxoplasma infection is widespread in the community, with
marked geographic variation. About 50–80% of adults in
continental Europe are infected, compared with 30% in the
UK. Antibody prevalence is highest in warm areas with high
rainfall where the infective sporocyst is more likely to
survive. Contact with cats and eating raw or undercooked
meat are also contributing factors.
Disease occurs sporadically, though outbreaks with a
common source have been reported, such as following the
consumption of unpasteurized milk.The highest incidence
of infection occurs in the late teenage years and early 20s.
Toxoplasma encephalitis
Arises in the immunocompromised host (e.g. AIDS). In the
pre-prophylaxis era, toxoplasma encephalitis was the AIDS
index diagnosis in up to one-half of cases, and the most
common cause of focal brain lesions in HIV/AIDS,
occurring in 3–40% of patients, usually when HIV infection
was advanced and CD4 count <200 cells/mm3.
Toxoplasma encephalitis is now rarely seen among
patients attending HIV clinics who are commenced on
prophylaxis when they become immunosuppressed; it is only
seen in ‘lay’ presenters (i.e. unknown HIV infection) and
patients who are poorly compliant with prophylactic therapy.
PATHOLOGY
Toxoplasma infection in the immunocompetent host
• Lymphadenopathy.
• Chorioretinitis.
Toxoplasma infection in the immunocompromised
host (e.g. AIDS)
Toxoplasmosis is at its most severe in immunocompromised
individuals.
Primary infection may cause
• Necrotizing encephalitis (widespread microscopic lesions).
• Brain abscesses, usually in the gray matter of the
diencephalon and cortex.
• Pneumonia.
• Myocarditis.
• Myositis.
• Reactivation of quiescent tissue cysts in the brain.
• Focal encephalitis.
ETIOLOGY AND PATHOPHYSIOLOGY
Humans ingest oocysts in cat litter or contaminated soil
(e.g. from gardening, washing vegetables, playing in sand
pits), or ingest tissue cysts in infected meat.
Bradyzoites are released from the ingested sporocyst and
penetrate intestinal cells, reach the lymphatic system, multiply
asexually to trophozoites and then migrate throughout the
body via lymphocytes. They disrupt and invade adjoining cells
324 Infections of the Nervous System: Protozoan
and, eventually, a tissue cyst forms, which is partly host in origin
and contains thousands of bradyzoites that are morphologically
identical to trophozoites but have a reduced metabolic rate.
These persist for the lifetime of the host in the brain and skeletal
and cardiac muscle, continually stimulating the immune system
and conferring immunity. IgG antibody reaches a maximum
concentration 2 months after infection and persists for life.
Acute disease is caused by a type III hypersensitivity reaction,
leading to intravascular thrombosis and tissue infarction.
Cyst reactivation is initiated by a reduction in cell mediated
immunity (CD4 count <100 cells/mm3) and a type IV
reaction, accompanied by round cell infiltration, granuloma
formation, and tissue necrosis. In chronic infection, cell-
mediated immunity forms the basis of the immune response.
CLINICAL FEATURES
Various types of presentations:
• Infection with Toxoplasma gondii is usually asympto-
matic, except for congenital infection and in the im-
munocompromised host.
• Encephalitis usually evolves quite rapidly (time from
onset to presentation is only a few days).
• Subacute focal (hemisphere > brainstem or cerebellum)
encephalopathy: hemiparesis, aphasia, apraxia, hemi-
sensory impairment, homonymous hemianopia, ataxia,
and cranial nerve palsies.
• Diffuse encephalopathy: reduced alertness/confusion
with subsequent evolution of focal neurologic signs over
weeks to months.
• Constitutional (systemic) symptoms: headache, fever
(47%), lethargy (43%) and seizures (29%), and disorien-
tation, altered mental state and coma with more diffuse
cerebral dysfunction.
• Acute onset of a focal neurologic deficit or seizures due
to intracerebral hemorrhage.
DIFFERENTIAL DIAGNOSIS
Focal brain lesions
• Primary CNS lymphoma: slower onset (patients present
within 1–2 weeks of onset of symptoms) and greater
involvement of the periventricular white matter.
• Progressive multifocal leukoencephalopathy: slower,
quite indolent, onset over several weeks, with lesions
confined to the white matter.
• Tuberculous brain abscess.
• Demyelination.
• Vasculitis related to varicella-zoster infection.
• Syphilis
• CMV.
• Stroke.
Encephalitis
• CMV: non-specific clinical and neuroimaging features
but in some cases CT or MRI show diagnostic
subependymal prominence (signal change and contrast
enhancement) and sometimes small areas of gray matter
enhancement. A low serum sodium may also be a clue.
• Herpes simplex.
Myelitis
• CMV.
• Herpes simplex.
• Varicella-zoster.
• Syphilis.
Other uncommon CNS infections in AIDS
• Candida albicans infection.
• Coccidioidomycosis.
• Histoplasmosis.
• Mycobacterium tuberculosis infection.
• Herpes zoster infection.
• Herpes simplex infection.
• Aspergillosis.
• Amebiasis.
• Trypanosoma cruzi infection.
• Nocardia.
INVESTIGATIONS
Serum antitoxoplasma antibodies
• Specific antitoxoplasma IgG is usually detectable and
supports the diagnosis but a low titer or an absence of
antibody does not exclude the diagnosis; about 3% of
toxoplasmic encephalitis patients are seronegative.
• Immunofluorescence assay may be less sensitive than
ELISA in detecting antitoxoplasma IgG.
CT brain scan (394, 395)
Single or multiple nodular low density areas (396), often at
the cortico-medullary junction or in the basal ganglia, with
little or no enhancement, or gyriform enhancement; or,
isodense ring-enhancing nodules in the basal ganglia. These
features are not diagnostic of toxoplamic encephalitis as
other opportunistic infections and lymphoma can produce
similar lesions.
MRI brain scan
• Often shows more lesions, that were not shown by CT.
• Multiple lesions of high intensity usually in the basal
ganglia (397, 398), with vasogenic edema and ring or
nodular enhancement on T1WI (399).
• Single lesions seen on MRI are more likely to be due to
lymphoma. Rarely, the CT and MRI may be normal in a
diffuse form of toxoplasmic encephalitis.
CSF
• Non-specific abnormalities.
• PCR to detect toxoplasma DNA in CSF is a promising
definitive diagnostic tool.
Brain biopsy
To demonstrate tachyzoites histologically.
DIAGNOSIS
• The diagnosis of CNS toxoplasmosis may be presumed
in patients with characteristic clinical and radiologic
findings and detectable antitoxoplasma antibody.
• The definitive diagnosis requires demonstration of
tachyzoites histologically or by detection of specific
toxoplasma DNA by PCR.
CLINICAL COURSE
Evolves rapidly if untreated.
 Toxoplasmic Encephalitis 325

394, 395 CT brain scan of 394 395

congenital toxoplasmosis (two
different patients). Note the tiny
calcified nodules near the lateral
ventricles (arrows) and the
prominent ventricles due to
atrophy.

396 CT brain scan with 396 397

contrast in a patient with HIV
infection and cerebral
toxoplasmosis.There is a solitary
lesion in the left occipital lobe
(arrows).

397, 398 T2W axial (397) and

T1W coronal (398) MRI with
contrast showing multiple lesions
in the basal ganglia and
peripherally due to toxoplasma.
(Courtesy of Professor J Best,
Department of Medical
Radiology, Royal Infirmary,
Edinburgh, UK.)

399 T1W MRI with contrast 398 399

(same patient as in 396)
confirms the presence of the
enhancing lesion, which resolved
with antitoxoplasma treatment.
(Courtesy of Professor J Best,
Department of Medical
Radiology, Royal Infirmary,
Edinburgh, UK.)
326 Infections of the Nervous System: Worm
MANAGEMENT
• HIV-infected, toxoplasma-seropositive, and a single
lesion on CT: proceed to MRI and, if this also shows
only a single lesion, then biopsy should be considered
because of possibility of lymphoma. Otherwise consider
an empirical trial of antitoxoplasma therapy, await
response, and if no improvement after 2–3 weeks,
consider stereotactic brain biopsy.
• HIV-infected, brain lesions on CT, but no specific toxo-
plasma antibody or receiving prophylactic trimethoprim-
sulfamethoxazole: consider for brain biopsy because of
the increased likelihood of other disease.
• HIV-infected, toxoplasma-seropositive, and multiple
ring-enhancing lesions on CT: start empiric antitoxo-
plasma therapy, await a response, and if no response,
consider brain biopsy (359).
PRIMARY THERAPY
• Pyrimethamine (200 mg loading dose orally followed by
75 mg/day by mouth) + sulfadiazine (100 mg/kg per
day, in four divided doses up to 8 g/day by mouth or
intravenously) + folinic acid (leucovorin calcium) (7.5 mg
daily by mouth). Or:
• Pyrimethamine and folinic acid (leucovorin calcium) (as
above) + clindamycin (600 mg four times a day by
mouth or intravenous injection).
Pyrimethamine is the most important drug. Adverse
effects occur in >40% of patients, usually rash and nephro-
toxicity, which are particularly related to sulfadiazine.
Hematologic toxicity of pyrimethamine (e.g. megaloblastic
anemia) can be ameliorated with folinic acid (leucovorin
calcium) (5–10 mg/day). Continue treatment for at least 3
weeks, up to 6 weeks if the patient does not show a complete
response. Up to 86% of responders show improvement by
the seventh day of treatment. If clinical or radiologic
improvement does not occur within 1–2 weeks of starting
empirical therapy for toxoplasmosis, an alternative diagnosis
should be pursued using stereotactic brain biopsy.
Maintenance therapy
Relapse of CNS toxoplasmosis is common in patients with
HIV infection so life-long maintenance therapy is indicated:
• Sulfadiazine (500 mg four times a day by mouth) +
pyrimethamine (25 mg daily by mouth) + folinic acid
(leucovorin calcium) (7.5 mg daily by mouth). Or:
• Clindamycin (600 mg four times a day by mouth) + pyri-
methamine and folinic acid (leucovorin calcium) (as above).
PRIMARY PREVENTION
In countries with a high background seroprevalence of
toxoplasma, HIV-infected patients with a CD4 cell count
<200/µl should have prophylaxis for toxoplasmosis
(trimethoprim and sulfamethoxazole). Many primary
prophylactic regimes for Pneumocystis carinii have antitoxo-
plasmal activity. Coinfected pregnant women whose CD4 cell
count is <200/µl warrant primary prophylaxis as maternal
reactivation may result in congenital toxoplasmosis, which has
a rapidly fatal course in the HIV-infected infant. HIV-infected
patients who are toxoplasma-seronegative should be advised
to wear gloves when changing cat litter or gardening and to
avoid eating undercooked meat, particularly lamb or pork,
unless it has been thoroughly frozen (–20°C [–4°F]).
CYSTICERCOSIS
DEFINITION
The larval or intermediate stage of infection with the pork
tapeworm Taenia solium; a cysticercus is a fluid-filled
bladder that contains the invaginated head or scolex of the
larval form of Taenia solium.
EPIDEMIOLOGY
• Prevalence: endemic (affects 2–4% of the general
population) in Mexico, Central and South America,
Poland, China, Africa, India and New Guinea where it is
the leading cause of adult-onset epilepsy. Becoming more
widespread in the United States, France, and Italy, and
less commonly other countries in Europe and Australasia
because of the massive emigration from endemic areas.
• Age: more common in adults than children.
• Gender: M=F.
ETIOLOGY
Accidental ingestion of eggs produced by adult Taenia
solium, or pork tapeworms.
PATHOPHYSIOLOGY
The adult Taenia solium, or pork tapeworm, which is 2–8 m
(6.5–26 ft) in length, resides (for up to 10 years or so) in
the small intestine of the human, which is its only known
host. It attaches to the intestine by its scolex or head. The
terminal, egg-bearing segments, or proglottids, occasionally
separate and are discharged in the feces. Infectious ova are
also deposited in the perianal area and can contaminate
fingers and other parts of the body.
Food or water that is contaminated with Taenia solium
eggs (ova) from human feces may be ingested by the pig,
which is the main intermediate host, or human beings
(fecal–oral route), also serving as intermediate hosts.
Larval stage
Human ingestion of food and water contaminated by
cysticercus ova is the most common means by which
humans contract systemic cysticercosis. The ingested eggs
hatch in the small intestine, develop into embryos or
oncospheres, and migrate through the mucosa of the small
intestine and enter the portal circulation from where they
are distributed to capillaries in the parenchyma of the brain,
subarachnoid space and ventricles, the eyes, and striated
muscles. Once in capillaries these oncospheres develop into
cysticerci, or encysted larvae, within about 2 months. Viable
encysted larvae consist of cysts with the larva projecting into
the center of the cyst from the wall to which it is attached
by its scolex. No further development of the worm occurs
while it is encysted, and it can remain in this stage for many
years. The cyst maintains a diameter of 10–20 mm
(0.4–0.8 in). There is little or no inflammation and the
patient is usually asymptomatic.
The same process occurs in pigs who ingest food and
water contaminated by cysticercus ova. The cyst (in pig
muscle) must be ingested (by humans) for the larva to
emerge and develop into an adult in the gut of the definitive
host. Thus humans can be intermediate as well as definitive
hosts, whereas pigs are only intermediate hosts, since they
cannot acquire the adult infection by eating cysts.
 Cysticercosis 327

Active stage • Cysts may have a normal morphologic pattern or may be

After an incubation period of <1–30 years (average complicated by progressive inflammation with
4.8 years), the parasite (larva) degenerates and dies, and the granulomatous meningitis and proliferative endarteritis,
disease enters the active phase. The cyst loses osmotic regu- associated with obstruction of the foramina of Luschka
lation, and swells to a diameter of 40–50 mm (1.6–2 in). An and Magendie and involvement of the cranial nerves.
inflammatory reaction is generated against parasite antigens Intraventricular cysts may cause hydrocephalus when
and the cyst develops into a granulomatous abscess, with a located at the foramen of Monro.
fibrous capsule, a granulomatous inflammatory infiltrate with
epithelioid giant cells, and an interior consisting of pus and CLINICAL FEATURES
the bladder-wall remnants. This inflammatory response is Diverse and depend on the number of cysticerci, their
responsible for symptoms such as seizures, enhancement of location in the brain and the immune status of the patient.
the cysts after the administration of contrast, and a lympho-
cytic response in the spinal fluid. Cysticerci located in the Presenting features
basilar subarachnoid space may induce an intense inflam- May comprise any combination of:
matory reaction, leading to hydrocephalus, cranial nerve • Non-specific ‘flu-like’ illness in the initial stage of larval
palsies and stroke due to a basal vasculitis. invasion.
• Epileptic seizures: the most common manifestation of
Inactive stage the active stage; caused by parenchymatous cysts.
The abscess may then undergo progressive mineralization, • Raised intracranial pressure.
with collagen and calcium deposition (the inactive stage) • Meningoencephalitis.
and without surrounding edema or an inflammatory • Ventriculitis.
response. • Hydrocephalus.
Human ingestion of raw or undercooked ‘measled’ • Hemiparesis.
muscle of pig (pork) contaminated with mature cysticercus • Cranial nerve palsies.
usually causes asymptomatic bowel infestation with the • Acute cerebellar ataxia.
tapeworm, as the human, like the pig, becomes an • Behavioral disturbance.
intermediate host. This does not necessarily lead to, and is • Asymptomatic (the cysts being discovered radiologically).
not a prerequisite for, the development of systemic
cysticercosis. Ingested cysticerci invaginate into the mucosa Other features
of the small intestine and then develop to adulthood. The • History of travel to, or residence in, an area where
adult worm elongates up to a length of 2–8 m (6.5–24 ft), cysticercosis is endemic.
and may survive in situ for up to 25 years. The terminal part • Low grade fever.
of the worm containing the eggs is passed in the feces. • Palpable subcutaneous nodules in the soft tissues of the
limbs.
PATHOLOGY
• Multiple calcified lesions in the muscles of the thigh, leg, DIFFERENTIAL DIAGNOSIS
and shoulder and in the brain. • Hydatid disease with cysts produced by Echinococcus
• The brain is affected in 90% of cases of human cysti- granulosus.
cercosis: leptomeninges (especially the basilar cisterns) • Viral encephalitis: varicella, coxsackie, echovirus.
(55%), ventricular system (more often in the fourth • Brain tumor: primary or secondary.
ventricle) (15%), and in the parenchyma (30%). • Drug toxicity (e.g. phenytoin).
• Eosinophilic meningoencephalitis due to parasites:
Intraparenchymal cysticercosis – Angiostrongylus cantonensis.
• Cysticerci in the brain parenchyma are located in the gray – Gnathostoma spinigerum.
matter at the gray-white matter junction and are solitary – Paragonium westernensis.
in 25–75% of patients. They often appear as an enlarged
larva surrounded by an abscess wall with adjacent gliosis. INVESTIGATIONS
• The cysts may be alive, but the majority (60%) are dead Radiography
and calcified. • Plain skull x-ray shows calcification in the brain
parenchyma, typically 1–2 cm (0.4–0.8 in) in diameter,
Racemose cysticercosis surrounded by a calcified sphere of 7–12 cm (2.8–4.7 in)
• A proliferating form of larval tapeworm that consists of diameter.
multiple interconnected bladders of different sizes that • Soft tissue radiography of thighs, and limbs for evidence
lack scolices. of calcified larvae.
• Occurs in the subarachnoid space and cisterns at the base
of the brain, sylvian fissures, and wider parts of the fourth
ventricle.
• Cysts collect in grape-like clusters with tiny points of
attachment to the pia arachnoid, or the larvae migrate
within the ventricles.
• ‘Complex arachnoid cysts’: cysts that lie within major
sulci or fissures in which a wall composed principally of
inflamed meninges develops once the larva has aged,
decayed, and died.
328 Infections of the Nervous System: Worm
CT (400, 401)
CT shows single or multiple hypodense cysts that are
localized or generalized and contain a small, asymmetrically
located ‘off-center’, internal, hyperdense nodule (with or
without calcification) corresponding to the dead and
hyalinized larval scolex (calcification occurs where cysts have
died). The cyst fluid is of CSF density. The cysts or nodules
enhance with intravenous contrast as the cysticerci
degenerate. This occurs early on, together with edema and
mass effect, but the enhancement wears off as the lesion ages
and the edema disappears. CT may reveal complications,
which include hydrocephalus and basal meningitis.
MRI (402, 403)
MRI shows similar features to CT, with the cysts of CSF
signal. MRI is more sensitive than CT for detecting edema
(which indicates lesion activity; edema occurs as the parasite
dies) and non-calcified cysticercosis lesions in the ventricles
and subarachnoid space, such as in the basal cisterns.
Blood
• Full blood count and film: leukocytosis due to peripheral
eosinophilia
• ESR: elevated.
• Serum immunochemistry: ELISA for IgM antibodies
against the cysticercus antigen, and the enzyme-linked
immunoelectrotransfer blot (EITB), which has a
sensitivity of greater than 93% and a specificity of 100%.
CSF
• CSF is negative in 49–63% of cases of the
intraparenchymal form; pleocytosis, eosinophilia, elevated
protein, and occasionally hypoglycorrhachia occur in the
encephalitic, racemose and basilar meningitic forms.
• Immunochemistry: ELISA for IgM antibodies against the
cysticercus antigen shows a sensitivity of 87% and
specificity of 95% in active disease. False positives can occur
in neurosyphilis and meningeal tuberculosis. The EITB
has a sensitivity of about 80% and a specificity of 100%.
Other
Anal scrapings and fecal examination for ova and parasites:
frequently negative.
DIAGNOSIS
• A definitive diagnosis requires identification of the
proglottids or eggs of the larval form of T. solium in
stool. The gravid segments of the eggs must be examined
for their characteristic morphologic features.
• As this can be difficult to identify positively, a positive
diagnosis can be made by detecting antibodies to T.
solium by Western blot analysis. Biopsy can also be used
to make a positive identification.
TREATMENT
Treatment depends on the presenting syndrome, nature of
the neurologic impairment, location and activity of cysticerci
and host immune response.
Calcified neurocysticerci represent inactive cysts, and
neither require nor respond to anticysticercal drug treatment.
Anticysticercal drugs
• Praziquantel, an isoquinolone antihelminthic agent,
50 mg/kg of body weight, given daily for 15–30 days,
depending on the number and size of the cysts.
• Albendazole, an imidazole antihelminthic agent,
15 mg/kg body weight per day for 21 days, is the
preferred drug as its plasma levels increase by 50% when
used concurrently with dexamethasone, in contrast to
praziquantel whose bioavailability is decreased by 50%.
Albendazole produces an 80% reduction in total number
of cysts after a single course of therapy, compared to a
65% reduction after praziquantel.
Anti-inflammatory drugs
A host inflammatory reaction to the death of cysticerci as
a result of anticysticercal drug treatment may lead to
cerebral edema and increased intracranial pressure.
Concurrent treatment with:
• Prednisolone (1–2 mg/kg/day oral for 7 days), or
• Dexamethasone.
Surgery
• A CSF shunting procedure may be required for
hydrocephalus due to cisternal cysticercosis and chronic
arachnoiditis.
• Excision/decompression of large subarachnoid or
intraventricular cysts that obstruct CSF flow.
Anti-epileptic drug therapy
If required (i.e. symptomatic epileptic seizures).
Prevention
• Disposal of human feces in a sanitary manner.
• Cook or freeze all meat or fish thoroughly before it is eaten.
• Mass treatment with albendazole or praziquantel could
eliminate cestodes from the world, but this would be a
formidable task, given the widespread distribution of the
pork tapeworm.
PROGNOSIS
Initially treatment may seem to exacerbate neurologic
symptoms, with an increase in cells and protein in the CSF,
but then the patients improve and many become
asymptomatic, with a striking decrease in the size and
number of cysts on CT scanning.
Cisternal and racemose cysticercosis are less responsive
to anticysticercal drugs than parenchymal cysticercosis.
The outcome of patients with epilepsy due to
neurocysticercosis is better after anticysticercal drug therapy
than when the primary disease is left to follow its natural course.
This is true for both those in whom the cysticerci remain
unchanged for long periods and for those in whom there is an
intense inflammatory reaction that eventually destroys the
cysticerci. Also, there are fewer seizures after medical treatment
than after surgical removal of the cystic lesion.
 Cysticercosis 329

400 401

400, 401 Plain cranial CT scan showing multiple small hyperdense areas of calcification (arrows – dead cysts)
in a patient with inactive cysticercosis.

402 403

402, 403 MRI brain scan showing subtle inactive cysticercosis lesions (arrows).
330 Infections of the Nervous System: Prion

CREUTZFELDT–JAKOB • Inadequately sterilized neurosurgic instruments and

DISEASE (CJD) depth electrodes: 6 cases.
• Human gonadotrophin: 4 cases.
• Corneal transplant: 2 cases.
DEFINITION
A neurodegenerative condition that is the most common Sporadic, randomly distributed illness of unknown
clinicopathologic subtype of the transmissible spongiform cause (85% of cases)
encephalopathies or prion diseases.
The transmissible spongiform encephalopathies are all
characterized by the deposition in brain of an abnormal,
protease resistant, isoform of a membrane-bound
glycoprotein, the prion protein. Since the spongiform 404
change can be variable, the term prion disease is more
accurate.

EPIDEMIOLOGY
• Incidence: 1 per million per year.
• Age: median age of onset: 61 years; rare (but increasingly
reported [nvCJD]) younger than 30, and older than
80 years.
• Gender: M=F.

PATHOLOGY
Macroscopic
Normal or slightly atrophic brain.

Microscopic (404) 404 Microscopic section of the gray matter of cerebellum of a patient
A triad of: with CJD showing neuronal loss, reactive astrocytic proliferation and
• Neuronal loss. gliosis, and spongiform degeneration (vacuolation of the neuropil).
• Reactive astrocytic proliferation and gliosis.
• Spongiform degeneration (status spongiosus and
spongiform change: vacuolation of the neuropil [405, 405
406]): particularly in deeper laminae of the gray matter
of the frontal and temporal lobes, but also the gray
matter of the striatum, thalamus, tegmentum of the
upper brain stem, and cerebellar cortex.

Kuru plaques are also present: eosinophilic, round,

compact extracellular depositions of prion protein (PrP);
pathognomonic of a prion disease but found in only a few
sporadic cases.

Ultrastructural
Intraneuronal, complex, clear vacuoles whose membranous
septa look curled in profile.

ETIOLOGY
Inherited mutation in the PrP gene 406
Familial CJD (10–15% of cases)
Autosomal dominant pattern of inheritance; point
mutations or insertions in the prion protein gene located on
the short arm of chromosome 20. The codon 200Lys and
178Asp mutations (in association with codon 129Val/Met
polymorphism) are associated with neuropathologic changes
essentially indistinguishable from sporadic CJD.

Acquired
Iatrogenic transmission of CJD (<5% of cases)
• Human cadaveric pituitary-derived growth hormone
(hGH): >100 cases worldwide.
• The estimated risk of developing cadaveric hGH-induced
CJD for patients treated with cadaveric-derived hGH is
1 in 200–300. 405, 406 Neuronal vacuolation and spongiform change in the brain of
• Foreign dura mater grafts: 69 cases. a patient with CJD.
 Creutzfeldt–Jakob Disease (CJD)
PATHOGENESIS
• Transmissible to experimental animals following
inoculation or dietary exposure.
• Long incubation period, hence the initial concept of a slow
virus infection, but no infective agent has been found.
Prion hypothesis
• The transmissible agent is a proteinaceous infectious
particle, or prion.
• The prion appears to consist principally or entirely of a
modified abnormal, partially protease-resistant isoform
of a normal host-encoded cellular glycoprotein, the prion
protein (PrP).
• Normal prion protein, described as PrPC, is a constituent
of the surface of the neuronal cell.
• In the presence of mutations, now discovered in CJD
and other transmissible spongiform encephalopathies
(kuru, Gerstmann Straussler Scheinker syndrome [GSS],
fatal familial insomnia [FFI], and atypical prion disease),
PrPC may change into a disease-related isoform, PrPSc,
which differs from the normal cellular isoform by a post-
translational modification that appears to involve a
conformational change.
• The post-translational change in protein structure from
PrPC to the abnormal PrPSc is probably a critical
pathologic event, causing either loss of function of PrPC
or, less likely, toxicity due to gain of function of PrPSc.
• The structural change of PrPC to PrPSc occurs as an
inevitable event (predisposed by the change in primary
structure due to mutations in the PrP gene) in familial
disease, as an induced event by exogenous PrPSc in
transmitted cases (exogenous PrPSc interacts with
endogenous PrPC and induces the structural change),
and as a rare spontaneous event in sporadic disease.
Sporadic cases may also arise from a somatic mutation of
the PrP gene (in addition to spontaneous conversion of
the cellular isoform PrPC to PrPSc as a rare stochastic
event).
• The prion hypothesis may explain the paradoxic
observation that the disease can be genetically inherited,
transmitted, and sporadic.
• The clinical heterogeneity (see below) may reflect
differences in host genotype (e.g. polymorphism at
codon 129 of the PrP gene) and different isoforms of
PrPSc (e.g. types 1 and 2).
Genetic susceptibility to acquired iatrogenic
and sporadic CJD
• The general population has a common silent protein
polymorphism at position (codon) 129 of the human
PrP gene, where either a methionine (Met) or valine may
be encoded (present). About 40% of whites are
homozygous for the more frequent Met alleles, 50% are
heterozygous for Met, and 10% are homozygous for the
valine allele.
• Homozygosity at PrP 129 (present in about 50% of the
general population) appears to confer susceptibility to
iatrogenic and sporadic disease.
• Most patients with sporadic CJD are homozygous for
either allele. The new variant cases of CJD (see below)
are Met 129 homozygous, suggesting that about 40% of
the general population are susceptible.
331
• Most patients with iatrogenic CJD (treatment with
cadaveric pituitary-derived hGH) are also homozygous,
mostly for the valine allele at this codon.
• Heterozygosity for the PrP gene appears to be
protective.
Risk factors
• Iatrogenic routes of exposure.
• Growth hormone deficiency.
• Family history.
• Homozygosity for the valine or Met allele at codon 129
of the PrP gene.
• Mutations in the PrP gene.
• Occupational exposure to bovine prions.
CLINICAL FEATURES
• Variable (particularly with familial cases, and even within
single pedigrees).
• Insidious onset.
• Early behavioral abnormalities (initial symptom in about
10% of cases):
– Personality change, withdrawal, apathy, depression, sleep
disturbance.
– Agitation, fear and paranoia may prompt a psychiatric
referral.
• Rapidly progressive and profound dementia: forgetful,
confused, visual distortion and hallucinations.
• Myoclonus, usually stimulus-sensitive (>80% of patients).
• Motor abnormalities:
– Cerebellar ataxia.
– Extrapyramidal signs: tremor, rigidity, bradykinesia,
dystonic posturing; choreoathetosis.
– Pyramidal signs: weakness, spasticity, hyper-reflexia, and
Babinski signs.
• Generalized seizures may occur.
• Positive family history of CJD in 6–15% of cases.
Syndromes of iatrogenic CJD
• Psychiatric disturbance (e.g. anxiety and depression) and
progressive ataxia and clumsiness before the appearance
of dementia and myoclonus: iatrogenic CJD associated
with peripheral inoculation of prions (i.e. cadaveric hGH
cases).
• Progressive dementia: iatrogenic CJD associated with
central inoculation of prions (i.e. foreign dura mater or
neurosurgic instruments).
Clinical variants (the spectrum)
Heidenhain variant
Early pathologic involvement of the occipital cortex leading
to cortical blindness.
Brownell–Oppenheimer variant
Early and prominent ataxia (cerebellar ataxia is also
prominent in iatrogenic CJD due to pituitary-derived
hormones).
Thalamic variant
Insomnia and dysautonomia.
Spastic paralysis with dementia (Worster–Drought)
332 Infections of the Nervous System: Prion

Amyotrophic form • GSS disease: autosomal dominant inheritance, prominent

Loss of anterior horn cells causing significant wasting, cerebellar ataxia, dementia.
weakness and areflexia due to lower motor neuron changes. • Psychiatric illness (anxiety, depression).

More chronic and indolent form INVESTIGATIONS (see Table 36)

Progresses over more than 2 years.
New variant CJD
• Linked causally to bovine spongiform encephalopathy
(BSE), nvCJD is believed to be caused by the oral
transmission of the BSE agent through consumption of
bovine tissues containing significant infectivity (e.g. beef
products containing bovine spinal cord).
• Young age of onset (below 42 years of age).
• Early behavioral/psychiatric disturbance (anxiety,
depression), cerebellar ataxia and dysesthesiae.
• Absence of typical EEG changes, although the EEG is
abnormal.
• High signal changes in the pulvinar of the thalamus on
T2W MRI imaging of the brain.
• Clinical course is more prolonged and protracted, with
average duration of 13 months compared with a mean of
6 months in other types.
• Specific neuropathologic profile with extensive forma-
tion of cerebellar prion plaques resembling those seen in
kuru: they have a dense eosinophilic center and pale
periphery surrounded by a zone of spongiform change.
• Homozygous for Met at codon 129 of the PrP gene.
• Associated with a specific pattern of protease-resistant PrP
on Western blot analysis. The biochemical signature of
the prions is distinct from other types of CJD and
matches that of animals experimentally infected with BSE.
DIFFERENTIAL DIAGNOSIS
• Alzheimer’s disease with myoclonus, but the course is
usually more prolonged.
• Non-convulsive status epilepticus.
• Metabolic/toxic encephalopathy (e.g. drugs).
• Bilateral subdural hematomata.
• CNS vasculitis.
• Subacute sclerosing panencephalitis (SSPE).
• Infiltrating corpus callosum glioma.
• Huntington’s disease.
• Motor neuron disease, but normal cognition.
CT or MRI brain
• Scans are normal (45%) or show cerebral atrophy (30%).
• T2W and PDWI MRI may reveal high-signal changes in
the basal ganglia (407) and thalamus (5%) (e.g. the
‘pulvinar sign’ in variant CJD) or in scattered areas such
as the cortex (7%). The sensitivity and specificity of these
findings are uncertain.
• Diffusion-weighted MRI, which rapidly detects tiny
changes in water mobility, such as shifts from the
extracellular to the intracellular space when cellular
homeostasis is disturbed, has been reported to not only
show basal ganglia abnormalities but also gross
abnormalities involving most of the cerebral hemispheres.
• MRI is probably the imaging modality of choice, though
both MRI and CT are insensitive. Their main role is to
exclude other differential diagnoses.
EEG
• Early: non-specific disorganization and generalized slow
wave activity.
• Later (within 12 weeks of onset of symptoms):
– Slow background rhythm.
– Periodic sharp wave complexes (408–411):
bisynchronous, and most commonly anterior and central
(but may be lateralized and localized: occipital
preponderance in Heidenhain’s variant);
duration: 100–600 ms;
amplitude: up to 300 mV;
may be monophasic, biphasic, triphasic or multiphasic;
repetitive, occurring every 0.5–2.0 seconds;
may be associated with myoclonic jerks;
may be activated by startle;
present in >60% of cases, particularly sporadic CJD, rarely
in ‘peripheral’ iatrogenic CJD;
non-specific: also occur in several encephalopathies,
epilepsy and post ictal states, or during barbiturate
overdose and deep anesthesia.
• 20–40% of patients do not exhibit a typical EEG (cf.
nvCJD).

Table 36 Investigation findings in Creutzfeldt–Jakob disease

Disease ‘Typical EEG’ 14-3-3 +ve CSF High signal on MRI brain Other
Sporadic CJD + (65%) + (90%) + (>70%) (caudate and putamen)
Familial CJD ± ± ± PRNP analysis
Iatrogenic CJD
CNS route ± ? ?
Peripheral route – ± (50%) ±
New variant – (100%) ± (50%) + (>70%) (posterior thalamus) Tonsil biopsy
% of cases with a positive investigation, where known, are in parentheses
PRNP = prion protein
 Creutzfeldt–Jakob Disease (CJD) 333

407 408

408 Electroencephalograph showing periodic triphasic wave

complexes that are rather simple in contour and recurring every
0.7–0.8 seconds, against a slow polymorphous background, in a patient
with rapidly progressive dementia and myoclonus due to CJD.
Occasionally, the periodic discharges begin unilaterally and may
resemble periodic lateralized epileptiform discharges.

407 T2W MRI from a patient with pathologically proven CJD. Note 409
increased signal (whiteness) of the basal ganglia (arrows). Normally the
basal ganglia become darker due to iron deposition with age.There is
also a minor degree of atrophy. Also note the increased signal in the
pulvinar (arrowheads).This was variant CJD.

409–411 Serial electroencephalographs, every 3 days, from a patient

with CJD showing the progressive evolution of periodic triphasic wave
complexes and the background rhythm.

410 411
334 Infections of the Nervous System: Prion

CSF DIAGNOSIS
• CSF has normal or slightly raised protein. Diagnostic criteria for classical CJD
• Immunoassay for the 14-3-3 brain protein. The 14-3-3 Sporadic CJD
protein is a non-specific marker of central nervous system Definite:
neuronal injury or death. A positive test is highly sensitive • Neuropathologically confirmed and/or
(90%) and specific for CJD when used in carefully • Immunocytochemically confirmed PrP positive (Western
selected patients with dementia. blot) and/or
• Neuron-specific enolase (NSE) concentrations may be • SAF.
increased early (>35 ng/ml; sensitivity 80%, specificity
92%) and when myoclonus and periodic sharp complexes Probable:
appear, and return to normal in the late stage. Raised • Progressive dementia.
NSE levels in CSF also reported in brain trauma, tumor, • Typical EEG.
and acute stroke including SAH. The enzyme is localized • At least two of the following clinical features:
in neurons and neuroendocrine cells and is synthesized – Myoclonus.
completely in the CNS. – Visual or cerebellar disturbance.
• Two-dimensional gel electrophoresis to detect two – Pyramidal/extrapyramidal dysfunction.
proteins, p130/131, with an apparent molecular weight – Akinetic mutism.
of 26 and 29 kDa and an isolectric point of 5.2 and 5.1:
highly specific; positive predictive value up to 100%, Possible:
negative predictive value about 69%. • Progressive dementia.
• Two of the clinical features listed above.
Molecular genetic analysis • No EEG done or atypical EEG.
Molecular genetic analysis of DNA in blood, CSF or brain. • Duration <2 years.
The prion protein gene (PRNP) blood test is a genetic test
for mutations that cause familial prion disease. The PRNP Accidentally transmitted CJD
is sequenced for the presence of pathogenic mutations, and • Progressive cerebellar syndrome in a pituitary hormone
the polymorphism risk factor found at codon 129 on the recipient.
PRNP gene. It is important to perform, even if no family • Sporadic CJD with a recognized exposure risk (e.g. dura
history is apparent, because mutations are commonly found mater transplant).
in apparently sporadic cases because of incomplete
penetrance, non-paternity, adoption, or the gene-carrying Familial CJD
parent having died before the age of onset of the prion • Definite or probable CJD plus definite or probable CJD
disease from another cause. in a first-degree relative.
Mutations occur at codons 102, 105, 117, 14, 178, 180, • Neuropsychiatric disorder plus disease-specific prion
198, 200, 210, 217, 232, and insertions in the PrP gene. protein (PRNP) mutation.

Tonsil biopsy Diagnostic criteria for nvCJD

Western blot analysis of tonsil material obtained by biopsy
of tonsil or lingual tonsillar remnants under local anesthetic
by means of a disposable tonsil-biopsy kit may allow
antemortem detection of prion protein expressed in the
lymphoreticular system.
1 (a) Progressive neuropsychiatric disorder.
(b) Duration of illness >6 months.
(c) Routine investigations do not suggest an alternative
diagnosis.
(d) No history of potential iatrogenic exposure.

Brain biopsy 2 (a) Early psychiatric symptoms.

Biopsy is mainly indicated to diagnose a suspected treatable
cause of the clinical state, such as CNS vasculitis or SSPE.
Rarely indicated to diagnose CJD because it:
• Carries a small but definite risk of brain hemorrhage and
infection.
• May miss the diagnosis because of the patchy nature of
prion immunostaining.
• Neurosurgic instruments have to be destroyed after biopsy
in all positive cases to prevent iatrogenic transmission.
(b) Persistent painful sensory symptoms.
(c) Ataxia.
(d) Myoclonus or chorea or dystonia.
(e) Dementia.
3 (a) EEG does not show the (typical) appearance of
classical CJD (or no EEG performed).
(b) Posterior thalamic high signal on MRI brain scan
(407).

Neuropathology • Definite: 1(a) and neuropathologic confirmation of

The demonstration of proteinase-resistant PrP in brain is nvCJD.
the neuropathologic diagnostic marker. This can be • Probable: 1 and four-fifths of 2 and 3(a) and 3(b).
undertaken at post mortem by light microscopy of various • Possible: 1 and four-fifths of 2.
brain regions and antemortem, in some laboratories, by
immunohistochemistry with antibodies against the prion
protein and molecular genetic analyses of PrP performed on
DNA extracted from blood leukocytes (PrP Western blot
and/or preparation of scrapie-associated fibrils [SAF]) and
identifying a mutant PrP genotype or the presence of PrPSc.
 Further Reading 335

TREATMENT
• At present, no effective curative therapy is available,
treatment is symptomatic.
• Patients should be nursed similarly to others with
infectious disease, using disposable pins and EMG and
LP needles.
• Anti-epileptic drugs may be required for seizures,
nasogastric tube or percutaneous endoscopic gastrostomy
for feeding, intermittent or indwelling bladder catheters
for urinary incontinence, and appropriate posturing and
regular turning to prevent bedsores.
PREVENTION
• Avoid risk factors: hGH is now manufactured using
DNA recombinant technology, thereby eliminating the
need for human sources.
• Genetic counselling coupled with prenatal DNA
screening is possible but the apparent incomplete
penetrance of some of the inherited prion diseases
increases the uncertainty of predicting the future for an
asymptomatic individual. Problems common to all
predictive testing programmes are also likely to arise.

CLINICAL COURSE AND PROGNOSIS

Rapid progressive decline to akinetic mutism and death over
2–12 months; about 10% have a protracted clinical course.

FURTHER READING
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336 Infections of the Nervous System
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PROTOZOAN INFECTIONS
Toxoplasmic encephalitis
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 Chapter Twelve 337

Inflammatory
Disorders of the
Nervous System
ACUTE DISSEMINATED EPIDEMIOLOGY
ENCEPHALOMYELITIS • Incidence: uncommon; most frequent after non-specific
(POST INFECTIOUS upper respiratory tract infections of undetermined
ENCEPHALOMYELITIS) (ADEM) etiology.
• Age: any age.
• Gender: either sex.
DEFINITION
An acute inflammatory demyelinating disease of the brain PATHOLOGY
and spinal cord characterized by widespread perivascular Macroscopic
inflammation and demyelination and caused by an The brain is congested and swollen (412).
autoimmune attack on the brain, most commonly as a result
of a viral infection which activates autoreactive T cells that Microscopic
recognize myelin-specific proteins. The disease is one of Perivascular inflammation (macrophages, plasma cells, and
immunoregulatory failure rather than immunosuppression. T lymphocytes) and demyelination of the white matter tracts
of the cerebral hemispheres, brainstem, spinal cord and optic
nerves.

ETIOLOGY
412 Viral infection
Exanthematous
• Measles: complicates 1 in 1000 cases of measles; in
countries where vaccination is not routine.
• Varicella-zoster: <1 : 10 000 (more commonly causes
acute ataxia).

Non-exanthematous
• Influenza A upper respiratory tract infection.
• Mumps.
• Epstein–Barr virus.
• Rubella: <1 : 20 000 (more commonly causes a toxic
encephalopathy).

Bacterial infection
• Mycoplasma pneumoniae.

Immunization
• Vaccination (vaccinia, rabies).
• Tetanus antitoxin.

No recognizable preceding illness sometimes

412 Ventral surface of a swollen, hemorrhagic brain affected by acute

hemorrhagic encephalitis.
338 Inflammatory Disorders of the Nervous System
PATHOPHYSIOLOGY
ADEM is thought to be an autoimmune disease, partly
because of the inability to isolate an infectious agent from the
CNS, and because of experimental models of autoimmune
diffuse white matter encephalomyelitis that can be induced in
animals, or accidentally in humans, by injection of the myelin
antigens, myelin basic protein, proteolipid protein, or myelin
oligodendrocyte glycoprotein. A very small inoculum of
activated T cell clones that recognize small fragments of
myelin basic protein and proteolipid protein can induce CNS
inflammation and destruction of normal brain white matter
by the immune system. The disease can range from acute
hemorrhagic leukoencephalitis with massive fibrin deposition
and a substantial neutrophilic hemorrhagic lesion to a chronic
demyelinating disorder with a lymphocytic infiltrate, which is
similar to multiple sclerosis.
It is believed that a viral infection activates circulating
autoreactive T cells that recognize myelin-specific proteins,
and these T cells migrate into the CNS and recruit neutrophils
in a bystander fashion, triggering massive multifocal tissue
destruction. The mechanism of T cell activation is unknown.
CLINICAL FEATURES
• Preceding upper respiratory tract or gastrointestinal tract
infection is common.
• Latent interval between the acute viral illness and the
onset of neurologic symptoms.
• Acute/subacute onset.
• Fever, headache, malaise.
• Skin rash.
• Progressive focal neurologic signs:
– Hemiparesis or paraparesis.
– Sensory defects, depending on location of lesions in brain
and spinal cord.
– Ataxia.
– Optic neuritis.
– Other cranial nerve palsies.
• Raised intracranial pressure:
– Headache.
– Vomiting.
– Papilledema.
– Obtundation.
SPECIAL FORMS
Acute hemorrhagic leukoencephalitis is
• A more aggressive form of ADEM.
Epidemiology
• Affects children and adults and both sexes equally.
Pathology
• Swollen hemorrhagic brain with herniation.
• Widespread necrotizing hemorrhagic lesions in the white
matter and brainstem.
• Perivascular neutrophilic infiltrate with varying numbers
of lymphocytes.
• Blood vessels impregnated with fibrin (fibrinoid necrosis).
• Widespread demyelination, usually in regular patches,
and around areas of hemorrhage.
• Gray matter is also frequently involved.
Clinical
• Latent period after the initial illness ranges from 1–20
days but, unlike ADEM, tends to last just a few days or
may even be unnoticeable.
• Fever (temperature up to 42°C) and malaise.
• Mild neck rigidity.
• Progressive focal neurologic signs and raised intracranial
pressure.
Laboratory
• Peripheral blood neutrophil pleocytosis and high ESR.
• CT/MRI scan: abnormal; brain swelling, similar to
ADEM, but with much more extensive lesions, and a
hemorrhagic component.
• CSF:
– High pressure (>300 mm water).
– Cells: neutrophil pleocytosis (may be >1000); hundreds
of red cells.
– Protein: raised.
– Glucose levels: normal.
Prognosis
Rapid clinical course (more rapid than ADEM), progressing
to delirium and coma; patients are more likely to die.
Diagnosis
Diagnosed at autopsy in most cases.
DIFFERENTIAL DIAGNOSIS
• Viral encephalitis (see p.292): direct infection of the CNS
(e.g. by arbovirus, herpes simplex virus, cytomegalovirus)
rather than activation of autoreactive T cells by the
primary infection. The presence of a persistent
neutrophilic instead of lymphocytic CSF pleocytosis in
ADEM is against a direct viral infection of the CNS.
• Leptospirosis meningoencephalitis: a biphasic illness, with
a prodrome of chills and conjunctival suffusion and the
presence of leptospiras in the blood and CSF. In the
second phase, many develop neurologic complications
with a neutrophilic pleocytosis in CSF.
• Lyme disease (see p.316).
• Brain abscess (see p.284).
• Brain tumor (see p.357).
• Multiple sclerosis (see p.340): may have the same under-
lying pathophysiology and clinical presentation but has
a chronic relapsing and remitting, or progressive course.
• Meningitis: viral, bacterial, tuberculous, cryptococcal.
• Stroke (see p.192): massive carotid territory infarction
with temporal lobe swelling compressing the posterior
cerebral artery against the brainstem and causing
additional posterior infarction.
• Transverse myelitis (see p.561): Mycoplasma pneumoniae.
INVESTIGATIONS
CT brain scan
Scans show diffuse low attenuation throughout the gray and
white matter of one or both hemispheres with mass effect
(midline shift, subfalcine herniation, uncal herniation,
effacement of basilar cisterns, entrapment of lateral
ventricles) but may be normal.
 Acute Disseminated Encephalomyelitis (Post Infectious Encephalomyelitis) (ADEM) 339

MRI brain scan PROGNOSIS

• MRI is more sensitive than CT. Some patients make remarkable recoveries, even after
• Areas of increased signal on T2WI in the white matter prolonged periods of profound coma, so very aggressive
are present which may be quite extensive and enhance supportive therapy should always be entertained.
with contrast (413).
• The lesions occur mostly in the cerebrum, but are also Major sequelae
found in the brainstem and cerebellum and spinal cord. • Measles: frequent.
When they predominate in the latter, they may mimic • Rubella: rare.
spinal cord or brainstem tumor. • Vaccinia: 10%.
• The lesions may not resolve completely, and result in • Varicella: very rare.
diffuse atrophy.
• No new lesions should appear on MRI after 6 months Case fatality rate
from the start of the disease. • Measles: 20%.
• Rubella: 20%.
CSF • Vaccinia: 10%.
CSF is normal in about one-third of patients. Two-thirds • Varicella: 5%.
show a mild mononuclear cell pleocytosis and protein
elevation. Viral and bacterial culture, PCR for viral DNA,
myelin basic protein (which may be found by
radioimmunoassay), and immunoglobulin G (which may be
elevated) are indicated.

Blood
• Full blood count and ESR.
• Blood biochemistry.
• Blood viral serology: acute and convalescent sera may
establish the specific infecting agent but usually are not
of help in differentiating acute encephalitis caused by
direct infection from encephalitis caused by immune-
mediated perivenular demyelination.
413
Other
• Chest x-ray.
• Throat and rectal swabs.
• Urinalysis.
• EEG: abnormal: non-specific diffuse slow wave activity.

DIAGNOSIS
• There are no consistent abnormalities in the blood or
urine.
• A definitive diagnosis requires pathologic examination.

TREATMENT
Prevention
Vaccination: the cessation of immunization with vaccinia
virus and the introduction of vaccines for measles, mumps
and rubella viruses has proved highly effective.

Acute treatment
• Supportive care: lowering temperature with antipyretic
agents, maintaining an adequate fluid intake, treating
epileptic seizures if they develop and reducing intracranial
pressure if raised.
• There is no conclusive evidence that hyperimmune
gamma globulin, corticosteroids or adrenocorticotropic
hormone (ACTH) are of benefit (or no benefit).

413 T2W MRI from a young patient who became confused and
neurologically unwell about 2 weeks after a dose of chickenpox. Note
the extensive white matter and basal ganglia increased signal which also
extended into the brainstem.
340 Inflammatory Disorders of the Nervous System

MULTIPLE SCLEROSIS (MS) Epidemiologic evidence points to environmental factors

DEFINITION
A chronic autoimmune inflammatory demyelinating disease
of the CNS in which the lesions are disseminated in time
and space (different sites in the CNS are affected at different
points in time).
EPIDEMIOLOGY
• Prevalence: higher in temperate climates further from the
equator (e.g. Hobart, Tasmania, Australia, 76/100 000);
lower in tropical and subtropical climates close to the
equator (e.g. tropical Queensland, Australia, 12/100 000).
• Age: rare before puberty and beyond 60 years of age.
• Age of onset: <20 years: 20% of cases; 20–50 years:
50–60% of cases; >50 years: 20–30% of cases.
• Gender: F>M (2 : 1).
• Race: Northern European ancestry most common;
uncommon in Australian aboriginals, Maori, Chinese,
Japanese, black African.
PATHOLOGY
Multiple plaques of demyelination in the white matter of
the CNS.
Acute lesion
• Demyelination of nerve fibers in the white matter of the
CNS.
• Loss of oligodendrocytes.
• Perivenular infiltration of T and B lymphocytes,
macrophages (filled with myelin debris) and plasma cells.
• Secondary axonal degeneration.
at a young age:
• Prevalence of MS increases with increasing latitude.
• Risk of MS for an individual corresponds to the risk of
their area of residence before the age of about 15 years.
Genetic factors
Also likely to be relevant:
• A family history of MS is present in about 10% of people
with MS.
• The concordance rate for MS in monozygotic twins is
25%, 2.5% in dizygotic twins and 1.9% in non-twin
siblings.
• HLA associations with MS:
– HLA-A3, HLA-D7, and HLA-DR2 common in
Caucasians with MS (HLA-DR2: present in >60% of
people with MS and 15–20% of controls).
– HLA-DR4 common in Arabs with MS.
PATHOPHYSIOLOGY
Exposure to an unidentified non-self antigen that ‘mimics’
constitutive peptides of myelin evokes an antigen-specific,
T cell mediated immune response. Lymphocytes, macro-
phages and humoral factors enter the CNS and the
blood–brain barrier breaks down. B-lymphocytes produce
oligoclonal immunoglobulin G (IgG) in the CSF. Sensitized
T cells produce cytokines which may damage
oligodendrocytes and myelin. Nerve conduction is blocked
in demyelinated axons and can be restored by remyelination.
In contrast, axonal loss leads to a permanent loss of
neurologic function, as the CNS axonal regenerative
capacity is severely limited.

Chronic lesion
• Some axonal loss and remyelination.
• Glial cell proliferation resulting in discrete gray colored 414
areas of gliosis (or sclerosis) that are called plaques.

Sites of demyelination
Any part of the CNS, particularly:
• Periventricular white matter of the cerebral hemispheres
(414–416).
• Optic nerves (417).
• Cerebellum.
• Brainstem.
• Spinal cord (particularly subpial regions of the spinal
cord) (418, 419).

The peripheral nervous system is not affected.

ETIOLOGY
• Unknown, but likely to be a misdirected autoimmune
disease (because of the predilection of women, the
human leukocyte antigen (HLA) association, the
relapsing and remitting course, and the finding of
immunologically active cells in the brain, spinal cord and
CSF). This, and other evidence, suggests that MS is an
autoimmune disease resulting from an immune attack on
the myelin sheaths and axons in the CNS by autoreactive
T lymphocytes and autoantibodies. 414 Section of one cerebral hemisphere (parietal lobe) showing
• Environmental factors, such as a virus infection (e.g. a lack of staining due to periventricular demyelination in the white
herpes virus-6), may trigger immune-mediated matter. (Courtesy of Professor BA Kakulas, Royal Perth Hospital,
demyelination in genetically predisposed individuals. Western Australia.)
 Multiple Sclerosis (MS) 341

CLINICAL FEATURES Nature

Onset
• Subacute onset of neurologic symptoms over several
hours to days. Infrequently the symptoms evolve quickly
over minutes or slowly over weeks or months.
• The onset is monosymptomatic in about 50% of cases.
The remainder have initial symptoms of multiple lesions
within the CNS.
The symptoms usually reflect dysfunction of the optic
nerves, brainstem or spinal cord.
Reduced visual acuity
Reduced visual acuity, which varies from a slight dulling of
color vision to complete monocular blindness, together with

416

415, 416 Autopsy specimens of brain, coronal sections, showing

periventricular demyelination (arrows).

415

417 418

417 Optic neuritis.Transverse section of the optic nerve at autopsy, 419

showing demyelination of the optic nerve in a patient with optic
neuritis due to multiple sclerosis.

418 Transverse section of the thoracic spinal cord showing a large

plaque of demyelination in the dorsal columns (arrow) in a multiple
sclerosis patient who had a high stepping gait due to sensory ataxia in
the lower limbs. (Courtesy of Professor BA Kakulas, Royal Perth
Hospital,Western Australia.)

419 Transverse section of the spinal cord showing a large plaque of

demyelination (arrows) in almost one-half of the spinal cord in a
multiple sclerosis patient with a Brown–Sequard syndrome. (Courtesy
of Professor BA Kakulas, Royal Perth Hospital,Western Australia.)
342 Inflammatory Disorders of the Nervous System
pain around the eye that is exacerbated by eye movement or
touching the eye, are symptoms of optic neuritis (see p.489).
The signs include a central or paracentral scotoma in most
patients, particularly using a red target (most of the optic
nerve fibers transmit information from the macular), and a
swollen optic disc (papillitis) in the acute phase if there is
demyelination of the anterior part of the optic nerve (420).
Optic disc pallor due to optic atrophy ensues later (421).
Weakness in one or more limbs or the face
Weakness in one or more limbs or the face due to corticospinal
tract demyelination: may be described as heaviness, tiredness
or stiffness, dragging of one leg, or a tendency to fall.
Altered sensation of the face, trunk or one or more limbs
• Trigeminal neuralgia (tic douloureux) (see p.509) (brain-
stem).
• Lhermitte’s symptom: electric shock-like sensation down
the back on flexing the neck: (cervical spinal cord).
• Numbness starting in the feet and spreading up to the
waist: (cervical or thoracic cord).
• Reduced temperature sensation in a warm bath/shower
or when swimming: (spinothalamic tract).
• Feeling of a tight band wrapped around the trunk or
limbs, or swelling of limbs: (posterior columns).
• Clumsy or functionally useless hand despite normal
power and coordination: (posterior columns and dorsal
root entry zone).
Unsteady gait
Weakness and spasticity, proprioceptive loss (sensory ataxia),
spinocerebellar dysfunction, vestibular dysfunction, reduced
or double vision, and other comorbidities such as pain and
arthritis.
Double vision
Internuclear ophthalmoplegia due to lesion of the medial
longitudinal fasciculus (MLF), which connects the nuclei of
cranial nerves III and VI (422). Elicited by asking the
patient to look laterally to one side and noticing a slower
rate of adduction, or a failure of adduction, of the adducting
eye (ipsilateral to the lesion) and horizontal jerk nystagmus
of the fully abducting eye. Subtle forms can be detected if
the examiner watches the patient from the side, in the
direction of attempted lateral gaze (i.e. not ‘front-on’) , and
following the visual axes during rapid voluntary eye
movements (saccades) from one side to the other and back;
and then watching from the other side. The lesion may be
unilateral (which is more commonly due to cerebrovascular
disease than demyelination) or bilateral (which is more
commonly due to demyelination). With rostral MLF lesions,
near the IIIrd nerve nucleus, vergence (ability to converge
the eyes) may be impaired, whereas with caudal MLF
lesions, near the VIth nerve nucleus, vergence is preserved.
Vertigo
Sensation of rotation or spinning, causing nausea and ataxia
(intra-axial vestibular nerve, vestibular nucleus in the lateral
medulla, and pathways from the vestibular nucleus to the
vestibular cortex), rarely in isolation and often occurring
together with other brainstem symptoms.
Sphincter and sexual disturbances
Bladder dysfunction may be divided into a failure to empty
(caused at least in part by detrusor sphincter dyssynergia),
failure to store, or a combination of both. Frequency,
urgency and precipitancy of micturition (85%), urge incon-
tinence (63%), hesitancy and interrupted stream (45%) and
retention of urine may be early symptoms of spinal cord
demyelination and are very common in later stages. Bowel
dysfunction occurs in more than half of patients. Impotence
is also common.
Mental changes
After several years, many patients experience emotional
instability, anxiety, depression, euphoria and mildly impaired
cognitive function (short-term memory, attention, and
speed of processing).
Fatigue
Many patients with long standing MS complain of fatigue.
Pain
Occurs in up to two-thirds of patients. In most it is chronic,
but in about 10% it is acute and paroxysmal. Examples
include trigeminal neuralgia; brief (1 minute) dysesthetic
burning pain in one or more extremities that is provoked by
movement, tactile stimulation, or hyperventilation; and
painful tonic seizures. The latter can occur with or imme-
diately after the dysesthetic burning pain, or independently.
They are brief, frequent and often intensely painful episodes
in which the limbs on one side may adopt a tetanic posture.
They may be precipitated by movement or sensory
stimulation and usually remit completely after 4–6 weeks.
The three main types of chronic pain are dysesthetic
extremity pain, chronic back pain and painful leg spasms.
Epileptic seizures
Epileptic seizures may occur but are uncommon.
Precipitating and exacerbating factors
• Trauma (including surgery), infections, vaccinations,
emotional stress, and fatigue may possibly precipitate
attacks of MS.
• Pregnancy and the early post partum period can mildly
increase the risk of exacerbation of symptoms of MS but
the long term outcome is not affected.
• Physical exercise (Uhthoff’s symptom), an increase in body
temperature (i.e. hot weather, hot baths), increased illu-
mination, eating, drinking, smoking and menstruation may
exacerbate neurologic symptoms. The pathophysiology of
Uhthoff’s symptom is unknown, although a reversible
conduction block in demyelinated nerve fibers secondary to
an increase in body temperature or to changes in blood
electrolyte levels or pH is believed to play a role.
• Immunization can precipitate relapses of MS, so the
potential benefits and risks of immunization need to be
carefully considered.
HISTORY
• Establish the onset and nature of the neurologic
symptoms, any associated or exacerbating factors, and
the clinical course.
• Enquire about previous neurologic symptoms such as
blurred vision, blindness, double vision, weakness, altered
feeling (numbness, tingling), and disturbances of bladder
function.
 Multiple Sclerosis (MS) 343

PHYSICAL EXAMINATION Bacteria (brucellosis, chlamydia, tularemia), and myco-

• Assess the presenting neurologic impairments and bacteria (tuberculosis, atypical mycobacteria).
functional disabilities (e.g. spastic paraparesis). Fungi (histoplasmosis, coccidioidomycosis, cryptococcosus).
• Search for other ‘silent’ neurologic signs of previous Spirochetes (treponemal infections such as syphilis).
subclinical demyelination (e.g. optic atrophy, internuclear Parasites (toxoplasmosis, leishmaniasis).
ophthalmoplegia). – Occupational and environmental exposure to organic or
inorganic agents (e.g. methotrexate, talc, metals).
DIFFERENTIAL DIAGNOSIS – Neoplasia: lymphoma (e.g. intravascular lymphoma).
Multifocal neurologic syndrome – Autoimmune disorders (Wegener’s granulomatosis,
• Inherited ataxias (see pp.437, 441). Churg–Strauss syndrome).
• Vitamin B12 deficiency (see p.463). • Infection:
• Vasculitis: – Acute post infectious encephalomyelitis.
– Infection: Borrelia burgdorferi (Lyme disease), meningo- – Subacute leukoencephalitis cause by human herpes virus-6.
vascular syphilis. – Progressive multifocal leukoencephalopathy (JC
– Isolated granulomatous angiitis of the CNS. papovavirus).
– Polyarteritis nodosa. • Leukodystrophy.
– Systemic lupus erythematosus (facial rash, arthritis, • Brain, foramen magnum or spinal arteriovenous
pericarditis, pleuritis). malformation or tumor(s) (primary or metastatic).
– Behçet’s disease. • Cervical spondylitic myeloradiculopathy.
• Granulomatous inflammation: • Tethered spinal cord (see Spinal dysraphism, p.139).
– Sarcoidosis. • Multiple emboli to the CNS.
– Infection: • Multiple pathologies.

420 421

420 Optic neuritis. MRI orbits, axial plane, of the optic nerve, showing 421 Optic atrophy.
swelling of the optic nerve (arrow) in a patient with optic neuritis due
to multiple sclerosis.

422

422 Bilateral internuclear ophthalmoplegia.

344 Inflammatory Disorders of the Nervous System
Optic neuropathy
• Leber’s hereditary optic neuropathy: a maternally
inherited disease, usually leading to severe bilateral visual
loss, and associated with several mitochondrial DNA
point mutations; the major ones at nucleotide positions
11 778, 3460, and 14 484 (see p.491).
• Other hereditary optic neuropathies.
• Ischemic optic neuropathy.
• Neurosyphilis.
Acute non-compressive spinal cord syndrome
Vascular
• Anterior spinal artery infarction: paraparesis with loss of
pain and temperature sensation, develops over minutes
to hours, and usually persists if infarction occurs.
• Intramedullary hemorrhage.
Inflammation of the spinal cord
• MS: usually a partial cord syndrome (e.g. unilateral loss
of pain and temperature, deafferentation of one limb, or
an asymmetric incomplete paraparesis) develops over
hours to days with partial or complete recovery over
several weeks.
• Transverse myelitis: complete loss of sensory and motor
function below the level of the lesion, resulting in a
flaccid, areflexic paraplegia; develops over hours to days,
commonly after an infection (e.g. upper respiratory
tract).
• Acute necrotizing myelitis: tuberculosis, lymphoma,
carcinoma.
• Connective tissue disease: systemic lupus erythematosus.
• Sarcoidosis.
Infection of the spinal cord
• Herpes zoster.
• Herpes simplex types I and II.
• HIV.
• Tuberculosis.
• Syphilis.
Chronic non-compressive spinal cord syndrome
Inherited
Hereditary spastic paraparesis: usually a family history of
autosomal dominant inheritance.
Vascular
Dural arteriovenous malformation: the most common type
of spinal angioma. Usually affects the thoracolumbar
segments and tends to present in middle-aged men as a
chronic progressive myelopathy with symptoms that may
fluctuate or be aggravated by exercise. A combination of
upper and lower motor neuron signs may be present.
Inflammation of the spinal cord
• MS.
• Sarcoidosis.
Infection of the spinal cord
• Herpetic necrotizing myelitis.
• Cytomegalovirus.
• Varicella-zoster granulomatous myelitis.
• Human T lymphocyte virus-1 (HTLV-1) associated
myelopathy (‘tropical spastic paraparesis’) in adults from
endemic regions or with other risk factors (e.g. Afro-
Caribbeans). A progressive spastic paraplegia develops
over a number of years. However, sphincter disturbance
is the rule and considerable neuropathic lower limb pain
is common.
• Tuberculosis.
• Syphilis.
• Toxoplasmosis.
• Schistosomiasis.
Intramedullary tumor of the spinal cord
• Astrocytoma.
• Ependymoma.
• Lymphoma.
• Lipoma.
• Hemangioma.
• Metastases.
Metabolic
• Vitamin B12 deficiency: presents over weeks or months as
a subacute spinal cord syndrome with intense paresthesia
and a combination of pyramidal and dorsal column signs.
• Adrenomyeloneuropathy: an X-linked inherited disorder
that affects males and some heterozygous females with a
progressive myelopathy. A peripheral neuropathy and
adrenal insufficiency may be present.
Toxic/iatrogenic
• Radiation myelopathy (see p.565): steadily progressive
spastic paraplegia, months to years after radiotherapy.
Pathologically there is necrosis of the irradiated cord
segments with obliterative changes in blood vessels in the
same region.
• Lathyrism: endemic in parts of India and presents as a
subacute or chronic spastic paraparesis in people who
regularly ingest chickling pea vetch over several months.
It is thought to be caused by a toxin in the chickling pea.
Degenerative
• Syringomyelia (see p.541).
• Motor neuron disease (see p.534): purely motor; usually
a combination of lower and upper motor neuron signs.
INVESTIGATIONS
MRI of the brain
MRI is the imaging investigation of choice. T2W images
show:
• Areas of increased signal (brightness) in the white matter
which can be anywhere in the brain but are typically seen
in the immediate periventricular white matter and corpus
callosum (423–428).
• The areas of brightness can be of varying size, may show
some swelling, and may be multiple or only a few.
• A small proportion of patients with definite MS will have
a normal MR.
• It is important to differentiate other causes of bright
spots which are non-pathologic from MS plaques, for
example enlarged perivascular spaces which are usually
small. Normal young persons are allowed to have up to
three white spots (if small).
T1W images show:
• Low signal areas (dark spots), but the T1W image is not
so sensitive and demonstrates fewer lesions than T2W.
 Multiple Sclerosis (MS) 345

423, 424 MRI of brain in the 423 424

sagittal plane, proton density
image (423), and axial plane
T2W image (424), showing
multifocal areas of high signal
intensity adjacent to the
corpus callosum (423) and
lateral ventricles (424) due
to demyelination (arrows).

425 T2W MRI showing 425 426

multiple areas of increased
signal in the periventricular
white matter. The involvement
of the corpus callosum (lesions
right down at the top of the
lateral ventricles) is said to be
characteristic of MS.

426 T1W MRI following

contrast (same patient) shows
that some of the lesions
enhance (arrows) and some
do not, indicating that they are
of different ages and confirming
the most likely diagnosis to
be MS.

427, 428 MRI cervical spine,T2W image, 427 428

in the axial plane (427) and sagittal plane
(428), showing a focal area of high signal
intensity in the high left cervical spinal cord
posteriorly (arrows) due to demyelination,
in a patient who presented with symptoms
and signs of left dorsal column dysfunction
(ascending tight feeling in left leg like a
stocking around it).
346 Inflammatory Disorders of the Nervous System
• To differentiate MS from other causes of white matter
bright spots it is sometimes necessary to give intravenous
contrast; MS will show patchy enhancement of some
abnormal areas reflecting its typical multiphasic course.
Other diseases such as ADEM (see p.337) are monophasic
so all the abnormal areas should either enhance or not.
• Differential diagnosis: the appearance of MS on MR
while typical, is non-specific. A similar picture can occur
in other conditions (see below).
Differential diagnosis of brain MRI mimicking MS
• Subcortical arteriosclerotic encephalopathy or
Binswanger’s disease.
• Multiple metastases.
• Vasculitis.
• Sarcoidosis.
• Leukodystrophies.
• Encephalitis:
– Viral: HIV, progressive multifocal leukoencephalopathy,
subacute sclerosing panencephalitis (measles), acute
disseminated encephalomyelitis.
– Bacterial: tuberculosis.
Spirochetal: syphilis, neuroborreliosis, or Lyme disease.
• Alzheimer’s disease.
• Radiation therapy.
• Chemotherapy.
• Cyclosporine use.
• Hyperperfusion syndrome.
• Chronic inflammatory demyelinating polyneuropathy.
• Subacute combined degeneration of the spinal cord
(vitamin B12 deficiency).
CT scan of the brain
• May demonstrate plaques of demyelination, particularly
after double-dose contrast, but it is non-specific and
rather insensitive, so is not recommended.
• Main role is to exclude other differential diagnoses such
as tumors.
CSF
• Cell count: increased (5–50 lymphocytes/mm3) in two-
thirds of patients during an acute attack; normal
(<3–4 cells/mm3) in two-thirds of patients in remission.
• Protein: mildly elevated, up to 1.0 g/l (100 mg/dl), in
about one-third of patients.
• IgG/albumin ratio: raised (>25%), in two-thirds of
clinically definite MS.
• IgG index (compares IgG/albumin ratio in the CSF and
blood): abnormal in about 90% of patients with clinically
definite MS.
• Oligoclonal IgG bands (429): present in about 90% of
patients with clinically definite MS; not specific; found in
other immune-mediated CNS diseases.
429 Isoelectric focusing in an agarose gel at stable pH (range 5.0–9.5)
demonstrating the presence of oligoclonal bands (arrows) in the CSF
(top) and not the serum (bottom).The oligoclonal bands are different
clones of IgG that have migrated electrophoretically in the stationary
pH gradient until a steady state is reached when all the components
are concentrated or focused as sharp bands at their respective
isoelectric points.The bands are visualized by immunofixation.To be
positive, two or more oligoclonal bands must be detected in the CSF
that are not present in the serum of the patient.
• Viral serology and culture.
• VDRL, TPHA.
Electrophysiologic studies
At least 90% of patients with clinically definite MS have a
persistent abnormality detected by visual, auditory or
somatosensory evoked potentials, but the utility of these
studies in identifying other sites of previous subclinical
demyelination has been superseded to a large extent by MRI
of the brain and spinal cord:
• Visual evoked potentials: delayed conduction in about
90% of clinically definite MS.
• Brainstem auditory evoked potentials: abnormal in half
of clinically definite MS.
• Somatosensory evoked potentials: abnormal in 70% with
clinically definite MS.
EEG
If considering a diagnosis of encephalitis.
DIAGNOSIS
• Clinical and MRI evidence of at least two CNS lesions
that are consistent with demyelination occurring at
different sites in the CNS and at different times.
• The diagnosis can be classified according to the degree
of certainty as clinically ‘definite’, ‘probable’ or ‘possible’.
N.B. MS should only be considered if all of the symptoms
and signs cannot be explained by a single neurologic lesion
and the history, examination and special investigations fail to
identify other conditions that can cause multiple CNS lesions.
DIAGNOSTIC CRITERIA FOR MS FOR RESEARCH
PURPOSES (POSER ET AL., 1983)
Clinically definite MS
1 Two attacks and clinical evidence of two separate lesions, or
2 Two attacks; clinical evidence of one lesion and
paraclinical* evidence of another, separate lesion.
The two attacks must involve different parts of the CNS,
must be separated by a period of at least 1 month, and must
each last a minimum of 24 hours.
*Paraclinical evidence of a lesion: the demonstration by means
of various tests and procedures of the existence of a lesion of
the CNS which has not produced signs of neurologic
dysfunction but which may or may not have caused symptoms
in the past. Such tests and procedures include the hot bath
test, evoked response studies, tissue imaging procedures
(including MRI), and reliable, expert neurologic assessment.
429
 Multiple Sclerosis (MS)
Laboratory-supported definite MS
1 Two attacks; either clinical or paraclinical evidence of one
lesion; and CSF oligoclonal bands or increased IgG
(serum levels of either must be normal).
2 One attack; clinical evidence of two separate lesions; and
CSF oligoclonal bands or increased IgG.
3 One attack; clinical evidence of one lesion and
paraclinical evidence of another, separate lesion; and CSF
oligoclonal bands or increased IgG.
Clinically probable MS
1 Two attacks and clinical evidence of one lesion (the two
attacks must involve separate parts of the CNS. Historic
information cannot be considered as a substitute for the
clinical evidence.); or
2 One attack and clinical evidence of two separate lesions; or
3 One attack; clinical evidence of one lesion and
paraclinical evidence of another, separate lesion.
Laboratory supported probable MS
Two attacks and CSF oligoclonal bands or increased IgG.
NEW DIAGNOSTIC CRITERIA FOR MS
(MCDONALD ET AL. [2001])
• Incorporate MRI into the overall diagnostic scheme, and
add guidelines for the diagnosis of primary progressive
disease.
• Some problems with these criteria are discussed by Poser
and Brinar (2001).
TREATMENT
Acute treatment to accelerate recovery from the acute attack.
Mild relapse of relapsing-remitting MS
No specific treatment required, as most resolve spontaneously.
Moderate–severe relapse of relapsing-remitting MS
• Methylprednisolone: 1000 mg in 100 ml 5% dextrose,
infused intravenously over 30–60 minutes, daily for 3 days,
or 500 mg daily for 5 days. This therapy accelerates the
rate of recovery (i.e. reduces the duration of relapse) but
has no effect on long term outcome. Potential adverse
effects include mood alterations, psychosis, acne, fluid
retention, hyperglycemia, and osteonecrosis.
• Prednisolone: 60 mg, oral, daily for 1 week, 30 mg daily
for the second week, and 15 mg daily for the third week
is a more convenient and less expensive alternative but
there is no definitive evidence that it is better than
placebo.
• Adrenocorticotropic hormone injections, given in
reducing doses over 4 weeks (40 U i.m., b.d. for week 1;
40 U i.m., b.d. for week 2; 20 U i.m., daily for week 3),
may be effective but are rarely used nowadays.
Long term treatment to prevent relapses and
progression of disability
Relapsing-remitting MS with at least two relapses in the
previous 2 years
Several new drug treatments to reduce the relapse rate are
now available (see below) but they are all expensive, have to
be given by injection, their long term effects are not yet
known, and definite evidence of a clear effect on progression
of disability is lacking:
347
• Interferon beta-1b (IFN-β-1b), 8 million international
units (MIU) every second day, subcutaneously reduces the
number of relapses (i.e. the attack rate) by about one-
third, the severity of the relapses and the number of
demyelinating lesions seen on MRI of the brain. Short
term adverse effects include systemic ‘flu-like’ symptoms,
injection site reactions, liver enzyme elevations, anemia,
mild leukopenia, thrombocytopenia and possibly
depressive symptoms. Active, severe depression, pregnancy
and breastfeeding are contraindications to its use.
Neutralizing antibodies to IFN-β are detectable in about
38% of patients by the third year of treatment and seem to
attenuate the treatment effect; further research is needed
to determine their clinical significance. IFN-β-1b is a
recombinant interferon beta made in bacterial cells. The
mechanism of action of IFN-β in MS remains unknown.
• Interferon beta-1a (IFN-β-1a), 6 MIU once a week,
intramuscularly (Avonex; CSL Ltd) or 6–12 million units
three times a week subcutaneously (Rebif; Serono Australia
Pty Ltd). Interferon β-1a is a recombinant interferon-β
made in mammalian cells which, like IFN-β-1b also
reduces the annual relapse rate by about one-third and
significantly delays the progression of disability, compared
with placebo, in relapsing multiple sclerosis, and has similar
adverse effects.
• The most important determinant of clinical efficacy is the
total dose of interferon-β.
• Glatiramer acetate (previously called copolymer 1)
(Copaxone; Aventis Pharma Pty Ltd), 20 mg per day by
daily subcutaneous injection, reduces relapse rate at 2 years
by about 29% and improves disability in relapsing-remitting
MS. Adverse effects include a transient injection site
reaction, sometimes with focal lipoatrophy, and a transient
self-limiting systemic reaction characterized by flushing or
chest tightness with palpitations, anxiety or dyspnea. It is a
mixture of random polymers of alanine, glutamine, lysine
and tyrosine. It approximates the antigenic structure of
myelin basic protein (MBP) sufficiently to be cross-reactive
with monoclonal antibodies and T cells generated to MBP,
a putative target antigen in MS. Glatiramer acetate is an
alternative to interferon-β therapy in relapsing-remitting
MS, and should particularly be considered in patients who
do not respond to, or do not tolerate, interferon-β.
• Intravenous immunoglobulin 0.15–0.2 g/kg body-
weight administered monthly in relapsing-remitting MS
is well tolerated and may improve clinical disability and
reduce annual frequency of relapses by about 59%.
The data from randomized trials indicate that, compared
with placebo, the odds of freedom from relapse at the end
of 2 years are:
• 1.37 (95% CI: 0.82–2.34) for glatiramer acetate.
• 1.68 (0.88–3.16) for interferon β-1a.
• 2.38 (1.25–4.25) for interferon β-1b.
• 2.07 (1.07–4.00) for intravenous immunoglobulin (i.v. Ig).
• 2.04 (1.42–2.93) for azathioprine.
A randomized trial is currently comparing early
azathioprine with interferon-β treatment.
The cost of generic azathioprine 150 mg daily is about
GBP 80 yearly, excluding the costs of blood counts and liver
function tests, compared with about GBP 3300 per year for
i.v. Ig, excluding day case costs each month, and about GBP
10 000 per year with the other new drugs.
348 Inflammatory Disorders of the Nervous System
Recent accelerated deterioration in primary or
secondary progressive MS
• Intravenous high dose methyl-prednisolone infusion
(500 mg over 5 days).
• The chemotherapeutic agent, mitoxantrone, may have a
future role in the management of patients with recent
onset, severe and rapidly progressive disease.
Sustained deterioration in primary or secondary
progressive MS
• Interferon β-1b slows the progression of disability and
reduces the accumulation of MRI brain lesions in patients
with secondary progressive MS. Further studies are
needed to determine its place in this context. The effect
of interferon-β in primary progressive MS is unknown.
• Oral low-dose methotrexate (7.5–12.5 mg once a week
indefinitely) significantly reduces the rate of progression
of disability in progressive MS. It is generally well
tolerated, but requires regular monitoring of full blood
count and liver function. Adverse effects include nausea,
hair thinning, bone marrow suppression, hepatotoxicity,
opportunistic infection and pneumonitis. It is important
to name the day (e.g. Monday) of the week on which the
methotrexate is to be taken in order to avoid the possi-
bility of the patient taking the dose daily instead of weekly.
Further clinical trials are needed to determine whether
higher doses of oral methotrexate are more effective, and
to determine the relative benefits of methotrexate therapy
and interferon-β therapy in progressive MS.
Symptomatic relief
Rehabilitation by a multidisciplinary team plays a crucial role
in management of MS.
Spasticity
• Attend to any factors which may exacerbate spasticity,
such as noxious stimuli due to urinary tract infection,
infected pressure sores or ulcers, tight clothing or an
uncomfortable orthosis.
• Educate patients to understand and manage their spasticity.
• Correct posture: avoid positions which favor the pattern
of spasticity.
• Physiotherapy: aims to inhibit spasticity by facilitating a
normal pattern of movement, improving postural tone
and re-learning selected movements. Muscle stretching
is also important.
• Pharmacology:
– Oral agents:
Baclofen, 5 mg b.d., increasing slowly to 10–25 mg three
times daily if tolerated and required: the most effective
oral agent.
Diazepam 5–10 mg three times daily.
Dantrolene.
Vigabatrin.
Tizanidine, an L2 alpha adrenergic antagonist.
Cannabis.
– Intramuscular injections of botulinum toxin A injections
for focal spasticity (i.e. hip adductors). Effective when
combined with regular physiotherapy.
– Nerve blocks: preferably on predominantly motor nerves,
such as obturator nerves. Pre-test with a reversible local
anesthetic such as bupivacaine before resorting to dilute
phenol or alcohol.
– Intrathecal baclofen: test with an initial bolus injection
for functional benefit and analgesia; abdominal wall
subcutaneous reservoir and pump, connected by catheter
to the subarachnoid space between L3/4 with the
catheter tip located around T12 or higher.
• Surgery.
Bladder dysfunction
Detrusor hyper-reflexia:
• Clean intermittent self-catheterization (CISC): the most
effective.
• Anticholinergic agents (reduce urgency but may increase
residual volume):
– Oxybutynin hydrochloride 5 mg tablets, 25–5.0 mg
every 6–8 hours.
– Propantheline bromide (Pro-Banthine) 15 mg, four
times daily.
– Amitriptyline 25–100 mg daily.
• Intravesical capsaicin, which has a toxic effect on the C-fiber
afferents in the bladder wall that drive the abnormal spinal
detrusor reflex, reduces detrusor muscle hyperactivity and
may help patients with severe detrusor hyper-reflexia whose
bladder has very limited storage capacity. The effect lasts
1–5 months, and may respond to repeat infusions.
• Indwelling suprapubic catheter if the combination of
medication and CISC is not effective or practical.
Nocturia. Desmopressin spray (DDAVP) reduces the
volume of urine produced.
Bowel dysfunction
• Diet.
• Lactulose.
• Suppositories.
• Loperamide for urgency.
Sexual dysfunction
• Erectile dysfunction:
– Psychotherapy and psychosexual counselling.
– Sildenafil: a phosphodiesterase type-5 (PDE-5) inhibitor
which increases cyclic GMP levels in the penis and enhances
the smooth muscle relaxant effects of the nitric oxide
(NO)/cyclic GMP pathway, increasing penile blood flow.
There are three doses (25 mg, 50 mg, 100 mg). The usual
starting dose is 50 mg; the 25 mg dose is used in younger
men, men with renal or hepatic impairment and those men
on CYP3A4 inhibitors (erythromycin, cimetidine, and
retroviral drugs). The tablet should be taken at least 1 hour
before anticipated sexual activity and will remain effective
for up to 4 hours. A large meal and alchol intake may delay
the absorption. It is effective in 70–80% of men with
erectile problems. Adverse effects are mild and include
headache, facial flushing, indigestion and rhinitis. It is
contraindicated in men who take nitrate medication
(including glyceryl trinitrate and amyl nitrate) or any form
of NO donors, because of potential hypotensive effects.
– Yohimbine, an L2 alpha agonist.
– Intracorporeal papaverine or prostaglandin injection.
– Surgically implanted prostheses.
• Lack of vaginal lubrication and loss of sensation:
lubricating gels.
Bulbar dysfunction
• Speech (dysarthria predominantly):
– Speech pathologist assessment and guidance: advice on
breathing and articulation patterns, and augmentative com-
munication aids.
• Swallowing dysfunction (oral and pharyngeal phases):
 Multiple Sclerosis (MS)
– Speech pathologist (± videofluoroscopy) assessment and
guidance: education, dietary modification, positioning
strategies (e.g. ‘chin tuck’ and ‘head turn’), thermal
stimulation (i.e. using ice to stimulate the faucial arches,
which delays triggering of the swallow reflex).
– Assisted feeding, via percutaneous gastrostomy, may be
required in severe cases where swallowing is no longer
safe and the patient and carer agree.
Visual dysfunction
• Monocular blindness or scotoma, diplopia and oscillopsia:
– Difficult to manage.
– Referral to low vision clinics can be helpful.
– Botulinum toxin injections of oculomotor muscles may
reduce persistent oscillopsia.
• Acquired pendular nystagmus may respond to converg-
ing prisms and isoniazid (and possibly gabapentin).
Cognitive dysfunction
Adequate assessment and clarification of the deficits allows
informed discussion with patient and carer, constructive
planning to minimize or overcome these deficits and, in
some cases, cognitive rehabilitation.
Depression
The treatment of depression is similar to that of a patient
who does not have MS but particular attention needs to be
paid to adverse effects, as they may exaggerate existing
problems such as sexual dysfunction:
• Psychologic counselling.
• Tricyclic antidepressants.
• Serotonin reuptake inhibitors.
Tremor and ataxia
• Physiotherapy: improve the patient’s posture and seating
and supply adequate support.
• Oral medication:
– Clonazepam 0.5–2.0 mg two or three times daily.
– Thioridazine (Mellaril) 10–50 mg two or three times daily.
– Ondansetron, a 5-hydroxytryptophan-3 (5-HT3)
antagonist, 8 mg i.v.
– Carbamazepine.
– Isoniazid and pyridoxine.
– Propranolol.
– Buspirone.
• Surgery. Stereotactic thalamotomy, lesioning the
ventrolateral nucleus of the thalamus, is beneficial in
about half of cases but carries a risk of hemiparesis and
dysphasia. Electrode implantation and stimulation in the
same area appears more promising.
• Botulinum toxin type A injections (40 mouse units) into
the flexor and extensor compartments of the forearm is
not helpful, particularly if there is pre-existing weakness.
Temperature lability
• The rather cumbersome cooling suits may be helpful in
selected cases.
• 4-aminopyridine (fampridine), a potassium blocking
agent, improves symptoms and signs in MS, probably by
prolonging the repolarization phase of the action
potential and thus helping to restore nerve conduction
in demyelinated nerve fibers.
Fatigue
• Psychologic counselling.
349
• Amantadine 100 mg in the morning and afternoon.
• 4-aminopyridine (fampridine), and 3-4-diaminopyridine,
a potassium channel blocking agent, may have a role.
Pain
• Trigeminal neuralgia (see p.509):
– Carbamazepine 200–400 mg three times daily.
– Baclofen 10–20 mg three times daily.
– Misoprostol, a prostaglandin E1 analogue.
• Dysesthetic burning pain in the extremities:
– Paroxysmal: avoid precipitating maneuvers such as
movement, tactile stimulation, and hyperventilation, if
possible; consider bromocriptine 2–5 mg b.d.
– Chronic: tricyclic antidepressants, e.g. amitriptyline, may help.
• Painful tonic seizures: muscle relaxants, e.g. baclofen, may help.
• Chronic back pain: physiotherapy incorporating heat
pads and transcutaneous electric nerve stimulation.
• Painful leg spasms: baclofen.
CLINICAL COURSE
Symptoms usually persist for several weeks and then gradually
but incompletely resolve over 1 or 2 months. Vision fre-
quently improves in 1 or 2 weeks and often returns to near
normal. Occasionally, symptoms are short lived and paroxys-
mal (e.g. recurrent short episodes of ataxia). The course is
relapsing and remitting in about 80% of patients. Relapse may
occur at any time. The average relapse rate is about 0.5 attacks
per year but is very variable. The first 3 months following
delivery of a child is associated with about a threefold increase
in relapse rate. Complete recovery usually follows the initial
attack but later relapses are associated with increasing residual
disability. In some patients, the course becomes progressive.
A chronic progressive course occurs from onset in the other
20%, particularly if onset occurs after 40 years of age with
spastic paraparesis due to spinal cord dysfunction. These
patients also tend to have a worse prognosis.
PROGNOSIS
• Life expectancy from onset of symptoms is very variable.
• Mean survival: 30 years; 10% die within 15 years and a
small percentage die within several months or years. In
one study, the 25 year survival rate was 74%, compared
with 86% for the general population.
• Most deaths are due to advanced chronic disability and
not acute attacks.
• After 25 years, one-third of MS patients are still working
and two-thirds are still ambulating.
Adverse factors for long term survival free of disability
• Late age of onset.
• Male sex.
• Cerebellar dysfunction (ataxia) at onset.
• Short interval between the first two relapses.
• Progressive clinical course.
• Spinal cord axonal loss and reduced N-acetyl aspartate as
measured by magnetic resonance spectroscopy.
Favorable factors for long term survival free of disability
• Early age of onset.
• Female sex.
• Sensory dysfunction (paresthesia) at onset.
• Relapsing-remitting clinical course.
• Longer inter-attack interval.
• Low initial relapse rate.
• Fewer lesions on baseline MRI.
350 Inflammatory Disorders of the Nervous System
NEUROSARCOIDOSIS
DEFINITION
A chronic, multisystem, granulomatous, inflammatory
disease of unknown etiology in which any part of the
nervous system (and indeed any organ of the body) may be
affected by exaggerated T helper lymphocyte immune
responses to a variety of antigens (self or non-self). This
results in an accumulation of mononuclear inflammatory cells
(mostly T helper lymphocytes and mononuclear phagocytes),
non-caseating epithelioid granulomas, and derangements of
normal tissue architecture in affected tissues.
EPIDEMIOLOGY
• Prevalence:
– Systemic sarcoidosis: 1–50 per 100 000 population.
– Neurosarcoidosis: 5 per 100 000.
• Incidence: systemic sarcoidosis: 10.9 per 100 000 for
whites; 35.5 per 100 000 for blacks.
• Age: any age (3 months–old age), but commonly 20–55
years of age.
• Gender: M=F.
PATHOLOGY
Site
Sarcoidosis often affects multiple organ systems:
• Lungs (about 87%).
• Lymph nodes (28%).
• Skin (18%).
• Eyes: conjunctivae, iris (15%).
• CNS (5–16%)
– Intracranial:
Meningeal: diffuse granulomatous meningitis or
meningo-encephalitis, or circumscribed granulomas,
causing thickening of the arachnoid, anywhere over the
surface of the brain or spinal cord but particularly around
the optic chiasm, hypothalamus, basal cisterns and
subependymal region of the third ventricle.
Parameningeal.
Parenchymal lesions: anywhere but particularly in the
periventricular regions and in the Virchow–Robin spaces
where they form granulomatous masses up to several
centimeters in diameter. Cerebral infarction may also
occur due to sarcoid angiitis.
Hypothalamus.
Pituitary.
Ependymal linings of ventricles and choroid plexus (may
cause hydrocephalus).
Cranial nerves (any nerve, but mostly facial nerve,
involved by granulomatous infiltration or compression
by mass lesions).
– Spinal cord: granulomatous meningitis, vasculitis or
circumscribed granulomas within the leptomeninges or
parenchyma of the spinal cord.
• Peripheral nervous system (6–18%):
– Polyradiculopathy.
– Symmetric polyneuropathy (pure sensory, pure motor,
sensori-motor).
– Mononeuritis multiplex.
• Muscle.
• Liver.
• Kidneys.
• Testes.
Microscopic findings in the nervous system
• Non-caseating epithelioid granulomata (430):
– An aggregate of tightly clustered mononuclear
epithelioid histiocytes (phagocytes) with eosinophilic
cytoplasm and oval nuclei surrounded by a rim of T
helper-inducer lymphocytes and, to a far lesser extent, B
lymphocytes.
– Giant cells of the Langhan’s or foreign-body variety may
be present in the granuloma. Tend to form in the
perivascular spaces and walls of small penetrating arteries
and veins of the meninges and parenchyma.
• Lymphocytic infiltrate, often perivascular and associated
with neuronal loss, reactive gliosis, loss of myelin, and
residual scars.
• Basal leptomeningitis.
• More diffuse leptomeningeal and ependymal disease.
• Intra-axial granulomatous masses.
• Granulomatous necrotizing angiitis that predominantly
affects veins (causing a phlebitis or venulitis) and small
arteries of the meninges and brain.
PATHOGENESIS
• Uncertain.
• An exaggerated helper-inducer T lymphocyte cellular
immune response to a variety of antigens or self-antigens.
• Since the activated helper-inducer T lymphocytes release
mediators that attract and activate mononuclear
phagocytes, it is likely that the process of granuloma
formation is secondary to the exaggerated helper-inducer
T cell process.
ETIOLOGY
Hypotheses
• A class of antigens, non-self or self, trigger only the
helper-inducer T cell arm of the immune response.
• An inadequate suppressor arm of the immune response,
such that helper-inducer T cell processes cannot be shut
down in a normal fashion.
• Inherited (and/or acquired) differences in immune
response genes, such that the response to a variety of
antigens is an exaggerated helper-inducer T cell process.
CLINICAL FEATURES
Systemic manifestations
• Present in 98% of patients with neurosarcoidosis.
• Symptoms include exertional dyspnea and dry cough due
to interstitial lung disease.
• Signs include skin rash (i.e. erythema nodosum), uveitis,
lymphadenopathy and arthritis.
Neurologic manifestations
• The presenting manifestation in about 2% (0.3–2.5%) of
cases of sarcoidosis, concurrent with systemic
involvement in about 5% of patients, and may precede
systemic involvement by up to 18 months.
• Meningitis:
– Aseptic meningitis.
– Chronic granulomatous basal meningitis.
• Epilepsy: secondary to meningitis; mass lesion; cerebral
infarction.
• Raised intracranial pressure:
– Intraparenchymal mass lesion.
– Hydrocephalus.
 Neurosarcoidosis 351

• Uni- or multi-focal neurologic deficits: INVESTIGATIONS

– Stroke syndrome. Blood
– Multifocal changes in CNS white matter. No peripheral blood findings are diagnostic of the disease:
– Vasculopathy: ophthalmoscopy may reveal periphlebitis, • Full blood count: anemia, increased number of
as yellowish-white focal or diffuse sheathing of retinal monocytes.
veins. Hard exudates, sometimes termed taches de bougie • Serum urea and electrolytes, glucose, liver function tests,
because of their resemblance to candle-wax drippings, uric acid: may be abnormal.
often accompany the periphlebitis and can leave white • Serum calcium: elevated.
choreoretinal scars. • Serum immunoglobulins: hypergammaglobulinemia.
• Single or multiple cranial neuropathies: • Serum angiotensin-converting enzyme (ACE): elevated
– Anterior optic neuropathy (431, 432). in about two-thirds of patients but it is neither sensitive
– Facial palsy: with enlarged parotid glands (uveoparotid (sensitivity varies from 56–86%) nor specific (high). The
fever). false positive rate in a normal population is about 2–4%.
• Neuroendocrine (hypothalamic and pituitary The level of serum ACE correlates with the severity of
dysfunction): diabetes insipidus (polyuria, polydipsia, the lung disease and the presence or absence of
disordered thirst). extrathoracic disease.
• Subacute or chronic myelopathy. • Serum lysozyme: elevated in about two-thirds of cases,
• Peripheral neuropathy: less specific than elevated ACE.
– Guillain–Barré syndrome. • Serum beta2-microglobulin: elevated in about two-
– Polyradiculopathy. thirds, less specific than elevated ACE.
– Symmetric polyneuropathy (pure sensory, pure motor,
sensori-motor).
– Mononeuritis multiplex.
• Myopathy.

430 Biopsy showing a sarcoid granuloma characterized by an 430

aggregate of tightly clustered mononuclear epithelioid histiocytes and
multinucleated giant cells.

431 432

431, 432 Ocular fundi of a patient with anterior optic neuropathy due to sarcoidosis (431, right eye; 432, left eye). He presented with subacute
onset of an island of blurred vision in the inferior visual field of the left eye and mild ocular pain bilaterally. Examination showed normal visual acuity
bilaterally, an enlarged blind spot and an arcuate scotoma infero-nasally on the left, and asymmetric optic disc swelling being greater in the left eye
(432). Note the nerve fiber layer hemorrhages in the left fundus.
352 Inflammatory Disorders of the Nervous System
Imaging
• Chest x-ray: may show bilateral hilar adenopathy (433)
but occasionally a similar pattern is seen in lymphoma,
tuberculosis, brucellosis and bronchogenic carcinoma.
• Gallium scan: more sensitive than chest x-ray and the
appearance of diffuse uptake in the lungs (or parotid,
salivary and lacrimal glands), even in the absence of
clinical involvement, is relatively specific but not
diagnostic.
• CT brain scan without and with contrast: hydrocephalus,
leptomeningeal thickening and enhancement, intra-axial
mass lesions, extra-axial mass lesions.
MRI brain/spinal cord scan
Several patterns may be visible on cranial MRI (434) (CT
is much less sensitive):
• Chronic basal leptomeningitis with thickened enhancing
meninges involving the hypothalamus, pituitary stalk,
optic nerve (435) and chiasm.
• Communicating hydrocephalus.
• Involvement of the lenticulostriate arteries by spreading
up the Virchow–Robin spaces causing thrombosis and
granulomatous angiitis.
• Parenchymal nodules (granulomas) which may be iso- or
hyperdense, may calcify and appear as a mass lesion and
may or may not enhance. These may cause obstruction to
the ventricles. They occur particularly around the skull base,
pituitary, pons, hypothalamus and periventricular region.
• Diffuse high signal areas in the white matter on T2W
images indistinguishable from MS may also occur.
• Extra-axial sarcoid may mimic a meningioma by causing
a dural enhancing mass with hyperostosis.
• Spinal sarcoid may mimic leptomeningeal metastases.
Cerebral angiography
Changes suggestive of cerebral angiitis may occur.
CSF
• Mild pleocytosis (mostly lymphocytes).
• Mild increased protein.
• Increased T4 : T8 lymphocyte ratio.
• Low CSF glucose in 20–39% of cases.
• Elevated CSF ACE, oligoclonal banding and increased
IgG index in nearly one-third of patients may occur.
EMG
• Compound muscle action potentials and sensory nerve
action potentials: normal or mild to moderately
decreased.
• Motor and sensory nerve conduction velocities: mild to
moderately decreased.
• EMG features of chronic partial denervation may be
present.
Kveim test
A suspension of sarcoid tissue is injected intradermally and
produces a sarcoid granuloma in about 75% of patients with
subacute active sarcoidosis and in about two-thirds of those
with chronic sarcoidosis of >2 years duration. False-positives
occur in <5% of cases.
Tissue
• Bronchoalveolar lavage: abnormally increased T4 : T8
lymphocyte ratio: relatively specific but not diagnostic.
• Bone marrow: non-caseating granuloma.
• Biopsy of muscle (even in the absence of myopathic
symptoms), lymph node, conjunctiva, skin, lung, liver or
brain may reveal the diagnosis.
• Nerve biopsy:
– An axonopathy sparing unmyelinated fibers.
– Marked loss of myelinated fibers.
– Demyelination is not prominent nor is it in the usual
central predominant pattern seen in vasculitic
neuropathies.
– Epineural and perineural granuloma with or without
periangiitis and panangiitis.
• Brain biopsy: in most cases involving intracranial mass
lesions which are difficult to access safely with stereotactic
brain biopsy, biopsy can be deferred until a trial of
steroids is given if sarcoidosis can be inferred clinically.
Other
• Skin: skin-test unreactivity (anergy).
• Urine: 24 hour urinary calcium level: typically elevated.
but not diagnostic, of sarcoidosis.
DIFFERENTIAL DIAGNOSIS
Meningo-encephalitis
• Granulomatous inflammation:
– Infection by bacteria (brucellosis, chlamydia, tularemia),
mycobacteria (tuberculosis, atypical mycobacteria), fungi
(histoplasmosis, coccidioidomycosis, cryptococcosus),
spirochetes (treponemal infections such as syphilis), and
parasites (toxoplasmosis, leishmaniasis).
– Occupational and environmental exposure to organic or
inorganic agents (e.g. methotrexate, talc, metals).
– Neoplasia (lymphoma).
– Autoimmune disorders (Wegener’s granulomatosis,
Churg–Strauss syndrome).
– Histiocytosis X:
• Viral encephalitis (see p.292): HIV infection (see p.301).
• Carcinomatous meningitis
• Granulomatous angiitis of the CNS (see CNS vasculitis,
p.227). The meningeal inflammatory reaction is
consistently localized to blood vessel walls and typically
produces extensive disruption of the vascular wall.
• Meningiomatosis
• Limbic encephalitis associated with occult neoplasm (see
p.401).
Multifocal white matter disease
Multiple sclerosis.
Mass lesions
• Primary brain tumor (see p.357): glioma (including optic
nerve glioma), meningioma, germ cell tumor, leukemia,
primary CNS lymphoma.
• Metastatic brain tumor (see p.396).
• Granulomatous inflammation: syphilitic gumma, tuber-
culoma, cryptococcoma, toxoplasmosis, histiocytosis X.
• Spinal cord glioma, ependymoma, myelitis.
Non-caseating granulomas
Non-specific: found in infections and malignancy.
Increased level of serum ACE
• Youth.
• Hyperthyroidism.
 Neurosarcoidosis 353

• Diabetes. • Prednisone 60 mg (1 mg/kg) oral, daily for 4–6 weeks,

• HIV infection. followed by a slow taper over 3–6 months or longer.
• Leprosy. • If steroids fail, or cannot be tapered eventually, other
• Tuberculosis. immunosuppressive agents, such as cyclophosphamide,
• Coccidioidomycosis. azathioprine, and cyclosporine (4–6 mg/kg/day, which
• Histoplasmosis. inhibits interleukin-2 secretion by T cells) allow
• Amyloidosis. reduction of steroids to 30–50% of the original dose.
• Multiple myeloma. • Surgery may be indicated for hydrocephalus, expanding
• Hodgkin’s disease. mass lesions, or mass lesions causing increased
• Lymphoma (including intravascular lymphoma). intracranial pressure.
• Malignant histiocytosis. • Cranial irradiation of intracranial neurosarcoidosis that is
• Primary biliary cirrhosis. refractory to treatment with steroids may be successful.
• Whipple’s disease.
• Gaucher’s disease. PROGNOSIS
• Silicosis. • Most patients respond to treatment and can have
• Asbestosis. medication withdrawn over months but about one-third
will relapse, often in the same location as the initial
DIAGNOSIS disease.
A positive biopsy finding of non-caseating granulomas in • Neurosarcoidosis limited to peripheral nerves and cranial
the context of characteristic clinical features, blood test nerves may respond spontaneously.
(elevations of serum gamma globulin, ESR, or serum ACE), • Intracranial neurosarcoidosis, such as mass lesions or
chest x-ray evidence of enlarged hilar and mediastinal lymph hydrocephalus, have a more malignant course and a
nodes, gallium scan, defects in cell mediated immunity, and higher rate of relapse.
MRI and CSF findings, having excluded other causes of • Patients with relapsing disease and more ominous clinical
granulomatous inflammation. features (e.g. intracranial neurosarcoid such as mass lesions
or hydrocephalus) should probably remain on low-dose
TREATMENT steroids as a maintenance dose between exacerbations.
Inferred from experience with pulmonary sarcoidosis; no
controlled studies:

433 434

435
433 Chest x-ray showing bilateral hilar adenopathy due to sarcoidosis.

434 T1W MRI of the brain stem following contrast. Note the thin rim
of enhancement (arrows) around the brain stem. It is unusual to see
this in sarcoid, but its presence should certainly prompt the diagnosis,
though is not specific for sarcoid.

435 MRI of the orbits, coronal plane, after gadolinium injection

showing brightness, due to contrast enhancement, of the dural sheath
of the optic nerves (arrows) bilaterally in the patient in 431, 432, with
bilateral optic neuropathy due to sarcoidosis.
354 Inflammatory Disorders of the Nervous System

CAVERNOUS SINUS SYNDROME CLINICAL FEATURES

Cranial nerve palsy
• Oculomotor (IIIrd) nerve: almost all patients; pupil is
DEFINITION involved in three-quarters of cases and generally parallels
Involvement of two or more of the IIIrd, IVth, Vth (V1, the severity of the ophthalmoplegia.
V2), or VIth cranial nerves or oculosympathetic fibers on • Abducens (VIth) nerve: 95% of patients.
the same side. • Trochlear (IVth) nerve: 30% of patients; may be difficult
to confirm in the presence of a partial IIIrd nerve palsy.
EPIDEMIOLOGY • Trigeminal (Vth) nerve: 40% of patients.
• Incidence: rare. • Optic nerve or chiasmal dysfunction: 40% of patients.
• Age: any age; mean age: 40 years.
• Gender: M=F. Horner’s syndrome
• 5–10% of patients.
PATHOPHYSIOLOGY • Difficult to diagnose in the presence of IIIrd nerve palsy
The cavernous sinus (really a venous plexus) lies within a without pharmacologic pupillary testing.
dural envelope that funnels upper cranial nerves to the orbit.
Consequently, small lesions, adjacent to or within the HISTORY
cavernous sinus, can produce dramatic localizing signs. • Age of onset.
• Presence or absence of pain.
ETIOLOGY • Speed of progression.
Tumor: 30–70% of all cases • Past infections and tumors.
Malignant tumors: two-thirds
In marked contrast to the high incidence of benign tumors Tumor
causing chiasmal compression: Average age: 47 years:
• Nasopharyngeal cancer: 22–46% of tumors. • Nasopharyngeal cancer: preferentially involves the VIth
• Metastases: 16–33%. nerve and mandibular division of the Vth nerve.
• Lymphoma: 0–18%. • Metastases: often present with rapid complete ophthal-
• Pituitary adenoma: 9–22%. moplegia.
• Lymphoma: other signs may be present, such as
Benign tumors abdominal mass.
One-third. • Pituitary adenoma: lateral extension tends to involve the
• Meningioma: 4–9% of tumors. IIIrd nerve and ophthalmic division of the Vth nerve.
• Chordoma: 2–11%. Apoplectic onset usually, and involves the oculomotor
• Neuroma: 0–8%. nerves with a relative frequency ratio of about 4 (IIIrd
nerve), 2 (VIth nerve) and 1 (IVth nerve).
Aneurysm or fistula: 5–35% of all cases • Benign tumors: a single cranial nerve is involved for long
• Cavernous carotid artery aneurysm. periods.
• Carotid-cavernous fistulas.
Aneurysm
Trauma: 5–25% of all cases • Average age: 52 years.
• Typically progressive, painful involvement of multiple
Surgery: 10% of all cases cranial nerves.
• Multiple cranial nerves are affected in two-thirds, VIth
Inflammation (idiopathic cavernous sinusitis): nerve only in one-quarter, and IIIrd nerve only in 10%.
0–23% of all cases • Despite IIIrd nerve involvement, the pupil on the
The Tolosa–Hunt syndrome eponym, with its promise of involved side is often the same size or smaller than the
making a specific diagnosis on clinical grounds, has not normal pupil, perhaps because the parasympathetic fibers
proved reliable. One of the five patients who helped are less vulnerable within the cavernous sinus.
establish the Tolosa–Hunt syndrome later was shown to • Painful onset in almost all patients.
have a meningioma. A generic description, such as • Sudden onset in about 10% of cases.
idiopathic cavernous sinusitis, seems preferable. Overlap
with orbital inflammatory pseudotumor and idiopathic Trauma
multiple cranial neuropathy syndromes suggest a similar • Average age: 30 years.
underlying mechanism. • Usually severe head trauma with basal skull fractures.

Infection: 0–5% of all cases Inflammation (idiopathic cavernous sinusitis)

Spread of fungus or bacteria, usually from the sphenoid • Average age: 35 years.
sinus: • Painful, non-specific inflammation of the superior orbital
• Mucormycosis. fissure.
• Meningitis.
• Bacterial sphenoid sinusitis. Infection
• Septic cavernous sinusitis. • Underlying diabetes common.
• Rapid, complete ophthalmoplegia.
Diabetes: 1% of all cases • Life-threatening.
 Cavernous Sinus Syndrome 355

DIFFERENTIAL DIAGNOSIS PROGNOSIS

Unilateral ophthalmoplegia Tumor
• Orbital inflammatory pseudotumor syndrome. • Malignant tumors: rapid deterioration.
• Idiopathic multiple cranial neuropathy syndrome. • Benign tumors: prolonged course.
• Wernicke’s encephalopathy.
• Myasthenia gravis. Aneurysm
• Typically progressive, prolonged course.
Rapid onset, severe ophthalmoplegia • One-quarter have some recovery of eye movements;
• Trauma. residual damage often consists of elevator paresis and
• Pituitary apoplexy. mild ptosis due to permanent damage to the superior
• Carotid aneurysm. division of the IIIrd nerve.
• Mucormycosis.
• Metastatic tumor. Inflammation (idiopathic cavernous sinusitis)
Remitting course, usually self-limiting.
Bilateral cavernous sinus syndrome: <10% of all cases
• Nasopharyngeal carcinoma. Infection
• Lymphoma. Life-threatening and usually fatal, despite intensive antibiotic
• Leukemia. treatment.
• Craniopharyngioma.
• Pituitary apoplexy. Close clinical follow-up is essential and the MRI should
• Mucormycosis. be repeated if a sustained remission is not forthcoming.

INVESTIGATIONS
• Contrast-enhanced MRI brain scan (436) is the key
investigation: it clearly demonstrates any tumor mass or
aneurysm large enough to cause a cavernous sinus
syndrome, and usually shows carotid-cavernous fistulas,
clues to bacterial or fungal nasal sinusitis and adjacent
basilar meningeal enhancement. Idiopathic cavernous
sinusitis is often not apparent on non-contrast imaging
but, after contrast injection, the affected cavernous sinus
usually appears mildly or moderately enlarged. Abnormal
signal tissue, which may have mass effect in the cavernous 436
sinus (similar to muscle on T1WI and to fat on T2WI),
may extend into the orbital apex. The differential diagnosis
includes sarcoid, meningioma, lymphoma, metastatic or
local spread of tumor, infections like actinomycosis.
• MR angiography or catheter contrast carotid
angiography.
• CSF, including cytology: if meningitis, lymphoma, or
leukemia is suspected.
• Tensilon test: if myasthenia gravis is suspected.

DIAGNOSIS
Idiopathic cavernous sinusitis is a diagnosis of exclusion,
made only after the passage of considerable time (at least 6
months) after the onset of acute painful ophthalmoplegia to
confirm complete or almost complete remission and
eliminate the possibility of a subacute infection or a subtle
tumor in the cavernous sinus. MRI enhancement of a mildly
enlarged cavernous sinus supports, but does not establish,
the diagnosis; it may also be caused by infection, lymphoma,
meningioma, dural arteriovenous malformation.

TREATMENT
• Specific medical (anti-microbial, anti-inflammatory) or
surgical treatment, depending on the cause.
• Idiopathic cavernous sinusitis may respond to
corticosteroid therapy but patients need to be carefully
observed for a facilitated fungal infection. 436 T1W coronal MRI with contrast of a 20 year old man with a
painful right ophthalmoplegia, visual loss, sensory disturbance in the V1
distribution.This section was taken just posterior to the orbital apex.
Note the enhancement (whiteness, arrow) around the right optic
nerve which extended from the orbital apex.
356 Inflammatory Disorders of the Nervous System
FURTHER READING
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 Chapter Thirteen 357

Tumors of the
Central Nervous
System
BRAIN TUMORS – Neuroblastoma.
• Pineal cells: pineal cell tumors (pineocytoma, pineo-
blastoma).
DEFINITION
Neoplastic lesions of the brain which may be benign or Cellular derivatives of the neural crest
malignant, and primary or secondary (metastatic). • Arachnoid cells:
– Meningioma (15%) (see p.374).
EPIDEMIOLOGY – Meningeal sarcoma.
• Incidence: • Schwann cells:
– Primary brain tumors (benign and malignant): – Schwannoma (7–8%) (see p.383).
12–15/100 000/year (adults); 2–5/100 000/year – Neurofibroma.
(children).
– Primary benign CNS tumor: 7 (95% CI: 3–13) per Other cells
100 000 per year. • Adenohypophyseal cells (see p.379): pituitary adenoma
– Primary malignant CNS tumor: 3 (95% CI: 0.7–7) per (10%), pituitary carcinoma.
100 000 per year. • Reticuloendothelial cells: primary cerebral lymphoma
– Secondary brain tumors (metastases): 4 (95% CI: 1–9) (see p.385).
per 100 000 per year. • Vascular cells: hemangioblastoma (see p.392).
• Age: • Glomus jugulare cells: glomus jugulare tumors.
– Adults: supratentorial tumors predominate (e.g. glioma, • Connective tissue cells: sarcomas.
meningioma, pituitary adenoma, metastases).
– Children: infratentorial tumors predominate (e.g. Embryonal remnants
medulloblastoma, ependymoma, astrocytoma, pinealoma). • Ectodermal derivatives: craniopharyngioma (2–3%) (see
After 10 years of age, the incidence of neuroepithelial p.377).
tumors increases steadily with increasing age to a peak • Notochord: chordoma.
incidence of 20/100 00/year at age 70 years. • Germ cells (see p.388): germinoma (0.5%).
• Gender: M=F overall. • Derived from the three germ layers: teratoma.
– Men: gliomas more common; women: meningiomas and
nerve sheath tumors are more common.

PATHOLOGY
A. Histologic classification of brain tumors. (A more recent
World Health Organization classification also exists
[Kleihues and Cavenee, 2000; De Angelis, 2001].)

Neuro-epithelial (50%): cellular derivatives of the

neural tube
• Glial cells (Gliomas, see p.364)
• Neurons:
– Embryonal tumors: medulloblastoma (20% of all
childhood tumors, <5% of adult brain tumors) and
primitive neuroectodermal tumors.
– Gangliocytoma/ganglioglioma.
– Dysembryoblastic neuroepithelial tumor (DNET).
358 Tumors of the Central Nervous System

Metastases to the brain (15%) (437) Cytotoxic edema

Carcinoma of the lung, breast and kidney, and malignant Cytotoxic edema is excessive intracellular fluid that is caused
melanoma (438). by an increase in permeability of the cell membrane due to
failure of the cell membrane pump that maintains ion and
B. An alternative classification of brain tumors. fluid homeostasis. Although cytotoxic edema
characteristically occurs in response to cerebral hypoxia and
Primary brain tumors ischemia, it also occurs in brain tumors.
Histologically malignant
• Glioma: ETIOLOGY
– Astroglial neoplasm: No specific etiologic factor (e.g. infectious agent, chemical,
Astrocytoma (439)*. electric field) has been identified.
Anaplastic astrocytoma.
Glioblastoma multiforme. Risk factors
– Oligodendroglioma*. • Ionizing radiation of the cranium, usually for childhood
– Ganglioglioma*. malignancy: the only unequivocal risk factor for glial and
– Ependymoma. meningeal neoplasms can increase the incidence of
• Lymphoma. meningioma by a factor of 10 and the incidence of glial
• Medulloblastoma. tumors by a factor of 3–7, with a latency of 10 years to
• Primitive neuroectodermal tumors. more than 20 years after exposure.
• Germ-cell tumors: • Family history of cancer: present in 16% of patients with
– Germinoma. primary brain tumor. Several neurocutaneous syndromes
– Teratoma. are associated with specific tumor types: neurofibromatosis
– Embryonal carcinoma. types 1 and 2 is associated with glioma, meningioma,
– Choriocarcinoma. acoustic neuroma (see p.383); tuberous sclerosis with
– Endodermal-sinus tumor (yolk-sac tumor). astrocytoma (see p.143); and von Hippel–Lindau disease
• Pineal cell tumors. with hemangioblastoma (see p.392); Turcot’s syndrome
• Chordomas. with glioblastomas, medulloblastomas, and colon
• Choroid-plexus carcinomas. carcinoma; and Li-Fraemeni syndrome with multiple
familial tumors including glioblastoma.
*It is not quite clear whether these should be considered
benign or malignant histopathologically. Heritable syndromes and CNS tumor associations
Neurofibromatosis
Histologically benign or malformative • Visual pathway gliomas.
• Meningioma. • Other glial tumors.
• Pituitary adenoma • Meningioma.
• Acoustic neuroma.
• Craniopharyngioma. Tuberous sclerosis
• Pilocytic astrocytoma. • Subependymomas.
• Epidermoid tumor. • Glial tumors.
• Colloid cyst.
• Choroid plexus papilloma. Turcot’s syndrome
• Hemangioblastoma. Medulloblastoma.

Metastatic brain tumors Naevoid basal cell carcinoma

• Single or multiple metastases. Medulloblastoma.
• Meningeal carcinomatosis.
Ataxia telangiectasia
C. Other pathology. Medulloblastoma.

Cerebral edema von Hippel–Lindau disease

Vasogenic edema
Vasogenic edema is excessive extracellular fluid that is caused
by an increase in permeability of the capillary endothelium
(which allows plasma to move from the intravascular
compartment into the extracellular space) and the absence
of any lymphatic drainage in the brain. Consequently, the
fluid accumulates and further increases the mass effect of
the tumor. It is the most common type of cerebral edema
associated with brain tumors and occurs predominantly in
the cerebral white matter.
Cerebellar hemangioblastomatosis.
Head trauma has been followed by meningiomas and
even gliomas at the site of previous trauma but this is likely
to be coincidental rather than causal.
PATHOGENESIS
Oncogenesis
• Oncogenes may be expressed inappropriately in
neoplastic cells, and potentiate or initiate cell mitosis. For
example, oncogenes such as c-sis, c-erbB, gli, N-ras, and
c-myc are expressed in astrocytomas, and encode growth
factors, or their receptors (e.g. the B subunit of platelet-
derived growth factor is encoded by the c-sis oncogene).
 Brain Tumors
• Tumor-suppression genes may be lost by neoplastic cells.
For example, deletions have been identified on
chromosome 3p in hemangioblastomas due to von
Hippel–Lindau disease, chromosomes 10 and 17 in
astrocytomas, chromosomes 17 and 22 in acoustic
neuromas, and chromosome 22 in meningiomas.
• Many malignant tumors produce factors that stimulate
and induce angiogenesis, such as endothelial-cell growth
factor, thus increasing the blood supply to the tumor and
possibly enhancing its growth.
• Astrocytomas secrete immunosuppressive substances,
such as transforming growth factor β2 which render the
host immune response to the tumor as inadequate.
• Tumors may cause edema in the surrounding brain, per-
haps by secreting factors that increase vascular permeability.
Neurologic dysfunction
The brain and spinal cord lie in the cranial cavity of the skull
and the spinal canal and are protected by the strong bones
of the skull and vertebral column. However, because the
cranial cavity and spinal canal is a closed inexpandible
system, lesions such as tumors which grow and occupy space
within this closed system ultimately compress, displace and
cause dysfunction of normal brain and spinal cord and other
structures. Headache may be caused by compression and
displacement of pain sensitive structures such as blood
vessels and meninges or by raised intracranial pressure.
437 Coronal section through the brain showing multiple metastases
(arrows) in the medial thalamus and the superior and medial aspect of
the contralateral temporal lobe. (Courtesy of Professor BA Kakulas,
Royal Perth Hospital,Western Australia.)
438
438 Axial section through the brain showing multiple areas of
hemorrhage into metastases of malignant melanoma. (Courtesy of
Professor BA Kakulas, Royal Perth Hospital,Western Australia.)
359
CLINICAL FEATURES
Clinical features depend on the site of origin of the tumor
in the CNS, the pathologic type of tumor, the rate and
nature of its growth, and the degree of brain edema.
Epileptic seizures
The presenting feature in 20–50% of patients with brain
tumors and may be partial or generalized.
Raised intracranial pressure syndrome
This may be a result of the mass itself, associated cerebral
edema, or obstruction of the CSF pathways causing
hydrocephalus:
• Headache is a presenting symptom in about 30% of cases
(see Idiopathic intracranial hypertension, p.477) but
tumor is a very rare cause of headache.
• Vomiting may occur with or without nausea and be
projectile. It is usually associated with headache.
• Altered higher mental function and level of consciousness may
manifest as increasing lethargy and a general slowing down or
take the form of an acute and profound deterioration.
• Other features include an unsteady gait, urinary incon-
tinence, obscurations of vision (see p.477), papilledema
(in fewer than half of patients) and false localizing signs
such as bilateral abducens (VIth) nerve palsies.
437
439
439 Axial section through the pons and cerebellum showing a cystic
astrocytoma of the cerebellum (arrow). (Courtesy of Professor BA
Kakulas, Royal Perth Hospital,Western Australia.)
360 Tumors of the Central Nervous System
Focal neurologic symptoms and signs
These reflect the anatomic site of the tumor (e.g. blindness
with optic nerve glioma) or a consequence of it (i.e.
compression of the posterior cerebral artery causing occipital
lobe infarction):
• Hemiparesis, hemianopia, or dysphasia of gradual onset
is typical of supratentorial tumors.
• Altered higher mental function and behavior manifesting
as apathy, lack of initiative, tiredness, weakness, dullness,
a change in personality and social behavior, forgetfulness,
and self-neglect, may reflect focal dysfunction of the
frontal and temporal lobes (i.e. frontal lobe or corpus
callosum tumor) or raised intracranial pressure due to
hydrocephalus, for example.
• Ataxia, dysarthria, and brainstem and cranial nerve signs
suggest a posterior fossa tumor.
Associated features
May include:
• A congenital syndrome associated with tumors:
neurofibromatosis, tuberous sclerosis, von
Hippel–Lindau disease.
• Local effects of tumors: proptosis, epistaxis.
• Signs of systemic malignancy: cutaneous melanoma,
clubbing, cachexia.
Specific tumor syndromes
See specific tumors (pp.364–405).
DIFFERENTIAL DIAGNOSIS
• Chronic subdural hematoma (see p.177).
• Brain abscess (see p.284)): fever.
• Demyelination: encephalitis, multiple sclerosis (see
p.340).
• Idiopathic intracranial hypertension: headache,
papilledema, no focal neurologic signs (see p.477).
• Stroke: ischemic or hemorrhagic: onset is usually sudden
(as it can be also with hemorrhage into a brain tumor
[440]) (see p.192).
• Metabolic or toxic encephalopathy: may cause seizures
and altered consciousness.
INVESTIGATIONS
CT brain scan with and without contrast
• Images most brain tumors and their consequences such
as mass effect, cerebral edema and hydrocephalus.
• The tumor density may be lower, the same or higher
than that of the normal surrounding brain. Surrounding
edema appears as low density.
• Following intravenous contrast injection, most
histologically malignant and metastatic tumors enhance,
as do many benign tumors.
• CT scan with contrast images almost all tumors above
the tentorium but not below the tentorium, when the
only CT sign may be obstructive hydrocephalus or
displacement of the fourth ventricle.
• If MRI is not available, it is sometimes necessary to
introduce contrast (e.g. metrizamide or air) into the
intrathecal space, by lumbar or cisternal puncture, to
outline posterior fossa structures, provided the
intracranial pressure is not raised.
MRI brain scan
• More sensitive than CT, particularly for demonstrating
low grade astrocytomas and multiple metastases, and
tumors in the skull base, pituitary fossa and suprasellar
region, posterior fossa, craniocervical junction and spine
• Gadolinium enhanced MRI may increase sensitivity
further.
• MRI is therefore particularly useful for the investigation
of patients with adult-onset epileptic seizures and no
other clinical or CT abnormality.
• Magnetic resonance spectroscopy can quite accurately
predict histologic diagnosis and may, in the future,
obviate the need for stereotactic biopsy.
Skull x-ray
Can be useful if CT or MRI is not available for
demonstrating:
• Calcification within a tumor (usually benign).
• Displacement of a calcified pineal gland.
• Bone hyperostosis adjacent to meningioma.
• Enlargement and erosion of the pituitary fossa
(adenoma, craniopharyngioma, carotid aneurysm).
• Osteolytic lesions in the skull (myeloma, primary bone
tumor, secondary carcinoma).
• ‘Copper beating’ pattern of the skull vault or separation
of the skull sutures (children) due to raised intracranial
pressure.
Other investigations guided by the clinical setting
• Chest x-ray helps to eliminate an obvious primary or
secondary lung tumor.
• Mammography: to exclude primary breast carcinoma.
• Abdominal ultrasound: to exclude primary renal cell
carcinoma and liver metastases.
Tumor biopsy
Indications
• To establish the tissue diagnosis if there is clinical and CT
or MRI brain scan evidence of a solitary or even multiple
intracerebral lesions which could be neoplastic.
• To exclude treatable lesions such as brain abscess,
lymphoma, meningioma, and tuberculoma.
440
440 Axial section through the pons and cerebellum showing
hemorrhage into a malignant glioma. (Courtesy of Professor
BA Kakulas, Royal Perth Hospital,Western Australia.)
 Brain Tumors 361

N.B. A vascular malformation needs to be excluded distinguish between recurrence of tumor and post-radiation
before undertaking stereotactic biopsy. necrosis.

Not necessary if DIAGNOSIS

• Patient has features suggestive of a very poor prognosis
for survival and functional improvement, even after
multimodality therapy (e.g. substantial disability due to
progressive major neurologic or cognitive deficits; and
elderly [but biologic age and the opinions of the patient
and family need to be considered in a decision for non-
interventional management]). Care is required to be sure
that a treatable condition such as brain abscess or
lymphoma has been excluded.
• CT or MRI brain scan reveals multiple deposits
characteristic of metastases and there is a known,
histologically-confirmed, primary tumor.
• Characteristic clinical and neuroradiologic features of a
glioblastoma.
Can be delayed if
Epileptic seizures only (which are mild or controlled by anti-
epileptic drug therapy) and a solitary intracerebral lesion.
Serial clinical assessment and CT scan is required to monitor
the clinical progress and rate of tumor growth. Biopsy is
indicated if there is any deterioration.
Risks
MR or CT guided stereotactic biopsy has a morbidity of
<5% and mortality of <1%; the 30 day morbidity associated
with biopsy is usually transient or related to the rapid
progression of the primary disease process.
CSF
Seldom useful and lumbar puncture can be dangerous in the
presence of an intracranial mass because of the risk of
transtentorial herniation and/or brainstem coning.
Positron emission tomography (PET)
Reveals areas of increased metabolism in tumors that are
actively growing and this can be helpful when trying to
The tumor type (e.g. glioma), but not the grade, can
commonly be diagnosed confidently from the combination
of the clinical features, neuroanatomic location of the tumor
and neuroimaging characteristics.
However, in practice a tissue biopsy is required to
exclude other differential diagnoses that can simulate a brain
tumor (i.e. abscess, other inflammatory lesions, metastases,
and other contrast-enhancing neuropathologies) and to
establish the histologic diagnosis and grade of the tumor, so
that realistic discussions can take place with the patient and
family about the prognosis and management decisions. For
example, a proportion of patients with apparently innocuous
focal lesions on MRI, and many patients diagnosed by CT
to have low grade astrocytomas, will be shown to have a
non-contrast-enhancing malignant anaplastic astrocytoma
with a worse prognosis.
TREATMENT
A multidisciplinary neuro-oncology team approach
(neurosurgeons, radiation therapists, neuro-oncologists,
endocrinologists, rehabilitation teams, neuropsychologists,
social workers, nurses) is required.
General
Malignant brain tumor
• Education of patient and family: involve GP, liaison
nurses, and palliative care team as appropriate.
• If the patient is considered to have a very poor prognosis,
good primary medical practice (including judicious use
of glucocorticoid treatment) and the use of home
nursing and hospice care are generally appropriate. The
facility for additional neuro-oncologic follow up should,
however, be retained as an option as even without
treatment some of these patients survive longer than
expected, and are at risk of major steroid-related
complications and even misdiagnosis.

Table 37 Treatment and prognosis of brain tumors

Tumor Surgery Adjuvant therapy Prognosis
Glioblastoma Biopsy/PR RT ± CH for recurrence ≤12 months median survival
‘Low-grade’ glioma CR/PR ± RT – 5-year survival: 50%
Pilocytic astrocytoma CR – 5-year survival: 100%
PR – 5-year survival: >80%
Cerebral lymphoma Biopsy RT ± CH 12–18 months median survival
Metastases CR/PR RT 4 months median survival
Medulloblastoma/PNET CR RT ± CH for recurrence 5-year survival: >50%
Meningioma CR RT if aggressive Recurrence 1%/year even after ‘CR’
Acoustic neuroma CR – Excellent if CR
Craniopharyngioma CR/PR ± RT/brachytherapy Good if CR
± Cyst aspiration
Pituitary adenoma CR/PR ± RT Good long term survival
CR: complete resection; PR: partial resection; RT: radiotherapy; CH: chemotherapy; PNET: primitive neuroectodermal tumor
362 Tumors of the Central Nervous System
Medical
Raised intracranial pressure, transtentorial herniation and
impending brainstem coning
• Mannitol 0.5–1.0 g/kg intravenously as a 10–20%
solution over 10–20 minutes may ‘buy time’ to arrange
surgical decompression if considered appropriate. Beware
of precipitating acute heart failure, particularly in the
elderly, due to fluid overload. Infusions should be
repeated no more than four or five times within 48 hours
because of electrolyte imbalance.
• Consider urgent CSF drainage via a burr hole.
Cerebral vasogenic edema
• Dexamethasone 12 mg orally as a loading dose followed
by 4 mg every 6–24 hours and gradually reducing over
a few weeks. A favorable response is often evident clini-
cally within 24–48 hours, and sometimes within 4 hours.
• Analgesics and anti-emetics for headache, nausea and
vomiting. Take care not to sedate the patient because this
complicates the evaluation of a genuine change in
conscious level and other neurologic functions.
Epileptic seizures
Anti-epileptic drug therapy with the usual medications such
as valproate or carbamazepine, and advice about driving (see
p.76). Anti-epileptic drug treatment is not required as
‘routine prophylaxis’ if seizures have not occurred.
Specific antitumor chemotherapy
• Lymphoma: if widespread systemic disease.
• Leukemia.
• Choriocarcinoma.
• Pituitary tumors (see p.379): e.g. bromocriptine,
carbergoline.
• Primary malignant brain tumors: see Gliomas, p.364.
Surgery
Surgery has two roles: (1) to establish the histologic
diagnosis of the tumor; and (2) to treat the patient by
excising or debulking the tumor, and decompressing the
brain (i.e. ventriculoperitoneal shunt) if appropriate.
Establish histologic diagnosis
• Stereotactic surgery under CT or MRI guidance for
deep-seated tumors, including some gliomas and many
lymphomas, or
• Open craniotomy or burr hole: a preliminary diagnosis
can be made at the time of the operation based on smear
and frozen section techniques, and a definitive diagnosis
based on paraffin sections.
Complete removal
• Benign capsulated tumors, such as meningiomas,
pituitary tumors, acoustic neuromas and choroid plexus
papillomas, can often be completely excised but the
benefits of complete removal need to be weighed against
the possible resultant neurologic deficit (e.g. with
meningiomas of the cavernous sinus).
• Cerebellar pilocytic astrocytoma in childhood can be
cured if removed totally.
• Medulloblastoma and ependymoma which are
completely resected have the best long term results.
• Solitary brain metastasis may be completely removed. This
provides a tissue diagnosis in the one-third of patients who
have no evidence of systemic cancer, achieves good
palliation of symptoms, and improves median survival in
those with stable extracranial disease from 7 months with
radiotherapy alone to 12 months, and functionally
independent survival from 4 months to 9 months. Older
age (>60 years) increases the hazard of dying by 2.7 times,
compared with younger patients, in both treatment groups.
Partial removal/debulking
Infiltrative malignant tumors can be removed partially or
debulked (remove necrotic tissue and reduce the mass
effect) quite safely and effectively with adjuncts such as
MRI, stereotactic craniotomy and operating microscopes.
The purpose is to establish a histologic diagnosis, relieve
symptoms of raised intracranial pressure (and thereby reduce
corticosteroid requirements, seizure frequency and intensity,
and focal neurologic deficits), and reduce tumor bulk before
radiotherapy. However, it is controversial whether median
survival times are improved.
Any benefits of cytoreductive surgery probably become
less with increasing age of the patient and increasing tumor
malignancy. The limited survival benefit bestowed by even
the most exacting cytoreductive operation for malignant
glioma, and particularly glioblastoma, is related to the
invasive and infiltrative potential of malignant glioma.
Generally, peritumoral invasion extends for 2 cm (0.8 in)
beyond either the macroscopic tumor margin or the borders
defined by enhanced CT. In most locations the likelihood
of iatrogenic brain dysfunction prohibits excision of
infiltrated peritumorous brain. Even when extensive
peritumorous brain resection has been undertaken tumor
recurrence at the margin of resection is almost inevitable.
Ventriculoperitoneal shunt
Can relieve obstructive hydrocephalus.
Radiotherapy
Indications
• Radiosensitive tumors such as pineal germinomas,
lymphoma and leukemic deposits are usually treated with
external beam brain irradiation. An optimal total dose of
50–60 Gy (5000–6000 rads or cGy) in 30 fractions over
5–6 weeks is conventional. The addition of a radiosensi-
tizer during radiotherapy has not significantly improved
survival times. Doses >60 Gy (>6000 rads) are associated
with a high incidence of acute and short term adverse
neurologic effects and later cerebral radionecrosis with
no benefit in either median or longer term survival.
• Tumors unamenable to surgery such as multifocal
lymphoma or diffuse brain stem glioma.
• Following surgery for glioma or brain metastases (see
pp.364, 396).
• Multiple brain metastases: radiotherapy is the standard
treatment, resulting in a median survival or 3–7 months,
depending on prognostic factors.
• Medulloblastoma in childhood: postoperative
craniospinal irradiation is given to reduce the risks of CSF
tumor seeding.
 Brain Tumors
• Stereotactic radiosurgery (focused radiation given to a
stereotactically localized area of the brain; e.g. proton
beam gamma knife) for treatment of metastases and
recurrent glioma. Less likely to cause these adverse effects
of irradiation but preliminary experience for malignant
glioma is disappointing.
Adverse effects
• Determined by the total dose given, the number of
fractions given, the inherent vulnerability of the exposed
tissue, the amount of irradiation absorbed by the exposed
tissue, and the time that has elapsed since the irradiation.
• Acute reactions may occur within days of an excessive
dose (i.e. during treatment), sometimes as low as 30 Gy
(3000 rads). Transient exacerbation of the neurologic
deficit and headache, nausea and vomiting occur due to
cerebral edema, which responds to corticosteroid
treatment, but higher doses can result in coma and
death.
• Early delayed reactions may occur rarely several weeks
after irradiation. Focal neurologic deficits evolve
progressively due to focal demyelination, which usually
recovers.
• Late delayed reactions may occur months or years after
total doses of irradiation exceeding 50 Gy (5000 rads).
Epileptic seizures and focal neurologic deficits, including
optic nerve and chiasm dysfunction, evolve progressively
due to focal brain necrosis and edema caused by
progressive occlusive radiation vasculopathy. The
condition can be very difficult to differentiate clinically
from tumor recurrence and may stabilize or progress.
• Late reactions may occur years after even low doses of
radiotherapy and manifest as intracranial tumors:
schwannomas and meningiomas in particular, and
gliomas to some extent.
Late sequelae related to craniospinal irradiation
Neuropsychologic:
• Diminished memory.
• Diminished intellect.
• Diminished academic achievement.
• Emotional adjustment.
• Adaptic behavior.
Neuroendocrine:
• Growth hormone deficiency.
• Hypothyroidism (decreased thyroid stimulating hormone
[TSH]).
• Hypogonadism (decreased follicle stimulating hormone
[FSH], decreased luteinizing hormone [LH]).
Skeletal:
• Diminished height due to vertebral body hypoplasia.
Cardiac:
• Cardiomyopathy.
Ocular:
• Cataract formation.
363
Secondary malignant neoplasia:
• Secondary CNS tumors, particularly meningiomas and
malignant gliomas.
• Thyroid tumors.
• Bone, soft tissue and skin tumors.
New experimental approaches
Suicide genes, such as herpes simplex thymidine kinase (HS-
tk), have been transfected into tumor cells using a retroviral
vector. The transfected cells are rendered sensitive to the
cytotoxic effects of ganciclovir.
PROGNOSIS
• Benign tumors: complete removal achieves a cure. Even
with incomplete removal, prolonged survival is possible
with repeated operations and adjuvant therapy.
• Malignant tumors: prognosis is poor, despite surgery and
radiotherapy; therefore, palliation of distressing
symptoms is often the goal of therapy.
• Anaplastic astrocytoma: median survival time with
radiotherapy and chemotherapy: 36–48 months.
• Mixed anaplastic astrocytoma and glioblastoma: median
survival time with brain irradiation: 9–11 months; 10%
of patients with glioblastoma survive 2 years.
• Secondary deposits from the bronchus, gastrointestinal
tract and melanoma have a worse prognosis than breast
or renal metastases to the brain.
PROGNOSTIC FACTORS
Favorable prognostic factors for adult supratentorial
tumors
• Epileptic seizure as the initial presenting symptom.
• Young age (<45 years).
• Absence of focal neurologic signs (i.e. hemiparesis).
• Absence of mental signs (confusion, altered awareness,
personality change).
• Absence of contrast enhancement on cranial CT scan.
• Presence of cystic change on CT (a circular low density
area before enhancement, with clear cut margin).
• Presence of diffuse low density on CT (diffuse, poorly
demarcated low density without contrast enhancement).
• Presence of calcification on CT.
N.B. Histologic grading of tumors may not be accurate
in determining the prognosis. Furthermore, error can occur
when a small sample is taken for biopsy and the examined
tissue does not reflect the biology of the entire tumor,
particularly if features indicative of malignancy are missed.
364 Tumors of the Central Nervous System

GLIOMAS About 80% of gliomas are ‘high grade’ (malignant,

anaplastic), and 20% ‘low grade’.

DEFINITION Glioblastoma multiforme

A glioma is any neuroepithelial tumor of the brain and arises Macroscopic
from glial cells such as astrocytes (astrocytoma and other • Sites: about half occupy more than one lobe or are
astroglial neoplasms), oligodendrocytes (oligodendro- bilateral, and 5% show multicentric foci of growth.
glioma) and ependymal cells (ependymomas). The term • Appearance: variegated: mottled gray, red, brown or
does not imply any degree of differentiation. orange, depending on the degree of necrosis and the
presence, degree and age of hemorrhage (441).
CLASSIFICATION OF GLIOMAS ACCORDING TO • Highly vascular.
NEUROEPITHELIAL CELLS OF ORIGIN • Mass effect.
• Astrocytes.
– Astrocytoma (25–30% of brain gliomas): Microscopic
Pilocytic astrocytoma. • Very cellular with pleomorphism of cells and
Low grade astrocytoma. hyperchromatism of nuclei.
Anaplastic astrocytoma. • Astrocytes with fibrils and astroblasts, tumor giant cells,
Pleomorphic xanthoastrocytoma. mitotic cells.
Subependymal giant cell astrocytoma. • Vascular proliferation with hyperplasia of endothelial cells
– Glioblastoma multiforme (50% of gliomas). of small vessels.
• Oligodendrocytes: • Necrosis, hemorrhage and thrombosis of vessels.
– Oligodendroglioma (10–20% of gliomas).
– Anaplastic oligodendroglioma. Growth
• Ependymal cells: • Arises from anaplasia of mature astrocytes.
– Ependymomas (5% of all brain gliomas, 8% of gliomas in • Highly malignant.
childhood). • May extend to the meningeal surface or the ventricular wall.
– Anaplastic ependymoma. Malignant cells, carried in the CSF may form distant foci on
– Myxopapillary ependymoma. spinal roots or cause widespread meningeal gliomatosis.
– Subependymoma. • Extraneural metastases are rare, and usually involve bone
• Choroid plexus tumors (papilloma, carcinoma). and lymph nodes after craniotomy.
• Colloid cysts.
• Mixed gliomas (oligoastrocytoma, anaplastic oligoastro- Anaplastic astrocytoma
cytoma). • Moderate hypercellularity and pleomorphism.
• Vascular proliferation.
EPIDEMIOLOGY
The most common primary brain tumors in adults. Astrocytoma (grades 1 and 2)
• Incidence: 6 (range 2–10) per 100 000 per year. Macroscopic
– Gender-specific incidence (per 100 000 per year): • Sites: anywhere in the CNS, particularly the cerebral
Males Females hemispheres (usually in adults, aged 20–40 years) and
Glioblastoma 2.8 1.8 the cerebellum (442), hypothalamus, optic nerve and
Astrocytoma 1.7 1.3 chiasm and pons (the latter of which are more common
Oligodendroglioma 0.15 0.10 in children and adolescents).
Ependymoma 0.15 0.15 • Appearance: solid, grayish white, firm, relatively avascular
tumor, almost indistinguishable from normal white
• Age: any age: matter. Calcium deposits may be present.
– Glioblastoma: peak incidence in middle adult life: mean • Often forms large cavities or pseudocysts.
age 56 years.
– Anaplastic astrocytoma: mean age 46 years. Microscopic
– Oligodendroglioma: any age: most often 20–40 years; • Well differentiated astrocytes of fibrillary type and less
early peak at 6–12 years. frequently plump gemistocytic (gemistos-filled) type.
– Ependymoma: peak incidence at 5 years of age: • Mildly hypercellular, with pleomorphism (443).
Supratentorial: any age. • No vascular proliferation or necrosis.
Infratentorial: 40% occur in the first decade of life; make • Glial fibrillary acidic protein.
up 5–10% of childhood tumors. • Many cerebral astrocytomas are mixed astrocytomas and
• Gender: M>F (2:1). glioblastomas.

PATHOLOGY
• Malignant tumors of glial cells.
• Tumors are graded in various ways. A simple and
reproducible method is based on four histologic features:
pleomorphism of cells and presence or absence of nuclear
atypia, mitosis, endothelial/microvascular proliferation
and necrosis. Any two features classify a tumor as grade
3, and three or four features constitute a grade 4 tumor.
Growth
• A slowly growing, infiltrative tumor.
• May transform to a higher grade tumor.
Oligodendroglioma
Many oligodendrogliomas have deletions of chromosomes 1p
and 19q, and molecular changes such as these may prove to
be the defining criteria for this kind of tumor.
 Gliomas 365

Macroscopic • May extend to the pial surface or ependymal wall, and

• Sites: commonly frontal lobe (40–70%), deep in white metastasize distally in the ventriculosubarachnoid spaces
matter; sometimes lateral ventricle; and rarely in other (accounts for about 10% of gliomas with meningeal
parts of the CNS. dissemination; less frequent than medulloblastoma and
• Appearance: multi-lobular, pink-gray, moderately firm, glioblastoma).
and relatively avascular. • Malignant degeneration (greater cellularity and numerous
• Tends to encapsulate and form calcium and small cysts. and abnormal mitoses) in about a third of cases.
• Little or no surrounding edema.
Ependymoma
Microscopic Macroscopic
• Oligodendrocytes: small, round nucleus and a halo of • Sites: most commonly the wall of the fourth ventricle (70%)
unsustained cytoplasm. Cell processes are few and stubby, (444); other sites include the lateral ventricles of the brain
seen only with silver carbonate stains. and the conus or filum terminale of the spinal canal.
• Calcification is common, mainly in relation to zones of • Appearance: gray-pink, cauliflower-like, firm tumors in
necrosis. the fourth ventricle; large (up to several centimetres in
• Myelin basic protein. diameter), gray-red, softer tumors in the lateral ventricles.
• Many oligodendrogliomas are mixed oligodendroglioma- • May be cystic.
astrocytomas. • Not encapsulated but well defined and homogeneous.
• More clearly demarcated from surrounding brain than
Growth astrocytomas.
• Slow.

441 442

441 Coronal section of the brain at autopsy showing a large 442 Autopsy specimen, section in the axial plane through the
hemorrhagic and necrotic glioblastoma multiforme in the temporal cerebellum and pons, showing a cystic cerebellar astrocytoma in an
lobe causing mass effect with compression of the lateral ventricle and adult. On CT scan (see 452), the mass is partly enhancing, partly cystic
shift of the midline. and has some calcification.

443 444

443 Histologic section of astrocytoma of the brain showing 444 Section through the medulla and floor of the fourth ventricle at
hypercellularity, pleomorphism of cells and mitoses (arrow). autopsy showing an ependymoma in the floor of the fourth ventricle
(arrows).
366 Tumors of the Central Nervous System

Microscopic • CT brain scan shows small ventricles and multifocal areas

• Cells tend to form canals (rosettes) or circular arrange-
ments (pseudorosettes).
• Some are densely cellular and anaplastic (epithelial ependy-
momas); others are more differentiated and form papillae.
• Ciliary bodies.
Growth
• Derived from differentiated ependymal cells lining the
ventricles of the brain and the central canal of the spinal
cord.
• Grow into the ventricle or adjacent brain tissue, and
fourth ventricle ependymomas may extend through the
foramina of Luschka and Magendie.
• Neuraxis dissemination if uncommon (<10%).
ETIOLOGY (see Brain tumors, p.357)
Astrocytoma Primary genetic changes Secondary changes
Astrocytoma p53 mutation
Chromosome 22q loss
Anaplastic p16 gene loss/inactivation E.g.VEGF,
astrocytoma Chromosome 19q loss proteinases
Glioblastoma EGFR mutation of over-expression
multiforme p16 deletions
Mutations in the gene for phosphatase
and tensin homologues (PTEN)
Chromosome 10 loss
Overexpression of platelet-derived
growth factor A and its receptor,
platelet-derived growth receptor α
EGFR: epidermal growth factor receptor
VEGF: vascular endothelial growth factor
CLINICAL
• Epileptic seizures (partial or generalized) are the present-
ing symptom in at least half of patients with oligodendro-
glioma and low grade (grades 1 and 2) astrocytoma, and
develop later in another 10–25% of such patients.
• Focal neurologic symptoms and signs occur referable to
the site of the tumor (e.g. temporal lobe: altered
personality, mood, character, complex partial seizures;
frontal lobe: mild hemiparesis, word-finding difficulty;
cerebellum: limb and gait ataxia). Usually the signs are
not confined to one lobe and it can be difficult enough
to localize the lesion to one region of a hemisphere.
• Diffuse encephalopathy (e.g. cognitive decline, headache),
evolving over a few weeks or months in about a third of
patients with glioblastoma and anaplastic astrocytoma.
• Headache and other features of raised intracranial pressure.
• Cranial or spinal radiculopathies due to meningeal
oligodendrogliosis.
• The onset of symptoms is occasionally abrupt, due to
hemorrhage into the tumor (e.g. glioblastoma,
oligodendroglioma), or rapid expansion of edema.
• Symptoms have often been present for 3–6 months
before the diagnosis is made.
RARE GLIOMAS
Gliomatosis cerebri
• Rare.
• Diffuse infiltration of an entire hemisphere or the entire brain.
• No discrete tumor mass.
• No distinctive clinical syndrome; usually non-specific
cognitive decline, headache, seizures, and papilledema.
of low attenuation (despite the diffuse brain involvement
by tumor).
Choroid plexus papilloma
• Rare: one-fifth as common as ependymoma.
• Occur mainly in childhood: 75% in the first decade.
• Arises from plexus epithelium in the lateral (50%) and
fourth (40%) ventricles commonly, and the third (10%)
ventricle occasionally.
• Takes the form of a giant choroid plexus. May increase
CSF formation.
• Benign usually.
• Occasionally there is carcinomatous transformation with
CSF seeding and malignant meningitis.
• Presents with raised intracranial pressure (often
aggravated acutely by hemorrhage) due to obstructive
hydrocephalus or, less commonly, cerebellar or brainstem
signs if the tumor is in the fourth ventricle.
• The CSF protein is raised.
• Treatment is surgical: excision (which can be difficult)
and/or shunting.
Colloid cyst
• Rare.
• Congenital.
• Site: anterior portion of third ventricle, between the
interventricular foramina and attached to the roof of the
third ventricle (445); derived from ependymal cells.
• Size: usually small (1–4 cm [0.4–1.6 in] in diameter).
• Shape: oval or round, smooth external surface, filled with
gelatinous material containing a variety of mucopoly-
saccharides.
• Histologically benign.
• Neurologically asymptomatic usually.
• May present in adult life with symptoms of hydro-
cephalus which may be acute (paroxysms of generalized
headache that is markedly affected by head position, and
sometimes with loss of consciousness) or chronic
(dementia and gait disturbance).
• CT scan shows a hyperdense cyst that may enhance with
i.v. contrast (446, 447).
• Differential diagnosis includes craniopharyngioma,
choroid plexus papilloma, and ependymoma.
• Treat, if necessary, with ventriculo-peritoneal shunt or
decompression of the cyst by aspiration under
stereotactic guidance.
Optic nerve glioma (see p.372)
OTHER NEUROEPITHELIAL TUMORS
Medulloblastoma
• Accounts for about 20% of all childhood brain tumors
and 50% of cerebellar tumors in children.
• Arises from primitive neuronal cells, usually in the
midline cerebellar vermis (448).
• May fill the cavity of the fourth ventricle (usually
posteroinferiorly) and cause hydrocephalus (449),
infiltrate the floor of the fourth ventricle or adjacent
cerebellar hemispheres or brainstem. Medulloblastoma
may seed through the cranial or particularly the spinal
subarachnoid space, via the CSF, or metastasize to bone,
bone marrow or lymph nodes (rare).
 Gliomas 367

• Symptoms include raised intracranial pressure, cerebellar dysfunction, 445

or back pain with signs of spinal cord compression or nerve root
dysfunction.
• When presenting in older patients (20% occur in young adults), about
half are lateral within the cerebellar hemisphere. Calcification is seen in
20% (449), cystic change in 60–80%.
• Appears hyperdense on CT (449), may contain calcification and may
enhance moderately with contrast.
• On T1WI they are hypointense and on T2WI isointense. Midline
sagittal views are best for visualizing the origin from the superior velum
of the fourth ventricle. Contrast enhancement is moderate.
• Contrast MRI is the best method of detecting seedlings.
• Treatment is by surgery with gross total resection.
• Radiotherapy is comprised of craniospinal axis treatment to 36 Gy
(3600 rads), and 54 Gy (5400 rads) to the primary site. Neuro-
endocrine or neuropsychologic sequelae may be anticipated in younger
patients receiving craniospinal irradiation.
• Chemotherapy is effective in high risk patients.
• 60–80% of patients experience long term disease-free survival.
• The chance of survival is reduced in patients with CSF or neuraxis
dissemination or extra-axial disease.

445–447 Cranial CT scan in 446 447

the axial (446) and coronal
(447) planes, and autopsy
brain specimen cut in the
axial plane (445) showing a
midline colloid cyst in the
third ventricle in the region
of the foramen of Monro
(445) (arrows).

449
448 T1W MRI with contrast 448
of a medulloblastoma in a 2
year old.The lesion arises
posteroinferior to the fourth
ventricle.

449 CT scan without

contrast of the
medulloblastoma in 448.
Note the high density and
calcification.There is
secondary hydrocephalus.
368 Tumors of the Central Nervous System

Pineal cell tumors (pinealomas) • Enhancement may be diffuse or ring-like (455).

• Arise from the pineal gland.
• May compress the rostral dorsal midbrain tectum causing
Parinaud’s syndrome (dilated pupils which do not react
to light but may continue to react to accommodation,
supranuclear impairment of upward gaze and vergence,
and retractory nystagmus).
• Compression of the cerebral aqueduct leads to
hydrocephalus and raised intracranial pressure.
INVESTIGATIONS
Brain imaging (CT and MRI scan)
Astrocytoma and glioblastoma
• The frontal and temporal lobes are common sites, but
they may be supra-tentorial (450, 451) or infra-tentorial
(452–454).
• Appear as mixed component lesions with mass effect,
white matter edema and rapid growth.
• The central necrosis of malignant glioblastoma is shown
as a low density area on CT.
Oligodendroglioma
• Common sites are the frontal and temporal lobes and
within the ventricles.
• Mass effect and low density on CT (unless calcification
or hemorrhage have occurred) are typical, and in the less
malignant forms white matter edema is absent.
• Calcification is frequent (456).
• Hemorrhage and cyst formation appear in 20%.
• Skull erosion may occur.
• Enhancement occurs in 50%.
• On MRI they appear hypointense on T1WI and
hyperintense on T2WI.
• The overall appearance depends on the mix of more
malignant cells with the purer oligodendrocytic elements.
Ependymoma
• In children, most common in the fourth ventricle (444,
457, 458).

450 451 450, 451 CT with contrast

(450) and T2W MRI (451)
of a left occipital low grade
astrocytoma. Note how
difficult it is to see on CT, and
the minimal mass effect.

452 453 452 CT scan with contrast

showing a cystic cerebellar
astrocytoma in an adult.The
mass is partly enhancing,
partly cystic and has some
calcification.The autopsy
specimen is shown in 442.

453, 454 CT with contrast

showing a brain stem glioma
(453) extending into the
posterior part of the corpus
callosum(454). Note the low
density in the brainstem and
the thickened low density of
the corpus callosum (arrows).
 Gliomas 369

• In teenagers and adults, more common in the lateral ventricles or brain 454
parenchyma (20%).
• 40–50% contain calcification, typically punctate.
• Tend to spread by seeding throughout the subarachnoid space.
Contrast is essential to detect seed metastases.
• Frequently causes hydrocephalus.
• Enhances mildly with contrast.
• On MR they appear hypointense on T1WI and intermediate on T2WI.
• Ependymomas also occur in the spine, accounting for 50–60% of spinal
cord tumors in 20–40 year olds, and 25% of spinal cord tumors in
children (see Spinal cord tumors, pp).

CSF
• Pressure: increased in some cases.
• Cells: acellular or occasional pleocytosis of 10–100 cells/mm3 or more,
mostly lymphocytes, occasional blood.
• Protein: normal or mildly increased in low grade astrocytoma, increased
>1.0 g/l (100 mg/dl) in many cases of glioblastoma.
• Cytology: malignant cells may be identified.

454 CT with contrast 455 456

showing a brain stem glioma
extending into the posterior
part of the corpus callosum.
Note the low density in the
brainstem and the thickened
low density of the corpus
callosum (arrows). See also
453.

455 CT brain scan with

contrast of a primary tumor,
probably an astrocytoma.
Note the central necrosis,
thick rim of enhancement
and surrounding edema
(arrows).

456 CT scan with contrast

of a frontal oligodendro-
glioma. Note the calcification
(whiteness) and considerable 457 458
mass effect.The tumor has
reached this size partly
because of its position in the
relatively ‘silent’ frontal lobes.
There is relatively little
edema.

457, 458 CT brain scan

with contrast (457) and
PDW MRI (458) of an
ependymoma.There is a large
enhancing mass closely
related to the fourth
ventricle without calcification.
370 Tumors of the Central Nervous System
Pathology
Tissue biopsy
Aims to establish the tissue diagnosis if there is clinical and
CT or MRI brain scan evidence of a mass lesion and to
exclude treatable differential diagnoses such as brain abscess,
lymphoma, meningioma, and tuberculoma. About 50% of
patients between 30 and 50 years of age who have a non-
enhancing lesion on CT suggestive of a low grade glioma turn
out to be harboring a high grade malignant glioma. These
patients should undergo early biopsy or surgical resection for:
• Histology.
• Cytology.
• Immunohistochemistry.
• DNA index: a rapid estimate, using flow cytometry
techniques, of the DNA content of a tumor cell
compared with that of a normal diploid cell. It may
identify patients who may benefit from more intensive
therapy for certain tumors (e.g. medulloblastoma).
Biochemical tests
Tumor markers in serum and CSF (e.g. alpha fetoprotein
and beta-human chorionic gonadotrophin [βHCG]).
DIAGNOSIS
Based on appropriate clinical features and imaging studies
followed by tissue biopsy or surgery.
PROGNOSIS
Glioblastoma
• Median survival:
– 14 weeks if steroids and maximally feasible surgical
resection only.
– 35 weeks (i.e. an additional 5 months) with a combin-
ation of surgery and radiation therapy. Adjuvant chemo-
therapy modestly increases survival at 1 year but this
disappears by 2 years.
• 18-month post operative survival: 15%.
• 2-year survival after treatment: 5–10%.
Anaplastic astrocytoma
• Median survival: 27 months–3 years.
• 18-month post operative survival: 62%.
• 2-year survival: 50%.
Astrocytoma
Mean survival after first symptom:
• Cerebral astrocytoma: 67 months.
• Cerebellar astrocytoma: 89 months.
• Cystic cerebellar astrocytoma: particularly benign.
Surgical excision of juvenile cerebellar astrocytoma leads
to a 10-year survival rate of >80%. Indeed, 10% survive
25 years after excision of the cyst.
• Pilocytic astrocytomas of the cerebral hemispheres: gross
total removal of the tumor can improve 5-year survival
to 85% and 10-year survival to about 80%.
Oligodendroglioma
• Survival is variable, from weeks to many years, after
surgical confirmation of the histologic diagnosis median
survival – 16 years.
• Recently recognized to be uniquely sensitive to chemo-
therapy: 75% of patients with malignant oligodenroglioma
now respond to treatment with a regimen of procabazine,
lomustine and vincristine, and 50% recover completely.
Chemotherapy is probably not curative in patients with
low-grade oligodendroglioma but it can produce sus-
tained remissions with durable clinical improvement.
• Eventually, most oligodendrogliomas, like astrocyomas,
progress and become malignant.
Ependymoma
• Median survival: 12 months.
• 5-year disease-free survival: 30–60%.
• 10-year survival; 10–15%.
Prognosis is worse with young age, incomplete resection,
metastases, brainstem invasion, or radiation therapy doses
<45 Gy (<4500 rads).
Prognostic factors
Favorable
• Good clinical performance status (WHO): independent
in activities of daily living and self care: 80% chance of
survival free of disability for 6 months.
• Young age at diagnosis.
• History of epileptic seizures as a presenting feature.
• Partial or complete surgical resection compared with
biopsy alone.
• Low tumor grade.
• Absence of necrosis.
• Complete surgical resection.
• Treatment with radiotherapy.
Poor
• Poor clinical performance: functionally disabled and
dependent (e.g. often confined to bed or chair) at the
time of treatment.
• Increasing age.
• Tumor histology (anaplastic astrocytoma or glioblastoma
multiforme) and grade (high).
These data mean that patients older than 60 years of age
who are disabled due to glioblastoma multiforme will derive
little benefit from aggressive treatment whereas a 35 year
old with minimal neurologic deficit and post-resection
histology showing anaplastic astrocytoma has a high
probability of remaining well for 18 months or longer if
treated with the optimal schedule of high dose radiotherapy.
TREATMENT
• A multidisciplinary neuro-oncology team approach
(neurosurgeons, radiation therapists, neuro-oncologists,
endocrinologists, rehabilitation teams, neuro-
psychologists, social workers, nurses) is required.
• Indicated if the benefits of treatment (e.g. survival with
an acceptable quality of life) are likely to outweigh the
risks and toxicity of treatment.
• Determined by the age and functional status of the
patient, and the site and pathology of the glioma. For
some gliomas such as optic gliomas (which are frequently
associated with neurofibromatosis), thalamic glioma or
brainstem gliomas, the site clearly restricts treatment
options. The site also influences biologic behavior. For
example, cerebellar gliomas behave differently from
supratentorial tumors with the same histology.
 Gliomas
Glioblastoma and anaplastic astrocytoma
Surgery
• Only partial resection is possible due to the multicen-
tricity and the diffusely infiltrative nature of the tumor.
• Attempted gross total resection is associated with longer
survival and improved neurologic function.
• Median survival is about 14 weeks if steroids and
maximally feasible surgical resection only are given.
Radiotherapy
• A total of up to 60 Gy (6000 rads) given in fractions of
1.8–2.0 Gy (180–200 rads) each weekday for 3–6 weeks
significantly prolongs survival.
• Median survival is about 35–38 weeks (i.e. an additional
5 months) if radiation therapy is combined with surgery.
Chemotherapy
• Various chemotherapy regimes have been used but none
has consistently been shown to have a substantially
favorable influence on outcome. Single agent nitrosurea
therapy or BCNU (carmustine) or temozolomide is used
widely as adjunctive therapy after surgery and radiotherapy,
or after glioma recurrence, with a small improvement in
survival. A combination of drugs (e.g. procarbazine,
lomustine, and vincristine [PCV]) can achieve somewhat
longer survival if there is an oligodendroglial component.
• Relapse is invariably due to recurrence within 2 cm
(0.8 in) of the original lesion. This is because malignant
glioma cells have an inherently high chemoresistance
(and radioresistance) with a large capacity for DNA repair
and because of failure of drug delivery.
• Therapeutic approaches designed to improve drug
delivery include supraophthalmic intracarotid arterial
infusion, osmotic opening of the blood–brain barrier,
and the use of implantable polyanhydride polymers
impregnated with chemotherapeutic agents.
Astrocytoma
Surgery
• For young patients (<35 years of age), extensive surgical
resection generally leads to an improved outcome, if it can be
performed safely. They can be followed without administering
radiotherapy. If surgery is not performed, the patient’s pro-
gress should be followed closely. Subsequent indications for
surgery include a need for a tissue diagnosis, clinical neuro-
logic deterioration that can be treated surgically, impending
herniation, hydrocephalus and uncontrollable seizures.
• Older patients (>35 years ) should undergo early biopsy
or surgical resection. The extent of surgical resection is
probably not as important as it is in younger patients,
partial excision (especially the cystic part) may preserve
survival free of dependency for several years.
Radiotherapy
• Improves survival.
• Radiotherapy should be given to most patients older than
35 years, independent of the extent of surgical resection,
because this is associated with a 5-year survival of 30% or more.
• The radiation field should be limited to the tumor bed
with large margins; whole brain irradiation increases the
likelihood of late radiation damage.
371
• Two randomized, controlled trials have demonstrated
equivalence in survival and time to disease progression
between patients with low-grade astrocytoma who
received focal radiotherapy at low dose (50.4 or 45.0 Gy
[5040 or 4500 rads]) at the time of diagnosis and those
who received a high dose (64.8 or 59.4 Gy [6480 or
5940 rads]). However, higher doses of radiation were
associated with a higher incidence of fatigue, malaise,
insomnia, and poor emotional functioning, suggesting
that lower doses are the superior treatment.
• Immediate radiotherapy (after surgery or biopsy) is
associated with a significantly delayed time to disease
progression, compared with deferral of radiotherapy, but
does not improve overall survival. Consequently, patients
with low-grade astrocytoma who are neurologically
normal or whose seizures are controlled, whether or not
they have undergone tumor resection, should be
followed until there is evidence of tumor progession.
• Some astrocytomas, such as those causing focal neurologic
signs (e.g. hemiparesis), require immediate intervention
(surgical debulking followed by radiotherapy to the
involved field, with a total dose ≤54 Gy [≤5400 rads]).
There is no indication for the routine use of chemotherapy
in the treatment of astrocytomas.
Chemotherapy
There is no indication for the routine use of chemotherapy
in the treatment of astrocytomas.
Oligodendroglioma
Recently recognized to be uniquely sensitive to chemotherapy.
Surgery
Excision of anaplastic oligodendrogliomas.
Radiotherapy
• After surgery, for mixed oligodendrogliomas and
astrocytomas (i.e. as for astrocytomas).
• Total dose of 54 Gy improves symptoms and probably
prolongs survival.
• Not indicated for well-differentiated oligodendrogliomas
(cf. Chemotherapy).
Chemotherapy
• Effective for anaplastic oligodendrogliomas: PCV.
• Chemosensitivity linked to loss of heterozygosity at
chromosomes 1p and 19q.
• Agents that appear to have some efficacy against recurrent
oligodendroglial tumors include melphalan, thiotepa,
temozolomide, carboplatin, cisplatin, and etoposide.
Ependymoma
Surgery
Surgery (gross total resection) followed by radiotherapy.
Controversies concerning radiation fields (local field versus
craniospinal treatment) are ongoing.
Chemotherapy
Chemotherapy may be of value in infants to defer radiation
therapy in patients with recurrent disease Chemotherapy
combined with radiotherapy may also be useful for cerebral
ependymoblastomas.
372 Tumors of the Central Nervous System
OPTIC NERVE GLIOMA
DEFINITION
Glial tumor (usually pilocytic astrocyoma) of the optic pathway.
EPIDEMIOLOGY
• Incidence: uncommon: about 1% of primary intracranial
tumors; about 2–5% of all brain tumors in childhood, about
5% (1.5–7.5%) of children with neurofibromatosis-1 (NF1).
• Age: 50% present before the age of 5 years, 90% before age
20. Chiasmal lesions are more frequent in adolescents than
in children.
• Gender: F>M (2:1).
PATHOLOGY
• The vast majority are pilocytic astrocytomas (histologically
identical to pilocytic astrocytomas elsewhere in the CNS),
WHO grade 1 (459, 460); anaplastic astrocytoma occurs
rarely.
• Two architectural forms:
– Diffuse expansion and obstruction of the optic nerve
without extensive subarachnoid spread.
– Predominant infiltration of the subarachnoid space leaving
the mildly involved nerve surrounded by a rim of tumor
tissue.
• Most are slowly growing and grow along optic pathways
(causing enlargement of the optic nerve [50%], optic chiasm
[45%], or optic tract [5%]) and invade the subarachnoid
space, causing hyperplasia of the overlying arachnoid mater,
known as arachnoid gliomatosis. Optic nerve gliomas may
also invade the anterior hypothalamus and cause obstruction
of the foramen of Monro and obstructive hydrocephalus.
Tumor growth is generally limited by dura.
ETIOLOGY AND PATHOPHYSIOLOGY
15–20% of optic gliomas occur in patients with neurofibro-
matosis; 50–70% of optic gliomas in children are associated
with neurofibromatosis; 15–25% (50–70% of children) are as-
sociated with neurofibromatosis (see p.147).
CLINICAL FEATURES
• Slowly progressive visual deterioration: dimness of vision
with decreased visual acuity and color vision; abnormal
pupillary function; constricted fields, followed by variable
visual field defects, depending on the location of the tumor,
that can be monocular, binocular, eccentric, centrocecal
homonymous, heteronymous, and bitemporal, and
progressing to blindness; and optic atrophy with or without
papilledema. Papilledema with or without a field cut implies
involvement of the hypothalamus and obstructive
hydrocephalus whereas papillitis and central visual field loss
suggests an orbital lesion.
• Ocular proptosis due to the orbital mass.
• Nystagmus, if chiasmatic involvement.
• Hypothalamic and pituitary dysfunction occur occasionally
in gliomas involving the optic chiasm (e.g. accelerated linear
growth due to precocious puberty; adiposity, polyuria,
somnolence).
• Secondary hydrocephalus.
DIFFERENTIAL DIAGNOSIS
• Optic neuritis (see p.489): sarcoidosis, multiple sclerosis.
• Optic nerve hamartoma (NF1, see p.147).
• Meningioma (see p.374): medial sphenoid, olfactory
groove, intraorbital.
• Pituitary adenoma (see p.379).
• Diencephalic glioma: gliomas arising in the hypothalamus
or thalamus.
• Hand–Schuller–Christian disease.
• Craniopharyngioma (suprasellar epidermoid cyst) (see
p.377).
INVESTIGATIONS
CT brain scan
Coronal, sagittal and axial studies:
• The optic nerve appears enlarged (fusiform or nodular) and
tortuous.
• Calcification is rare.
• Enhancement is variable.
• There may be cystic components.
• The optic canal may be enlarged (also visible on plain films
of the orbit) if the tumor extends that far back.
• The tumor may be bilateral and extend back into the chiasm.
MRI scan
• The appearance is similar to that on CT but the detail is
more clearly seen.
• The lesion appears isointense on T1WI (461) and iso- to
hyperintense on T2WI (462).
• It is impossible to separate the tumor from the nerve
radiologically (as opposed to meningiomas where it is often
possible to distinguish the tumor from the nerve).
• MRI also defines the intracranial portion of the tumor better
than CT.
• Magnetic resonance spectroscopy enables assessment of the
biochemical composition of focal areas within the tumor and
other regions of the brain.
Visual evoked potentials
Help establish and localize the lesion and establish the
functional integrity of the visual system.
Blood for DNA analysis
Mutation of the NF1 gene located on chromosome 17q11.2.
Chiasmal biopsy
Contraindicated since it is the main cause of visual deterioration
and is associated with significant but unexplained mortality.
DIAGNOSIS
The clinical diagnosis of an optic pathway tumor is confirmed
by CT or MRI scan, and the pathology by tissue biopsy.
TREATMENT
• Depends on the nature of the symptoms, and the location
and rate of growth of the tumor; there is no universal
approach to treatment
• Children with symptomatic optic pathway glioma,
particularly if it involves the chiasm and either the optic
nerves or the posterior regions of the visual pathway, should
be closely followed, particularly for the development of
precocious puberty (e.g. signs of premature secondary
sexual characteristics, or accelerated linear growth rate,
detected by yearly measurements of height and weight
plotted on standard pediatric growth charts) and evidence
of reduced visual acuity, color vision or visual fields or
changes on slit lamp examination and fundoscopy.
 Optic Nerve Glioma
• Treatment is indicated for progressive proptosis or loss of
vision, or neuroradiographic progression.
• Therapeutic options include surgery, radiation, chemo-
therapy, or a combination of these modalities.
• A blind eye due to intraorbital glioma can be removed
surgically for cosmetic reasons or to prevent potentially
further extension of the tumor into the chiasm (which must
be very rare). Surgery has a limited role in the treatment of
chiasmatic gliomas that may or may not also involve the
optic nerve or the posterior portion of the visual pathway.
Otherwise, surgical excision is generally inappropriate
because the short term risks outweigh the longer term
benign course.
• Radiotherapy should be reserved primarily for patients with
isolated intraorbital gliomas and residual useful vision,
progressive (either visual or radiographic) isolated optic nerve
gliomas (because tumor progression may be halted, at least
temporarily) or extraorbital (e.g. optic chiasm) optic pathway
glioma, but the long term efficacy for disease control is
questionable. As many patients are children, and as these
459
459, 460 Histology of optic nerve glioma showing infiltration of the
optic nerve by glioblasts and astrocytes.
462 T2W axial MRI of the brain in NF1 showing areas of increased
signal in the basal ganglia bilaterally, worse on the right, also visible in
the periventricular white matter (arrows).The precise nature of these
is the subject of debate.
461 T1W MRI of the orbits showing an optic nerve glioma in NF1. Note
the thickened optic nerves bilaterally (arrows).
461
373
tumors may be quite extensive, large volumes of normal
young brain may be included in the radiation portal; there are
significant potential neurocognitive and endocrinologic
sequelae of radiotherapy to consider before embarking on this
treatment, let alone the theoretical possibility of radiotherapy
inducing more malignant transformation of the tumor.
• There are few data to support the efficacy of chemotherapy
in intraorbital glioma. The combination of carboplatinum
and vincristine appears promising for extraorbital optic
pathway glioma but this therapy still remains experimental.
PROGNOSIS
• May vary from extreme indolence to rapid progression
but most are very slow-growing.
• Optic pathway gliomas in children with NF1 infrequently
progress once the tumors have come to medical
attention: in one study, demonstrable tumor growth or
progression of visual disturbances occurred in only 3 of
26 children over a mean follow-up period of 4.2 years.
• 20-year survival rate: 40–50%.
460
462
374 Tumors of the Central Nervous System
MENINGIOMA
DEFINITION
A generally benign tumor, which originates from
meningothelial cells of the dura mater or arachnoid.
EPIDEMIOLOGY
• Incidence: 7.8 per 100 000 per year (2 per 100 000 per
year in symptomatic patients). Most are asymptomatic
tumors discovered incidentally at autopsy. 15–20% of all
primary intracranial tumors and the most common
benign brain tumor.
• Age: 40–70 years old; highest incidence in seventh
decade.
• Gender: F>M (2:1).
PATHOLOGY
• Arise from the arachnoid cap cell in the arachnoid layer
of the meninges and almost always have a dural
attachment.
• Rarely arise from arachnoidal cells within the choroid
plexus, forming intraventricular meningiomas.
Macroscopic
• Firm, gray and sharply circumscribed; clearly demarcated
from brain tissue (463).
• Takes the shape of the space in which it grows: may be
flat and plaque-like, or round and lobulated.
• Sites of origin:
– Olfactory groove:
Arise from arachnoidal cells along the cribriform plate in
the floor of the anterior cranial fossa.
May reach enormous size before coming to medical
attention.
– Tuberculum sellae.
– Lesser wing of sphenoid bone (sphenoidal ridge):
May grow medially and compress structures in the wall
of cavernous sinuses.
May grow anteriorly into the orbit.
May grow laterally into the temporal bone.
– Parasagittal surface of the frontal and parietal lobes (falx
meningioma).
– Sylvian region.
– Superior surface of the cerebellum.
– Cerebellopontine angle.
– Spinal canal.
• Extend to dural surface and often invade and erode
cranial bones or excite an osteoblastic reaction; some give
rise to an exostosis on the external surface of the skull.
• Most are histologically benign, 5% are atypical and 2%
show frankly malignant, invasive qualities.
Microscopic
Cells
• Uniform with round or elongated nuclei.
• Visible cytoplasmic membrane.
• Tend to encircle one another, forming whorls and
psammoma bodies (464–466).
Histologic features suggesting malignant change
• Hypercellularity.
• Mitotic figures.
• Nuclear atypia.
• Necrosis.
• Invasion of surrounding brain.
Histologic classification
• Groups:
– Classic: meningothelial, syncytial, transitional, fibro-
blastic, psammomatous, angiomatous, microcystic,
secretory, clear cell, choroid, lymphoplasmacyte-rich
and metaplastic variants.
– Atypical.
– Papillary.
– Anaplastic.
• Grades:
1 Benign (the vast majority).
2 Atypical.
3 Anaplastic.
4 Sarcomatous.
Cytogenic and molecular
There are multiple deletions on chromosome 22 in nearly
all fibroblastic meningiomas and one-third of meningo-
thelial meningiomas.
ETIOLOGY AND PATHOPHYSIOLOGY
• The cell of origin, the arachnoid cap cell, has a slow rate
of cell division.
• Tumorigenesis is probably the result of exogenous or
endogenous factors acting alone or together.
Exogenous factors implicated in the development
of meningiomas
• Prior irradiation to the scalp or brain (definite):
increased risk and earlier age of onset of meningioma.
• Trauma (possible).
• Viral infection (possible).
Endogenous factors implicated in the development
of meningiomas
• Hormones: progestins, androgens, glucocorticoids.
Meningiomas occur twice as often in women as in men,
they are more common in people with breast carcinoma
and they may enlarge during pregnancy. They express
estrogen and progesterone receptors, and some may
express D1 dopamine receptors. Androgens may
regulate progesterone receptors in meningioma cells
and may induce synthesis of EGFR.
• Growth factors: platelet-derived growth factor and
epidermal growth factor.
• Genetic:
– Loss of one chromosome 22q, which is also the
molecular characteristic of NF2 (in nearly half of cases),
or a partial deletion of chromosome 22q (in another
20% of cases).
– Mutations in the NF2 gene in sporadic meningiomas.
CLINICAL FEATURES
Small (<2.0 cm [0.8 in] diameter) surface
meningiomas
Asymptomatic: do not compress neural tissue.
 Meningioma 375

Parasagittal fronto-parietal meningioma 463

• Partial seizures.
• Slowly progressive spastic paraparesis.
• Altered sensation of one leg and later both legs.
• ‘TIA-like’ presentations of sudden onset of leg ± arm
weakness or sensory change.

Olfactory groove meningioma

• Anosmia: ipsilateral (rarely reported by patient) or
bilateral, due to compression of the olfactory bulb.
• Blindness: ipsilateral or bilateral, often with ipsilateral
optic atrophy and contralateral papilledema (Foster
Kennedy syndrome).
• Frontal lobe syndrome later: abulia, confusion,
forgetfulness, inappropriate jocularity (Witzelsucht), due
to compression of the inferior frontal lobe.

Tuberculum sellae meningioma

• Visual failure: a slowly advancing bitemporal hemianopia
with a sella of normal size.
• Visual field defects are often asymmetric due to
involvement of the optic chiasm and optic nerve.
• No hypothalamic or pituitary deficits usually.

Sphenoidal wing meningioma (medial)

Loss of vision and optic atrophy ipsilaterally (optic nerve
compression at the optic foramen), sometimes with papilledema
in the contralateral eye (Foster Kennedy syndrome). 463 Axial section of brain showing a large, round, gray and vascular
left frontal meningioma (arrows). (Courtesy of Professor BA Kakulas,
Sphenoidal wing meningioma (lateral, near Royal Perth Hospital,Western Australia.)
superior orbital fissure)
• Exophthalmos ipsilaterally: slowly developing.
• Diplopia (compression of cranial nerves III, IV and VI).
• Upper facial sensory disturbance (compression of cranial
nerve V1).
• A family history may be present. 464

464–466 Histologic sections of a meningioma showing arachnoid cells

arranged in whorls and prominent vascularity. (Courtesy of Professor
BA Kakulas, Royal Perth Hospital,Western Australia.)

465 466
376 Tumors of the Central Nervous System
DIFFERENTIAL DIAGNOSIS
Tuberculum sellae meningioma
• Pituitary adenoma.
• Aneurysm of the terminal carotid artery.
Sphenoid ridge meningioma
• Sarcoma arising from skull bone.
• Orbitoethmoidal osteoma.
• Benign giant cell bone cyst.
• Optic nerve tumors.
• Orbital angioma.
• Metastatic carcinoma.
INVESTIGATIONS
CT brain scan (467, 468)
• Meningiomas arise from any dural surface and push the
brain away.
• They are usually rounded or lobulated, iso- or slightly hypo-
dense lesions that have well-defined, sharply demarcated
contours and enhance strongly with i.v. contrast.
• There may be an enhancing dural ‘tail’ extending from the
tumor margin.
• White matter edema varies from none (usually) to extensive
(occasionally).
• Thickening of the adjacent bone (hyperostosis) may be
visible.
• Calcification is occasional though can be dense.
• Large dilated venous sinuses around the tumor may be
visible.
• The mass effect is usually less than for a similar sized intrinsic
tumor as the slow growth allows time for the normal brain
to shift and adapt to the presence of the meningioma.
MRI brain scan
• Meningiomas are often isointense to gray matter on
T1WI and T2WI, so if small may be overlooked.
• They enhance strongly with i.v. contrast (gadolinium).
• Their other features are as described for CT.
Cerebral angiography
• There is usually enlargement of the meningeal arteries
(branches of the external carotid) which supply the
meningioma.
• Some arterial supply may come from the internal carotid
arteries also.
• The venous drainage is usually to the intracranial dural
venous sinuses.
• Some centres offer particulate embolization of
meningiomas prior to surgery to reduce the vascularity
and blood loss during tumor removal.
CSF
Increased protein; may be very high (2.0–4.0 g/l
[200–400 mg/dl]) with olfactory groove meningioma.
DIAGNOSIS
• Some meningiomas reach an enormous size before the
diagnosis is established.
• Diagnosis is suggested by contrast-enhanced CT and MRI,
and angiography, but is confirmed histologically.
TREATMENT
Conservative
Incidentally discovered meningiomas can be followed safely
with CT or MRI.
Surgical excision
• The mainstay of therapy.
• Effective for accessible surface tumors that can be totally
resected, such as meningiomas of the convexity dura, falx,
lateral sphenoid wing, frontal base and posterior-fossa dura.
A cuff of normal dura should be removed to reduce the
chance of marginal recurrence.
• Tumors that lie beneath the hypothalamus, along the
medial part of the sphenoid bone and parasellar region and
anterior to the brainstem are the most difficult to remove
surgically. They are inoperable if they invade adjacent bone.
Stereotaxic radiosurgery
Appropriate for some well localized (i.e. not adjacent to the
optic nerve or other critical structures) and small (<3 cm
[<1.2 in] in diameter) meningiomas, particularly in the skull
base.
Radiotherapy
Fractionated, external beam, radiation therapy can delay
regrowth or recurrence and is indicated if the tumor is
inoperable, incompletely resected or histologically aggressive.
Interstitial brachytherapy
• Used for recurrent benign and malignant meningiomas
that have failed to respond to standard therapies, are
amenable to repeat operation, and have a residual tumor
thickness that does not exceed a few millimetres.
• Both stereotactic and open craniotomy techniques have
been used for placement of the radiation sources (e.g.
iodine-125).
Cytotoxic chemotherapy
Little success to date. Hydroxyurea appeared promising in
preliminary reports. But shown recently to be ineffective.
Biologic therapies
Experimental (e.g. hormone receptor antagonists).
PROGNOSIS
• Slow rate of growth.
• Not always curable; the rate of recurrence depends on
the site of the tumor, its biologic aggressiveness, and the
completeness of the resection.
• Complete excision is associated with permanent cure in
many cases; invasive growth leads to recurrence in about
2% of patients per year (i.e. 20% at 10 years).
• Subtotal resection and malignancy are associated with a
higher rate of recurrence: for benign meningiomas, the
5 year rate of survival free of progression is about 90%
and at 10 years about 75%; whereas for malignant menin-
giomas, 5 year survival free of progression is only about
50%. More than 80% recur after partial resection.
• Histology alone may be inadequate to characterize
accurately the biologic behavior of meningiomas. Age is
an important independent prognostic factor for survival.
 Craniopharyngioma 377

467 CRANIOPHARYNGIOMA

DEFINITION
A rare, congenital cystic tumor which arises from cell rests
(embryologic remnants of pharyngeal epithelium in
Rathke’s pouch) above the pituitary fossa and gives rise to
a suprasellar mass that compresses and infiltrates adjacent
local structures, causing endocrine or visual symptoms in
children and young adults.

EPIDEMIOLOGY
• Incidence: rare, 2–3% of all brain tumors.
• Age: children predominantly, but may present in adults
of all ages.
• Gender: M=F.

ETIOLOGY AND PATHOGENESIS

• Congenital.
• The tumor arises from cell rests (embryologic remnants
of Rathke’s pouch) above the pituitary fossa at the
junction of the infundibular stem and pituitary gland.

PATHOLOGY
• Usually the tumor lies above the sella turcica, depressing
the optic chiasm and extending up into the third
468 ventricle.
• Less often it is subdiaphragmatic, within the sella, where
it compresses the pituitary body and erodes one part of
the wall of the sella or a clinoid process, but seldom does
it balloon the sella like a pituitary adenoma.
• A cystic tumor, containing dark albuminous fluid,
cholesterol crystals, and calcium deposits; it is partly calci-
fied by the time it is 3–4 cm (1.2–1.5 in) in diameter.
• Infiltrates locally.
• The sella beneath the tumor becomes flattened and
enlarged.

CLINICAL FEATURES
Presents in children and young adults with any one or a
combination of the following syndromes:
• Hypothalamic dysfunction: hypopituitarism (growth
failure in children: delayed physical and mental
development, diabetes insipidus, adiposity, amenorrhea,
disturbed temperature regulation, sexual dysfunction).
• Progressive or intermittent optic nerve or chiasm
compression (visual loss).
• Obstructive hydrocephalus (raised intracranial pressure:
headaches, vomiting).
• Frontal lobe symptoms (mental dullness, confusion,
spastic leg weakness).
467, 468 CT brain scan pre- (467) and post (468) i.v. contrast. Pre-
contrast the meningioma appears similar to adjacent brain and is
causing relatively little displacement of the normal brain for its size. Post
i.v. contrast there is intense enhancement (whiteness) making the
tumor very obvious. Note the rounded shape, the flat surface against
the inner skull table where it arises from the dura, the small granular
calcifications (white spots), and the relative lack of white matter edema
and mass effect. Also see 715 and 716 for spinal meningioma.
378 Tumors of the Central Nervous System

INVESTIGATIONS DIFFERENTIAL DIAGNOSIS

Imaging • Optic nerve/chiasm tumor (see p.372).
• Skull x-ray and CT brain scan may reveal calcification in • Meningioma (see p.374)): medial sphenoid, olfactory
the region of the pituitary gland. groove.
• CT and MRI scan reveal a mass immediately superior to • Pituitary adenoma (see p.379).
or arising out of the pituitary fossa (469, 470). The mass • Chondroma.
may be at least 2 cm (0.8 in) in diameter. It may • Hypothalamic glioma.
compress the optic chiasm and indent the third ventricle. • Supraclinoid carotid artery aneurysm.
Large tumors may obstruct the foramen of Monro. • Choroid plexus papilloma.
Typical features include calcification, solid and cystic • Colloid cyst of the third ventricle.
elements, and enhancement with contrast, usually in a
young person (471, 472). The calcification and cystic
elements are better appreciated on CT but the tumor
definition is generally better seen on MRI (with
contrast). MRI T1W images may show increased signal
in the mass lesion due to the cholesterol content.

469 470

469, 470 Sagittal (469) and coronal (470) T1W MRI of the pituitary fossa after contrast injection showing an ovoid, 10 × 12 mm (0.4 × 0.5 in)
mass of homogeneous brain signal intensity (arrows) in the suprasellar cistern applied to the inferior surface of the optic chiasm, more on the right
than the left, and anterior to the infundibulum of the pituitary gland.The optic chiasm is mildly elevated on the right side.The pituitary gland
appears normal.The mass enhances mildly with contrast and is a craniopharyngioma.

471 472

471 T1W MRI (sagittal plane) of a craniopharyngioma (arrows) in a 472 T1W coronal MRI with contrast (same patient) shows the lesion
20 year old male. Note the mixed signal elements with cysts and enhances markedly and irregularly with a prominent cyst extending up
extension to the foramen of Monro. into the third ventricle. On MRI the calcification often associated with
these tumors is difficult to appreciate and CT may help.
 Pituitary Tumors 379

TREATMENT PITUITARY TUMORS

Treatment is controversial, because the risks of complete
surgical resection (memory deficits, appetite and behavioral
disturbances and endocrine dysfunction) have to be weighed
against the potential growth of any remaining remnants.
Surgery
• Surgical excision of all or part of the tumor (difficult to
remove completely).
• Corticosteroid therapy before and after surgery.
• Careful control of fluid and temperature balance post
operatively.
Radiation therapy
External-beam radiation if any residual tumor.
Palliation
• Stereotactic aspiration.
• Radiation therapy.
• Ventricular shunting.
PROGNOSIS
Mortality:
• 5–10% when complete surgical resection is attempted
(i.e. smaller tumors).
• Higher mortality when only partial removal is possible
(i.e. larger and more infiltrative).
• 10-year survival was 76% for patients undergoing surgical
resection and radiation and 17% for patients undergoing
resection alone in one uncontrolled series of 74 cases.
473
DEFINITION
Pituitary tumors are mostly benign epithelial neoplasms that
result from mutation and subsequent clonal expansion of
single adenohypophyseal parenchymal cells.
EPIDEMIOLOGY
• Incidence: 10–15% of intracranial neoplasms; occult
pituitary adenomas are found in up to 20% of random
post mortem examinations.
• Age: adults, mean age 60 years.
• Gender: M≥F.
PATHOLOGY
• Adenoma (473–475): benign slowly growing tumors.
However, prolactinomas may rapidly expand during
pregnancy and cause subacute onset of neurologic
dysfunction.
• Three-quarters secrete inappropriate amounts of pituitary
hormones and one-quarter are ‘non-functioning’.
• Tumors are classified histologically on the basis of
immunoperoxidase stains to identify specific hormones.
The most common hypersecretory tumors of the
pituitary are prolactin secreting, followed by adenomas
that secrete growth hormone, ACTH, and rarely
gonadotropin (10%) and TSH (<10%).
• Gonadotrophic pituitary adenomas are inefficient
producers and secretors of the gonadotroph hormones:
LH, FSH, and the α-subunit of the pituitary
glycoprotein hormones. Even when gonadotrophin
hypersecretion occurs, no distinctive clinical endocrine
phenotype is present.
• Non-secreting adenomas, which comprise about 20–25%
of all pituitary tumors, are usually chromophobe
adenomas.

473–475 Histologic sections of a pituitary tumor at low, medium and

high power showing pleomorphic cells.

474 475
380 Tumors of the Central Nervous System

ETIOLOGY AND PATHOPHYSIOLOGY Local pressure on the optic chiasm, optic nerves, or
Unknown. rarely optic tract
Visual field defects in one or both eyes:
CLINICAL FEATURES • Lateral visual field defects (classically bitemporal hemianopia).
Most patients present with symptoms and signs of: • Scotomas.
• Complete blindness.
Hypersecretion of one or occasionally several
pituitary hormones Visual field testing by confrontation is insensitive and should
Hyperprolactinemia (prolactinoma) be followed by formal analysis. Goldmann perimetry is highly
• Women (pre-menopausal): dependent on the operator whereas computerized field testing
– Infertility. with a field analyser (Allergan Humphrey) gives highly
– Amenorrhea, oligomenorrhea, or normal periods. reproducible results and takes about 15 minutes for each eye.
– Galactorrhea.
– Decreased libido. Local pressure on the cavernous sinus
– Vaginal dryness and dyspareunia. Cranial nerve palsies: III, IV, V, VI.
– Delayed menarche.
• Men: Local pressure on the temporal lobes
– Decreased libido. Temporal lobe epilepsy.
– Impotence sometimes.
– Galactorrhea unusually. Local pressure on the third ventricle
– Reduced growth of facial and body hair. Obstructive hydrocephalus.
– Small, soft testes.
– Apathy. Other presentations
– Weight gain. • Headaches: non-specific, inconstant, seldom severe,
relieved by analgesics frequently and almost immediately
Growth hormone excess (growth hormone-producing by somatostatin in some patients.
adenoma) • Asymptomatic pituitary mass detected by CT or MRI.
• Gigantism in children. • Pre-operative diabetes insipidus is extremely rare in
• Acromegaly in adults. primary pituitary disease and suggests involvement of the
hypothalamus or pituitary infarction.
ACTH (corticotropin) excess
• Rare. DIFFERENTIAL DIAGNOSIS
• Cushing’s disease (476). Suprasellar lesions
Craniopharyngiomas, optic gliomas, chondromas, hypothala-
Hyposecretion of pituitary hormones due mic gliomas, supraclinoid carotid artery aneurysms, choroid
to pituitary gland infarction, hemorrhage plexus papillomas, and colloid cysts of the third ventricle.
or local pressure
Hypopituitarism Intrasellar lesions
• Hypogonadism: Pituitary adenomas, arachnoid cysts, and rare tumors of the
– Women: neurohypophysis.
Oligomenorrhea or amenorrhea.
Reduced libido. Perisellar lesions
Dyspareunia. Meningiomas, metastases, dermoids, teratomas, arachnoid
– Men: cysts, and cholesteatomas may occur in any of several
Reduced libido and potency. locations around the sella.
Reduced facial and body hair.
Gonadal atrophy. Parasellar lesions
• Hypoprolactinemia: Cavernous carotid aneurysms, cavernous sinus thrombosis,
– Failure to start and maintain lactation in women. temporal lobe neoplasms, and gasserion ganglion neuromas.
– No defined clinical entity in men.
• Hypothyroidism: mild with inappropriately low TSH in Retrosellar lesions
an otherwise well patient. Chordoma, basilar artery aneurysm.
• Growth hormone deficiency:
– Poorly defined clinical entity in adults. Infrasellar lesions
– Reduced body muscle : fat ratio. Sphenoid sinus mucocele, carcinoma, granuloma, and other
• Hypoadrenalism: nasopharyngeal tumors.
– Tiredness and malaise, especially in the afternoon and
evening. Empty sella syndrome
– Postural hypotension, pallor, anorexia and nausea. The major cause of asymptomatic sellar enlargement:
– No subtle electrolyte changes as the adrenal zona • The suprasellar subarachnoid space (arachnoid mater and
glomerulosa is intact. CSF) extends/herniates into the sellar cavity through an
– Loss of secondary sexual hair in women. incompetent diaphragm, thus compressing and flattening
the pituitary gland inferiorly and posteriorly, stretching
the stalk, and eventually causing hormone disregulation.
 Pituitary Tumors
• Primary empty sella: arises in the absence of any previous
known pituitary disease. It is most commonly seen in
middle-aged obese women and may be associated with
raised intracranial pressure.
• Secondary empty sella: may follow idiopathic intracranial
hypertension, spontaneous regressive changes of pituitary
adenomas, and surgery (i.e. the meninges and CSF
herniate downwards to fill the void created by pituitary
involution as a result of other pathology such as pituitary
surgery, irradiation, hemorrhage or tumor necrosis).
• Usually asymptomatic.
• Symptoms may include headache, occasional mild
endocrine abnormalities, CSF rhinorrhea, and, rarely,
visual disturbances. These are more commonly symptoms
of the cause than the empty sella itself. Hypopituitarism,
diabetes insipidus, and visual field defects are much less
common with the empty sella syndrome than pituitary
lesions.
• These patients are generally investigated for suspected
pituitary adenoma because of sellar enlargement
discovered on plain x-rays. A ballooned sella without
erosion is characteristic of the empty sella. Empty sella is
now diagnosed more easily with high resolution CT and
MRI.
• The evolution appears to be wholly independent of the
sellar dimensions and of the grade of the disease at
diagnosis.
Pituitary apoplexy (see p.268)
Chiasmal hemorrhage, subarachnoid hemorrhage,
meningitis.
476
381
Hyperprolactinemia
Hypothalamic and infundibular lesions (loss of inhibitory
control of prolactin secretion), renal failure, and drugs
(phenothaizines, butyrophenones, benzodiazepines,
reserpine, morphine, alpha methyldopa and isoniazid).
INVESTIGATIONS
Pituitary hormones
• Hormones are stable for several days in plasma at room
temperature except for ACTH, which must be collected
on ice and separated as soon as possible.
• Serum prolactin levels >100 μg/l (>100 ng/ml) (normal
<15 μg/l [<15 ng/ml]) are almost always due to tumor.
Levels from 15–100 μg/l (15–100 ng/ml) may be due
to tumor but are more commonly due to other
disorders, particularly drugs. Distortion or damage of the
hypothalamus or pituitary stalk by a functionless pituitary
adenoma may result in modest hyperprolactinemia.
• Assay of ACTH from the right and left petrosal sinuses,
and comparing the values with those of the superior vena
cava can establish the pituitary as the source of excess
ACTH and often localizes the side of the adenoma as
well.
CT and MRI brain scan
• CT clearly shows calcified lesions such as
craniopharyngiomas.
• MRI shows surrounding soft tissue structures (e.g.
pituitary stalk, optic chiasm) and can be performed
repeatedly without risk of excessive exposure to x-rays.
• MRI is more sensitive than CT for detecting
microadenomas (477).
477
477 MRI brain scan (coronal T1W image with i.v. contrast) showing a
microadenoma on the left side of the gland (arrows).
476 Abdominal and axillary cutaneous striae in a patient with
Cushing’s disease due to an ACTH-producing pituitary microadenoma.
382 Tumors of the Central Nervous System

Microadenomas • The differential diagnosis on imaging includes

• On CT (thin section coronal with i.v. contrast)
microadenomas appear as low density areas within the
gland. Other signs include deviation of the pituitary stalk
away from the side of the adenoma, focal erosion of the
floor of the fossa and upward bowing of the superior
margin of the gland.
• On MRI (thin section coronal with i.v. contrast)
microadenomas are hypointense relative to the normal
gland on T1WI and of variable intensity on T2WI.
Dynamic scanning has been advocated for elusive
adenomas.
meningiomas, craniopharyngiomas, large aneurysms,
metastases, granulomas.
• Angiography may be necessary prior to surgery and to
exclude an aneurysm; MR is not reliable enough to
exclude an aneurysm as slow blood flow within it may
mimic a solid lesion.
Carotid angiography
Often a wise prelude to surgery to exclude an aneurysm of
the carotid siphon that may cause identical clinical and CT
features to those of an adenoma.

Macroadenomas DIAGNOSIS
• On CT or MRI these appear as masses arising out of the Patients present with a typical history and examination and the
pituitary fossa which may elevate and compress the optic diagnosis is confirmed by CT or MRI scan of the pituitary, and
chiasm and anterior cerebral arteries (478–481), and blood tests.
invade the cavernous sinus and encase the internal carotid
arteries laterally. Enhancement is usual. There may be
cystic elements.

478 479

480 481

478–481 Axial proton density MRI (478), axial T2W MRI (479), coronal T1W MRI pre-contrast (480), and coronal T1W post contrast MRI (481)
images showing a pituitary adenoma in the sella extending superiorly to compress the inferior aspect of the optic chiasm and elevate the A1
segment of the anterior cerebral artery, and inferiorly to depress the floor of the sella (arrows).There is no extension into the cavernous sinuses.
 Acoustic Neuroma 383

TREATMENT ACOUSTIC NEUROMA

• If panhypopituitarism is suspected, glucocorticoids should
be replaced before thyroid hormones.
• Trans-sphenoidal microsurgical resection is usually the first DEFINITION
line treatment for adenomas that hypersecrete or cause mass A histologically benign tumor of the vestibulocochlear nerve
effect. There should be no mortality, and any morbidity sheath, arising most frequently from the superior portion of
should be minor (about 10% of cases). The remission rate the vestibular nerve
after 5 years is about 80%. Extension into brain requires an
intracranial approach. Pre- and post operative endocrine EPIDEMIOLOGY
and neurologic evaluation is essential. Corticosteroid • Incidence: 1 per 100 000 per year; 0.8– 2.7% of autopsy
coverage should be provided during surgery. series.
• Prolactinomas are the major exception because they are • Age: adults.
usually treated with the dopamine agonist bromocriptine • Sex: M=F.
or cabergoline, which shrinks the tumor and decreases
prolactin secretion. Adverse effects include nausea and ANATOMY
hypotension (and cost). Surgery is an effective alternative, Cerebellopontine angle
particularly if pregnancy is desired or there is rapid visual • Apex: trigeminal nerve (V).
loss, with a 70–80% remission rate after 1 year. Post • Mid zone:
operative bromocriptine or cabergoline help control – Facial nerve (VII).
residual or recurrent tumor. Failing that, radiotherapy can – Vestibulocochlear nerve (VIII).
be considered. – Anterior inferior cerebellar artery.
• Growth-hormone-producing adenomas may be treated • Base:
with the somatostatin analogue octreotide (Sandostatin). – Glossopharyngeal nerve (IX).
• Standard fractionated supervoltage radiotherapy with – Vagus nerve (X).
20–25 treatments over 4–6 weeks may halve the low, long – Accessory nerve (XI).
term rate of tumor recurrence (from about 15% to 7%), but
causes adverse effects such as low grade neuronal damage, PATHOLOGY
radionecrosis, vaso-occlusive disease, and secondary tumors Site
of the CNS such as anaplastic meningiomas, and so it is less A tumor of Schwann cells (and not neurons), and most
often given as an adjunct to surgery. Furthermore, ready frequently occurs on the superior portion of the vestibular
access to MRI for regular post operative scans allows tumor nerve. Hence, it is doubly misnamed and should really be
recurrence to be diagnosed early so that further surgery can called a vestibular schwannoma.
be contemplated.
Growth
PROGNOSIS From its origin on the vestibular nerve, it grows gradually
Although residual cells in parasellar structures may account to fill the internal auditory meatus, compressing the
for local recurrences that follow seemingly complete surgical cochlear and facial nerves and ultimately compressing the
clearances, metastatic spread and direct macroscopic cerebellar peduncles, cerebellum, fourth ventricle, and
invasion of surrounding structures is rare. cranial nerves IX, X and XI (482).

ETIOLOGY
• Uncertain (sporadic) in most cases.
482 • Inherited as part of neurofibromatosis 2 in some cases (see
p.147): a familial syndrome, usually inherited as an
autosomal dominant trait due to a mutation on chromo-
some 22q1, and consisting of multiple cranial nerve
tumors, along with neuromas of the spinal nerve roots.

CLINICAL FEATURES
Depend on the site of origin of the tumor along the
acoustico-vestibular nerve bundle:

Internal auditory meatus origin

Otolaryngologic symptoms and signs
• Altered hearing (distorted, muffled hearing):
– Reduced hearing in whisper tests.
– Sensorineural hearing loss: Weber test lateralized to ‘good ear’.
– Tinnitus.
• Pressure in the ear.

482 Axial section of the pons and cerebellum showing a large

acoustic neuroma in the cerebellopontine angle (arrows). (Courtesy
of Professor BA Kakulas, Royal Perth Hospital,Western Australia.)
384 Tumors of the Central Nervous System

Cerebellopontine angle origin • They are rounded, may be very large and cause brainstem
Compression of nearby structures displacement.
• Atypical trigeminal neuralgia (V). • The main differential diagnosis is meningioma, which does
• Tic douloureux (V). not usually extend into the acoustic canal.
• Loss or reduction of corneal reflex.
• Facial numbness (V). Pure tone audiometry
• Hemifacial spasm. Sensorineural hearing loss.
• Progressive painless lower motor neuron facial weakness
(VII). Brainstem auditory evoked potentials
• Hoarse weak voice (X). Not usually necessary, but if so may reveal prolongation of
• Dysphagia (IX, X). waves I–III.

Compression of brainstem and raised intracranial DIAGNOSIS

pressure (hydrocephalus) The definitive investigation is gadolinium-enhanced MRI in a
• Headache. patient with a suggestive clinical history.
• Unsteadiness, clumsiness, poor balance.
• Vertigo. TREATMENT
• Spontaneous nystagmus*. • Treatment depends on a complex interplay of the needs
• Vomiting. and expectations of the patient, the size of the tumor and
• Hearing loss and/or tinnitus in the other ear. the local expertise.
• Altered mental state. • Treatments include expectant care with repeat scanning to
• Visual changes. assess tumor growth in elderly people and surgery with or
without radiotherapy.
*Nystagmus: • Surgical approaches and techniques vary but generally
Peripheral nystagmus Central nystagmus involve micro-surgical techniques, an ultrasonic surgical
Direction Fast phase in same direction, Usually changes aspirator, intraoperative monitoring of brainstem auditory
irrespective of direction direction evoked potentials and facial nerve function (by
of gaze electromyography), and access to intensive care facilities for
Horizontal or rotary/torsional May be bizarre immediate post operative care.
Never vertical Often vertical
Prognosis Decreasing severity Does not improve Mortality varies from 2–4% depending on the size of the
over 2 weeks significantly tumor. Other risks include deafness, facial palsy, vertigo, lower
cranial nerve palsy, brainstem damage, brainstem and cerebellar
DIFFERENTIAL DIAGNOSIS infarction.
• Trigeminal neuralgia (that fails to respond or responds The risks increase with the size of the tumor and decrease
erratically to standard treatment with carbamazepine). with the experience of the operating team. The chances of
• Eustachian tube obstruction. surgery preserving useful hearing are slight unless the tumor
• Cerebellopontine angle tumor: is small or medium sized; surgical resection of tumors <2.5 cm
– Acoustic neuroma: (75% of cases). (<1 in) in diameter carries a one in four to one in three chance
– Meningioma: (6% of cases). of preserving hearing. Surgical resection of an acoustic
– Cholesteatoma: (6% of cases): neuroma measuring <2 cm (<0.8 in) in diameter should
Epidermoid cyst. however provide an 80% chance of immediate preservation of
Arising from temporal bone. facial nerve function and a 95% chance of long term facial
– Glioma: (3% of cases). nerve function.
– Other types: (10% of cases):
Metastatic tumors. • Stereotactic radiotherapy can deliver highly localized levels
Osteomas. of radiation with minimal damage to surrounding
Osteogenic sarcomas. structures. Because of the morbidity of surgery, especially
Neuromas of trigeminal, facial or glossopharyngeal nerve. to the facial nerve and hearing, there is a move toward
Angiomas. stereotactic radiotherapy for tumors with a maximum
Papillomas of choroid plexus. diameter of <3 cm (<1.2 in), particularly in the elderly and
Teratomas. for those with bilateral acoustic neuromas.
Lipomas. • Combined surgery and radiotherapy. Surgery to debulk a
large tumor has a lower operative morbidity compared with
INVESTIGATIONS attempted total removal. Post operative stereotactic
CT or MRI brain radiotherapy in such cases may be a useful combination but
• MRI is the method of choice, though thin section CT with the long term effects remain to be evaluated.
i.v. contrast or air meatography are alternatives in patients
who cannot have or tolerate MRI. PROGNOSIS
• The standard MRI sequence is a T1W thin section Acoustic neuromas grow but the rate of growth seems to be
sequence through the petrous bones with i.v. contrast. slower in older people and they may not cause serious
• Acoustic neuromas show up as an enhancing mass, within symptoms; 0.8–2.7% of post mortem studies find an acoustic
the VIIIth nerve canal if very small (483), and extending neuroma that had not contributed to the death of the person.
into the cerebellopontine angle if larger (484).
 Primary CNS Lymphoma
PRIMARY CNS LYMPHOMA
DEFINITION
A tumor of lymphocytes or lymphoblasts, usually B cells,
confined to the CNS.
EPIDEMIOLOGY
• 1–2% of cases of non-Hodgkin’s lymphoma.
• 3% of all intracranial neoplasms.
• Marked increase in incidence in the last decade as part of
the AIDS epidemic but also within the immuno-
competent population (for unknown reasons).
• Age: median: 57 years (non-AIDS); young adults (AIDS).
• Gender: M>F (1.5:1).
483
483 MRI brain,T1W image with i.v. contrast showing a small left
intracanalicular acoustic neuroma (arrow).
484
484 MRI brain,T1W image of a large acoustic neuroma projecting
into the cerebellopontine angle (arrow).
385
PATHOLOGY
Macroscopic
• Multifocal mass deposits in the brain in two-thirds of cases.
• Solitary mass within the subcortical white matter in one-
third.
• Sites:
– Brain:
Supratentorial (75% of cases with brain lymphoma):
Periventricular lesions are frequent.
Corpus callosum (41%).
Deep central nuclei (33%).
Infratentorial (20% of cases with brain lymphoma).
Diffuse leptomeningeal (5% of cases with brain lymphoma).
Diffuse neuropil involvement: rare.
– Eye: posterior segment (retina and vitreous): present in
25% of cases with intracranial lymphoma.
• At autopsy, parenchymal lesions are always in contact
with either the leptomeninges or the ependymal surface.
Microscopic
• The tumor cell of origin is the lymphocyte or lymphoblast
(B cell, usually diffuse, large cell subtype: >2/3, T cell:
<1/3; this ratio is different to systemic lymphoma).
• The fine reticulum and microgliacytes are interstitial and
derived from fibroblasts and microglia (histiocytes).
• The tumor is highly cellular, with little tendency to necrosis.
Mitotic figures are numerous. The nuclei are oval or bean-
shaped with scant cytoplasm. The stainability of reticulum
and microglial cells, the latter by silver carbonate, serves to
distinguish this tumor microscopically. B cell markers
identify the tumor cell type.
• Most tumors are high-grade immunoblastic or diffuse
large cell type but many are arrested at relatively mature
stages of differentiation.
• Although B cell immunophenotype predominates in
immunocompromised (e.g. AIDS) and immuno-
competent (e.g. non-AIDS) cases, the tumor cells that
arise in immunocompromised patients are usually
polyclonal, tending to have high-grade histologic
characteristics (immunoblastic and small, non-cleaved
cells) and contain Epstein–Barr virus (EBV) genomic
material in about 80% of cases; whereas immuno-
competent patients usually have monoclonal, large-cell
lymphomas of B cell origin with a low-grade histologic
appearance and no evidence of EBV infection.
• The lymphocytes express either kappa or lambda light-
chain immunoglobulin. Molecular studies have also
demonstrated consistent profiles of light-chain and
heavy-chain immunoglobulin gene rearrangements in
primary, recurrent, and metastatic CNS lymphomas.
• Regardless of cell type, a perivascular pattern pre-
dominates, with malignant cells surrounding blood
vessels in concentric layers (resembling the inflammatory
response of encephalitis).
N.B. Systemic non-Hodgkin’s lymphoma, arising in lymph
nodes and other somatic organs, spreads to the CNS in about
25–30% of cases, and tends to infiltrate the leptomeninges
(sparing the parenchyma), particularly in the spinal region
(and causing spinal cord compression), in contrast to PCNS
lymphoma which tends to originate in the parenchyma.
386 Tumors of the Central Nervous System
ETIOLOGY
Predisposing factors
Immunosuppression (inherited or acquired)
• Congenital immunodeficiencies.
• Immunoglobulin A deficiency.
• Combined immunodeficiency syndrome.
• Immunodeficiency associated with systemic lupus
erythematosus (SLE) and rheumatoid arthritis (RA) and
organ-transplant recipients.
• Long term steroid treatment for SLE, sarcoidosis, RA,
and other autoimmune or inflammatory illnesses.
• AIDS due to HIV infection (see p.301).
Infection with EBV
May have a role in pathogenesis.
PATHOGENESIS
• HIV or other viruses (e.g. EBV), growth factors,
aberrant oncogene or tumor-suppressor gene expression,
and factors that induce genetic instability or DNA
damage or alter host or viral genome repair may lead to
cell hyperproliferation and clonal expansion.
• B cell hyperactivation is thought to contribute to the
development of lymphoma associated with HIV
infection.
CLINICAL FEATURES
• Gradual onset and evolution over several months.
• Expanding intracranial mass:
– Personality/behavioral/cognitive change or progressive
psychomotor retardation (24%).
– Cerebellar signs (21%).
– Headache (15%).
– Motor dysfunction (11%).
– Visual changes (8%): an ophthalmologic examination is
mandatory, seeking lymphomatous involvement in the
posterior segment of the eye.
• Seizures (13%).
• Multiple cranial and peripheral nerve root palsies: symptoms
and signs suggesting leptomeningeal involvement are
present in only about one-quarter of patients with lepto-
meningeal lymphoma; in most patients it is clinically silent.
• During the subsequent clinical course, hemiparesis occurs
in about half of patients, headache in about a third,
aphasia in a quarter and ataxia in a quarter.
INVESTIGATIONS
CT/MRI brain scan
Lesions are isotense or hyperintense on CT and are equally
visible on CT or MRI, though MRI may define the precise
extent and relationship to adjacent tissues more clearly
(485, 486). Lesions may be solitary (1/3) or multiple
(2/3) and tend to be located in the basal ganglia and other
deep gray matter nuclei, periventricular white matter and
less commonly adjacent to the meninges and in the
posterior fossa. They usually show:
• Enhancement with contrast (487).
• Mass effect.
• Rapid shrinkage with steroids.
The differential diagnosis includes other malignant
tumors, and in immunosuppressed patients, toxoplasmosis,
progressive multifocal leukocencephalopathy (PML) and
other opportunistic infections.
Secondary lymphoma tends to involve the leptomeninges
and CSF and may be very difficult to see with any imaging
modality. The only clue may be hydrocephalus.
CSF
Almost always abnormal:
• Protein: typically >1.0 g/l (>100 mg/dl) but may be normal.
• Cells: typically a slight lymphocytic pleocytosis
(<100 lymphocytes/mm3) but sometimes as few as only
2 cells/mm3.
• Cytology: identifies malignant tumor cells in only
25–30% of cases (the parenchyma tends to be involved).
The diagnostic yield may be increased by: multiple
CSF samples (cells may initially be misdiagnosed as
reactive atypical cells); immunocytochemical staining,
demonstrating a predominance of expression of kappa or
lambda light-chain immunoglobulin in the atypical
lymphoid cells; polymerase chain reaction.
• β2-microglobulin concentration (>160 nmol/l) in CSF
is another potential adjunctive marker of leptomeningeal
spread of CNS lymphoma.
Tissue biopsy
Stereotactic CT-guided brain biopsy
Diagnostic features are present in about one-third to one-half
and non-specific abnormalities in about one-half of specimens.
Pre-treatment with corticosteroids may foil diagnostic
attempts because they have a ‘lymphopenic’ effect on
primary CNS lymphomas (i.e. deplete biopsy specimens of
abnormal lymphomatous cells) and result in temporary
regression of the tumor mass and contrast enhancement on
CT scan.
Interpretation of biopsy and CSF cytologic specimens
should include evaluation of immunohistochemical markers
to demonstrate the largely monomorphous and probably
clonal nature of the neoplastic lymphomononuclear cell
infiltrates.
DIAGNOSIS
Pathologic – stereotactic biopsy.
TREATMENT
The treatment for primary CNS lymphoma depends on
whether it arises in a normal or immunocompromised host.
However, unlike other brain tumors, resection does not
have a therapeutic role. Chemotherapy is the first-line of
treatment (e.g. high dose methotrexate ± cranial
irradiation), and is associated with complete response rates
of 50–80% in immunocompetent patients. Chemotherapy
combined with radiotherapy is also very effective (median
survival >40 months) in immunocompetent patients, but
results in substantial delayed neurotoxic effects, particularly
in patients older than 60 years of age.
Immunocompetent patients
Radiation therapy alone
• Radiotherapy to total doses of 50–60 Gy (5000–6000 rads)
produces high control rates in systemic non-Hodgkin’s
lymphoma but, paradoxically, the same doses in primary
CNS lymphoma are associated with a 90% risk of local
relapse and, accordingly, poor long term survival.
• The mean survival is about 1.5 years (median
13 months) in patients treated with radiotherapy alone.
 Primary CNS Lymphoma 387

Combined chemotherapy and radiotherapy • Early experience with high-dose methotrexate-based

• Standard chemotherapy protocols for non-Hodgkin’s regimens with leukovorin rescue may produce a similar
lymphoma (e.g. CHOP [cyclophosphamide, doxorubicin, disease-free interval with minimal toxicity. This treatment
vincristine and prednisone-based therapy]) are not of achieves uniform CNS and CSF levels throughout the
benefit, probably because of poor penetration of the CNS neuroaxis and when given without radiation is only rarely
by the drugs. The blood–brain barrier is already disrupted associated with methotrexate leukoencephalopathy.
when primary CNS lymphoma is present but it repairs • Methotrexate therapy can be complicated by nephro-
rapidly as soon as the tumor responds to treatment. genic diabetes insipidus. To prevent crystallization of
• High-dose intravenous (intrathecal or intraventricular if methotrexate in the renal tubules and to promote its
positive CSF cytology) methotrexate, 1 g/m2 on days 1 renal excretion, aggressive hydration with intravenous
and 8, followed by radiotherapy, commencing on day 15, fluids and sodium bicarbonate and alkalinization of the
with a total dose of 45 Gy (4500 rads) in 25 fractions urine are mandatory. The sodium load, however, can
delivered to the whole brain over the next 38 days, and a induce polyuria and hyperosmolarity. Desmopressin
boost of 5.4 Gy (540 rads) in three fractions to the acetate can reduce urine flow and methotrexate
original disease site, improves 2-year survival to 70% and excretion but it increases the likelihood of toxicity.
overall mean survival to about 3.5 years. If CSF cytology
results are positive, cytosine arabinoside (cytarabine)
(60 mg) or methotrexate may be given via an intracerebral 485
ventricular reservoir. Intrathecal chemotherapy is restricted
to patients with positive CSF cytology because syn-
chronous intrathecal chemotherapy and cranial irradiation
are associated with an increased risk of neurotoxicity. To
minimize further late neurotoxicity no more chemo-
therapy is given after radiotherapy. Morbidity from radia-
tion encephalopathy can also occur in long term survivors.
• Other agents, such as high-dose cytosine arabinoside
(cytarabine) and cyclophosphamide, have also been used
alone or in combination.

485 T2W axial MRI brain scan of a patient with AIDS and a
lymphoma in the posterior corpus callosum (arrows). (Courtesy of
Professor J Best, Department of Medical Radiology, Royal Infirmary,
Edinburgh, UK.)

486 T2W axial MRI

of lymphoma in the 486 487
midbrain in a patient
with AIDS (arrows).
Note the increased
signal around the
aqueduct in the
posterior midbrain
(proven at autopsy).
(Courtesy of
Professor J Best,
Department of
Medical Radiology,
Royal Infirmary,
Edinburgh, UK.)

487 CT scan with

contrast shows
enhancement of the
white matter in a
‘rind’ around the
lateral ventricles
(arrows).This
appearance is typical
for lymphoma.
388 Tumors of the Central Nervous System
Surgery
Ineffective except in rare cases, because the tumors are
usually deep and multicentric.
Immunocompromised patients
• Treatment aims to reverse the immunosuppression,
which may lead to tumor regression.
• In patients with AIDS-associated primary CNS
lymphoma, therapy is not possible and the prognosis is
very poor, with an average survival of only 2.5 months,
despite the use of corticosteroids followed by cranial
irradiation.
PROGNOSIS
The natural history differs from other non-Hodgkin’s
lymphomas in that dissemination outside the neuroaxis is
uncommon; 90% of patients die of progressive local disease.
Survival
Radiation therapy alone
• Median survival: 13 (12–18) months if immuno-
competent, 3 months if AIDS-related primary CNS
lymphoma.
• Only 5–10% enjoy long term survival, despite increased
doses of radiotherapy.
• 10% of long term survivors suffer neurologic
deterioration in the absence of recurrence, suggesting a
possible long term effect of radiotherapy.
Combined chemotherapy and radiotherapy
• Median survival after methotrexate and radiation therapy:
40 months.
• Survival beyond 2 years: 70%; beyond 5 years: 25%.
GERM CELL TUMORS OF THE CNS
DEFINITION
Tumors of germ cell origin, which include the germinoma
(the most common), teratoma, embryonal carcinoma, yolk-
sac tumor, choriocarcinoma, and mixed types.
EPIDEMIOLOGY
• Incidence: uncommon.
• Age: predominantly school-aged children, adolescents
and young adults (5–30 years).
• Gender: M>F.
PATHOLOGY
• Analogous to germ cell tumors arising in the gonads.
• Tumors probably arise from totipotential germ cells,
which are capable of producing several different cell
subtypes. Consequently, they are composed of more than
one tumor type.
Sites
• Midline: neurohypophyseal and pineal regions: the most
common site is the pineal region, followed by the base
of the brain in the vicinity of the pituitary gland (e.g.
third ventricle, hypothalamus).
• ‘Multifocal’ germinoma: a localized, directly infiltrating,
disease characterized by multiple lesions involving the
pineal region, hypophysis, cavernous sinus, optic chiasm,
third ventricle wall, or anterior half of the lateral ventricle.
• Disseminated germinoma: a metastatic disease.
Growth
• Rapid.
• Tumors spread by direct infiltration or along the CSF
pathways in the subarachnoid space, seeding cranial and
peripheral nerve roots.
Histology
• Identical to the testicular seminoma: typically biphasic,
being composed of two distinct populations of cells. The
larger germ cells have abundant cytoplasmic glycogen and
alkaline phosphatase activity. The stroma contains variable
numbers of lymphocytes which are both T and B cells.
• Germinoma:
– Macroscopic: a firm, discrete mass, usually arising in the
pineal region, usually reaches 3–4 cm (1.2–1.6 in) in
greatest diameter. Inferiorly, it compresses the superior
colliculi and sometimes the superior surface of the cere-
bellum, and narrows the aqueduct of Sylvius. Anteriorly,
it may extend into the third ventricle and compress the
hypothalamus. It may also arise in the floor of the third
ventricle (a suprasellar germinoma or ectopic pinealoma).
– Microscopic: large, spherical epithelial cells separated by
a network of reticular connective issue, which contains
many lymphocytes.
– Growth: germinomas preferentially infiltrate the pineal
region, hypophysis, cavernous sinus, optic chiasm and
pathways, third ventricle wall, or anterior half of the
lateral ventricle.
• Embryonal carcinoma: the most primitive and undifferen-
tiated example of this group of tumors; immunocyto-
chemistry demonstrates alpha-fetoprotein in tumor cells.
 Germ Cell Tumors of the CNS 389

• Endodermal sinus tumors: these exhibit a tendency to INVESTIGATIONS

form structures resembling the yolk sac.
• Choriocarcinoma: a highly vascular tumor characterized by
differentiation into trophoblastic tissue; prone to massive
hemorrhage. Immunocytochemical methods readily
demonstrate chorionic gonadotrophin in tumor tissue.
• Teratomas: tumors with the ability to differentiate into
elements from all three germ layers. Teratomas may
contain mature components such as hair, teeth, cartilage,
muscle, and bronchial wall. These elements are arranged
in a haphazard, non-functional manner, but they can be
benign. Immature anaplastic elements may be found
alongside benign elements, or they may make up the
entire tumor. Teratomas may contain other tumor types,
especially embryonal carcinoma.
WHO classification of histology of germ cell
tumors of the CNS
• Germinoma.
• Embryonal carcinoma.
• Yolk-sac tumor (endodermal sinus tumor): produces
alpha-fetoprotein.
• Choriocarcinoma: produces the beta subunit of chorionic
gonadotrophin.
• Teratoma:
– Immature.
– Mature.
– With malignant transformation.
• Mixed germ cell tumors: numerous combinations of
diverse histology and prognosis.
Imaging
Epidermoid tumors
• May be intra- or extradural.
• Intradural tumors typically arise in the cerebellopontine
angle cistern, the suprasellar or the prepontine cisterns,
or the pineal region.
• Intradural tumors (less common) tend to fill the space in
which they arise in a rather insidious fashion.
• Usually tumors appear as low density mass lesions on CT
(may mimic CSF unless closely inspected) which tend to
envelop normal structures, and do not enhance with
contrast.
• Tumors appear hypointense on T1W MRI (488) and
hyperintense on T2WI (similar to CSF) (489), but on
proton density imaging are inhomogeneous and
hyperintense to CSF.
• Extradural epidermoid tumors (more common) arise in the
diploic space, the petrous or temporal bones and look like
rounded, well defined bony lesions with sclerotic borders.
488

ETIOLOGY AND PATHOGENESIS

Potential genetic predisposition
Associations with genetic disorders, phakomatosis, meta-
chronous and synchronous extracranial neoplasms.

CLINICAL FEATURES

Hypothalamic dysfunction
• Diabetes insipidus.
• Sleep disturbance (due to lack of melatonin nocturnal
rise in those with pineal germ cell tumors).
• Precocious puberty (boys with germinoma).

Midbrain compression by hydrocephalus or tumor 489

• Parinaud’s syndrome:
– Supranuclear paresis of upward gaze.
– Dilated pupils that react to accommodation but not to
light.
– Effects are due to compression of the tegmentum of the
upper midbrain by a dilated posterior part of the third
ventricle (hydrocephalus) rather than local pressure
effects of the tumor.
• Ataxia of the limbs.
• Chorea of the limbs.
• Spastic quadriparesis.

488, 489 T1W (488) and T2W sagittal (489) MRI of an epidermoid
of the planum sphenoidale.The lesion creeps along below the frontal
lobes (arrows) widening the space between the bone and the brain. It
does not enhance.
390 Tumors of the Central Nervous System

Dermoid tumors and teratomas DIFFERENTIAL DIAGNOSIS

• Tumors arise in similar sites to epidermoids except that Pineal region tumors
they favor the midline, whereas epidermoids favor sites Pineal parenchymal cell tumors (pinealoma)
away from the midline. • Pineocytoma.
• Tumors contain calcification, fat and bone as well as • Pineoblastoma.
cystic elements.
• On CT (490) they appear as mixed density lesions with Pineal germ cell tumors
calcification, fat and bony elements, but are better seen • Germinoma (atypical teratoma, resembling the
on MRI (491) seminoma of the testicle).
• On T1W MRI (492) the low signal of calcification or • Teratoma (with cellular derivatives of all three germ
bone and the high signal of fat suggest a dermoid. layers).
• Dermoids may rupture and CT or MRI may show fat • Glioma.
globules spread through the CSF.
Other tumors
Teratomas • Astrocytoma.
• Occur more often in males than females. • Glioblastoma.
• Tumors are common in the pineal region (they make up • Ependymoma.
one-third of pineal tumors) and the suprasellar cistern. • Meningioma.
• They may contain fat, bone, calcification, cysts and • Ganglioglioma.
dermal elements and may bleed.
• Enhancement is variable depending on the constituents. Cystic structures
• Teratomas make up one-third of pineal tumors (493, • Dermoid cyst.
494) mostly in males, and also in the suprasellar cistern. • Epidermoid cyst.
• Simple pineal cyst.
Blood tests
• β-subunit of HCG: may be increased in embryonal Pituitary region tumors
carcinoma, choriocarcinoma, and malignant teratoma. • Optic pathway astrocytoma.
• Alpha-fetoprotein can be detected in embryonal • Pituitary adenoma.
carcinoma and endodermal sinus tumors (embryonal • Craniopharyngioma.
tumor with histologic features similar to those found in
the visceral yolk sac). DIAGNOSIS
A definitive diagnosis predicting histology and malignancy
Pituitary function serum tests (if the tumor is in the cannot be achieved by CT or MRI alone; surgical biopsy or
pituitary region) resection is required to establish firmly an accurate
• Testosterone, sex hormone binding globulin and free histologic diagnosis that guides the extent of adjuvant
androgen index. therapy.
• Estradiol.
• FSH. PROGNOSIS
• LH. Prognosis is governed by the most malignant component in
• Thyroxine and TSH. the tumor.

CSF Good prognosis

• Cells: may reveal lymphocytes and tumor cells (which 10-year survival rate >85%:
have seeded the subarachnoid space). • Solitary pure germinoma.
• Alpha-fetoprotein. • Mature teratoma.
• β-subunit of HCG.
Intermediate prognosis
Biopsy • Germinoma with an elevated level of serum β-HCG.
Frameless stereotactic surgery is a safe and effective method • Extensive (>4 cm [1.6 in] diameter) or multifocal
of sampling deep intracranial tissues, carrying a 0–0.5% mor- germinoma.
bidity rate, but biopsy of a small specimen of a large tumor • Disseminated germinoma.
may lead to an erroneous pathologic diagnosis when a het- • Immature germinoma.
erogeneous tumor is encountered. It is particularly recom- • Mixed germ cell tumors consisting of germinoma with
mended for patients with multifocal or disseminated tumors. either mature or immature teratoma.
Open surgical resection provides a more accurate
histologic diagnosis, and thereby facilitates more appropriate Poor prognosis
and adequate treatment than stereotactic biopsy. • Teratoma with malignant transformation.
Furthermore, surgical resection or significant bulk reduction • Embryonal carcinoma.
of a solitary mass may enhance the efficiency of adjuvant • Yolk sac tumor.
therapy, particularly in the case of malignant germ cell • Choriocarcinoma.
tumor. • Mixed germ cell tumors including a component of
embryonal carcinoma, yolk sac tumor, choriocarcinoma,
or teratoma with malignant transformation.
 Germ Cell Tumors of the CNS 391

490 491

490–492 CT (490),T2W axial (491) and T1W sagittal 492

(492) MRI of a dermoid tumor in the brainstem (unusual
site).The lesion is very difficult to see on CT apart from its
displacement of the IVth ventricle. Note the ‘tail’ of the
lesion visible on MRI (arrow) giving a clue as to its origin.

493

494

493, 494 Axial CT with contrast (493) and T1W sagittal MRI without contrast (494) of a pineal teratoma. Note the mass
in the pineal which enhances (arrows).
392 Tumors of the Central Nervous System
TREATMENT
Management is determined by the histologic and serologic
diagnosis and extent of disease.
Pineal region tumors
• Frequently non-germinomatous germ cell tumors.
• Huge masses should be biopsied. If malignant,
neoadjuvant chemotherapy should be given before the
second radical surgical resection.
• Smaller tumors can be debulked safely, and if malignant,
radically removed.
• Shunting procedures for hydrocephalus, such as
ventriculo-peritoneal shunt, are rarely necessary and may
lead to fatal peritoneal metastases.
• Histologically verified pineal germinomas can be
remarkably reduced in size only through a course of low-
dose radiotherapy or chemotherapy alone (see
Germinomas, below).
Neurohypophyseal and hypothalamic
region tumors
• Preferentially infiltrate the optic pathways.
• Biopsy or partially remove when possible.
Suprasellar tumor confined to the optic pathways:
• Usually germinomas (see below).
• May require craniotomy for biopsy.
Germinoma (solitary or multifocal)
• Highly radiosensitive and historically associated with a
high surgical mortality.
• Radiotherapy to the localized field, via appropriate
irradiation ports, following active chemotherapy, can be
curable. A reduced dose of 24 Gy (2400 rads) in daily
fractions of 2 Gy (200 rads) or less, minimizes adverse
effects of radiotherapy such as cognitive retardation and
neuroendocrine deficiencies (growth hormone deficiency
occurs with radiation doses >24 Gy (2400 rads) to the
posterior hypothalamus).
• Prophylactic craniospinal or ventricle irradiation is not
indicated because of associated morbidity in the growing
child.
• Adjuvant pre-radiation chemotherapy, with a combina-
tion including either cisplatin or carboplatin and
etoposide, may decrease the total dose of radiation
necessary for inducing tumor resolution, and enhance
control in malignant germ cell tumors. Chemotherapy
alone is insufficient, and is often associated with an early
relapse of disease.
• Disseminated germinoma should be treated with
craniospinal irradiation.
• If the initial treatment was 24 Gy (2400 rads) of local
irradiation, recurrent germinoma can be treated with the
same or a larger dose of radiotherapy, and the
craniospinal field can be selected.
Malignant germ cell tumors
Examples include mixed germ cell tumors, with numerous
combinations of diverse histology and prognosis, such as a
mixed germ cell tumor composed of immature teratoma
with embryonal carcinoma:
• High incidence of subarachnoid dissemination and spinal
metastases.
• Craniospinal radiotherapy with a high dose local boost,
and intensive combination chemotherapy (regimens
including ifosfamide, cisplatin [or carboplatin] and
etoposide) is used.
• High dose chemotherapy with autologous bone marrow
transplant or peripheral blood stem-cell support has not
been successful to date but may have a role in the salvage
setting of patients with relapsed or disseminated non-
germinomatous germ cell tumors in the CNS.
• Daily oral etoposide cycles may be employed in patients
with extracranial germ cell tumors who have failed to
respond to first-line chemotherapy but have shown a
response to salvage therapy; and also as a maintenance
chemotherapy in patients with poor prognosis non-
germinomatous germ cell tumors.
• Malignant teratomas should be surgically removed if
possible because this can be curable, but its applicability
depends on the site and size of the tumor.
COMPLICATIONS OF TREATMENT AND
THEIR MANAGEMENT
Lack of neurohypophyseal and pituitary hormones
• Infertility, hypogonadism, small stature.
• Caused by tumor invasion or high-dose radiotherapy.
• Pituitary hormone replacement therapy is required by
most children.
Lack of regulation of essential endocrine
processes (e.g. sleep cycle)
Oral melatonin may improve sleep disturbance in children
with pineal tumors.
VON HIPPEL–LINDAU DISEASE (VHL)
DEFINITION
A rare autosomal dominantly inherited, and occasionally sporadic,
neuroectodermal disorder that is characterized by a predisposition
to tumor development in the retina, cerebellum, spinal cord,
pancreas and kidneys; and usually presents in early adulthood
with visual or neurologic symptoms due to a hemangiomatous
malformation of the retina or an associated hemangioblastoma
of the cerebellum. It is one of the phakomatoses (disseminated
hereditary hamartomas), along with conditions such as
Sturge–Weber syndrome and von Recklinhausen’s disease. Dr
Eugen von Hippel, a German ophthalmologist, first described
the familial nature of retinal hemangioblastomas, and Dr Arvid
Lindau, a Swedish ophthalmologist, first recognized that
cerebellar and retinal hemangioblastomas are part of a larger
‘angiomatous lesion of the CNS’ and the condition is inherited.
EPIDEMIOLOGY
• Prevalence: 1 in 40 000.
• Age: mean age of onset 26 years; range 1–78 years:
– Retinal hemangioblastoma: mean age at diagnosis 25
years (range 1–67 years).
– Cerebellar hemangioblastoma: mean age at diagnosis
30 years (range 1–78 years).
– Renal cell carcinoma: mean age at diagnosis 37 years
(range 16–67 years).
• Gender: M=F.
 von Hippel–Lindau Disease (VHL)
PATHOLOGY
Capillary hemangioblastomas
Comprising endothelial cells and pericytes of:
• Retina (45–59% of patients), bilateral in half .
• Cerebellum (44–83%), brainstem (up to 18%), spinal cord
(13–44%), or adrenal glands. Cerebellar hemangioblastoma
is the most common primary intrinsic tumor in the posterior
fossa in adults (10% of all cerebellar tumors). Up to 20% of
cerebellar hemangioblastomas secrete erythropoietin
sufficient to cause symptomatic polycythemia. Spinal cord
hemangioblastomas have a predilection for the conus
medullaris and craniocervical junction, and are associated
with a syringomyelic lesion in >70% of cases.
Additional lesions
Present in some cases, including:
• Angiomas and cysts of the liver, pancreas, and kidneys
(59–63%).
• Adenomas of the liver, epididymis and adrenals.
• Renal cell carcinoma (24–45% of patients, onset beyond age 20
years): secretes erythropoietin which can cause polycythemia.
• Pheochromocytoma (7–18%): probably of neural crest origin,
generally considered benign but can metastasize.
• Ectopic paraganglioma, histologically identical to pheochro-
mocytoma, may arise in the carotid body, glomus jugulare,
periaortic tissues, spleen and kidney.
• Pancreatic islet cell tumor: probably of neural crest origin,
more frequent in patients with pheochromocytoma; islet cell
tumors are capable of metastasizing and may become
symptomatic with biliary obstruction or endocrinopathy.
• Papillary cystadenoma of the epididymis: (10–26% of men
with VHL), when bilateral are virtually pathognomonic of
VHL disease; histologically similar lesions are seen in the
broad ligament of females with VHL disease.
ETIOLOGY AND PATHOPHYSIOLOGY
• Inherited:
– Autosomal dominant inheritance.
– High penetrance (i.e. a high proportion of people with
the gene develop the disease; penetrance is in excess of
90% by 60 years of age).
– Variable expression (i.e. the severity of the disease varies
substantially between affected patients, even within a
family), although some families seem to have a
propensity for pheochromocytoma.
• The gene responsible for VHL is located on the short
arm of chromosome 3, 3p25-26, the same region that is
associated with renal cell carcinoma, and close to the
locus of the RAF-1 oncogene.
• The VHL disease gene is a tumor suppressor gene, a
gene whose normal function is to regulate cell growth.
When both copies of the gene are inactivated by means
of mutation or loss (e.g. recombination or somatic
deletion), cell growth is unchecked and tumors result.
• Patients with VHL disease inherit the germ line mutation
on the short arm of one allele of chromosome 3 from the
affected parent, and one normal allele from the
unaffected parent.
• A ‘two-hit hypothesis’ has been proposed to explain the
development of tumors: the abnormal germ line
mutation is present in all cells, but only those cells in
target organs that develop a second mutation in the
normal allele go on to develop tumors.
393
• The susceptible target organs in VHL disease can be
grouped as:
– Cerebellar and retinal cells (resulting in heman-
gioblastomas).
– Neural crest cells (resulting in pheochromocytomas,
paragangliomas, and possible islet cell tumors).
– Glandular viscera (resulting in renal, pancreatic,
epididymal and endolymphatic sac tumors).
CLINICAL FEATURES
• Symptoms usually do not become evident until late
adolescence or adulthood.
• Progressive visual loss:
– Presenting symptom in up to 50% of patients due to
enlargement of the retinal angioma (bilateral in half of
cases), exudative or tractional retinal detachment,
vitreous hemorrhage, macular edema or epiretinal
membrane formation causing macular distortion.
– Ophthalmologic examination may reveal a decrease in
visual acuity, a visual field defect, enlargement of the
‘feeder’ retinal vessels leading to a peripheral retinal
capillary hemangioma (495) and exudative changes
(signs of lipid deposition) in the macula.
• Progressive ataxia of limb movements, speech
(dysarthria) and swallowing (dysphagia) due to cerebellar
hemangioblastoma, or symptoms of increased intracranial
pressure such as headache, nausea, and vomiting:
presenting symptoms in about 20% of patients.
• Spinal pain, focal sensory and motor deficits from spinal
tumors.
• Polycythemia due to production of erythropoietin by
cerebellar hemangioblastomas and renal cell carcinomas.
• Episodes of uncontrolled hypertension, perspiration,
headaches and anxiety attacks due to massive release of
catecholamines by pheochromocytoma.
A thorough search for other manifestations of the disease
(see Pathology, above) is also required.
DIFFERENTIAL DIAGNOSIS
• Cerebellar tumor.
• Cerebellar degeneration.
• Multiple sclerosis.
495
495 Ocular fundus showing a peripheral retinal capillary hemangioma
with enlarged ‘feeder’ retinal vessels. (Courtesy of Dr AM Chancellor,
Tauranga, New Zealand.)
394 Tumors of the Central Nervous System
INVESTIGATIONS
• Hemoglobin and packed cell volume (?polycythemia).
• Fluorescein angiography.
• CT or MRI brain scan (496, 497): the lesion(s) appears
cystic with a solid nodule against the wall (which may be
very small and difficult to see without contrast)
(498–500) but can also appear completely solid or
cystic. Hydrocephalus is frequent.
• Cerebral angiography (501): shows a vascular nodule
with an adjacent avascular mass comprising a tightly
packed cluster of small vessels about 1–2 cm (0.4–0.8 in)
in diameter, with or without draining veins.
• MRI and angiography are good for demonstrating
additional small and possibly asymptomatic lesions.
• Plasma and 24-hour urine catecholamine (vanillyl-
mandelic acid [VMA] and metadrenaline) analysis.
• Abdominal ultrasound.
• Abdominal MR or CT scans to image the kidneys,
adrenals, liver and pancreas. Abdominal CT scan is more
sensitive than ultrasound for detecting small renal cysts
and carcinomas.
• DNA analysis.
DIAGNOSIS
Clinical
• Positive family history of retinal or CNS
hemangioblastoma.
And:
• One hemangioblastoma or visceral lesion (renal tumor,
pancreatic cyst or tumor, pheochromocytoma, papillary
cystadenoma of the epididymis); renal cysts and
epididymal cysts are too frequent in the population to be
reliable markers of VHL disease.
Or:
• Negative family history of retinal or CNS
hemangioblastoma.
And:
• Two or more hemangioblastomas.
Or:
• Negative family history of retinal or CNS hemangioblastoma.
And:
• One hemangioblastoma and a visceral lesion.
Genetic
DNA analysis identifying a mutation or loss of the gene
responsible for VHL disease on the short arm of
chromosome 3, 3p25-26.
SCREENING
The malignant potential of the visceral disease makes early
diagnosis mandatory.
Asymptomatic affected patient
• Annual physical and neurologic examination, blood
pressure measurement, plasma normetanephrine (and
metanephrine), plasma catecholamines (norepinephrine and
epinephrine) and 24-hour urine collection for catechola-
mines, metanephrines and vanillylmandelic acid (VMA).
• Annual indirect ophthalmoscopy, looking for signs of the
peripheral lesions or the secondary exudative response in
the macular region, with fluorescein angioscopy when
deemed necessary, but not routinely.
• MRI of the brain and spine every 3 years to age 60, then
every 5 years.
• Annual abdominal (renal, adrenal and pancreatic)
ultrasound, with abdominal CT scan every 2–3 years,
pending renal findings.
Asymptomatic at-risk relative
• Annual physical and neurologic examination, and blood
pressure measurement.
• Annual plasma normetanephrine (and metanephrine),
plasma catecholamines (norepinephrine and epinephrine)
and 24-hour urine collection for catecholamines,
metanephrines and vanillylmandelic acid (VMA) from
age 10 years.
• Annual indirect ophthalmoscopy from age 3 years, with
fluorescein angioscopy when necessary.
• MRI of the brain and spine every 3 years from age 11 to
age 60, then every 5 years.
• Annual abdominal ultrasound from age 11, with ab-
dominal CT scan every 2–3 years, pending renal findings.
PREDICTIVE TESTING
The discovery of the specific gene means that a particular
family’s genetic mutations can be mapped, and reliable
preclinical diagnosis in close relatives of affected individuals
is possible by analysing the individual’s DNA for the family’s
mutation. Skilled counselling based on full knowledge of
the disease, its natural history, and the impact of a positive
and negative diagnosis on the individual and other family
members is essential.
TREATMENT
• Small peripheral retinal angiomas (<3 mm [<0.1 in]) are
best treated by argon laser photocoagulation, whilst
cryotherapy is used for larger peripheral tumors. Larger
retinal lesions may require penetrating diathermy or local
resection. As treatment of small lesions is more successful
there is further impetus to screen patients at risk regu-
larly. Treatment may increase the vascular leakage from
the tumor and produce an exudative retinal detachment.
• Cerebellar hemangioblastoma should be removed
surgically if possible: craniotomy with opening of the
cerebellar cyst and excision of the mural hemangio-
matous nodule may be curative. Recurrences may occur.
• Renal cysts and carcinomas can be removed via a partial
nephrectomy if detected early. If bilateral nephrectomy
is necessary, a delay of 1 year is usually advocated
between nephrectomy and transplantation to ensure that
no metastases will occur.
• Pheochromocytoma is usually treated with adrenalectomy.
• Pancreatic islet cell tumors are treated with partial
pancreatectomy.
PROGNOSIS
• Vision: patients have >70% chance of retaining vision of
6/18 or better with small retinal tumors, and 50%
chance with larger tumors (>4 mm [0.2 in]).
• Renal cell carcinoma develops eventually in most long
term survivors. More unusual and less serious
complications include renal, pancreatic, and ependymal
cysts, although the malignant potential of these lesions,
especially those in the kidneys, remain unclear.
• Mean age at death is about 41 years, median 49 years.
• Cause of death is renal cell carcinoma, and less
commonly cerebellar hemangioblastoma.
 von Hippel–Lindau Disease (VHL) 395

496, 497 MRI brain 496 497

scans.T1W image
sagittal plane (496),
showing capillary
hemangioblastomas
as low densities in
the dorsal medulla
and upper cervical
spinal cord (arrows);
T2W image axial
plane (497),
showing a capillary
hemangioblastoma
as a high density
mass in the dorsal
medulla and floor of
the fourth ventricle
(arrows). (Courtesy
of Dr AM
Chancellor,Tauranga,
New Zealand.)

498–500 T1W 498 499

midline sagittal (498)
and T2W axial (499)
MRI of a cerebellar
hemangioblastoma.
Note the lesion is
mainly cystic, but
there is a small
nodule near the
superior aspect
(arrow). Following
contrast on a T1W
coronal image (500),
the nodule is seen to
enhance (arrow).
This appearance is
typical of a cerebellar
hemangioblastoma.

500 501

501 Vertebral angiogram, lateral view, showing a cerebellar hemangio-

blastoma (arrows). (Courtesy of Dr AM Chancellor,Tauranga, New
Zealand.)
396 Tumors of the Central Nervous System

METASTASES TO THE CNS PATHOLOGY

Skull and dura metastases
Common sources
DEFINITION • Carcinoma of the breast and prostate.
Dissemination of tumor cells beyond their primary site to • Multiple myeloma.
the CNS.
Meningeal (craniospinal) metastases
EPIDEMIOLOGY About 5% of neurologic metastases; widespread dissemination
• Incidence: 4 (95% CI: 1–9) per 100 000 per year in one of tumor cells throughout the meninges and ventricles.
study and 14 (95% CI: 12–16) per 100 000 per year in
another study. The commonest cause of multiple Common sources
intracranial masses in the Western world, and the • Adenocarcinoma of the breast, lung, and gastrointestinal
commonest cause of a solitary cerebellar mass in patients tract.
over 40 years old; 20–40% of patients with cancer. • Carcinoma of the prostate.
• Age and gender: any age and either sex (depending of • Melanoma.
course on the nature of the primary malignancy). • Leukemia.

Brain metastases
• May be solitary (up to half of cases) or multiple.
• Metastases form a circumscribed mass, usually solid but
sometimes cystic.
• They may be hemorrhagic, particularly metastases from
melanoma and choriocarcinoma, and sometimes lung,
breast, thyroid, and kidney.
• They excite considerable vasogenic edema but little glial
reaction.

Common sources (in adults)

• Carcinoma of the lung (the source of 30% of brain
metastases; 35% of bronchial carcinomas metastasize to the
brain), breast (15% of brain metastases), gastrointestinal
502 tract (particularly colon and rectum), kidney and thyroid.
• Malignant melanoma (75% of melanomas metastasize to
the brain) (502).

Uncommon sources (in adults)

• Carcinoma of the gallbladder, liver, testicle (57% of
testicular tumors metastasize to the brain), uterus, ovary
and pancreas.
• Rhabdomyosarcoma.
• Ewing’s tumor.
• Lymphoma.
• Carcinoid.

Atypical sources
Carcinoma of the prostate, esophagus, oropharynx and skin
almost never metastasize to brain.

Complications
• Mass effect.
• Hemorrhage: renal, thyroid, choriocarcinoma,
melanoma, retinoblastoma, lung, breast; in fact, in
patients with recurrent or multiple unexplained
intracranial hemorrhages, think of hemorrhagic
metastases.
• Calcification: mucinous adenocarcinoma: colon,
stomach, ovary, breast; osteosarcoma, chondrosarcoma.

502 Multiple sections through the brain in the coronal plane showing
multiple areas of hemorrhage into metastases of malignant melanoma.
(Courtesy of Professor BA Kakulas, Royal Perth Hospital,Western
Australia.)
 Metastases to the CNS 397

ETIOLOGY AND PATHOPHYSIOLOGY DIFFERENTIAL DIAGNOSIS

Metastases to the skull and dura
Hematogenous usually, via the systemic circulation (e.g.
carcinoma of the breast) or via Batson’s vertebral venous
plexus: a valveless venous system that runs the length of the
vertebral column from the pelvic veins to the large venous
sinuses of the skull, bypassing the systemic circulation (e.g.
carcinoma of the prostate).
Metastases to the brain
Hematogenous usually, via the systemic circulation.
CLINICAL FEATURES
Metastases to the skull and dura
• Skull convexity metastases: usually asymptomatic.
• Skull base metastases: usually cause dysfunction of the
pituitary gland or the cranial nerve roots.
Metastases to the craniospinal meninges
• Headache.
• Backache.
• Cranial and peripheral neuropathies or radiculopathies
(particularly the cauda equina).
• Dementia.
• Hydrocephalus.
• Primary brain tumor: glioblastoma multiforme: similar
clinical features.
• Paraneoplastic syndromes (see p.401) not due to
compression or invasion of the nervous system by tumor.
• Brain abscess.
• Cerebritis/encephalitis.
• Subdural hematoma: occasionally a carcinoma
metastasizes to the subdural surface and compresses the
brain, mimicking a subdural hematoma.
• Stroke: hemorrhagic (e.g. into a tumor) or ischemic (e.g.
tumor embolism causing brain infarction).
• General paralysis of the insane (see p.312): can mimic the
diffuse cerebral disturbance seen in some patients with
metastases.
• Psychologic: if only headache and vomiting are present.
INVESTIGATIONS
CT brain scan
If metastases are suspected, a contrast-enhanced CT scan is
the first line investigation.
Bony (skull) metastases
These are readily recognized on CT (503) and bone scans
(504).

Metastases to the brain

Similar to glioblastoma multiforme (see p.364).

Syndromes
• Focal or multifocal neurologic dysfunction (e.g. seizures,
aphasia, focal weakness, ataxia), which is usually insidious
in onset and progressive; but can be abrupt in onset
following hemorrhage into a tumor, or embolism of
tumor or thrombus (marantic endocarditis) causing
cerebral infarction.
• Raised intracranial pressure (e.g. headache).
• Diffuse encephalopathy: headache, confusion, forget-
fulness, depression.

503 CT brain scan on 503 504

bone settings showing
multiple lucent lesions
in the skull vault
(arrows) due to
prostatic secondaries.

504 Nuclear bone

scan of a patient with
disseminated
carcinoma of the
breast showing
multiple hyperdense
areas of increased
tracer uptake due to
bony metastases in the
skull and spine.
398 Tumors of the Central Nervous System

Brain metastases Meningeal metastases

These are:
• Iso- or hypodense to normal brain.
• Located near the gray-white matter junction usually.
• Show marked contrast enhancement (may be ring
enhancement) (505, 506).
• Mass effect.
• Substantial white matter edema.
• May be difficult to detect with imaging unless there are
discrete nodules.
• Hydrocephalus may be present.
• Occasionally contrast enhancement of the meninges may
be seen (MRI is more sensitive than CT for that)
(507–510).
• Parenchymal metastases are present in about 40% of cases.

505 506 505 CT brain scan

with contrast showing
multiple enhancing
peripheral nodules
(arrows) typical of
metastases.These
were from a primary
carcinoma of the lung.

506 CT brain scan

with contrast showing
multiple partially
calcified metastases
from a primary
carcinoma of the
colon.

507 508 507, 508 T1W sagittal MRI with

contrast (507) and T2W sagittal
MRI (508) showing multiple
enhancing nodules on the nerve
roots (arrows) in a patient with
malignant meningitis.
 Metastases to the CNS 399

MRI brain scan DIAGNOSIS

• More sensitive to small lesions than CT (511, 512) and
may demonstrate multiple lesions when CT only demon-
strated one large one (thus helping to establish the diag-
nosis of metastases).
• Variable appearance of lesions, depending on the type and
presence of hemorrhage or calcification, but generally they
appear as masses with edema that enhance.
CSF
Meningeal metastases
• Pressure: normal or increased.
• Cells: normal or lymphocytic pleocytosis, cytology
(cytocentrifugation, Millipore filtering, cell typing).
• Protein: normal or elevated.
• Glucose: normal or low.
• Biochemical markers of cancer: lactate dehydrogenase,
beta glucuronidase, β2-microglobulin and carcino-
embryonic antigen.
• CT and MRI brain scan, before and after the injection of
contrast, are the most sensitive tests for the diagnosis of
brain metastases.
• Surgery has an important role in establishing the
diagnosis (e.g. frameless stereotactic biopsy or resection),
even for patients known to have a primary cancer
elsewhere because a new brain lesion in these patients
may not necessarily be a metastasis.
TREATMENT
• Aims to obtain local control of the brain tumor and to
preserve neurologic function.
• Corticosteroids.

509 T1W axial MRI with 509 510

contrast of the brainstem
showing multiple enhancing
nodules. Note the peripheral
sites and the brainstem
encasement (arrows)
indicating that these are in
the leptomeninges. (Courtesy
of Dr D Collie, Dept of
Neuroradiology,Western
General Hospital, Edinburgh.)

510 CT brain scan with

contrast showing marked
enhancement of all the
meninges (arrows) in a patient
with malignant meningitis
secondary to neuroblastoma
metastases. (See 509.)

511 T1W axial MRI without

contrast through the upper
brainstem showing a small
mass at the left petrous apex 511 512
adjacent to the carotid
siphon (arrows).This was a
solitary metastasis from a
lung primary in a patient
presenting with pain in the
left side of the face.

512 T1W MRI with contrast

showing multiple tiny
enhancing areas (arrows)
including one in the left side of
the upper pons (arrowhead).
These were breast carcinoma
metastases and the patient
had complained of mild
headache and had a left Vth
nerve palsy.The CT scan had
been normal.
400 Tumors of the Central Nervous System

Single brain metastases • Median survival free of functional disability is

• If the primary extracranial tumor is under control and if 2.5 months.
the metastasis is surgically accessible: surgical resection is • Older age (>60 years) increases the hazard of dying by
performed followed by whole brain irradiation to a dose 2.7 times, compared with younger patients.
of at least 20 Gy (2000 rads) in five fractions (and up to
two fractions per day, each of 2 Gy [200 rads] to a dose Multiple metastases
of 40 Gy [4000 rads]). • Untreated: median survival is 1 month; nearly all die
• If the primary extracranial tumor has progressed during from the brain tumor.
the previous 3 months, radiotherapy alone is sufficient. • Steroid treatment: median survival is 2 months.
• If the metastasis is surgically inaccessible and small • Whole brain irradiation: median survival is 3–6 months.
(<3 cm): stereotactic biopsy is performed, followed by
whole brain irradiation or preferably, entry into a trial Meningeal metastases
comparing whole brain irradiation with radiosurgery and • Median survival is 5.8 months.
whole brain irradiation. Stereotactic radiosurgery delivers • Treatment rarely stabilizes neurologic symptoms for
a high dose of focused radiation to a defined volume. more than a few weeks.
The three principal sources of radiation are x-rays (linear
accelerator), γ-rays (Gamma Knife – cobalt 60), and Independent prognostic factors for
charged particles (proton beam). The linear accelerators improved survival
are the most commonly used. • Age <65 years.
• Karnofsky performance status (high). (The Karnofsky
Multiple brain metastases performance score is a clinical grading scale which assigns
• Whole brain irradiation: the standard treatment. It gives patients a score ranging from 10–100 according to their
significant palliation. Radiosensitive tumors include ability to perform daily tasks.)
lymphoma, germ cell tumors, and small cell lung cancer. • Control of primary cancer.
Relatively insensitive tumors include melanoma, renal cell • Metastatic spread limited to the brain.
carcinoma, and thyroid carcinoma.
• Surgery to relieve significant neurologic dysfunction from
a large surgically accessible lesion should be considered Table 38 Classification of paraneoplastic syndromes
in a patient whose primary cancer is under control and
who is able to withstand surgery. Clinical syndrome Some associated neoplasms
CNS
Recurrent brain metastases Encephalomyelitis: Small cell lung carcinoma
If stable primary disease and good performance status, – Limbic encephalitis
consider any of: – Brainstem encephalitis
• Re-operation. – Myoclonus-opsoclonus
• Re-irradiation. – Cerebellar degeneration
• Chemotherapy: for chemosensitive tumors such as small Subacute cortical cerebellar Breast, ovary, ?lymphoma
cell lung cancer, choriocarcinoma, and breast cancer. degeneration
• Brachytherapy: utilizes radioactive isotopes, usually
iridium 192 or iodine 125, directly implanted into the Opsoclonus Breast
tumor site by catheters placed stereotactically to deliver Necrotizing myelopathy Lymphoma (retroperitoneal)
a high dose or radiation to the target. Small cell lung carcinoma
• Stereotactic radiotherapy, preferably as part of a clinical trial.
Peripheral nervous system (PNS)
Meningeal metastases Subacute sensory neuronopathy Small cell lung carcinoma
• Radiation therapy to the symptomatic areas. Peripheral neuropathies associated
• Intraventricular methotrexate. with IgM paraproteins:
– Motor neuropathy Lymphomas, plasma cell
PROGNOSIS – Motor/sensory demyelinating dyscrasias
More than half of patients die from causes other than their neuropathy
brain metastases. – Axonal neuropathy
Single metastasis in patients with controlled Neuromuscular junction syndromes
extracranial cancer Lambert–Eaton syndrome: Small cell lung carcinoma
• Median survival is 7 months if treated with radiotherapy – With cerebellar degeneration Small cell lung carcinoma
alone, 10 months with surgical excision and 12 months Myasthenia gravis Thymoma
with surgical resection and radiotherapy. Muscle
• Median survival free of functional disability is 4 months Polymyositis-dermatomyositis Gynecologic, lung,
if treated with radiotherapy alone and 9 months if treated lymphoma
with surgical resection and radiotherapy.
N.B. Myasthenia gravis is not a bona fide paraneoplastic syndrome
Single metastasis in patients with progressive but there is a strong association with thymomas in middle-aged
extracranial cancer and elderly patients.
• Median survival is 5 months (with radiotherapy alone).
 Paraneoplastic Syndromes 401

PARANEOPLASTIC SYNDROMES CLASSIFICATION OF PARANEOPLASTIC

SYNDROMES (see Table 38)

DEFINITION
A term used to describe a number of disorders of the
nervous system which are manifestations of the remote
effects (predominantly autoimmune) of a systemic cancer,
and are not ascribable to nervous system metastases or to
destruction of vital systemic organs by the tumor or
treatment of the tumor.
Neurologic disorders that are clinically and pathologically
identical to paraneoplastic syndromes also occur in the
absence of cancer but it is the statistical relationship between
the presence of cancer and the specific neurologic disorder
that defines a given neurologic syndrome as paraneoplastic.
For example, among patients with Lambert–Eaton
myasthenic syndrome (LEMS) about 60% have small cell lung
cancer as the underlying cause and 40% do not. LEMS is
exceptionally rare in the general population yet it affects about
3% of patients with small cell lung cancer.
EPIDEMIOLOGY
• Incidence: rare.
• Age: adults, occasionally children.
• Gender: M=F.
PATHOLOGY
The nervous system may be affected at any site: cerebral
cortex, limbic system, brainstem, cerebellum, spinal cord,
spinal ganglia, peripheral nerve, neuromuscular junction,
and muscle, by different pathologies:
• Inflammatory (513–515): limbic encephalitis, brainstem
encephalitis, poliomyelitis-like syndrome, and posterior
root ganglionitis.
• Vascular: hypercoagulability, venous thrombosis, non-
bacterial or marantic endocarditis, intravascular
coagulopathies.
• Immunologic: myasthenic syndrome of Lambert–Eaton,
myasthenia gravis, polymyositis-dermatomyositis complex.
The pathology of subacute myelopathies and of sensory
and sensori-motor neuropathies is less clear.
Cerebellar degeneration
• Diffuse degenerative changes in the cerebellar cortex
(pallor of the Purkinje cells) and deep cerebellar nuclei.
• Perivascular and meningeal clusters of inflammatory cells.

513 514

515

513 Axial section through the pons showing

multifocal areas of gliosis and neuronal loss due to
paraneoplastic encephalitis.

514, 515 Low (514) and high magnification (515) sections showing
neuronal loss, gliosis and perivascular cuffing due to paraneoplastic
encephalitis.
402 Tumors of the Central Nervous System

Limbic encephalomyelitis (e.g. Lambert–Eaton syndrome: antibodies to voltage-gated

This syndrome results in subtotal neuronal loss,
neuronophagia, astrocytic gliosis, microglial proliferation,
and perivascular cuffing in the limbic structures, especially
the hippocampal gyrus, Ammon’s horn and amygdala.
Myelopathy
Spinal cord disorders associated with malignant tumors:
amyotrophic lateral sclerosis, subacute necrotizing
myelopathy, and subacute motor neuropathy.
calcium channels [VGCCs] of motor nerve terminals;
myasthenia gravis: antibodies to nicotinic acetylcholine
receptor of the motor endplate; each is associated with small
cell lung cancer [SCLC], can be induced in passive transfer
experiments, and responds to therapies which reduce
antibody titres). SCLC cells appear to express VGCCs.
Secretion of non-immune origin soluble factors by
the tumor (e.g. neurohormones, neurotransmitters)

Neuropathy CLINICAL FEATURES

• Subacute pure sensory neuropathy: the primary lesion is • The clinical manifestations precede (in about two-thirds
dorsal root ganglion cell degeneration associated with of patients) by months and rarely years, or accompany
secondary degeneration of the ascending tracts in the (in about one-third) the manifestations of the underlying
posterior columns and sensory fibers in peripheral nerves. cancer.
• Axonal or demyelinating peripheral neuropathy. • Onset: typically subacute, occasionally abrupt.
• Clinical course: rapid progression to a peak over a few
Lambert–Eaton myasthenic syndrome (LEMS) weeks to a few months followed by stabilization.
Reduced number of functional, voltage-gated calcium
channels (VGCCs) at motor nerve terminals results in Limbic encephalomyelitis
reduced release of acetylcholine from the presynaptic motor • Confusion, impaired recent memory (forgetfulness),
nerve terminals in this syndrome. hallucinations, depression, personality change, sleep
disturbances, and behavioral disorder (agitation, anxiety,
Dermatomyositis/polymyositis depression) occur.
Acute muscle necrosis: dermatomyositis is due to a humoral • Seizures, myoclonus, sensory ataxia and brainstem and
immune attack on muscle capillaries causing muscle fiber spinal cord signs may also occur.
infarcts and perifascicular inflammation and atrophy. • Occurs as a remote manifestation of SCLC or, less
commonly, transitional cell carcinoma of the bladder,
ETIOLOGY mediastinal teratoma, malignant thymoma, and testicular
Most common underlying cancers carcinoma.
• Small cell lung carcinoma.
• Breast carcinoma. Cerebellar degeneration
• Ovarian carcinoma. • Limb and gait ataxia, nystagmus and dysarthria, sometimes
• Lymphoma. with diplopia, vomiting and pyramidal signs are present.
• Carcinoma of the uterus, bowel and other viscera • May be the presenting feature of carcinoma of the lung,
account for a minority of cases. breast and ovary.
• Anti-neuronal antibodies are found in most cases,
PATHOPHYSIOLOGY particularly when associated with ovarian or other
Several mechanisms have been suggested as a possible gynecologic malignancies.
pathogenesis:
Opsoclonus-myoclonus-ataxia
Hypothesis Example • Presents as irregular, chaotic, rapid, jerky, dysconjugate
Autoimmune process LEMS movement of the eyes in all directions of gaze, myoclonic
jerks and ataxia.
Toxin secreted by tumor ACTH → Cushing’s syndrome • It is a rare complication of neuroblastoma in childhood
PTHRP → hypercalcemia and even rarer in adults with cancer.

Competition for essential substrate Utilization of glucose by Myelopathy

sarcomas → hypoglycemia • Presents as paraparesis, sometimes associated with spinal
Carcinoid tumors compete myoclonus and spinal muscular atrophy with muscle
with brain for tryptophan → fasciculations.
pellagra-like syndrome • A rare complication of lymphoma and small cell lung cancer.

Opportunistic infection Papovavirus → progressive Peripheral neuropathy

multifocal leukoencephalopathy
PTHRP: Parathyroid hormone-related protein.
Immune-mediated
Most paraneoplastic syndromes are autoimmune (either
humoral or cell-mediated) and result from the production of
antibodies directed against tumor-associated antigens that
cross-react with important elements of the nervous system
• Subacute pure sensory neuropathy (dorsal-root ganglionitis).
• Sensori-motor neuropathy:
– Four times more common than subacute pure sensory
neuropathy.
– Associated with cancer of the lung, stomach, colon,
breast, ovary, pancreas and testis; lymphoma and multiple
myeloma.
– Usually a distal, symmetric sensorimotor axonal
polyneuropathy.
 Paraneoplastic Syndromes 403

– Occasionally, mimics acute Guillain–Barré syndrome or Nutritional deficiencies

relapsing chronic inflammatory demyelinating Syndromes result from vitamin B1, B12 and folate
neuropathy, particularly in patients with seminoma. deficiencies due to anorexia, vomiting, diarrhea, dysphagia
– Associated with the presence of anti-neuronal nuclear and gastrointestinal resections.
antibodies.
– Anti-Hu-antibody-associated encephalomyelitis with Intracranial hemorrhage
sensory neuropathy most commonly features sensory Thrombocytopenia, liver failure, hemorrhagic secondary
symptoms such as paresthesias, painful neuropathy, deposits can cause syndromes.
motor weakness, and diplopia.
– May respond to plasmapheresis or steroids. Marantic (non-infectious or non-bacterial
• Multiple mononeuropathy. thrombotic) endocarditis
• Entrapment and pressure neuropathies due to cachexia. Small, sterile (non-infected) thrombi on heart valves,
• Nutritional neuropathies. particularly mitral valve, give rise to multiple embolic cerebral
(and renal, splenic, gastrointestinal) infarcts. Blood cultures are
LEMS (see p.664) usually sterile and echocardiography may be normal.
Associated with SCLC in about 60% of cases; about 40% of Arteriography may reveal aneurysmal dilatation of distal vessels.
have no evidence of cancer but often have associated
autoimmune diseases, such as vitiligo, pernicious anemia and Cerebral vein and dural sinus thrombosis
thyroid disease. Procoagulant state associated with malignancy.
Myasthenic syndrome:
• Proximal muscle fatiguability and weakness (which Disseminated intravascular coagulation
increases with exertion). The syndromes of intravascular coagulopathy, dural venous
• Muscle wasting. sinus thrombosis and marantic endocarditis are all thought to
• Depressed deep tendon reflexes that increase after muscle be related to a hypercoagulable state associated with elevated
activation. levels of fibrinogen, increased prothrombin and activated
• Symptoms of autonomic dysfunction, such as dry mouth, partial thromboplastin times, and accelerated turnover of
impotence and constipation. fibrinogen and platelets. Also, some chemotherapeutic agents,
such as asparaginase and corticosteroids, alter hemostasis.
Disorders of muscle
• Cachectic myopathy: significant muscle wasting is present DIFFERENTIAL DIAGNOSIS
(type II fiber atrophy) but power is usually retained. The If not known to have cancer
cause is unknown. • Degenerative diseases with a chronic and progressive
• Proximal muscle weakness: present in patients with overt course: the rapid development of neurologic disability
or occult malignancy of the lung, breast, and gastro- over a few weeks to a few months followed by
intestinal tract, and is usually characterized by atrophy of stabilization differentiates paraneoplastic syndromes from
type II more than type I fibers. EMG may show more chronic and progressive degenerative diseases.
myopathic motor unit potentials. • Stroke: occasionally, the onset of paraneoplastic
• Polymyositis/dermatomyositis (see pp.681, 684): syndromes can be so abrupt that the disorder can be
– About 20% of patients have associated cancer; usually confused with a stroke.
lung, colon, ovary or breast. The association with cancer
is greatest in middle-aged women. If known to have cancer
– Subacute proximal muscle weakness, sometimes with • Previous therapy:
associated dysphagia, voice change and respiratory – Radiation.
muscle weakness is characteristic. – Chemotherapy.
– Muscle pain is not severe and the skin rash is sometimes – Immunotherapy.
very trivial. • Metastases.
• Metabolic disturbance:
Secondary non-metastatic complications of – Renal failure.
malignancy – Liver failure.
Metabolic/endocrine • Nutritional deficiency:
• Hyperviscosity syndrome. – Wernicke–Korsakoff syndrome.
• Hyponatremia due to syndrome of inappropriate – Cancer cachexia.
antidiuretic hormone (SIADH) secretion. • Opportunistic infection (lymphoma, immunosuppression):
• Adrenal failure due to metastases to adrenal glands. – PML.
• Cushing’s syndrome due to aberrant ACTH secretion. – Cytomegalovirus.
• Renal failure. – Herpes virus.
• Hypoglycemia. • Vascular disorders:
• Hypercalcemia. – Hypercoagulability.
• Carcinoid syndrome. – Hypocoagulability.
• Non-cancer related:
Opportunistic infections – Alcohol.
These occur particularly in patients with lymphomas and – Diabetes.
undergoing immunosuppressive treatment.
404 Tumors of the Central Nervous System
INVESTIGATIONS
Investigations are indicated if neurologic symptoms are
typical of a paraneoplastic syndrome (typical syndrome,
subacute onset, and rapid evolution).
Anti-neuronal antibodies
Anti-Yo antibody (also called ‘type 1 anti-Purkinje cell
antibody’ [PCA-1], ‘APCA-1’ or ‘type 1 antibody’)
• Polyclonal antibodies, bind to cytoplasm of Purkinje cells
and proximal axon and dendrites, and fix complement.
• They are present in most cases of paraneoplastic subacute
cerebellar syndrome, dysarthria and ataxia, particularly
women with breast, ovarian or other gynecologic
malignancies, and less commonly in SCLC and lymphoma.
• The lack of detectable anti-Yo antibodies in some
patients suggests that the antibodies, per se, may not be
the cause but may reflect an immune response to an
epitope. Patients with seronegative paraneoplastic
cerebellar degeneration have a high frequency of other
autoimmune paraneoplastic syndromes (such as
Lambert–Eaton syndrome).
Anti-Hu antibody (also called ‘type 1 anti-neuronal nuclear
antibody’ (ANNA-1), or ‘type 1Ia antibody’)
• Antibody binds to nuclei of neurons of central and
peripheral nervous system, sparing nucleoli.
• The antibody is present in paraneoplastic encephalomyelitis,
sensory neuronopathy, and autonomic neuropathy.
• It is mainly associated with SCLC, but also with
neuroblastoma, and rarely non-SCLC, prostate cancer,
and seminoma.
Anti-Ri antibody (also called ‘type 2 anti-neuronal nuclear
antibody’ (ANNA-2), or ‘type 1Ib antibody’)
• Antibody binds to CNS but not peripheral nervous
system neuronal nuclei, sparing nucleoli.
• It is present in paraneoplastic opsoclonus, ataxia,
nystagmus, dizziness, dysarthria.
• The antibody is most frequently associated with breast
cancer (total number of cases described is still small), and
SCLC (one case).
Calcium channel autoantibodies
Detected in about 30% of patients with LEMS.
CSF
• Cells: nil (if late diagnosis).
• Protein: modestly elevated.
• IgG and IgG index: elevated.
• Oligoclonal bands: may be present.
• Anti-neuronal antibodies: may be present.
Nerve conduction studies and electromyography
• Sensory nerve action potentials (SNAPs): reduced or
absent in pure sensory neuropathy.
• Compound muscle action potentials (CMAPs): low
amplitude in LEMS.
• Nerve conduction velocities (NCV): normal motor NCV
in pure sensory neuropathy; synaptic transmission
(repetitive nerve stimulation): dramatic increase in
CMAP amplitude (by 2–20 times) following supra-
maximal stimulation of the motor nerve at rates of
>40 Hz in LEMS.
• Electromyography: features of neuropathy or myopathy
may be present.
Sural nerve biopsy
Shows a severe depletion of predominantly large myelinated
fibers, due to a neuronopathy, in pure sensory neuropathy.
If not known to have cancer, search for cancer
• Liver function tests, and abdominal ultrasound if indicated.
• Pelvic examination (rectal and vaginal), CT, ultrasound.
• Chest x-ray, CT scan.
• Mammograms.
• Testis examination, ultrasound.
• Lymph node examination.
• Stool guaiac (i.e. blood in feces), and endoscopy if
indicated.
• Tumor markers in blood:
– CEA (cf. gastrointestinal cancer; carcino-embryonic
antigen).
– PSA (cf. prostatic cancer; prostatic specific antigen).
– CA-125 (cf. ovarian cancer).
– BRCA1 (cf. breast cancer).
If known to have cancer
• Search for metastases:
– MRI of symptomatic area(s).
– CSF for malignant cells.
• Exclude metabolic problems:
– Serum creatine (renal failure).
– Liver function tests (liver failure).
DIAGNOSIS
Although the clinical features precede the diagnosis of the
underlying neoplasm in more than half of cases, diagnosis
during life can be difficult because clinical symptoms and
findings on ancillary investigations are not specific.
Diagnostic clues
• Associated statistically with cancer (the neurologic
disorder is known to occur with increased frequency in
patients with cancer).
• Subacute onset (the neurologic disorder develops acutely
or subacutely and generally stabilizes after a few months).
• Severe neurologic disability.
• CSF pleocytosis and increased IgG index (intrathecal
synthesis of IgG) is often present if the CNS is involved.
• One neural cell type or structure is often affected (e.g.
Purkinje cells in PCD, cholinergic synapse in LEMS).
• Specific autoantibodies in serum or CSF (anti-Hu, anti-
Yo, anti-Ri).
Diagnostic criteria
In a given patient a reasonably secure diagnosis can be made
in the presence of a ‘typical’ paraneoplastic neurologic
syndrome and:
• An appropriate underlying cancer (see Table 38, p.401).
However, although paraneoplastic syndromes are usually
associated with specific cancers, any cancer can cause any
paraneoplastic syndrome. In addition, the presence of
cancer and a neurologic syndrome may be coincidental
and not causal. For example, about 2% of people
diagnosed with motor neuron disease have, or develop
lung cancer within 2 years.
 Paraneoplastic Syndromes 405

• A well characterized antineuronal antibody in the serum Interfere with auto-reactive T lymphocyte activation
that has been associated with cancer, such as anti-Yo • Inhibit MHC recognition with anti-MHC monoclonal
antibody, which virtually establishes the diagnosis of antibodies.
cancer, particularly a gynecologic cancer, or anti-Hu • Compete for antigen binding with ‘design’ peptides.
antibody which virtually establishes the diagnosis of small • Inhibit T cell activation.
cell lung cancer. • Anti-CD4.
• Resolution of the syndrome when a cancer is discovered • Anti-TCR.
and adequately treated. However, most paraneoplastic
syndromes do not respond to treatment of the Induce tolerance: feed antigen
underlying neoplasm.
Suppress inflammation
TREATMENT • Corticosteroids.
Usually unsatisfactory; most patients fail to respond to either • Non-steroidal anti-inflammatory drugs.
treatment of tumor or suppression of immunity. The major
problems are that the pathogenesis is not fully understood, PROGNOSIS
the disorders cause neuronal destruction (so treatments Except on rare occasions, treatment of the associated cancer
need to be given early before the syndrome has evolved) and does not alter the clinical course.
the disease is uncommon for evaluation of treatments in
large controlled trials.

Treat the underlying tumor and remove

the antigen
• Surgery.
• Radiation.
• Chemotherapy.

Treat the paraneoplastic syndrome

Suppress humoral immunity
B-cells, antibody:
• Plasma exchange:
– Effective for LEMS.
– Fails to remove antibody from the CSF.
– Not effective for cerebellar degeneration, seropositive or
seronegative.
• Intravenous immunoglobulin. ?Effective for LEMS,
subacute cerebellar syndrome.
• Protein A immunoadsorption.
• Radiation of lymph nodes, brain.
• Immunosuppressive drugs (corticosteroids, azathioprine,
cyclosporine A, cyclophosphamide, chlorambucil,
methotrexate, tacrolimus [FK506]).

3,4-Diaminopyridine (up to 100 mg/day in divided

doses) is indicated in all patients with LEMS, with the
addition of prednisolone and azathioprine in non-smoking
patients who have severe symptoms and no evidence of
tumor. If severe symptoms develop in patients with SCLC
or smokers, then prednisone ± plasma exchange should be
considered. After control of symptoms the dosage can be
reduced to the most effective minimal dose.

Suppress cytotoxic T cells

CD8:
• Irradiation.
• Steroids.
• Cyclosporine.

Suppress helper T cells

CD4:
• Anti-CD4 antibodies.

Increase suppressor T cell function

• β-interferon.
406 Tumors of the Central Nervous System

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METASTASES TO THE CNS
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GLIOMAS PITUITARY TUMORS

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ACOUSTIC NEUROMA
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 Chapter Fourteen 407

Degenerative
Diseases of the
Nervous System
ALZHEIMER’S DISEASE (AD) 516

DEFINITION
A clinico-pathologic entity comprising clinical evidence of
dementia (sufficient to interfere with social and work
function) and histopathologic evidence of neurofibrillary
tangles and senile plaques in the brain.

EPIDEMIOLOGY
The most common cause of dementia, accounting for
almost half of cases.
• Incidence: 123 per 100 000 population per year.
• Prevalence: increases exponentially with age, roughly
doubling every 5 years from about 1% of the population
at age 65 to about 16–20% at age 85 years.
• Age:
– Predominantly a disease of old age but not an invariable
accompaniment of ageing.
– About 5% of cases are below retirement age.
– Seldom presents before 40 years of age except in Down’s
syndrome.
• Gender: M=F.

PATHOLOGY
Macroscopic
Brain atrophy (516, 517) is present: narrowed cerebral
convolutions and widened cerebral sulci, enlarged third and 516 Surface of the brain of showing prominent cerebral sulci due to
lateral ventricles (hydrocephalus ex vacuo). cerebral atrophy.

517

517 Coronal section of the brain of a patient with Alzheimer’s disease

showing considerable atrophy of the brain and dilatation of the
ventricles due to the severe brain atrophy (hydrocephalus ex vacuo).
408 Degenerative Diseases of the Nervous System

Microscopic which project to the cortex and hippocampus. A family of

Argyrophilic senile (neuritic) plaques (518–521)
• Plaques are large extracellular lesions in which the
principal component of the core of the plaque is the
insoluble 40–42/43 amino acid peptide called β-amyloid
protein which is a minor breakdown product of amyloid
precursor protein (APP).
• Plaques result from the accumulation of several proteins
and an inflammatory reaction around deposits of
β-amyloid.
• Degenerating nerve terminals in the plaques also contain
the microtubular protein tau.
• Amyloid burden and the number of plaques do not
correlate with the severity of the disease.
Neurofibrillary tangles (522–524)
• Tangles are intracellular lesions principally composed of
aggregations of an abnormal form of a cytoskeletal-
associated microtubular protein, tau, which is hyperphos-
phorylated. The aggregated neurofibrils are visualized as
paired helical filaments on electron microscopy.
• They are present, together with plaques, in the
projection neurons of the limbic and association areas of
the cerebral cortex, particularly the parietal cortex and
hippocampus, especially the CA1 zone and the
entorhinal cortex, subiculum, and transitional cortex of
the hippocampus.
• The number of tangles increases with the duration and
severity of disease.
• Tangles are not specific for AD however, they are also
found in other conditions such as dementia pugilistica,
subacute sclerosing panencephalitis, and tuberous sclerosis.
neurotrophic factors (small proteins), of which the
archetypal neurotrophin is nerve growth factor (NGF), are
important (protective) for the survival of cholinergic cells.
• Diminution of monoaminergic neurons and
noradrenergic, GABAergic and serotonergic functions
occur in affected neocortex.
• Decreased neuropeptide transmitters: substance P,
somatostatin, cholecystokinin.
ETIOLOGY
• Most cases are probably polygenic (caused by the action
of several different genes), and the penetrance of disease
is influenced by age and environmental factors (e.g.
possibly herpes simplex virus type 1 infection in the brain).
• The concordance rate is higher (1.2–2.7) in mono-
zygotic (MZ) and dizygotic twin pairs, suggesting the
contribution of genetic factors, but MZ twins are not
fully concordant, implicating non-genetic and environ-
mental factors are involved.
• Genetic factors appear to lead to quantitatively worse
disease but not to a qualitatively different pattern of brain
involvement. β-amyloid deposition seems to be the
neuropathologic factor most strongly influenced by
genetic factors.
518

Dystrophic neurites

Loss of neocortical neurons (>40%)

Loss is widespread (hippocampus, entorhinal cortex,
association areas of neocortex, and nucleus basalis of
Meynert [the substantia innominata] and locus ceruleus)
and predominantly a loss of cholinergic, noradrenergic, and
dopaminergic neurons. N.B. There is no loss of neocortical
neurons in the course of normal ageing.
518 Microscopic section of cerebral cortex, cresyl violet stain, showing
Loss of neuronal synapses neuronal loss and an extracellular senile or ‘neuritic’ plaque containing a
• Assessed using antibodies to synaptic proteins such as homogeneous central core of amyloid (arrow).
synaptophysin.
• The degree of synaptic loss is the best correlate with the
severity of dementia. 519
N.B. It is not known if senile plaques or neurofibrillary
tangles come first, or which is the primary factor causing
AD, but as these cellular changes progress, neurons are lost.

Associated pathologic states (525)

• Concomitant Parkinson’s disease changes (nigral
degeneration and Lewy bodies at various sites) are
present in about 20–30% of AD autopsies.
• Diffuse Lewy body disease (see p.430).
• ‘Punch-drunk’ syndrome, or ‘dementia pugilistica’:
neurofibrillary changes in boxers.

Chemical pathology
• A cholinergic deficit secondary to degeneration of 519 Microscopic section of cerebral cortex, Cajal stain, showing two
subcortical neurons (e.g. in the basal nucleus of Meynert) senile or ‘neuritic’ plaques (arrows).
 Alzheimer’s Disease (AD) 409

520 521

520 Microscopic section of cerebral cortex, silver stain, showing an 521 Amyloid in the walls of small blood vessels near senile plaques
extracellular senile or ‘neuritic’ plaque as a deposit of amorphous (amyloid or congophilic angiopathy).
material that contains a central core of amyloid, surrounded by
numerous short fibrils (resembling a bird’s nest) that represent
products of degenerated nerve terminals, mainly dendritic, containing
lysosomes, abnormal mitochondria, and often twisted tubules.

522 523

524 525

522–524 Microscopic section of brain showing neurofibrillary tangles 525 Microscopic section of brain showing granulovacuolar
as thick, fiber-like strands of silver-staining material, often in the form of degeneration of neurons in the pyramidal layer of the hippocampus.
loops, coils or tangled masses, in the nerve cell cytoplasm.
410 Degenerative Diseases of the Nervous System
Sporadic (most cases of AD)
Negative family history (50–75% of cases)
• Associations with advanced maternal age, head trauma,
history of depression, and the coexistence of herpes
simplex virus type 1 in the brain and carriage of an
apolipoprotein E (ApoE) ε4 allele.
• Postmenopausal estrogen replacement therapy has been
associated with reduced risk and delayed onset of AD in
elderly women. Estrogen is linked with preservation of
cholinergic neurons, increased secretase metabolism of
the APP and interaction with ApoE.
• The above associations have not been established as
causal, however (see Risk factors, below).
Positive family history in one or more first-degree
relatives (25–50% of cases)
• ApoE gene on chromosome 19q encodes ApoE.
Although no mutations have been found in ApoE, one
of its three genetic variants, ε4, substantially increases the
risk of AD. This is, therefore, a risk factor or
‘susceptibility’ gene (see below) rather than a causative
gene. The onset of AD is 10–20 years earlier in
individuals who are homozygous for the ApoEε4 allele
than in those with the ε2 or ε3 alleles, and it is 5–10
years earlier in individuals who are heterozygous for ε4.
• Presenilin-1 (PS-1) gene on chromosome 14: about 5%
(and up to 20%) of AD in the white population may be
attributed to homozygosity at this locus.
Familial variants of AD (rare)
Autosomal dominant inheritance of mutations in one of the
three known causative genes; tends to present clinically at a
younger age (40–60 years):
• Amyloid precursor protein gene on the long arm of
chromosome 21 which encodes APP (<1% of all early-
onset cases).
• PS-1 gene on chromosome 14q (50% of early-onset
cases): >50 mutations in the gene for PS-1 have been
identified in patients with early-onset AD.
• Presenilin-2 (PS-2) gene on chromosome 1 (15–20% of
cases).
Mutations in all these genes result in a shift in the
metabolism of APP to more of a 42–43 amino acid form of
β-amyloid (‘long Aβ’), as distinguished from the more
prevalent species of β-amyloid that has just 40 residues
(‘short Aβ’).
Genetic classification of Alzheimer’s disease (Table 39)
Down’s syndrome
An extra chromosome 21 (trisomy 21) and thus extra copy
of the β-amyloid precursor gene on chromosome 21 leads
to β-amyloid deposition and the brain changes of AD before
age 40, but not dementia until much older.
Risk factors for AD
Definite
• Old age (accumulation of β-amyloid in the brain with age).
• Family history of dementia (having a first-degree relative
with AD increases the risk around 3.5 times, perhaps
because vulnerability genes are shared by family members).
• ApoE allele status. The ApoE gene may be involved in
neuronal repair:
– ApoE is produced predominantly in astrocytes and is
carried by the low-density lipoprotein receptor into
neurons, where it binds to neurofibrillary tangles.
– ApoE exists in three major isoforms (E2, E3, and E4)
encoded by three alleles (ε2, ε3 and ε4) of the ApoE gene.
The three variants of ApoE vary in their affinity for β-
amyloid. The ApoE4 variant increases the rate of
deposition of fibrillar β-amyloid, resulting in the β-pleated
sheets that stain with birefringent stains for amyloid.
– In the general population, 75–85% have the ε3 allele,
10–15% have ε4, and 5–10% have ε2. In AD, ε4 is over-
represented (40% [32–58%]) and ε2 is under-represented
(4%).
– Up to 30–40% of the risk for late-onset AD is
attributable to alleles at the ApoE locus.
– The ε4 allele is associated with a threefold
(heterozygotes) to eightfold (homozygotes) increased
risk of sporadic and familial late-onset AD. However,
even among homozygotes for ε4, only about 50%
develop dementia by age 90 years.
– The ε2 allele may be protective.
– Although ApoE4 is an important risk factor for AD, it is
neither essential for the development of the disease, nor
specific for the disease. Hence, testing for ApoE
genotype is not advised.
• Down’s syndrome.
Possible
• Ethnic group: AD could be less common in some non-
white groups (Asians, Black Africans, Native Americans)
due to unknown genetic or environmental differences.
• Head injury: neuronal injury may trigger the deposition
of β-amyloid.
• Lower educational attainment and socioeconomic status.
• Herpes simplex virus type 1 infection of the brain.
• Aluminum in drinking water: aluminum is neurotoxic
and may been found in the brain in people with AD, but
the aluminum hypothesis remains controversial.
• Susceptibility loci on chromosomes 9 and 10. The locus
on chromosome 10 probably modifies risk for AD by
modulating long β-amyloid-42 levels.
• High blood pressure and other vascular risk factors.
• High plasma homocysteine.
Possible protective factors
• Anti-inflammatory drugs: AD may involve inflammatory
mechanisms.
• Estrogen replacement therapy.
• Education and premorbid intelligence: greater cognitive
reserve may allow better compensation for disease pathology.
PATHOGENESIS
The amyloid hypothesis
The β-amyloid gene encodes a large protein, APP, which is a
transmembrane protein, with the β-amyloid motif extending
from the exterior to half-way through the cell membrane. The
APP gives rise to β-amyloid, a fragment of 40–42 amino acids.
There are at least three different forms of β-amyloid, depending
on the site of RNA splicing. Seven different mutations in the
gene for the APP have been found, all of which increase the
production of β-amyloid 1–42 (β-A4) leading to fibrillar
aggregation toxic to neurons. The amyloid hypothesis is that
mutations in the APP and presenilin genes are associated with
increased cellular production of β-A4, which is toxic to
 Alzheimer’s Disease (AD) 411

neurons. The ApoE ε4 allele does not increase production
of β-A4, but promotes an increase in the rate of β-amyloid
deposition as compared with Apoε3. AD may be a restricted
form of cerebral amyloidosis, in which β-amyloid fibril
deposition is essential, but not necessarily the sole cause, and
that neurofibrillary tangles are caused by damage from
aggregated β-amyloid.
CLINICAL FEATURES
• Insidious onset.
• Memory decline/forgetfulness:
– Defects in learning/encoding new verbal and visual-
spatial information are apparent. Impaired antegrade
episodic memory is the earliest neuropsychologic deficit,
and is due to plaques and tangles in the transentorhinal
region, which deafferent the hippocampal complex.
Elaborate encoding strategies are ineffective whereas they
substantially improve learning in normal elderly people.
– Defects in retrieving information with minimal cueing is
present (episodic or autobiographical memory is pre-
dominantly affected, with early loss of memory for
everyday events).
– There is relative preservation of immediate short term
memory (e.g. digit span) early on.
• Focal ‘cortical’ neurologic signs such as dysphasia,
dyscalculia, dysgraphia (dysphasic or dyspraxic), visual-
spatial-perceptual dysfunction, ideomotor and dressing
dyspraxia, agnosia for objects or faces, and sensory inat-
tention occasionally mark the onset of the disease. Other-
wise, focal cortical dysfunction becomes apparent later.
• Paranoia and other personality or behavioral changes may
be present.
• Myoclonic jerks and occasionally seizures occur in some
patients.
• Muscular rigidity and signs of corticospinal tract
dysfunction may occur in the late stages.
• Gait disorder: short-stepped, slower gait and poor
balance often appear late in the disorder.
• Primitive reflexes and other frontal release signs.
• Urinary incontinence.
• Akinesia and mutism.
mislay items, get lost when alone, or fail to recognize people
(i.e. they may have anosognosia). Changes in family roles are
also important clues; a person who normally deals with family
finances for example may have recently had to abrogate the
responsibility because of failing attention and memory.
Psychologic, medical, psychiatric, neurologic and social
factors that may contribute to a patient’s intellectual decline
should also be evaluated. In many cases it is quite clear from
the history and examination that dementia is present, but
in others a more formal assessment is necessary by means of
a formal neuropsychologic evaluation.
DIFFERENTIAL DIAGNOSIS
Dementia
• Alzheimer’s disease: 50–55%.
• Vascular dementia (see p.261): 15–20%.
• Diffuse Lewy body disease (see p.430): 15–25%.
• Parkinson’s disease (see p.420): 5–10%.
• Brain injury: alcohol, head trauma: 5%.
• Other causes: 5%:
– Normal pressure hydrocephalus (see p.473).
– Intracranial mass lesion: frontal or temporal lobe tumor,
chronic subdural hematoma.
– Metabolic/toxic: chronic drug intoxication (e.g. alcohol,
barbiturates, sedatives), chronic hepatic encephalopathy.
– Endocrine: hypothyroidism, Cushing’s syndrome.
– Autoimmune: SLE.
– Nutritional: vitamin B12 deficiency (see p.463);
Wernicke– Korsakoff syndrome (see p.460).
– Syphilis (general paresis of the insane) (see p.312); HIV
(see p.301).
– Pick’s disease and other frontal lobe dementias (see
p.414).
– Huntington’s disease (see p.417): subcortical dementia.
– Progressive supranuclear palsy (see p.432): subcortical
dementia.
– Creutzfeldt–Jakob disease (see p.330): myoclonus and
rapidly progressive dementia.
• Multiple causes (i.e. combinations of the above): 10–15%.

The Mini-Mental State Exam

(MMSE) evaluates a spectrum of Table 39 Genetic classification of Alzheimer’s disease
cognitive functions but is only a Type Chromosome Gene Age at onset % of cases
screening test and not necessarily
diagnostic, since an individual with a Early-onset familial AD 21q21 APP 45–64 <0.1% (<1% of
previous high level of intellectual early-onset cases)
ability may be demented but function Early-onset familial AD 14q24.3 S182 40s mean 1–2% (50% of early
at a level above that used as a cut-off PS-1 (28–62) -onset familial AD)
on the MMSE scale. Similarly, a score Early-onset familial AD 1q31-q42 STM2 50s mean <0.1% (15–20% of
within the range that is usually indica- PS-2 (42–68+) early-onset cases)
tive of dementia may be caused by
factors such as dysphasia or depression. Late-onset 12 α2-macro >65 30%
The MMSE should be combined with Late-onset familial AD 19q13 ApoE >60 40% (32–58%)
complementary tools such as the and sporadic; ApoE ε4
Functional assessment staging test allele associated
(FAST) which consists of seven stages Late-onset familial; ? ? >75 10–40%
incorporating 16 substages. and sporadic; not
The spouse, family and friends ApoE allele associated
should be interviewed. Patients with
APP: amyloid precursor protein; α2-macro: alpha2-macroglobulin mutation; ApoE:
dementia may be unaware of difficulties
apolipoprotein E; PS-1: presenilin-1; PS-2: presenilin-2
at work and any tendency to be for-
getful of appointments and names,
412 Degenerative Diseases of the Nervous System
Familial dementia
• Huntington’s disease.
• Familial prion diseases.
• Hereditary cerebral hemorrhages with amyloidosis,
Dutch type.
• Chromosome 17- and chromosome 3-linked forms of
frontal lobe dementia.
• Cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL).
Pseudo-dementia
• Depression: may cause a pseudodementia and may also
commonly accompany the earlier stages of AD. In
general, patients with cognitive impairment due to AD
underestimate the severity of their cognitive deficit, in
contrast to those with anxiety or depression.
• Drug intoxications: anticholinergics.
• Age-related cognitive impairment in ‘normal’ aged persons.
INVESTIGATIONS
• Full blood count and film.
• Thyroid function tests.
• VDRL/RPR, TPHA.
• Serum vitamin B12.
• Antinuclear antibodies.
• HIV serology.
• Cranial CT or MRI scan:
– The main findings are diffuse cortical atrophy (most
prominent in the temporal lobes) and large ventricles,
sulci and fissures (due to loss of brain substance).
– Atrophy is more prominent and rapid than in age-
matched normal controls. The degree of temporal
atrophy can be measured on CT (526) or MR, but the
findings are non-specific.
– The main reason for cross-sectional imaging is to exclude
a treatable cause of dementia (527).
• PET or SPECT scan shows reduced cerebral blood flow in
the posterior temporoparietal regions. PET may also demon-
strate reduced cerebral oxygen utilization in these areas.
• EEG: normal or shows generalized slow wave activity.
• CSF:
– Cells: normal.
– Tau levels: increased.
– β-A4 levels: reduced, possibly because the β-A4 is
deposited in plaques rather than remaining in solution.
High levels indicate that AD is not likely.
• Tropicamide eye drops: hypersensitivity of the pupillary
response in AD to a solution of dilute topical tropica-
mide has been reported and awaits further evaluation.
Genetic testing
• In the individual with cognitive impairment, genetic
testing can be used to increase diagnostic accuracy and
detect transmissibility.
• In the individual without cognitive impairment, genetic
testing can be used to predict disease development and
the approximate age of onset.
• The overall very low prevalence of genetic defects in AD
militates against indiscriminate screening for APP, PS-1
and PS-2 mutations in clinical practice.
Early-onset familial (autosomal dominant) AD
• Transmissibility of the disease is often clear from a very
strong family history in patients with early-onset dementia.
• The most relevant issue is predicting the development of
disease in cognitively unimpaired relatives of a proband.
Detection of one of the known APP, PS-1, or PS-2 muta-
tions in an unaffected relative predicts development of the
disease with almost 100% probability, but the accuracy of
the age of onset is less certain; it is within 2.5 SD from
the mean age of onset for the family with APP mutations.
Late-onset AD with a positive family history
A routine search for the known mutations seems limited.
Sporadic AD
• The ε4 allele of the ApoE gene is more common in
patients with sporadic late-onset AD (40%) than in
elderly controls (10–15%).
• ApoE genotyping should be used only as a diagnostic test
in patients who are clinically diagnosed with dementia and
the cause of the dementia is unknown, but is probably AD.
Among people over 60 years of age who have dementia, the
pre-test probability (or prevalence) of AD is about 66%.
Additional diagnostic tests aim to identify other causes of
dementia and improve the post-test probability of AD; a
cranial CT scan might identify a tumor, a B12 test may
disclose vitamin B12 deficiency, and an ApoE4/E4 genotype
increases the probability that the correct diagnosis is AD to
about 94%. If the patient has ApoE3/E4, the probability
increases from about 66% to 81%. If the patient has
ApoE2/E3, the probability of AD is reduced by half; i.e.
there is double the possibility that there may be another
cause for the dementia, particularly if the age of onset is
50–70 years, since the age of onset of AD is later with the
ApoEε2 allele. Detecting an ε4 allele in a demented patient
may therefore increase the likelihood of the diagnosis of AD.
• ApoE genotyping is not useful as a predictive test for AD
in an asymptomatic individual: the population at highest
risk of developing AD (ApoEε4/ε4 genotype) is only 2%
of the normal population and, even for this small group,
the period of risk extends over five decades (50s–90s)
and some may not develop AD at all.
DIAGNOSIS
• During life, the diagnosis is largely one of exclusion of
other causes of progressive dementia. A diagnosis of
probable AD can be made if dementia is manifest by
deficits in at least two areas of cognitive ability, including
memory, in a person showing progressive deterioration,
whose activities of daily living are also significantly
impaired, and in whom there is no evidence of an
alternative cause for the symptoms. The probability is
strengthened if the pattern of cognitive deficit is typical
of AD: early amnesia followed by apraxia and aphasia and
so on. The accuracy of such a diagnostic approach is
about 80–90%. The addition of neuroimaging and
SPECT scanning may improve this.
• The histologic diagnosis relies on quantitative and
qualitative features; both of the commonly used
diagnostic criteria depend on a plaque count.
TREATMENT
At present, treatment is symptomatic and not curative.
Dementia
• Life history booklet (memory book).
• Instruction tapes (memory tape).
 Alzheimer’s Disease (AD)
Acetylcholinesterase inhibitors
• Acetylcholinesterase inhibitors (donepezil, rivastigmine and
galantamine) are used as a specific symptomatic treatment
of cognition and behavior in mild to moderate dementia of
Alzheimer’s type, rather than dementia in general.
• They inhibit acetylcholinesterase and thus decrease
acetylcholine breakdown in the synaptic cleft.
• They do not affect the underlying disease process that
causes loss of neurons and synapses and leads to
intellectual and functional deterioration.
• All have broadly similar efficacy, equivalent to about
6–12 months delay in the course of the disease after
30 weeks treatment in about two-thirds of patients with
mild to moderate AD.
• Tacrine (tetrahydroaminoacridine): the first drug
approved for the treatment of AD in the USA in 1993,
but withdrawn in 2000 because of poor gastrointestinal
tolerance (peripheral cholinergic symptoms [nausea,
vomiting, diarrhea] and hepatotoxicity [rises in serum
transaminases]).
• Donepezil: approved in the USA and UK in 1997, and the
first drug to be licensed in the UK for AD. Easily
administered. Treating 4–6 patients with donepezil
10 mg/day results in a four-point improvement on the
ADAS-Cog scale in one patient, and benefits in functional
preservation. Donepezil has a favorable adverse effect
profile, devoid of hepatotoxicity and with improved
gastrointestinal tolerance, and simplified compliance,
prescribing and monitoring. Begin at a dose of 5 mg once
daily (clinically effective dose), taken at night (unless
insomnia), for the first 4–6 weeks. The dose can be
increased to 10 mg once daily if the lower dose is well
tolerated. Nausea (17% of patients), and diarrhea (17%),
and vomiting (10%) are the most common adverse effects.
They are predictable (i.e. cholinergic) and generally
transient, occurring on initiation or up-titration of the
drug. Other symptoms may include headache, fatigue
(8%), insomnia, dizziness (8%), muscle cramps (8%),
agitation, hallucinations, unpleasant dreams, and urinary
urgency. Dose reduction or morning administration may
526 CT brain scan of
patient aged 64 with
dementia attributed to
Alzheimer’s disease.The scan
has been done to
demonstrate the temporal
lobes preferentially by angling
the gantry along the long axis
of the temporal lobes, hence
the odd appearance. Note
the very atrophied medial
temporal lobes (arrows).
527 CT scan at the level of
the lateral ventricles in the
same patient.There is
atrophy, but not much in the
way of vascular disease,
therefore the likely diagnosis
is Alzheimer’s disease.
413
alleviate some of these adverse effects. Use with caution in
patients with supraventricular conduction abnormalities,
peptic ulcers and obstructive airways disease.
• Rivastigmine: a pseudo-irreversible acetyl- and butyryl-
cholinesterase inhibitor which is selective for the CNS and
has regional selectivity within the brain for the cortex and
hippocampus. Treating 8 patients with rivastigmine (6–12
mg/day) produces a four-point improvement on the
ADAS-Cog scale in one patient, and significant improve-
ment in global outcome and function. Dosage: initially 1.5
mg orally twice daily for a minimun of 2 weeks, increasing
by 1.5 mg twice daily every 4 weeks if well tolerated.
Maintain patient on highest well-tolerated dose up to a
maximum of 6 mg twice daily. Adverse effects include
nausea (47%), vomiting (31%), diarrhea (19%), headaches
(17%), dizziness (21%), and abdominal pain (13%) with
6–12 mg/day. These are usually transient and minimized
by gradual titration and taking the drug with food.
• Galantamine: reversibly and competitively inhibits
acetylcholinesterase and enhances the response of nicotinic
receptors to acetylcholine. Clinical trials have shown that
galantamine in maintenance doses of 24 or 32 mg per day
significantly improves cognitive function and slows the
progression of functional decline over 6 months relative to
placebo. Tablet sizes of galantamine are 4 mg and 8 mg,
with a liquid preparation (4 mg/ml) which is useful for
titration. Dose can be titrated from 4 mg twice daily to
8 mg twice daily over 4 weeks according to tolerance and
benefit, but start with 4 mg daily in patients with hepatic
impairment. Galantamine is contraindicated in patients with
severe renal impairment, but no dose adjustment is required
for mild to moderate renal impairment (creatinine clearance
rate >9 ml/min). It is well tolerated. With 8 mg daily, most
adverse effects occur in the first 4 weeks: nausea (6%),
vomiting (4%), diarrhea (5%), anorexia (6%), agitation (15%.
• If used, cholinesterase inhibitors should be given within
the first 5 years of the disease, while there are more
remaining cholinergic neurons, and while the patient is
still functioning and independent.
526 527
414 Degenerative Diseases of the Nervous System
Possible neuroprotective agents
• Selegiline (10 mg/day): a monoamine oxidase B
inhibitor that also facilitates catecholaminergic activity.
• Alpha-tocopherol (vitamin E, 2000 IU a day): an
antioxidant that traps oxygen free radicals. It may be
protective against AD. Adverse effects (diarrhea) are
infrequent. Vitamin E may interact with warfarin and
lead to bleeding problems.
• Lamotrigine 300 mg/day.
• Estrogen.
• Folic acid.
• Ginkgo biloba.
Possible predictors of response to drug treatment
ApoE genotyping.
Depression
• Can coexist with AD and should be treated appropriately
(i.e. supportive counselling and, if necessary, antidepres-
sant drug therapy).
• Selective serotonin reuptake inhibitors (SSRIs) are a
good choice because of their relatively short half-lives,
and minimal anticholinergic, adrenergic and histaminic
adverse effects; tricyclic antidepressants often aggravate
the situation due to their anticholinergic action.
Behavioral disturbance
• Identify the specific problem behavior, document relevant
antecedents and consequences, and search for any medical
illness, physical symptoms or iatrogenic factors (drug
adverse effects or interactions) which may be contributory.
• Pharmacologic treatment of behavioral symptoms should
be reserved for drug-responsive symptoms that are causing
at least moderate distress to the patient or caregivers.
• Thioridazine or fluoxetine, beginning in low dose and
increased slowly, may be effective. Haloperidol is a potent
antipsychotic with minimal anticholinergic action in low
dose (0.5 mg once or twice daily).
• Newer antipsychotic drugs such as risperidone and
olanzapine appear to be at least as effective as
conventional neuroleptics but with fewer undesirable
adverse effects, particularly on the extrapyramidal system.
Prevention
• Recent advances in understanding AD in cases with a
more straightforward pathogenesis, such as Down’s
syndrome or APP gene mutations, give rise to the hope
that rationally based preventive therapy aimed at
reducing β-A4 production or aggregation into amyloid
may one day replace current symptomatic treatments,
which are of minor and probably temporary efficacy.
• Vitamin E may be protective against AD, and therapy
with 1000 IU twice daily may be considered.
• Estrogen replacement therapy may reduce the risk and
delay the onset of AD in postmenopausal women, but
this was not found in a recent randomized trial.
• There is also insufficient evidence to support the use of
antioxidant agents (other than vitamin E perhaps), anti-
inflammatory agents, monoamine oxidase B inhibitors,
folic acid, or antihypertensive drugs.
• Antiviral and anti-inflammatory agents to prevent viral
reactivation, and the use of vaccines against herpes simplex
virus type 1 in infancy, may also have promise if an
infective component to the etiology of AD is confirmed.
CLINICAL COURSE AND PROGNOSIS
• When the patient first presents they often have only a
relatively circumscribed cognitive impairment, typically
a memory deficit. As the disease progresses, cognitive
impairment becomes generalized.
• Average survival after diagnosis is 5–10 years.
FRONTOTEMPORAL DEMENTIA
ASSOCIATED WITH MUTATION IN
TAU (PICK’S DISEASE, LOBAR
ATROPHY)
DEFINITION
Frontotemporal dementia (FTD) is a term used to describe
patients with one of three major clinical syndromes (frontal
variant FTD [dementia of frontal type], semantic dementia
[progressive fluent aphasia], and progressive nonfluent apha-
sia), progressive focal atrophy of the frontal and/or tempo-
ral lobes, and, in some patients, mutations in the gene for
the microtubule binding protein tau, and characteristic tau-
positive inclusions in affected neurons.
Pick’s disease is one cause of localized cerebral atrophy, or
‘lobar atrophy’ and frontotemporal dementia. Pick’s disease
was a nosologic entity or syndrome complex, first described
by Arnold Pick of Prague in 1892, characterized clinically by
dementia, personality changes, speech disturbances,
inattentiveness, and occasionally also extrapyramidal
phenomena, and pathologically by circumscribed atrophy of
the gray and white matter of the frontal and/or temporal
lobes predominantly; but any region of the brain may be
involved. Later, Alzheimer (1911) and Altman (1923) drew
attention to the underlying pathology of ‘ballooned cells’
(Pick cells), neuronal argyrophilic inclusions (Pick bodies) and
the absence of fibrillary tangles and senile plaques.
EPIDEMIOLOGY
• Incidence: not uncommon, but frontotemporal
dementias account for up to 10% of all cases of dementia,
and even more in the presenium.
• Age: middle-aged and elderly; usually mid-50s.
• Gender: F=M.
PATHOLOGY
A primary tauopathy.
Macroscopic (528, 529)
• Atrophy:
– Frontal and/or temporal lobes predominantly, caused by
neuronal loss in the cerebral cortex and amygdala, with
less marked changes in the hippocampus.
– Parietal lobes less frequently affected.
– Gyri of affected lobes: paper thin (thinned cortical
ribbon), grayish appearance.
– White matter of affected lobes.
– Corpus callosum.
– Anterior commissure.
– Caudate nucleus.
– Thalamus, subthalamic nucleus, substantia nigra, and
globus pallidus sometimes.
• Enlarged ventricles.
 Frontotemporal Dementia Associated with Mutation in Tau (Pick’s Disease, Lobar Atrophy) 415

• Thickened overlying pia-arachnoid. There are three common clinical presentations: (1) Frontal
• Relative sparing of the pre- and postcentral, superior variant FTD (dementia of the frontal type) – a frontal
temporal, and occipital convolutions. dysexecutive syndrome with social conduct disorders and
disinhibition. There is orbitobasal frontal atrophy. (2)
Microscopic (530, 531) Temporal lobe variant FTD (semantic dementia) – a
• Loss of neurons, most marked in the first three cortical progressive fluent aphasia with impairment of semantic
layers. verbal memory. There is asymmetric anterolateral temporal
• Loss of medullated fibers in white matter beneath atrophy with relative sparing of the hippocampal formation,
atrophic cortex (probably due to neuronal loss). typically worse on the left side. (3) Progressive nonfluent
• Astrocytic gliosis of cortex and subcortical white matter. aphasia – there is left peri-sylvian atrophy.
• Mild granulovacuolar degeneration of neurons in the
hippocampus (525). 528
• The tau protein is the major component of
neurofibrillary tangles and other pathologic features of
frontotemporal dementia; tau positive inclusions are
found in neurons and glial cells. The different tau
isoforms are deposited in characteristic patterns in
different diseases (e.g. the tau deposition of AD includes
all 6 isoforms, whereas the tau deposited in Pick’s disease
consists of only 3-repeat tau isoforms.
• Pick cells: swollen (‘ballooning’), achromatic surviving
neurons of frontal cortex (531).
• Pick bodies: argyrophilic straight fibrils within the
cytoplasm of some surviving neurons, predominantly in
the cortex of the medial temporal lobes, and particularly
in atrophic hippocampi. They are both tau- and 529
ubiquitin-positive.
• Senile plaques are not present.

ETIOLOGY AND PATHOPHYSIOLOGY

• Usually sporadic and of unknown etiology.
• A subgroup of these disorders are familial, due to mutations
in the tau gene. They are probably transmitted as an
autosomal dominant trait with polygenic modification.

CLINICAL FEATURES
• Gradual onset, frequently before the age of 65 years.

528 Lateral view of the brain showing severe circumscribed atrophy

of the left frontal and temporal lobes.

529 Asymmetric section through the brain in the axial plane at the
level of the thalami showing atrophy of the frontal lobes.

530, 531 Histologic section of brain showing loss of neurons,

astrocytic gliosis and swollen (‘ballooning’) surviving neurons.

530 531
416 Degenerative Diseases of the Nervous System

Frontal lobe dysfunction • Creutzfeldt–Jakob disease: a rapidly progressive dementia

• Abulia. that may be indistinguishable from that seen in Pick’s
• Apathy. disease.
• Behavioral change: disinhibited and inappropriate, • Gerstmann–Straussler–Scheinker syndrome: dementia
stereotyped and perseverative behavior. and cerebellar ataxia or extrapyramidal dysfunction.
• Personality change: varying from emotionally dull, inert, • Corticobasal degeneration: language disturbances and
lacking initiative, spontaneity and impulse, and taciturn, to frontal lobe-type behavior may be seen but there is
emotional, social and sexual indifference or disinhibition. usually evidence of limb dystonia, ideomotor dyspraxia,
• Inattention. myoclonus, and anasymmetric akinetic-rigid syndrome
• Loss of judgement and insight. with late-onset of gait or balance disturbances.
• Difficulty planning. • Depression: the profound apathy of frontal lobe dementia
• Variable memory loss. may be erroneously attributed to depression. However,
• Motor perseveration. the absence of neurovegetative symptoms and depressive
• Speech reduction: decreased fluency followed by ideation (e.g. guilt, worthlessness) should be clear.
echolalia and mutism. • Mania: manic symptoms are reported in about one-third
• Hyperorality. of cases.
• Prominent grasp and suck reflexes. • Schizophrenia: persecutory ideas and bizarre, hypo-
• Unable to perform sequences of motor tasks. chondriacal delusions may occur in some cases and
• Unable to cope with unaccustomed problems. suggest schizophrenia.
• Deterioration of social and work habits. • Obsessive compulsive disorder: compulsive hoarding and
• Gait impairment. ritualized routines occur in up to one-quarter of cases of
Pick’s disease, but primary obsessive compulsive disorder
Temporal lobe dysfunction usually occurs in young people.
• Dysphasia: receptive (slow comprehension), jargon • Primary progressive aphasia:
aphasia, dysnomia. – Linguistic disturbance varying from agrammatic, non-
• Forgetfulness. fluent speech to fluent aphasia with comprehension
• Disorientation in time and place. deficits, due to focal cerebral atrophy in the perisylvian
• Behavioral change: lighthearted, anxious or happy, region of the dominant hemisphere.
physically active and on the move constantly, talkative, – Social conduct, judgement, insight and memory are
occupied with trivia, and attentive to all passing incidents. preserved, as well as the capacity to develop strategies to
• Bulimia. circumvent any impairments.
• Altered sexual behavior. – It is uncertain whether this disorder is a prodrome of
• Apraxia involving articulatory, buccofacial, limb and AD, a discrete disorder without progression to global
truncal movements. dementia, or part of a spectrum involving both. Long
term follow-up studies are required.
Exceptionally
• Cerebellar ataxia. INVESTIGATIONS
• Extrapyramidal syndrome: shuffling gait, rigidity, • Neuropsychologic evaluation: frontal or temporal lobe
pseudocontractures of limbs. dysfunction.
• CT or MRI brain: striking atrophy of the cortex and
DIFFERENTIAL DIAGNOSIS white matter of the frontal and/or temporal lobes.
• AD: • Dynamic/ functional neuroimaging, such as SPECT and
– May coexist with Pick’s disease. PET, is often more informative than static techniques
– Frontal lobe presentations of AD (e.g. behavioral such as CT and MRI, and shows an anterior perfusion
disturbance) are unusual, particularly before 65 years. deficit, in contrast to AD which usually shows posterior
– Atrophy is relatively mild and diffuse. perfusion deficits.
– Paired helical filaments, not straight fibrils of Pick bodies. • EEG: normal.
– More severe granulovacuolar degeneration of neurons.
• Vascular dementia: e.g. Binswanger’s disease: DIAGNOSIS
– May share clinical features with frontal lobe dementia • Neuropathologic.
syndromes, such as irritability, jocularity, hyperactivity, • The best clinical predictors for the early diagnosis include
and mood fluctuation. ‘frontal dementia’, early ‘cortical’ dementia with severe
– Neurologic signs are common. frontal lobe disturbances, absence of apraxia, and absence
– CT scan usually reveals diffuse or multifocal white matter of gait disturbance at onset.
disease.
• Dementia with Lewy bodies (see p.430). TREATMENT
• Alcoholic brain damage: No specific treatment.
– May affect the frontal lobes.
– Patients with Pick’s disease may also abuse alcohol, CLINICAL COURSE
however. Progressive.
• Huntington’s disease:
– Involuntary choreiform movements are usually, but not PROGNOSIS
always, present. The average time from diagnosis to death is about 8 years,
– Positive family history. i.e. longer than in AD.
 Huntington’s Disease (HD)
HUNTINGTON’S DISEASE (HD)
DEFINITION
An autosomal dominant inherited disorder characterized by
progressive involuntary choreiform movements, cognitive
decline, and emotional and psychiatric disturbance, due to
severe neuronal loss, initially in the neostriatum and later in
the cerebral cortex, as a result of an increase in the number
of trinucleotide CAG repeats in the HD gene on
chromosome 4p16.3 that encodes the protein huntingtin.
EPIDEMIOLOGY
• Prevalence: 1 per 10 000; all races.
• Age of onset: average: 35–42 years, but may start in
childhood (juvenile or Westphal variant) or old age.
• Gender: M=F.
PATHOLOGY
Macroscopic
• Atrophy of the caudate nuclei and frontal lobes (532, 533).
532
532 Coronal section through the frontal lobe of one cerebral
hemisphere from a patient with advanced Huntington’s disease (left)
and a person with a normal brain (right) showing severe atrophy of
the caudate nucleus and frontal lobe with dilatation of the frontal horn
of the lateral ventricle of the brain of the patient with Huntington’s
disease on the left.
534
534, 535 Normal cerebral cortex (534) and cerebral cortex of frontal lobe in Huntington’s disease (535).
417
• Ventricular dilatation, most marked in the frontal horns
of the lateral ventricles.
Microscopic (534, 535)
• Loss of neurons occurs first in the striatum (putamen and
caudate nucleus), and later to a lesser extent throughout
the brain in most of the gray matter of the cerebral
hemispheres and cerebellum.
• Neuronal loss is predominantly of medium sized spiny
neurons which make up 80% of the neurons in the
striatum; larger neurons are spared.
• Neurons in the striatum and cerebral cortex have
intranuclear inclusions of huntingtin and ubiquitin.
• Reactive gliosis occurs with prominent characteristic
astrocytes in the basal ganglia.
• Biochemically, GABA, acetylcholine, substance P, and dyno-
phin are decreased in the striatum. The dopaminergic nigro-
striatal pathway and dopamine concentrations are preserved.
• An imbalance between GABA, acetylcholine, and dopa-
mine may account for the involuntary choreiform
movements.
533
533 Brain at post mortem of a patient with severe Huntington’s
disease showing atrophy of the caudate nuclei and frontal lobes
bilaterally.
535
418 Degenerative Diseases of the Nervous System

ETIOLOGY AND PATHOPHYSIOLOGY Emotional/psychiatric disturbance

• Autosomal dominant inheritance with high penetrance. Many patients develop depression and suicidal thoughts.
• Gene defect: an abnormally expanded and unstable
polymorphic CAG trinucleotide repeat (37–121 copies; Oculomotor abnormalities
normal range 11–34, median 19) in the HD (initially • Fixational instability.
called IT-15) gene on the short arm of chromosome 4 in • Saccadic pursuit.
the 4p16.3 region. • Difficulty initiating saccades.
• The CAG repeat of the HD gene encodes a • Slow, hypometric saccades.
polyglutamine stretch proportional to the number of
triplets.The mutant protein product of the HD gene is Family history of HD
an elongated protein with 40–150 glutamine residues, Not always known or volunteered.
called huntingtin. It fails to show any homologue to
known proteins. The transcript is cytoplasmic and widely SPECIAL FORMS
expressed in all cell types, but is most severe in the Juvenile Westphal variant
striatum, hippocampus, cerebellar granular cell layer and • Onset in childhood and adolescence.
Purkinje cells of the brain. Translation of the mutant • Usually associated with paternally inherited mutations
huntingtin protein appears to be necessary for patho- with large numbers of trinucleotide repeats.
genesis. However, the brain pathology of HD cannot be • Rigidity develops in the trunk and proximal limb muscles
accounted for by the pattern of expression of huntingtin and spreads to involve all muscle groups.
and its function is not known. Theories include: • Progressive dementia, mask-like faces and bilateral
(1) Loss of function: unlikely with triplet repeats. increased reflexes and extensor plantar responses.
Dominant-negative effect: a mutated gene from one • Seizures.
chromosome interacts with subunits of a normal protein • Death within a few years of onset.
to inactivate it.
(2) Gain of function: the expansion allows a protein to DIFFERENTIAL DIAGNOSIS
do what it normally does but also a new additional and Chorea (see p.122)
pathologic function, possibly unrelated to the function Hereditary
of the normal protein. Huntingtin may induce defective • Autosomal dominant spinocerebellar ataxia.
mitochondrial function, resulting in impaired oxidative • Benign familial chorea: dominant inheritance, childhood-
phosphorylation and cell death by excitotoxicity. onset, not severe.
• The number of CAG repeats correlate inversely with the • Paroxysmal choreoathetosis.
age of onset of the illness, and directly with severity and, • Dentato-rubro-pallido-luysian atrophy (DRPLA).
to some extent, with neuropathology and clinical features. • Wilson’s disease.
• The biochemical basis of the disease is unknown but may • Neuroacanthocytosis.
be a defect in energy metabolism. In HD brain there is
evidence of glucose hypometabolism, increased lactate Other
concentrations, and a decrease in activities of • Systemic lupus erythematosus.
predominantly complexes II and III of the mitochondrial • Polycythemia rubra vera.
respiratory chain in the caudate nucleus. Apoptotic cell • Thyrotoxicosis.
death appears to occur. • Drugs: levodopa, amphetamine-like drugs, lithium,
carbamazepine, phenytoin.
CLINICAL FEATURES • Rheumatic (Sydenham’s) chorea.
About half of patients first present with a movement • Pregnancy.
disorder and the other half with an emotional, cognitive, • Oral contraceptives.
behavioral or psychiatric disturbance. • Anoxic encephalopathy.
Homozygous individuals are not phenotypically different • Post-infectious encephalomyelitis.
from heterozygous individuals. • Viral encephalitis.
• Stroke.
Involuntary, irregular, predominantly
choreiform, movement disorder Other movement disorders
• Initial symptoms: commonly a sense of restlessness or • Tardive dyskinesia: dopamine receptor-blocking drugs
being fidgety. (e.g. phenothiazines, neuroleptics).
• Chorea of the fingers and wrists, and later the more • Idiopathic orofacial dyskinesia.
proximal muscle groups of the upper limbs, the face and • Hemiballismus.
tongue (causing dysarthria and dysphagia) and the legs,
causing the gait to become unsteady and assume a bizarre, Dementia
bouncing quality due to irregular involuntary movements. • AD.
• Other movement disorders, such as dystonia and • Vascular dementia.
myoclonus, may occur. • Parkinson’s disease.
• Pick’s disease.
Slowly progressive subcortical dementia • Creutzfeldt–Jakob disease.
Initially manifests as forgetfulness, slowness of central process- • Vitamin B12 deficiency.
ing, diminished attention and concentration and reduced • Hypothyroidism.
insight and judgement. May not be prominent in the elderly. • Neurosyphilis.
 Huntington’s Disease (HD) 419

• HIV infection. 536

• Non-convulsive status epilepticus.

Depression

INVESTIGATIONS
Predictive testing
• Refer to a specialist Huntington’s disease predictive
testing team for assessment and intervention by
neurologist, geneticist, psychiatrist, psychologist, and
social worker. The ‘patient’ being tested needs to have
no clinical features of HD (otherwise they are embarking
on a diagnostic test), to be psychologically equipped to
deal with the news of a positive or negative blood test
result, and to understand the implications of the result
on other members in the family. This also needs to be
appreciated and anticipated by the team.
• Blood DNA analysis: expanded CAG trinucleotide repeat
(>37 repeats) in the gene on chromosome 4p16.3.

Differential diagnosis
• Cranial CT or MRI scan: to exclude intracranial
structural lesion, diffuse cerebral atrophy or a multi- 537
infarct state. In moderate to severely affected HD
patients, there is flattening (atrophy) of the head of the
caudate nuclei, and atrophy of the frontal lobe with
widening of the cortical sulci anteriorly and
dilated/rounded frontal horns of the lateral ventricles
(536–538). Increased signal on T2W MRI has been
described in the basal ganglia.
• Full blood count and blood film looking for
acanthocytes.
• Thyroid function tests.
• VDRL/RPR, TPHA.
• Copper and ceruloplasmin.
• Antinuclear antibody.
• Blood DNA analysis: expanded CAG trinucleotide repeat
in a gene on chromosome 4p16.3 in HD.

DIAGNOSIS
Positive family history (if available), appropriate clinical
findings, and blood DNA analysis reveals expanded CAG
trinucleotide repeat in the gene on chromosome 4p16.3.

538

536 CT scan from a patient with very early symptoms of Huntington’s

disease.The small caudate nuclei are outlined in white on one side.
Note the prominent anterior horns of the lateral ventricles secondary
to the caudate atrophy, but the rest of the brain appears relatively
normal.

537 CT scan from an advanced case of Huntington’s disease. Note

the generalized cerebral atrophy and particularly small caudate nuclei
(outlined in white).

538 Cranial CT scan, axial plane, showing dilatation of the sulci of the
frontal lobes and of the frontal horns of the lateral ventricles due to
atrophy of the frontal lobes and caudate nuclei in a patient with
advanced Huntington’s disease.
420 Degenerative Diseases of the Nervous System
TREATMENT
• No treatment has been shown to be effective in slowing
the course of the neurologic deterioration, although
there is a preliminary report of functional, motor and
cognitive impairment in five patients after human fetal
neural allografts into the right striatum, then after a year,
the left striatum.
• Coenzyme Q10 (ubidecarenone), an essential cofactor of
the electron transport chain, reduces cortical lactate
concentrations if given orally in a dose of 360 mg/day
for >2 months. If correction of lactate production has a
favorable effect on symptoms or disease progression, this
may be a possible therapy. Ubiquinone (coenzyme Q) is
an integral part of the functioning respiratory chain. It
serves to shuttle electrons between complexes I and II
and complex III and functions as an antioxidant and as
a respiratory chain activator.
General
Information and support for patients and families about the
disease and its implications.
Symptomatic
Chorea
• Haloperidol: beginning with 0.5 mg twice daily and
increasing slowly until an adequate response or to 20 mg
per day is probably the most effective treatment.
• Tetrabenazine 50 mg three times daily.
• Chlorpromazine (thioridazine), beginning with 10 mg
three times daily and increasing until control of
movements up to 150 mg per day.
• Olanzapine 5–10 mg daily combined with valproate (a
mood stabilizer) 125 mg twice daily to 500 mg three
times daily.
• Reserpine beginning 1 mg per day and increasing slowly
to as high as 15 mg per day.
• Others: amantadine, bromocriptine, thiopropazate,
lithium.
Depression
• Amitriptyline or imipramine beginning with 50 mg at
night and increasing until effective, or until adverse
effects intervene.
• SSRIs.
Psychosis
Antipsychotic medication, as appropriate.
PROGNOSIS
• Slowly but inexorably progressive, leading to death on
average about 15–20 years after symptom onset. A few
patients have a more chronic course and survive beyond
20 years.
• The progression of the disease is slow in patients with a
late age of onset of symptoms.
539 Section through the mid-brain showing normal pigmentation of
the substantia nigra (arrows).
PARKINSON’S DISEASE (PD)
DEFINITION
A slowly progressive, age-related, degenerative disorder of
the CNS, characterized clinically by tremor, bradykinesia,
rigidity, and disturbed postural reflexes (parkinsonism) and
pathologically by loss of dopaminergic cells in the pars
compacta of the substantia nigra, with typical neuronal
inclusions known as Lewy bodies. It is named in honor of
James Parkinson who, in 1817 wrote a classic monograph
An Essay on a Shaking Palsy.
EPIDEMIOLOGY
• Incidence: 20 (95% CI: 12–27) per 100 000 per annum.
Incidence increases progressively with advancing age.
• Prevalence: prevalence of probable and possible PD
combined: 128 (95% CI: 109–150) per 100 000 popu-
lation (crude prevalence), and 168 (95% CI: 142–195)
per 100 000 population (age adjusted prevalence). It
occurs in every racial and cultural group.
• Age-specific prevalence: 60–69 years: 342 per 100 000
population; 70–79 years: 961 per 100 000; ≥80 years:
1265 per 100 000 population.
• Age: mean age of onset 60–65 years; onset <40 years of
age in about 8% of patients.
• Gender: M≥F: age adjusted prevalence: 171 per 100 000
men, 164 per 100 000 women.
PATHOLOGY
• Loss (>50%) of melanin-containing, pigmented, dopa-
minergic neurons in the substantia nigra, locus ceruleus
and dorsal motor nucleus of the vagus nerve (particularly
the ventrolateral substantia nigra pars compacta which
projects to the posterior putamen, with less involvement
of the medial tegmental pigmented neurons that project
to the caudate nucleus) (539–544).
• Eosinophilic intracellular cytoplasmic inclusions, known
as Lewy bodies (which contain phosphorylated
neurofilaments, ubiquitin, phospholipids and other
cytoskeletal components) in the brainstem and other
parts of the brain (545, 546).
• Dopamine deficiency (>80%) in the nigrostriatal pathway
and relative hyperactivity of striatal (putamen and caudate
nucleus) cholinergic activity. Clinical features don’t
emerge until 60–80% of nigral neurons and striatal
dopamine are lost.
539
 Parkinson’s Disease (PD) 421

540 Section through the pons 540 541

showing normal pigmentation of the
locus ceruleus in the tegmentum
immediately anterolateral to the
fourth ventricle (arrows). (Courtesy
of Professor BA Kakulas, Royal Perth
Hospital,Western Australia.)

541 Axial sections through the mid

brain (above) and pons (below) of a
patient with Parkinson’s disease
showing lack of pigmentation in the
substantia nigra and the locus
ceruleus due to loss of melanin-
containing pigmented dopaminergic
neurons.

542 543

542, 543 Microscopic sections of the substantia nigra at low 544

magnification power showing normal melanin-containing, pigmented,
dopaminergic neurons (542), and reduction in the number of normal
melanin-containing, pigmented, dopaminergic neurons (543).

544–546 Microscopic sections of the substantia nigra at high

magnification power showing normal melanin-containing, pigmented,
dopaminergic neurons (544), and reduction in the number of normal
melanin-containing, pigmented, dopaminergic neurons, and the
presence of an eosinophilic intracellular cytoplasmic inclusions (Lewy
bodies) in the neurons (arrow) (545, 546).

545 546
422 Degenerative Diseases of the Nervous System
PATHOPHYSIOLOGY
The dopamine in the basal ganglia participates in a complex
circuit of both excitatory and inhibitory pathways that are
part of a loop that connects the cortex to the thalamus via
the basal ganglia and back to the frontal cortex and serves
to modulate the motor system. The pathophysiologic
hallmark of parkinsonism is hyperactivity in the subthalamic
nucleus (STN) and medial/internal globus pallidus (GPm).
Loss of dopaminergic neurons in the substantia nigra pars
compacta (SNc) results in dopamine deficiency in the
nigrostriatal pathway, which reduces the normal inhibition of
the nigrostriatal pathway on GABA-enkephalin neurons in the
putamen. This increases the activity in the GABA/enkepha-
linergic putaminal neurons that project to, and inhibit, the
lateral globus pallidus (GPl). The GPl, which sends GABAergic
inhibitory projections to the STN and the GPm, is now
inhibited and so the inhibitory tone of GPl on the STN and
GPm is reduced. The STN, which exerts a powerful excitatory
drive on to the GPm and substantia nigra reticulata (SNr), now
increases its activity well above normal to excite the GPm/SNr.
The GPm and SNr are the major output nuclei of the basal
ganglia, and finally project, via inhibitory GABAergic pathways,
to the ventrolateral thalamus (VL) on their route to the pre-
motor cortices. The increased inhibitory GABAergic outflow
from neurons in the GPm/SNr leads to increased inhibition of
thalamocortical projection neurons and decreased activation of
the precentral motor fields, resulting in bradykinesia. Excessive
tonic discharges are not the only physiologic abnormality of the
basal ganglia in PD; phasic oscillations in neuronal firing appear
to be responsible for tremor.
Pathogenesis of cell death
Unknown but probably related to a cascade of events involving:
• Oxidative stress.
• Mitochondrial dysfunction.
• Excitotoxicity.
• A rise in intracellular free calcium.
ETIOLOGY
Unknown. PD may be due to a complex interaction among
genetic and environmental factors that may differ in
individuals, or alternatively, it may not be one condition
with a single cause at all, but a common clinical
manifestation of different types of insults to the substantia
nigra (e.g. hereditary, toxic, infectious).
Heredity/genetic susceptibility
• 5–10% of patients with PD have a positive family history
of a similar disease.
• PD is inherited in perhaps 1–2% of cases (both autosomal
dominant and recessive inheritance are known).
• Three genes for PD have been characterized among
families in which PD is clearly inherited as a mendelian trait:
– α synuclein gene mutations (Park 1): a single amino acid
substitution in the gene on chromosome 4q21-q23 has
been shown to segregate with PD in a large Italian
kindred with autosomal dominant inheritance.
α synuclein is a major component of the Lewy body.
– Parkin gene mutations (Park 2): various deletion
mutations and point mutations in the parkin gene cause
autosomal recessive PD. The parkin gene product, parkin
protein, is a ubiquitin protein ligase (E3), a component
of the ubiquitin system, which is an important ATP
dependent protein degradation machine, and a
component of Lewy bodies.
– Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1): a
deubiquitinating enzyme.
• Prevalence of PD in first-degree relatives is 1.3–2.1%, which
is about double what is expected. The lifetime risk of PD
in first-degree relatives of sporadic cases is as high as 17%.
• For the vast majority of patients (98% or more) who have
no family history, there may be no genetic contribution
or several genes may be responsible.
Environmental toxins
• N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP),
a synthetic opiate derivative, causes a form of parkinsonism
that strongly resembles PD both clinically and in response
to levodopa. However, a widely distributed equivalent of
MPTP has not been discovered as yet.
• Only a few cases of parkinsonism induced by other toxins
(e.g. pesticides, herbicides, solvents, mercury) have been
documented.
• PD is more common in non-smokers and rural dwellers
but these may be epiphenomena.
Infection
• Epidemics of Von Economo’s encephalitis (encephalitis
lethargica) swept Europe in the early 1920s and some
patients developed progressive parkinsonism but it was
not identical to PD and post-encephalitic parkinsonism
is now very rare.
• Influenza and whooping cough infection have been
associated with an increased risk of PD in two ecologic
studies but have not been confirmed.
CLINICAL FEATURES
Insidious onset:
• Tremor*: at rest, 4–5 Hz, rhythmic, involves hand (‘pill-
rolling’) ± leg, voice, jaw.
• Bradykinesia: diminished rate and range of movements
(e.g. impassive face [hypomimia] (547), reduced finger
tapping and arm swing).
• Rigidity: passively move the wrist and elbow joints through
their full range and note a uniform increased resistance to
passive muscle stretch (‘lead-pipe’ rigidity), with or
without a superimposed jerky ‘cogwheel’ character due to
a superimposed tremor that rhythmically interrupts tone.
• Postural instability: impaired equilibrium reactions/right-
ing reflexes: slow to correct balance and tendency to fall
backwards (retropulsion) or totter forwards (festination).
• Gait disturbances: stooped posture (548), arms flexed at
the side, narrow stance base, reduced or absent swinging
of one arm initially, followed by shortening of stride
length (short, shuffling steps), difficulty initiating gait,
stiffening of the trunk so that when the patient turns, the
whole body moves in one mass (en bloc), stooped
posture, festination and freezing. The gait has a narrow
base, irrespective of the severity of the disease. In
contrast, patients with ‘lower-half’ parkinsonism due to
diffuse cerebrovascular disease stand erect in a ‘stiff ’
military posture, with the shoulders back, arms extended,
and on a wide stance base, but also walk with a short
shuffling stepping pattern and freezing of locomotion.
• Asymmetry*: onset is usually unilateral, becoming
bilateral after a few years.
• A good response to levodopa therapy*.
*Best predictors of PD.
 Parkinson’s Disease (PD)
Additional features
• Many other features are due to the core features. For
example, infrequent blinking, facial immobility, soft
voice, the ‘reptilian stare’, saccadic ocular pursuit,
hypometric ocular saccades, drooling, micrographia,
flexed body posture at the trunk, neck, elbows and knees;
joint and muscle pain (e.g. frozen shoulder), and possibly
bursitis are a result of muscle rigidity and bradykinesia.
• Pain and sensory phenomena are common. Deep
cramping sensations in the limbs may be a primary
symptom or related to levodopa medication. Superficial
burning dysesthesiae also may occur.
• Anxiety and depression (30% of cases).
• Forgetfulness and dementia (30% of cases): must be
distinguished from depression, physical slowness, and
adverse effects of drug treatment.
• Confusion and hallucinations: usually due to
antiparkinsonian medications.
• Autonomic dysfunction: postural hypotension, urgency
of micturition, erectile impotence, excessive sweating, a
feeling of incomplete bladder emptying and constipation.
547 Typical expressionless facies of Parkinson’s disease.
423
• Dyskinesias: writhing, swinging movements of the limbs
and trunks. Typically occur in patients with advanced
disease and prominent motor fluctuations and caused by
excess levodopa, but may also occur with dopamine
agonists. Dystonic dyskinesia (sustained twisting
movements) may be painful and necessitate reduction of
levodopa dosage.
• A positive family history of PD is present in 4–16% of
cases.
The glabella tap sign (tapping the forehead repeatedly
with a finger fails to inhibit eye-blinking) is neither sensitive
nor specific. The deep tendon reflexes remain preserved and
the plantar responses flexor.
DIFFERENTIAL DIAGNOSIS
Benign essential tremor (see p.119)
Upper limb tremor which is worse with posture and action
(on attempted writing, the tremor is exacerbated and the
script becomes enlarged and irregular whereas in PD, the
tremor usually abates and the writing becomes smaller as the
script progresses across the page [micrographia]), there is a
positive family history, and the tremor responds to alcohol.
547 548
548 Flexed posture and difficulty initiating gait,
with small shuffling steps and diminished arm swing
due to Parkinson’s disease.
424 Degenerative Diseases of the Nervous System
Secondary parkinsonism
Disease of the basal ganglia and cortical-subcortical
connections:
• Inherited:
– Wilson’s disease (see p.157).
– Huntington’s disease (see p.417).
– Levodopa-responsive dystonia-parkinsonism (occurs in
childhood).
• Recurrent head trauma.
• Vascular parkinsonism (‘lower-half parkinsonism’)*:
ischemic or hemorrhagic stroke (often multiple): sudden
onset, pyramidal deficits, clasp-knife spasticity, flexor
spasms, erect posture, arms extended, wide stance base,
dementia, stepwise progression.
• Infection: encephalitis lethargica followed a worldwide
flu epidemic in 1918, AIDS in the current era.
• Tumor of the basal ganglia and cortical-subcortical
connections.
• Normal pressure hydrocephalus (see p.473): urinary
incontinence, greater involvement of the legs than arms
(‘lower-half parkinsonism’), early dementia.
• Drug-induced parkinsonism*: dopamine antagonists
(history of exposure, improvement after withdrawal, but
may take months):
– Dopamine receptor blockers:
– Antipsychotic agents (haloperidol, chlorpromazine,
fluphenazine, pericyazine and so on).
– Anti-emetic agents (metoclopramide, prochlorperazine).
– Dopamine storage and transport inhibitors:
– Reserpine, tetrabenazine.
– Methyldopa.
– Amiodarone.
– Calcium channel blockers.
• Toxins:
– Carbon monoxide.
– Methyl bromide.
– Manganese poisoning.
– N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP).
• Degenerative:
– Progressive supranuclear palsy (see p.432): early falling,
eye movement abnormalities, appreciably more
tone/rigidity in the neck than the limbs (axial rigidity).
– Multiple systems atrophy (see p.435): early postural
hypotension, other autonomic disturbance, cerebellar
ataxia.
– Alzheimer’s disease (see p.407): early prominent
dementia, particularly with dysphasia and dyspraxia.
– Hallevorden–Spatz disease.
– Corticobasal degeneration: rare, progressive, asymmetri-
cal akinetic rigid syndrome, usually begins with a
unilateral jerky, tremulous, akinetic, rigid and apraxic
limb held in a fixed dystonic posture (e.g. wrist and
thumb flexed) and displaying the alien limb syndrome.
The hand is severely apraxic, making it functionally
useless. No weakness or rest tremor. No response to
levodopa.
• Psychogenic: rare, sudden onset, precipitating factor(s),
tremor at rest and with action, no cogwheeling, no
fatiguing (decrementing amplitude of movements).
• Depression*.
*Common.
INVESTIGATIONS
Indicated if parkinsonism is atypical for idiopathic PD:
• Onset before the age of 40 years.
• Bilateral symptoms and signs at onset.
• Symmetrical disease.
• Early, severe autonomic failure.
• Early involvement of speech and balance:
– Early dysphagia.
– Early postural instability and falls.
– Early dementia.
• Absence of resting tremor.
• Oculomotor (restricted eye movements due to
supranuclear gaze palsy), cerebellar or pyramidal tract
signs (pseudobulbar palsy).
• Peripheral neuropathy.
• Poor initial response to adequate doses of levodopa.
• Family history of a movement disorder.
• Rapid or stepwise progression.
Serum copper and ceruloplasmin
In young patients to exclude Wilson’s disease.
Twenty-four hour urinary copper excretion
In young patients to exclude Wilson’s disease.
CT brain scan
• To exclude hydrocephalus, cerebral infarction or
hemorrhage, and a structural lesion such as AVM or
tumor (usually convexity meningioma causing
contralateral hemiparkinsonism).
• Usually shows non-specific generalized atrophy of the
brain (549).
MRI brain scan
• May show generalized atrophy.
• Prominent iron deposition (dark signal on T2WI) has
been described in severe forms of the disease.
• Some narrowing of part of the substantia nigra has been
demonstrated in some cases but both this and the
previous feature are very non-specific and hard to spot.
• A combination of putamenal hypointensity and
brainstem atrophy is a consistent finding in Parkinson-
plus syndromes and virtually excludes PD.
• The main problem with imaging of PD patients is their
inability to keep still.
Positron emission tomography
PET with 18F-fluorodopa is a form of metabolic imaging
which may indirectly provide a quantitative assessment of
presynaptic nigrostriatal dopaminergic function. PET and
18F-fluoro-deoxyglucose may provide an assessment of
regional metabolic rates of glucose.
Apomorphine test
The response of the patient to levodopa therapy can usually
be predicted by the apomorphine test (somewhat akin to
the edrophonium test for myasthenia gravis):
• Pre-treat the patient with domperidone 20 mg 8 hourly
for 24 hours before the first dose.
• Measure motor function at baseline:
– Alternate, unilateral hand-tapping on two points 20
cm(8 in) apart for 30 seconds (Hughes AJ, et al., Lancet,
1990; 336: 32–34.).
– Time taken to walk 12 m (39 ft).
 Parkinson’s Disease (PD)
– Clinical assessment of tremor and dyskinesia (0=nil,
1=mild, 2=moderate, 3=severe) scoring on a modified
Webster disability scale to assess 12 features of PD
(Kempster PA, et al., J. Neurol. Neurosurg. Psychiatry,
1989; 52: 718–723).
• Apomorphine 1.5 mg (0.15 ml) subcutaneously (or
50 μg/kg subcutaneously)
• Observe and measure motor function 30 minutes later.
• Motor response is judged to be positive if 2 or more of
the following are seen:
– >15% increase in tapping score over 30 seconds.
– >25% improvement in walking time.
– At least 2 points improvement of tremor score.
– An improvement of Webster’s score of 3 or more (out of
36).
• If no or poor response, a second dose of 3 mg
apomorphine (0.3 ml) is given 40 minutes after the first
dose, and patient observed for a further 30 minutes.
• The dose is increased in an incremental fashion every 40
minutes and the patient observed. If required, the third
dose is 5 mg s.c., and the fourth dose is 7 mg s.c. If no
response to 7 mg, the patient is deemed a non-
responder. If a mild response to 7 mg occurs, try 10 mg
(1.0 ml) as a maximum dose.
• 95% of cases of PD improve.
• 25% of cases of Parkinson-plus syndromes improve.
• Severe drowsiness during the test may occur in patients
with Parkinson-plus syndromes but not in patients with
PD.
DIAGNOSIS
A clinical diagnosis, which can be made when:
• There are two of the four cardinal clinical features of
parkinsonism: tremor (present in 80%), bradykinesia,
rigidity, and disturbed postural reflexes.
• There is no alternative cause for the parkinsonism.
549
549 CT scan from a typical patient with Parkinson’s disease (or with
head tremor/titubation).The scan is probably normal but any view of
the brain detail is completely obscured by the motion artefact from
the patient’s tremor!
425
• The patient responds to levodopa.
• The course is progressive.
However, the clinical diagnosis is incorrect in up to 25%
of patients, particularly early on in the clinical course. Clues
to an alternative diagnosis are the presence of additional
non-parkinsonian features and a partial or absent response
to levodopa and dopamine agonists (see below).
Clinical features raising doubts about the diagnosis of
idiopathic PD
• Early falls and instability.
• Severe dysarthria.
• Myoclonic jerks.
• Pyramidal signs.
• Cerebellar signs.
• Autonomic failure.
• Poor or absent response to levodopa.
• Pains not relieved by levodopa.
• Rapid clinical deterioration despite dopaminergic
treatment.
• Lack of typical levodopa induced dyskinesias.
• Atypical levodopa induced dyskinesias (e.g. torticollis,
antecollis, sustained dystonic spasm of facial muscle).
TREATMENT
• Most patients are best managed at home (i.e. as an
outpatient). An hour-by-hour diary of presence and
severity of parkinsonian symptoms and dyskinesias can be
helpful.
• Patients should be encouraged to keep as active as
possible.
• Beware of, and treat, concurrent symptoms such as pain
(e.g. with tricyclic antidepressants), anxiety (e.g. with
benzodiazepines), and depression (with antidepressants
or ECT).
• The mainstay of antiparkinsonian therapy is dopamine
replacement.
• There is no compelling evidence to suggest that early
medical treatment of PD affects the progression of the
disease. There is some evidence that treatment-related
adverse effects may be caused partly by the duration of
drug treatment. It is therefore best to delay treatment
until the patient begins to suffer disability and handicap.
Compelling indications for starting symptomatic
treatment are when employment is in jeopardy and when
falling becomes a risk; otherwise it is a decision based
upon the patient’s personal needs and whether the
symptoms bother the patient sufficiently to make it
worthwhile to pay for the tablets (if they have to) and
take them daily.
• Commence medical therapy at a low dose to minimize
risk of adverse effects such as mental confusion,
particularly in the elderly.
Neurotransmitter replacement therapy
Levodopa
• The most effective drug for PD; it improves most
features.
• A naturally occurring, large, neutral amino acid, most of
which is metabolized by catechol-O-methyltransferase
(COMT) to form an inactive metabolite, and some of
which is decarboxylated by an aromatic amino acid
decarboxylase to form dopamine.
426 Degenerative Diseases of the Nervous System
• Usually it is combined with a peripheral decarboxylase
inhibitor (carbidopa [Sinemet] or benserazide
[Madopar]), that does not cross the blood–brain barrier,
to minimize production of dopamine in the systemic
(peripheral) circulation and help prevent adverse effects
such as nausea and vomiting.
Sinemet: 100 mg levodopa + 10 mg carbidopa
100 mg levodopa + 25 mg carbidopa
250 mg levodopa + 25 mg carbidopa
Madopar: 50 mg levodopa + 12.5 mg benserazide
100 mg levodopa + 25 mg benserazide
200 mg levodopa + 50 mg benserazide
Early in the disease, low dose levodopa, 100 mg (or even
50 mg), in combination with decarboxylase inhibitor, 25 mg
(or even 12.5 mg), taken three to four times daily controls
most patient’s symptoms very well (the ‘honeymoon period’
of a few years). If not effective but tolerated, increase the dose
slowly to an effective dose (that improves function), which is
commonly about 500–600 mg per day, and which does not
cause adverse effects such as confusion and involuntary
movements. Failure to evoke substantial benefit should lead
to a re-evaluation of the diagnosis.
In the early stages of PD, the response to levodopa is
sustained, despite the relatively short half-life of levodopa
(about 90 minutes). Patients are often able to miss doses
without any deterioration in clinical response. As the disease
progresses, with continued loss of dopaminergic neurons in
the substantia nigra, the duration of benefit following a single
dose of levodopa diminishes, eventually mirroring the drug’s
plasma concentration curve. This phenomenon is known as
‘end of dose failure’ or ‘wearing off’ and is characterized by
increasing bradykinesia and tremor in the hour or two before
the next dose of levodopa is due. These predictable motor
fluctuations are best managed by aiming for relatively constant
levels of levodopa by reducing the time interval between each
dose and prescribing more frequent, and sometimes smaller,
doses of levodopa, keeping the total daily intake of levodopa
to 600–800 mg. Alternatively, slow-release levodopa
preparations or dopamine agonists (see below) may be used.
Subsequently, the patient may develop unpredictable
motor fluctuations that are independent of plasma levodopa
concentration and are attributed to postsynaptic changes in
the dopamine receptors and second messengers. Recurrent
swings between dyskinetic adverse effects of levodopa (‘on’)
and severe bradykinesia (‘off’) may occur, as may sudden
episodes of ‘freezing’. Individual levodopa doses may fail to
provide any benefit at all, known as ‘no-on’ phenomenon.
The addition of a dopamine agonist such as bromocriptine
(up to 20 mg/day, starting gently with 1.25 mg bd) or
pergolide or lisuride, 2 mg) may be helpful, or prescribing a
slow release form of levodopa. Controlled release levodopa
for patients with motor fluctuations results in fewer off
periods than with standard levodopa, a 5% increase in ‘on’
time and a reduction in end of dose dystonia but an increase
in dyskinesia.
Increasing the dose of levodopa to a maximum of 1–1.5
g daily (in 4–8 divided doses to smooth fluctuations in blood
levels) runs the risk of causing adverse effects which include
nausea, postural hypotension, neuropsychiatric problems
(mental confusion and hallucinations), and involuntary
movements of the mouth, tongue and limbs (peak dose
dyskinesia).
Anticholinergics
• Benzhexol (Artane), benztropine and trihexyphenidyl have
a role in young patients with early PD and prominent or
refractory resting (alternating) tremor.
• Benefit is modest.
• Begin with benzhexol or benztropine in a low dose of
1 mg (half a 2 mg tablet) once daily (even lower in the
elderly, in whom they may cause a confusional state) and,
if tolerated but not effective, increase slowly to 2 mg daily,
2 mg twice daily, up to a maximum of 5 mg three times
daily.
• Adverse effects include dry mouth, mental confusion,
hallucinations, blurred vision, and difficulty initiating
micturition and urinary retention.
• Contraindicated in glaucoma.
• Avoid if possible, or use with caution, in the elderly
because of the high incidence of confusion and only
modest antiparkinsonian benefit.
• Discontinue gradually; acute withdrawal of anticholinergics
may be associated with dramatic worsening of
parkinsonism.
Amantadine
• Anticholinergic (antimuscarinic) and weak dopamine
agonist activity: releases dopamine from body stores. It
may also work as a glutamate antagonist.
• May have a mild and temporary (up to 1 year)
antiparkinsonian effect in early stages of the disease and
may reduce dyskinesias in patients with motor fluctuations.
• Begin with 100 mg capsule in the morning and, if
necessary add another at mid-day.
• Lower dose in renal impairment; its elimination depends
on renal clearance.
• Adverse effects include skin mottling (livedo reticularis) in
half of patients, inflamed, swollen legs (erythromelalgia),
and anticholinergic effects.
Synthetic directly acting dopamine receptor agonists
Advantages (theoretical at least) over levodopa
• Do not require biologic conversion to an active agent and
therefore are not dependent on the presence of residual
dopaminergic neurons or a pool of decarboxylase enzyme.
• Long half-life which helps to smooth out motor
fluctuations and reduce ‘on-off’ phenomena.
• Less likely to cause dyskinesias.
• Lack of competition for absorption into the brain.
• Potential to stimulate selectively a subset of dopamine
receptors.
• Lack of potentially harmful oxidative metabolites.
• Fewer long term adverse effects.
Disadvantages over levodopa
• Less potent and therefore less antiparkinsonian effect.
• More likely to cause confusion: use cautiously in the
elderly because of possible acute psychotic reactions.
• May cause vasospasm, ankle swelling, pulmonary edema
and (rarely) pleuropulmonary or retroperitoneal fibrosis
(perform a chest x-ray before starting treatment).
Bromocriptine
• A D2 dopamine receptor agonist with weak D1
antagonistic effects.
• Acts for about 3–5 hours.
 Parkinson’s Disease (PD)
• Can be used as the sole agent in some cases or more
commonly, as adjuvant therapy with levodopa.
• Available as 2.5 mg tablets, or 5 mg and 10 mg capsules.
• Begin at a low dose 2.5 mg bd and increase slowly as
required and tolerated to a typical dose of 5 mg tds/qid
and a maximum dose of about 30–40 mg/day. Higher
doses (40–60 mg per day) tend to cause mental
confusion and postural hypotension.
• Adverse effects similar to levodopa can occur, but it is
more likely to cause confusion and commonly causes
initial nausea because it acts centrally as well a
peripherally, and stimulates dopamine receptors in the
vomiting center in the medulla.
Pergolide
• A combined D1 and D2 dopamine receptor agonist.
• Has a long motor benefit (4–6 hours).
• Use about one-tenth the dose of bromocriptine: begin
with 50 µg orally, twice daily, gradually increasing if
necessary up to a maximum of 1.5 mg orally, twice daily.
Lisuride
• D2 dopamine receptor agonist.
• Use about one-tenth the dose of bromocriptine.
Cabergoline
• Dose 3–5 mg/day.
• For patients with early untreated PD, monotherapy is
comparable to levodopa in terms of efficacy and delays
motor fluctuations compared to levodopa.
• For patients with motor fluctuations, carbergoline is
comparable to bromocriptine and pergolide and increases
‘on’ time by about 10%, reduces ‘off’ time by about 17%,
increases motor scores by about 37%.
Pramipexole
• Dose 3–5 mg/day.
• For patients with early untreated PD, monotherapy
improves motor scores by 20–30% compared with
placebo.
• For patients with motor fluctuations, pramipexole
increases motor and ADL scores by 20–25%, and reduces
‘off ’ time by about 30% compared with placebo; and
increases motor scores by 12% and ADL scores by 4%
compared to bromocriptine.
Ropinirole
• Dose 10–20 mg/day.
• For patients with early untreated PD, monotherapy
increases motor scores by 24% compared with placebo,
and controls symptoms in about 30% of patients. After 5
years monotherapy, patients have fewer dyskinesias than
if taking levodopa.
• For patients with motor fluctuations, ropinirole reduces
‘off’ time by 20%, and enables the levodopa dose to be
reduced by about 30%.
Apomorphine
• A combined D1 and D2 dopamine receptor agonist.
• Used in patients with motor fluctuations for rapid relief
from sudden ‘off’ periods.
• Given by s.c. injection (0.2–5 mg), either intermittently
or by continuous infusion, for ‘off’ periods.
427
• May also be given sublingually, and as a lozenge taken
orally.
• Equivalent potency to levodopa.
• Benefit occurs within 5–15 min, lasting 40–90 min.
• Adverse effects similar to those from levodopa can occur,
with the addition of yawning, drowsiness, and local skin
reactions or abscesses at injection sites.
• Oral domperidone is often given before each dose to
prevent nausea.
Selective inhibition of catechol-O-methyltransferase
(COMT) in the periphery
Entacapone
• Increases availability of levodopa for transport across the
blood–brain barrier by reducing peripheral levodopa meta-
bolism, thus extending the duration of action of each levo-
dopa dose by about 30–50 minutes, irrespective of
whether a standard or slow release form of levodopa is
used.
• Not indicated for early untreated PD, but indicated for
PD with motor fluctuations.
• It must be used in conjunction with levodopa and a
peripheral decarboxylase inhibitor.
• Adverse effects include dyskinesias and other
dopaminergic adverse effects, and require a reduction in
levodopa dose.
Selective inhibition of the major catabolic
enzyme of dopamine in the brain, monoamine
oxidase type b (MAO-B)
Selegiline HCl (deprenyl)
• Selectively inhibits MAO-B, one of the enzymes that
catabolizes dopamine in the brain, and thereby retards
the breakdown of dopamine and increases the duration
of action of dopamine.
• Does not inhibit MAO-A, so there is not the
requirement for dietary and drug restriction as there is
for patients taking MAO-A inhibitors. However, dietary
restrictions are required when used with moclobemide
(a reversible MAO-A inhibitor) due to increased
tyramine sensitivity.
• Metabolized to desmethyldeprenyl, methylamphetamine
and amphetamine in the (–) form.
• Does not usually exert a significant symptomatic effect
when given alone.
• 5 mg tablets, taken in the morning and, if necessary, at
midday to a maximum of 10 mg daily.
• When taken with levodopa it slightly improves the
duration of the levodopa effect and can smooth out early
wearing off, but it can also provoke or worsen dyskinesias
and psychiatric adverse effects.
• Adverse effects include nausea, insomnia, musculoskeletal
injuries, non-threatening cardiac arrhythmias, and
elevations in liver enzyme levels.
• Avoid concurrent use with fluoxetine and pethidine.
• Controversy as to whether it protects dopaminergic
neurons and slows the progression of PD; the presumed
mechanism may be that it reduces oxygen free radical
formation generated by the MAO-B oxidation of
dopamine, and prevents the activation of exogenous
neurotoxins. Those who believe this often use it as an
initial treatment.
• Controversy also as to whether it may be associated with
excess mortality.
428 Degenerative Diseases of the Nervous System
Problems with medical therapy
Nausea
• Start with low doses of levodopa/dopamine agonists,
such as half a tablet of the smallest dose, and increase by
half a tablet every third day, because the patient’s initial
tolerance is poor.
• Take the medication 30 minutes after food.
• If nausea persists, commence the peripherally-acting anti-
emetic drug domperidone, 10 mg, to be taken half an
hour before each dose of antiparkinsonian medication
(i.e. with food, followed by antiparkinsonian drug 30
minutes later). Avoid other anti-emetics which are
dopamine antagonists, such as metoclopramide and
prochlorperazine.
Postural hypotension
• Minimize dose of antiparkinsonian drugs (particularly
dopamine agonists, selegeline).
• Take (lower dose) antiparkinsonian drugs after meals.
• Elastic support/compression stockings (poorly tolerated).
• Small frequent meals.
• Head-up tilt of the bed at night.
• Caffeine, pseudoephedrine, indomethacin, domperidone.
• Fludrocortisone.
• Midodrine.
Motor fluctuations (see Table 40)
• After about 5 years of treatment, about half (30–80%) of
patients develop motor fluctuations.
• Motor fluctuations consist of variations in response to a
single dose of levodopa; i.e. swings between parkinson-
ism and dyskinesias.
• Patients oscillate between periods in which they respond
to the drug (‘on’ periods) and periods in which they do
not (‘off’ periods).
Table 40 Management of motor fluctuations and dyskinesias
Motor fluctuations
‘Wearing-off ’, end-of-dose deterioration
Take levodopa 30 minutes before meals
Smaller, more frequent doses of levodopa
Add dopamine agonist
Add COMT inhibitor (e.g. entacapone)
Add MAOI (e.g. selegilene)
Delayed ‘on’ response to levodopa
Take levodopa 30 minutes before meals
Low protein diet
Antacids, gastric prokinetic agents (cisapride)
Sudden ‘off ’ periods
Liquid levodopa
Subcutaneous or sublingual apomorphine
Low protein diet
‘On-off ’ phenomena
Higher, less frequent doses of levodopa
Dopamine agonist with levodopa
Apomorphine infusion
• Related to a reduction in the PD brain’s capacity to store
dopamine (because of progressive reduction in number
of nerve terminals capable of storing dopamine), leading
to a reduced capacity to buffer fluctuations in the plasma
levodopa concentration, and a translating of fluctuating
plasma levels of levodopa into fluctuating striatal
dopamine levels and motor response. Concurrently, there
is an increasing dependency on exogenously administered
levodopa to provide dopamine for stimulation of striatal
receptors. Accordingly, factors that interfere with
levodopa absorption, such as dietary protein or
alterations in gastrointestinal transit time, can lead to
‘off’ episodes.
• Can be controlled in the early stages by:
– Strategies that enhance levodopa absorption in the brain
(e.g. reschedule protein intake, low protein diet [to avoid
competition of neutral amino acids with L-dopa
absorption and entry into the brain]).
– Manipulation of the levodopa dose or use of the
sustained release formulations of levodopa.
– Entacapone, a COMT inhibitor that prolongs plasma
half-life of levodopa.
– Dopamine agonists.
• In advanced stages of the disease, fluctuations are
difficult to treat and patients frequently cycle between
‘on’ periods complicated by dyskinesia and ‘off’ periods
in which they are frozen and akinetic.
Dyskinesias (abnormal involuntary movements)
• Tend to develop in younger PD patients.
• Do not occur in normal individuals.
• Usually choreiform (dance-like).
• May be dystonic (sustained and often painful muscle
contractions) or myoclonic (sudden jerks).
• In the extreme, may be more disabling than the
parkinsonism itself.
Dyskinesias
Peak-dose dyskinesia
Reduce total levodopa dose
Add dopamine agonist to maintain motor response
Early morning dystonia
Slow-release levodopa at night
Long-acting dopamine agonist at night
Antispasmodic (e.g. baclofen)
End-of-dose dystonia
Slow-release levodopa
Long-acting dopamine agonist
‘Off ’ period dystonia
Liquid levodopa
Subcutaneous or sublingual apomorphine
Diphasic dyskinesia (beginning and end of dose)
Higher, less frequent doses of levodopa
Pallidotomy if refractory to drug manipulation
 Parkinson’s Disease (PD)
• May be monophasic (peak-dose dyskinesias), occurring at
the time of maximal clinical improvement; and biphasic
(onset- and end-of-dose dyskinesias), occurring at time of
disappearance and reappearance of parkinsonian symptoms.
• Cause is unknown; may be related to upregulation of
dopamine receptors or post-synaptic changes associated
with both PD and exposure to levodopa.
• Monophasic dyskinesias can be reduced by decreasing and
spreading the daily doses of antiparkinsonian medication, but
this may preclude a satisfactory antiparkinsonian response
and lead to the emergence of motor fluctuations in the form
of end-of-dose akinesia and ‘on-off’ phenomena.
• Biphasic dyskinesias can be alleviated by increasing the
daily dose of antiparkinsonian medication to maintain
constant high plasma levels of medication (e.g.
levodopa), but this may produce chaotic dyskinesias and
severe psychiatric disorders.
• Dyskinesias may also be alleviated to some extent by
coadministering various agents such as anticholinergics,
benzodiazepines, serotonin antagonists (e.g. fluoxetine),
beta-blockers, low dose clozapine (50 mg) (a
dibenzodiazepine derivative that blocks D1, D2 and D4
dopamine receptors) and riluzole (an inhibitor of
glutamatergic transmission in the CNS).
Neuropsychiatric problems (confusion, hallucinations,
delusions, psychosis)
• More frequent in older patients and those with advanced PD.
• Can be produced by all antiparkinsonian drugs, but
levodopa is the least likely to do so.
Can be minimized or treated by:
• Eliminating unnecessary psychoactive or sedative
medications.
• Withdrawing anticholinergics, amantadine and selegiline,
and then ergot-based dopamine agonists if necessary,
restricting antiparkinsonian therapy to levodopa-carbidopa.
• Using the lowest dose of antiparkinsonian medication
that will provide a satisfactory clinical response.
• Clozapine, an atypical neuroleptic, when given in small
doses (starting at 12.5 mg daily and seldom increasing
above 100 mg daily) to patients without dementia who
are experiencing hallucinations, may help control the
psychotic features and permit higher doses of
levodopa–carbidopa to be used, but weekly blood counts
are required because of the risk of agranulocytosis.
• Other ‘atypical’ antipsychotic agents: olanzapine, quetiapine.
• In patients with dementia, it may not be possible to
control parkinsonism without adversely affecting mental
function.
Depression
• May be an inherent component of parkinsonism or a
reaction to having a chronic progressive neurodegenera-
tive disorder.
• Treatment for PD should be the first consideration and
may itself improve the depression.
• Tricyclic antidepressants have anticholinergic properties
that may improve PD features in the early stages but may
aggravate mental function in patients with more
advanced disease.
• SSRIs that are free of anticholinergic effects, such as
fluoxetine or sertraline, are probably preferable but may
interfere with the antiparkinsonian effect of levodopa.
429
Surgery
Surgical treatments for PD are now enjoying a renaissance
with the development of models of basal ganglia circuitry,
refinements of stereotactic surgery (due to better stereotactic
frames, imaging by high resolution brain CT and MRI, and
intraoperative electrophysiologic microelectrode assessment)
and the limitations of existing medical therapy.
The main surgical ‘targets’ in the brain are the internal
(medial or posteroventral) globus pallidus (GPi) and the
subthalamic nucleus. The main surgical strategies are the
creation of lesions (i.e. destroying brain tissue) or high-
frequency deep-brain stimulation (DBS) via stimulating
electrodes (i.e. stimulating brain tissue).
Pallidotomy
Lesions in the posteroventral portion of the medial/internal
globus pallidus (GPm) presumably reduce the inhibitory
output from the medial globus pallidus and thereby improve
many of the ‘off’ period symptoms of PD (tremor, rigidity,
and bradykinesia on the side contralateral to the surgery and
some elements of gait). However, they do not improve the
patient’s level of function when ‘on’ except for elimination of
peak-dose levodopa-induced dyskinesias. Midline symptoms,
such as postural instability and abnormal gait, also improve
less. Any improvements are immediate and sustained for at
least 6 months.
Complications include homonymous hemianopia (up to
14%), facial paresis (up to 51%), and hemiparesis (up to 4%).
Because the optic tract is in intimate relation to the surgical
target in the ventral GPm, it is essential that the optic and
corticospinal tracts are identified by microelectrode recording
and stimulation, not only to avoid injury but also for precise
placement of the lesion at the most ventral, medial and
posterior aspect of the nucleus. The optimum size and site
of the lesion within the GPm remain to be determined. In
addition we do not know whether lesions in the GPm proper
and in the pallidofugal outflow axons are equivalent. Medical
therapy is usually still required after pallidotomy although
the response becomes smoother and more predictable.
Indications: relatively young (<60 years), cognitively
intact PD patients who maintain a response to levodopa but
who experience disabling off periods (akinesia/rigidity) or
troublesome levodopa-induced dyskinesias, particularly if
the signs are asymmetric.
Subthalamotomy
Lesions may improve motor signs but at present carry an
unacceptable risk of inducing hemiballismus or causing
midbrain hemorrhage due to its high vascularity.
Thalamotomy
• Effective predominantly for medically intractable tremor.
• A thermally induced lesion of the ventrointermediate
nucleus (Vim) of the thalamus improves contralateral
tremor in about 90% of patients.
• Recurrence of tremor occurs in about 5–10% of cases,
usually within the first 3 months.
• Lesioning the ventralis oralis anterior/posterior (rostral
to the Vim) may improve rigidity of the contralateral
limbs.
• Risks of this procedure are those of passing a needle
through the brain (intracerebral hemorrhage) and
thermolytic lesioning of structures adjacent to the target
site. Mortality varies from 0.4–6%.
430 Degenerative Diseases of the Nervous System
Deep brain stimulation (DBS)
• High frequency DBS (about 150 cycles per second)
functionally inhibits neuronal activity in specific brain
targets without the need to make a lesion. By connecting
an implanted stimulating electrode (diameter of 1.3 mm
[0.05 in] and length of 12 mm 0.5 in]) to a sub-
cutaneous pacemaker, target sites can be continuously
stimulated.
• Stimulation of Vim of the thalamus effectively and safely
suppresses tremor in >80% of patients, with benefits
sustained for >5 years in some patients.
• Chronic bilateral stimulation of the STN may
dramatically improve all cardinal features of PD and
medication requirements but hemiballism may emerge.
• Implantation of DBS into the GPm instead of the STN
is being investigated.
• The advantages of DBS over thermolytic lesioning are
that it is reversible and causes minimal or no damage to
the brain. However, it requires two surgical procedures
(one for targeting and another for definitive electrode
internalization), the life of the battery is limited to a few
years, and tolerance to the therapeutic efficacy may
develop.
Transplantation/cell implantation
Strategies are based on the notion that dopaminergic cells
implanted in the striatum can compensate for degenerating
nigral neurons. More than 150 patients have undergone
fetal nigral cell implantation with inconsistent clinical results;
some patients have shown benefit and adverse effects have
not been a major problem. The role of fetal nigral
transplantation as a treatment for PD needs to be better
defined by controlled trials.
PROGNOSIS
• Slowly progressive over several years.
• Symptoms are usually well controlled for the first few
years of treatment.
• About half of patients experience significant
complications of therapy after 5 years.
• Unless there is an intercurrent cause of death, patients
eventually become bedbound and die of septicemia due
to pneumonia or urinary tract infection, or pulmonary
embolism.
• The average duration of the disease from diagnosis to
death is about 13 years.
Prognostic factors
• Gait disturbance at presentation tends to indicate more
severe disease and a faster rate of progression.
• Tremor-dominant parkinsonism tends to have a more
benign course.
• Onset of PD after the age of 60 years is associated with
a greater likelihood of developing dementia, while
younger patients have a greater risk of developing adverse
effects associated with using levodopa long term.
DIFFUSE LEWY BODY DISEASE (DLBD)
DEFINITION
A syndrome, first reported in 1961, and still in the process
of being defined clinically and neuropathologically, that is
characterized clinically by:
• Fluctuating visual hallucinations and delusions.
• Parkinsonism (muscle rigidity and bradykinesia)
• Progressive dementia.
• A poor tolerance of neuroleptic drugs.
DLBD is defined pathologically by diffuse cortical Lewy bodies.
EPIDEMIOLOGY
• Incidence: not uncommon: up to 20% of cases of dementia.
• Age: elderly.
• Gender: M=F.
PATHOLOGY
Essential for the diagnosis of DLBD
• Lewy bodies in the neocortex (temporal>frontal=parietal),
limbic cortex (cingulate, entorhinal, amygdala), subcortical
nuclei, and brainstem (as opposed to nigrostriatal and brain-
stem Lewy bodies associated with Parkinson’s disease).
• Lewy bodies are intracytoplasmic, spherical, eosinophilic,
neuronal inclusion bodies composed of abnormally
ubiquinated neurofilament proteins (550). They are
immunoreactive to ubiquitin (hence are more readily
visualized with anti-ubiquitin immunocytochemical
detection), and are surrogate markers of neuronal loss.
α-synuclein immunocytochemistry is potentially the most
sensitive and specific technique for detecting and
quantifying Lewy bodies and Lewy neurites.
Associated but not essential for the diagnosis of DLBD
• Lewy-related neurites: found by means of ubiquitin
staining in the hippocampus (CA2/3 region), amygdala,
nucleus basalis of Meynert, dorsal vagal nucleus, and
other brainstem nuclei. They are a neurofilament
abnormality in which the proteins are present as a diffuse
aggregate that does not contain crystallin.
• Plaques (all morphologic types). Senile neuritic plaques,
often in similar numbers to those found in Alzheimer’s
disease, and β-amyloid deposition are common.
• Neocortical neurofibrillary tangles are few or absent.
• Regional neuronal loss occurs, particularly in brainstem (sub-
stantia nigra and locus ceruleus) and nucleus basalis of
Meynert. There is no evidence of significant neuronal loss in
the hippocampus and medial temporal and frontal cortices.
• Microvacuolation (spongiform change) and synapse loss.
• Neurochemical abnormalities and neurotransmitter deficits.
ETIOLOGY
Unknown.
CLINICAL FEATURES
The clinical presentation is typically delirium-like, with
fluctuating confusion, attentional deficits, and psychiatric
symptoms, particularly visual hallucinations. Rigid-akinetic
parkinsonism (usually mild), intermittent loss of con-
sciousness, and falls are also common.
• Consciousness: recurrent falls and/or transient clouding,
or loss, of consciousness occur.
 Diffuse Lewy Body Disease (DLBD)
• Cognition:
– Cognitive impairment is present, affecting memory, lan-
guage, visuospatial ability, praxis, and reasoning skills (e.g.
early prominent attention deficits, disproportionate diffi-
culties with problem solving and visual-spatial-perceptual
function). Cognitive impairment is persistent and rapidly
progressive but characterized by pronounced fluctuation,
varying between lucid intervals and episodic confusion.
– Hallucinations: usually persistent, well-formed, visual
hallucinations, and accompanied by secondary paranoid
delusions. Auditory hallucinations may occur.
• Extrapyramidal syndrome:
– Mild extrapyramidal features occur in some patients at
presentation but more commonly occur later or after
treatment with neuroleptic drugs (see below).
– Unusually severe extrapyramidal symptoms or sedation occur
after administration of standard doses of neuroleptic agents
(patients are ‘exquisitely’ sensitive to neuroleptic agents).
• Urinary incontinence: this may precede, but more
commonly soon follows, the onset of cognitive decline.
DIFFERENTIAL DIAGNOSIS
Cognitive decline
• Alzheimer’s disease (see p.407): behavioral/psychiatric
symptoms and urinary incontinence do not tend to occur
in early Alzheimer’s disease. The dementia does not show
marked fluctuation and accompanies significant neuronal
loss in the hippocampus and medial temporal and frontal
cortices. Neurofibrillary tangles and senile neuritic
plaques are common.
• Parkinson’s disease (see p.420) with or without
dementia: Lewy bodies are predominantly subcortical in
location (substantia nigra, locus ceruleus, substantia
innominata, and dorsal motor nucleus of the vagus
nerve), in contrast to DLBD where immunocyto-
chemically similar Lewy bodies are more widespread and
found in the neocortex as well as brainstem neurons.
• Vascular dementia (see p.261).
• Progressive supranuclear palsy (see p.432).
• Normal pressure hydrocephalus (see p.473).
• Creutzfeldt–Jakob disease (see p.330): rapidly progres-
sive cognitive decline and myoclonus.
Fluctuating cognitive function
Delirium due to drug toxicity (particularly anticholinergics or
catecholaminergics) or intercurrent illness.
550
550 A round eosinophilic (pink) Lewy body in the cytoplasm of a neuron.
431
Repeated falls, syncope, and transient loss of
consciousness
Transient ischemic attacks of the brain (see p.186).
Delusions and hallucinations
• Complex partial seizures.
• Delusional disorder (late paraphrenia).
N.B. Neuroleptic drugs, which are commonly the first choice
of medication for psychiatric symptoms and behavioral dis-
turbances in dementia, commonly induce severe sensitivity reac-
tion in DLBD patients, exacerbating motor and mental disability.
INVESTIGATIONS
• Neuropsychologic testing: global cognitive dysfunction
with marked impairment of tests sensitive to frontal lobe
dysfunction.
• CT brain scan: normal or generalized cortical atrophy.
• Blood: ApoEε4 and debrisoquine oxidase C4P2D6B:
increased frequency in DLBD.
• SPECT: reduced cerebral blood flow, similar pattern to
Alzheimer’s disease (see p.412).
• EEG: early generalized slowing of the background rhythm.
DIAGNOSIS
• Pathologic: at post mortem.
• Clinical diagnosis: consensus criteria (McKeith, et al.
[1996, 1999]):
1 Progressive cognitive decline of sufficient magnitude to
interfere with normal social or occupational function is
the central feature required. Prominent or persistent
memory impairment may not necessarily occur in the
early stages but is usually evident with progression.
Deficits on tests of attention and of frontal-subcortical
skills and visuospatial ability may be especially prominent.
2 Two of the following core features are essential for a
diagnosis of probable DLBD, and one is essential for
possible DLBD:
a Fluctuating cognition with pronounced variations in
attention and alertness.
b Recurrent visual hallucinations that are typically well
formed and detailed.
c Spontaneous motor features of parkinsonism.
3 Features supportive of the diagnosis are:
a Repeated falls.
b Syncope.
c Transient loss of consciousness.
d Neuroleptic sensitivity.
e Systematized delusions.
f Hallucinations in other modalities.
4 A diagnosis of DLBD is less likely in the presence of:
a Stroke, evident as focal neurologic signs or on brain imaging.
b Evidence of any physical illness or other brain disorder
sufficient to account for the clinical picture.
TREATMENT
• No response to a trial of levodopa.
• Some may respond to cholinesterase inhibitors (e.g.
rivastigmine).
PROGNOSIS
Progressive deterioration occurs over the next 2–5 years,
with increasing parkinsonism, cognitive decline and
psychiatric symptoms.
432 Degenerative Diseases of the Nervous System
PROGRESSIVE SUPRANUCLEAR
PALSY (PSP)
DEFINITION
A neurodegenerative disease of the basal ganglia and
brainstem, otherwise known as the Steele–Richardson–
Olszewski syndrome, which presents with a disturbance of
balance and downward gaze, and L-DOPA-unresponsive
parkinsonism, and subsequently causes progressive
dysphagia and dysarthria and death from complications of
immobility and aspiration.
EPIDEMIOLOGY
• Prevalence: 6.4 per 100 000 (five probable and one
possible case) (95% CI: 2.3–10.6).
• Age of onset: 40–60 years of age.
• Gender: M≥F.
PATHOLOGY
• Neurofibrillary degeneration is the cellular hallmark of
the disease.
• Main lesions are in the SNc, SNr, the globus pallidus, the
STN and the midbrain and pontine reticular formation.
• Loss of neurons and gliosis occurs in the periaqueductal
gray matter, the superior colliculus, subthalamic nucleus
of Luys, red nucleus, pallidum, dentate nucleus, pretectal
and vestibular nuclei and to some extent in the
oculomotor nucleus (551). Surviving neurons in these
areas contain neurofibrillary tangles. The cerebral and
cerebellar cortices are usually spared.
• Atrophy of the brainstem occurs causing dilatation of the
third ventricle and cerebral aqueduct, thinning of the
midbrain tegmentum (midbrain diameter <17 mm
[<0.7 in]), and dilatation of the fourth ventricle.
• There is decreased pigment in the substantia nigra and
locus ceruleus.
Molecular pathology
• Neuronal degeneration is associated with deposition of
hyperphosphorylated tau protein as neurofibrillary
tangles (similar to corticobasal degeneration, post-
encephalitic parkinsonism, post-traumatic parkinsonism,
some forms of frontotemporal dementia, and the
parkinsonism dementia complex of Guam).
• Tau neurofibrillary tangles appear on light microscopy most
commonly as globose tangles and on electron microscopy
as straight filaments with a diameter of 15–18 nm.
ETIOLOGY AND PATHOPHYSIOLOGY
• Unknown.
• PSP is considered a sporadic disorder but a few cases
show autosomal dominant inheritance.
• A genetically determined alteration in the microtubule-
binding protein τ (tau) may be responsible for neuronal
degeneration.
CLINICAL FEATURES
Typical
• Insidious onset of a progressive, symmetric (but may be
asymmetric) parkinsonian syndrome, unresponsive to
levodopa, characterized by:
– Staring, non-blinking, wide eyed (lid retracted) facies
(‘reptilian stare’).
– Axial (neck and trunk) dystonia and rigidity and
symmetric bradykinesia (552).
Retrocollis or dystonic arm.
Unsteady gait (wide-based, shuffling, the patient moves
‘en bloc’).
Postural instability.
– Sudden falls.
• Supranuclear ophthalmoparesis, initially involving vertical
(particularly downgaze) and subsequently horizontal eye
movements. The disproportionate hypometria of vertical
compared with horizontal sacccades produces a curved
course of oblique saccades. In some patients in whom full
vertical excursions are present, vertical saccades can only
be accomplished by moving the eyes in a lateral arc
instead of strictly vertically, in the mid line. The slowing
of vertical saccades probably reflects impaired function
of burst neurons in the rostral interstitial nucleus of the
medial longitudinal fasciculus (riMLF). As a consequence
of the downgaze paresis, patients have difficulty reading
and walking downstairs.
• Mild subcortical dementia characterized by slowness of
central processing time.
• Pseudobulbar palsy:
– Dysarthria (spastic: voice has a strained, harsh quality).
– Dysphagia.
– Emotionalism.
– Spasticity of lower and (less so) upper limbs.
– Hyperreflexia and extensor plantar responses.
– Bladder and bowel dysfunction in end stage disease.
• Frontal lobe signs (bradyphrenia, perseveration, primitive
reflexes: forced grasping, pout and palmo-mental reflex;
imitation and utilization behavior).
• Stuttering speech, torticollis and blepharospasm may
occur.
• Segmental dystonia or myoclonus may occur.
• Nocturnal disturbances: prolonged latency of sleep onset,
prolonged wakefulness, frequent early morning
awakenings, reduced total sleep time.
• No family history.
551
551 Axial section through the midbrain of a patient with progressive
supranuclear palsy showing midbrain atrophy with dilatation of the
cerebral aqueduct due to loss of neurons and gliosis in the
periaqueductal gray matter, the superior colliculus, substantia nigra,
subthalamic nucleus of Luys, red nucleus and to some extent in the
oculomotor nucleus.
 Progressive Supranuclear Palsy (PSP) 433

Atypical findings that do not exclude the diagnosis – Tremor is usually present; in PSP tremor is either absent,
• Appendicular (limb) more than axial rigidity. or not pronounced and of low amplitude.
• Narrow-based gait. – Responds to levodopa usually.
• Mild rest tremor. • Diffuse Lewy body disease.
• Upper limb apraxia. • Hydrocephalus.
• Upper limb ataxia. • Frontotemporal dementia with parkinsonism linked to
• Myoclonus. chromosome 17.
• Chorea. • Prion diseases (Creutzfeldt–Jakob disease, progressive
• Respiratory disturbance. subcortical gliosis).
• Whipple’s disease.
Absence of • Niemann–Pick disease type C.
• Unilateral presentation or pronounced asymmetry. • Vascular pseudo-parkinsonism.
• Early and prominent dysautonomia, particularly postural • Compressive midbrain syndromes (Parinaud syndrome),
hypotension. e.g. pinealoma, glioma.
• Prominent polyneuropathy. • Neurosyphilis.
• Pronounced rest tremor. • Corticobasal degeneration.
• Discriminative (‘cortical’) sensory loss.
• Alien limb sign. Corticobasal degeneration is a rare, sporadic, progressive
extrapyramidal degenerative disease of unknown etiology
DIFFERENTIAL DIAGNOSIS which is characterized by large pale ballooned neurons in
Supranuclear vertical gaze paresis the basal ganglia and the motor and pre-motor cortex. It
• Normal ageing. presents as an asymmetric akinetic rigid syndrome that
• Idiopathic Parkinson’s disease (see p.420): usually begins with a dystonic posturing of the hand with
– Asymmetric in onset. the wrist flexed and the thumb flexed across the palm. The
– Facies not so immobile and without lid retraction. hand becomes functionally useless because of a severe
– Blink rate not so reduced until advanced disease. apraxia rather than any weakness. There is no tremor at rest
– Absence of supranuclear ophthalmoparesis, particularly but attempted movement may evoke episodes of fine
of downgaze. myoclonus in the forearm flexor muscles that can be
– Absence of early pronounced gait imbalance. misinterpreted as an action tremor. Later the ipsilateral foot
– Absence of signs of pseudobulbar palsy (such as harsh, becomes involved followed by the contralateral limbs.
strained voice quality of spastic dysarthria) until late, if at all. However, symptoms and presentations vary, including
– Rigidity and bradykinesia are more appendicular than postural instability, athetosis, focal stimulus-sensitive
axial. myoclonus, action tremor, cortical sensory loss, supranuclear
gaze palsy, Babinski signs, and pseudobulbar palsy.
Behavioral manifestations include frontal-lobe-type behavior
552 Photograph of 552 and language disturbances. Dysarthria is a late sign. The
a man with intellect is usually preserved. No response to levodopa.
progressive
supranuclear palsy Other akinetic-rigid syndromes with
manifesting axial parkinsonian features
rigidity, downgaze • Idiopathic Parkinson’s disease (see above and p.420).
paresis, and • Multiple system atrophy.
bradykinesia. Here he • Cortico-basal degeneration.
tries to look down at • Pallidal, pallidoluysian, and pallidoluysonigral degenera-
the white handle of tions; dentato-rubro-pallido-luysian atrophy.
the inverted walking • Adult-onset Hallervorden–Spatz disease (see p.162): a
stick to help him very rare, sometimes familial, condition of progressive
initiate the first step. rigidity, bradykinesia, dystonia, dysarthria, and dementia
in childhood, or occasionally adulthood. Epileptic
seizures, chorea, cerebellar ataxia, muscle atrophy and
retinitis pigmentosa may also occur. Iron-containing
pigment deposited in the substantia nigra and globus
pallidus can be imaged by MRI.
• Huntington’s disease (see p.417).
• Wilson’s disease (see p.157).
• Cerebrovascular disease:
– Top of the basilar syndrome causing midbrain and
diencephalic infarction.
– Multiple infarcts in brainstem and basal ganglia.
• Subcortical gliosis.
• Prion disease.
434 Degenerative Diseases of the Nervous System
Subcortical dementia
• Diffuse Lewy body disease (see p.430).
• Advanced Alzheimer’s disease (see p.407).
• Vascular dementia (see p.261).
INVESTIGATIONS
Cranial CT scan
• May show enlargement of the third ventricle and
interpeduncular cistern due to atrophy of the midbrain.
• It is performed to exclude structural lesions,
hydrocephalus and multi-infarct states which may
produce clinical findings similar to PSP.
MRI brain
• Various signs of brainstem atrophy such as reduction in
size of part of the substantia nigra (as in Parkinson’s
disease) may be seen.
• A high signal in the periaqueductal gray matter is
present.
• Signal hypointensity within the putamen (as in other
parkinsonian syndromes) is seen.
DIAGNOSIS
Clinical diagnostic criteria
Possible PSP
• Onset of symptoms at 40 years of age or later.
• Either vertical supranuclear gaze palsy or slowing of
vertical saccades.
• Prominent postural instability with falls in the first year
of symptoms, and no evidence of other diseases that
could explain the symptoms.
Probable PSP
• The presence of a gradually progressive disorder.
• Vertical supranuclear gaze palsy.
• Other features of possible PSP or supportive criteria:
– Frontal/subcortical cognitive dysfunction.
– Axial rigidity.
– Pseudobulbar dysphagia and dysarthria.
– Blepharospasm/apraxia of eyelid opening.
Definite PSP
• A history of probable or possible PSP.
• Histopathologic evidence of typical PSP.
Exclusion criteria for possible or probable PSP
• Recent history of encephalitis or oculogyric crisis,
suggesting postencephalitic parkinsonism.
• Severe asymmetry or asymmetric onset of parkinsonian
symptoms (bradykinesia) and/or tremor-dominant
disease, and/or marked and prolonged levodopa benefit,
suggesting Parkinson’s disease.
• Hallucinations, especially if of early-onset or unrelated to
dopaminergic therapy, or delusions unrelated to therapy,
suggesting Lewy body dementia.
• Cortical dementia of Alzheimer’s type (amnesia and
aphasia or agnosia).
• Prominent cerebellar symptoms or unexplained
dysautonomia (early, prominent urinary incontinence or
marked postural hypotension), suggesting multiple
system atrophy.
• Alien hand syndrome, cortical sensory deficits, severe
limb apraxia, severe asymmetric bradykinesia, or focal
frontal or temporoparietal atrophy, suggesting cortico-
basal degeneration.
• Neuroradiologic evidence of relevant structural
abnormality (infarcts in basal ganglia or brainstem, lobar
atrophy).
• Ocular-masticatory myorhythmia, suggesting Whipple’s
disease (rule out by polymerase chain reaction [PCR], if
indicated).
• Disease course of <1 year or EEG abnormalities sug-
gestive of Creutzfeldt–Jakob disease.
• In about one-third of patients, the diagnosis is not made
with certainty during life.
TREATMENT
Symptomatic
• Antiparkinsonian agents such as levodopa, bromocriptine
and amantadine may reduce the symptoms in some cases
but a sustained response is rare.
• Zolpidem, a short-acting hypnotic drug which is
GABAergic and a selective agonist of the benzodiazepine
subtype receptor BZ1, may ameliorate motor symptoms
when used as a single 5 mg or 10 mg dose.
• Cholinergic treatments such as intravenous
physostigmine may improve cerebral metabolism and
some measures of neuropsychometric and oculomotor
performance.
• Speech and swallowing assessment and management.
• Physiotherapy.
• Occupational therapy.
PROGNOSIS
• Progressive clinical course leading to immobility and
anarthria. Pneumonia is the most common immediate
cause of death.
• Median survival is about 5 (2–17) years.
• Predictors of a shorter survival time: onset of falls during
the first year, early dysphagia, incontinence.
 Multiple Systems Atrophy (MSA)
MULTIPLE SYSTEMS ATROPHY (MSA)
DEFINITION
A sporadic, adult-onset progressive, degenerative disease of
unknown etiology which is clinically protean, characterized
by autonomic dysfunction, parkinsonism, and ataxia in any
combination, but a unifying cellular pathology featuring
glial cytoplasmic inclusions.
TERMINOLOGY
The term MSA was coined in 1969 by Graham and Oppen-
heimer in a report of a patient who developed autonomic
failure followed by cerebellar and then pyramidal signs and
died aged 62 years, just over 4 months after disease onset.
Autopsy revealed cell loss and gliosis (without Lewy bodies)
in the substantia nigra and striatum, olives, pons, cerebellum,
and intermediolateral cells columns of the spinal cord. This
established the notion of pathology in clinically relevant sites
being clinically silent. The term was proposed as a shorthand
to cover many cases described under different titles that
overlapped with each other (e.g. sporadic olivoponto-
cerebellar atrophy [OPCA], the Shy–Drager syndrome
[SDS], striatonigral degeneration [SND]) and which were
felt to be variants of the same disorder.
MSA is now considered a well defined clinicopathologic
entity with protean manifestations, rather than three
different diseases (OPCA, SDS, SND) with some clinical
features in common. It is one of the multisystem
degenerations, which is an umbrella term to describe a large
number of inherited and sporadic degenerative neurologic
diseases involving multiple areas of the brain, such as
Huntington’s disease, inherited OPCA, Machado–Joseph
disease, and progressive supranuclear palsy.
EPIDEMIOLOGY
• Prevalence: 4.4 per 100 000 (two probably and two
possible cases) (95% CI: 1.2–7.6).
• Age: middle-aged and elderly; mean age of onset:
54 years (range 31–78 years).
• Gender: M=F.
PATHOLOGY
Cell loss and gliosis of varying degrees and proportions
occurs, without Lewy bodies (unless they are incidental), in
the striatum (particularly the putamen), substantia nigra,
locus ceruleus, inferior olives, pontine nuclei, and cerebellar
Purkinje cells, as well as the intermediolateral cell columns
and Onuf ’s nucleus of the spinal cord. Other, more
widespread, pathologic changes may also be present.
Five cellular features are present: glial cytoplasmic inclu-
sions (GCIs), neuronal cytoplasmic inclusions, neuronal nu-
clear inclusions, glial nuclear inclusions, and neuropil threads.
The most characteristic cellular pathology is the argyrophilic
GCI in oligodendroglia (553). They are widely distributed,
more common in white matter than gray matter, more
common in motor fibers than sensory fibers, and may be flame
or sickle-shaped. Ultrastructurally, they are randomly arranged
tubules or filaments, of diameter 20–40 nm, and associated
with granular material. GCIs contain α-synuclein, a synaptic
protein also found in Lewy bodies in Parkinson’s disease. They
are present in the brains of all cases of MSA (i.e. 100%
sensitivity) but not all brains containing GCIs are from patients
with MSA (i.e. <100% specificity); they are also found in
435
corticobasal degeneration, progressive supranuclear palsy,
sporadic OPCA, SCA1 with multiple system degeneration, and
chromosome 17-linked dementia. This is analogous to the
situation vis-à-vis Lewy bodies in idiopathic Parkinson’s disease.
ETIOLOGY AND PATHOPHYSIOLOGY
Unknown.
CLINICAL FEATURES
Any combination of symptoms and signs of dysfunction of the:
• Cerebellum: dysarthria, ataxia (about 50% of patients).
• Extrapyramidal system: atypical parkinsonism, poorly
responsive to levodopa therapy in most patients.
• Pyramidal system: brisk reflexes, spastic quadriparesis
(about 50% of patients).
• Autonomic nervous system: postural hypotension,
impotence and urinary incontinence (almost all patients).
Most patients present with one of the three syndromes
listed below (OPCA, SDS, and SND) but progress so that
they usually end up having features of all three.
PREVIOUSLY DEFINED SUBGROUPS
Sporadic adult-onset OPCA
• Part of MSA and different from the inherited form.
• Cerebellar signs are almost always accompanied by
autonomic failure (e.g. urinary incontinence). As the
disease progresses, parkinsonism, which is unresponsive
to levodopa, usually also develops.
• Brisk reflexes.
• No family history.
Patients with inherited OPCA are not considered to have
MSA. They present younger, and have less autonomic signs
and parkinsonian features.
Shy–Drager syndrome (SDS)
In 1960, Shy and Drager reported two men with the clinical
and pathologic features of MSA:
• Progressive, primary orthostatic hypotension due to
autonomic failure due to loss of cells in the
intermediolateral column of the spinal cord.
• Neurologic signs of extrapyramidal, pyramidal and
cerebellar dysfunction.
• Cell loss and gliosis in the striatum, substantia nigra,
cerebellum, pons, olives, and intermediolateral cell columns.
553
553 Immunocytochemistry for ubiquitin shows positively-stained
(yellow) glial cytoplasmic inclusions in oligodendrocytes in the pons.
Magnification ×400.
436 Degenerative Diseases of the Nervous System

It is now inappropriate to use the term SDS to describe – Combined with other features such as parkinsonism, pyra-
parkinsonism with autonomic failure. midal and cerebellar signs, as may be the case with MSA.
• Secondary:
Striatonigral degeneration (SND) – Addison’s disease.
In 1964, Adams et al. described three patients with – Amyloidosis.
parkinsonism and brisk reflexes, two of whom had autonomic – Diabetes.
failure, one of whom had extensor plantar responses, and one – Drugs.
had cerebellar signs. In all three, autopsy showed evidence of
striatal neuronal loss, demyelination, and gliosis, principally Cerebellar ataxia
in the putamen and substantia nigra, but also in the olives and • Inherited spinocerebellar ataxia (see p.437).
the cerebellum (and the pons in one case). Incidental nigral • Multiple sclerosis.
Lewy bodies were found in one patient. • Posterior fossa/diencephalic arteriovenous malform-
The common clinical features are: ation/tumor.
• Parkinsonism. • Drug toxicity.
• Autonomic failure.
• Late cerebellar signs. Pyramidal signs
• Parasagittal meningioma.
Relative quantification of clinical features: • Multi-infarct state.
Parkinsonism Autonomic Ataxia
OPCA + ++ +++
SDS +++ ++ + 554
SND +++ ++ +

DIFFERENTIAL DIAGNOSIS
Parkinsonism
Parkinson’s disease (see p.420)
• Most MSA patients are initially diagnosed as having
idiopathic PD, and one-third retain this erroneous
diagnosis until they die.
• Between 4% and 22% (mean 8%) of brains in
parkinsonian brain banks are found to have MSA.
• The clue is that idiopathic PD causes parkinsonism with
or without autonomic failure but it does not give rise to
pyramidal or cerebellar signs.

Lewy body disease (see p.430)

Lewy body disease can cause parkinsonism with autonomic
failure but not pyramidal or cerebellar signs. 555
Progressive supranuclear palsy (see p.432)

Corticobasal degeneration (see p.433)

Drugs
Neuroleptics.

Wilson’s disease (see p.157)

Autonomic failure
• Primary:
– Pure autonomic failure (PAF) (isolated): a syndrome that
has several causes. It may be due to the rare dopamine-
beta-hydroxylase deficiency or may persist in isolated form
and be revealed at autopsy to be related to the pathology
of Lewy body disease or MSA. So, with the passage of
time, an initial syndrome of pure autonomic failure may
mature into clinical idiopathic Parkinson’s disease, Lewy
body disease, or MSA. Helpful distinguishing tests are
plasma norepinephrine concentrations in the supine 554, 555 T1W midline sagittal (554) and T2W axial (555) MRI of the
resting position (normal in MSA, low in PAF), and brain in a patient with a clinical picture of late-onset cerebellar ataxia
plasma arginine vasopressin in upright tilt (very little and additional extrapyramidal symptoms due to MSA (predominantly
increase in AVP in patients with MSA for the degree of olivopontocerebellar degeneration syndrome). Note the shrunken
hypotension, marked rise in AVP in patients with PAF for brainstem and the cerebellar atrophy (arrows).The supratentorial brain
the same degree of hypotension). appears relatively normal.
 Autosomal Dominant Cerebellar Ataxias
• Normal pressure hydrocephalus.
• Cervical spondylitic myelopathy.
• Amyotrophic lateral sclerosis.
INVESTIGATIONS
CT brain scan
CT is used to exclude some of the differential diagnoses and
to identify atrophy of the cerebellum and brainstem,
particularly the pons, inferior olives, vermis and cerebellar
peduncles.
MRI brain
• Atrophy of the brain, particularly the pons, inferior olives,
vermis and cerebellar peduncles (554, 555) is seen.
• Abnormally low signal intensity may be noted in the
putamen compared with the globus pallidus on T2W
images due the excess iron deposition.
• Linear signal changes along the outer/lateral margin of
the putamen, manifesting as slit-like hyperintensities (on
T2W and proton density sequences and hypodensities on
T1W sequences): a useful MRI feature to help
differentiate between Parkinson’s disease and MSA
predominantly affecting the extrapyramidal system.
PET
• 18F-fluorodeoxyglucose PET: decreased glucose
metabolism is found in cerebellum, thalamus, putamen
and cortex (i.e. forebrain glucose metabolic defects as
well as cerebellar).
• 11C-diprenorphine: decreased putamenal uptake.
• 18F-fluorodopa: decreased putamenal uptake (as in all
parkinsonian syndromes).
Cardiovascular autonomic function tests
• Plasma norepinephrine concentrations – normal or
slightly raised.
Electrophysiological studies
• Monitoring of individual motor units from the striated
component of the urethral sphincter shows features
consistent with loss of anterior horn cells in Onuf ’s
nucleus in the sacral cord: specificity 92%, sensitivity 62%.
DIAGNOSIS
• Clinical: progressive symptoms and signs of dysfunction
of at least two of the cerebellar, extrapyramidal and
autonomic systems.
• Pathological: see above.
TREATMENT
• The response to levodopa is usually transient, poor, waning,
or absent, because the striatum degenerates. In contrast, in
idiopathic PD, the nigra degenerates but the striatum is
normal, which is the reason that dopamine replacement
therapy is so effective. The responsiveness (or lack of) to
levodopa is therefore a clinical clue to the diagnosis.
• Orthostatic hypotension can often be managed
successfully with head-up tilt of the bed at night, elastic
support stockings, fludrocortisone, and desmopressin
(DDAVP). In addition, subcutaneous octreotide inhibits
release of vasodilator peptides, and oral vasoconstrictors
that may be effective include midodrine (a peripherally
acting α1-agonist), epedrine, and phenylpropanolamine.
437
• Impotence may be treated with sildenafil, intracavernosal
injections of papaverine, prostaglandin E, or implantation
of a penile prosthesis.
• Urinary frequency may be reduced by anticholinergics,
but they may precipitate urinary retention.
• Urinary retention with overflow may require bethanechol
chloride, a cholinergic muscarinic agonist, intermittent
self-catheterization, or an indwelling catheter.
• Constipation may improve with a high fibre diet and
bulk laxatives, or suppositories or enemas.
PROGNOSIS
• MSA has a more aggressive course than idiopathic PD,
and in most cases significantly shortens life.
• Median survival is about 6 years (range 0.5–24 years).
• Older age of onset is associated with shorter survival.
AUTOSOMAL DOMINANT
CEREBELLAR ATAXIAS
DEFINITION
A heterogeneous group of dominantly inherited late-onset
clinical phenotypes that include cerebellar ataxia, nystagmus,
dysarthria, dysmetria, intention tremor and ophthalmoparesis,
resulting from neuronal degeneration in the cerebellum and
cranial nerve nuclei. There may also be varying degrees of
dysfunction of the basal ganglia, brainstem, spinal cord, optic
nerve, retina and peripheral nerves, resulting in visual loss,
parkinsonism, hyperreflexia and spasticity.
EPIDEMIOLOGY
• Prevalence: about 1 per 100 000 throughout the world.
• Age: adult onset, after age 20 years.
CLASSIFICATION
Clinical, pathologic and genotypic
Early classifications emphasized the clinical features, leading
to designations such as ‘Holmes’ ataxia’ and ‘Marie’s ataxia’.
The pathology was then emphasized and the disorders were
given names such as olivocerebellar atrophy, olivoponto-
cerebellar atrophy, and cerebellar cortical atrophy. The clinical
and pathologic features were then correlated with inheritance
patterns, and Harding’s classification, including autosomal
dominant cerebellar ataxia types I, II, and II, was widely used.
Recently, knowledge of genotypes has been correlated with
clinical phenotype and pathology, and previous classifications
have been refined . Each aspect of the classification has a role;
genotypes are likely to provide the firmest basis for genetic
counselling and for investigations into pathogenesis, while
clinical and pathologic information may be more relevant to
prognosis and management.
Disorders of trinucleotide repeats
The spinocerebellar ataxias comprise five of the eight
neurologic disorders caused by an increase in the number
of CAG repeats that encode expanded sequences of
glutamine residues. The other three are spinal and bulbar
muscular atrophy, Huntington’s disease, and DRPLA.
These disorders are characterized by autosomal dominant
or X-linked inheritance, onset in midlife, a progressive
438 Degenerative Diseases of the Nervous System
course, anticipation (a tendency toward earlier onset in
successive generations), preponderance of unstable repeats
from the paternal chromosome, and correlation of the
number of CAG repeats with the severity of disease and the
age at onset. The abnormal proteins in each disorder are
expressed in a wide range of tissues and are not limited to
the affected brain regions.
PATHOLOGY
Microscopic
Loss of neurons and degenerative changes in various
combinations of sites that include:
• Pontine and olivary nuclei.
• Cerebellar dentate nuclei.
• Cerebellar Purkinje cells.
• Basal ganglia (substantia nigra, subthalamic nuclei, red
nuclei).
• Spinal cord (Clarke’s columns, spinocerebellar tracts,
anterior horn cells).
• Peripheral nerves (dorsal root ganglia).
For example, in Machado–Joseph disease (MJD), SCA 3,
there is sparing of the inferior olivary nuclei and Purkinje cells
but substantial involvement of the dentate nucleus and
substantia nigra. In SCA 1 and SCA 3, intranuclear inclusions
are found in neurons that die. The formation of intranuclear
inclusions involves the ubiquitin-proteasome complex.
Macroscopic
Atrophy of the brainstem and cerebellum (556, 557).
ETIOLOGY AND PATHOPHYSIOLOGY
• Autosomal dominant inheritance.
• Gene mutations on chromosomes 3,6,11,12,14,16,19
identified to date (Table 41). Five genotypes that involve
increases in the number of CAG repeats have been
identified. There is a direct correlation between the size
556
of the (CAG) repeat and earlier age of onset
(anticipation). The repeat number increases with paternal
transmission of disease (imprinting). The proteins
encoded by each mutation all have an increased number
of glutamine residues. The resulting proteins are not
homologous, and the functions of these so-called ataxins
are unknown. The neuronal selectivity that characterizes
each subtype of spinocerebellar ataxia has been correlated
with the degree of accumulation of intraneuronal
ubiquinated components containing fragments of the
respective protein. Non-degraded fragments of the
glutamine repeat have a key role in the selectivity of
neuronal death.
• The SCA 6 gene, located on chromosome 19q13, encodes
the α1A-voltage-dependent calcium channel subunit.
Intriguingly, point mutations in the SCA 6 gene may cause
familial hemiplegic migraine and episodic ataxia.
CLINICAL FEATURES
• Family history of similarly affected members.
• Slow, gradual onset.
Phenotypically heterogeneous:
• Cerebellar ataxia, dysarthria, dysmetria, and intention
tremor ±:
– Supranuclear ophthalmoplegia.
– Optic atrophy.
– Pigmentatory retinopathy.
– Dementia.
– Extrapyramidal dysfunction (see Table 41).
The clinical syndrome may vary remarkably, even within the
same disease and members of the same family. For example,
there are three phenotypes of MJD (SCA 3). Cerebellar ataxia
and ophthalmoplegia are common to all types of MJD. Facial
and lingual fasciculations, and staring due to lid retraction are
other uncommon but helpful diagnostic features.
557 Brainstem from a patient with autosomal dominant cerebellar
ataxia (left) and a normal brainstem (right), showing the severe atrophy
of the midbrain, pons and medulla in the ataxic patient (left).The
brainstems have been disconnected from the brains and spinal cords
by cuts through the cerebellar peduncles, midbrain and medulla.
556 Ventral surface of the brain showing severe atrophy of the
medulla, pons and cerebellum.
557
 Autosomal Dominant Cerebellar Ataxias 439

Type 1 MJD • Middle age (40 years, mean).

• Early symptom onset, typically around 25 years. • Ataxia and ophthalmoplegia with or without pyramidal signs.
• Pyramidal signs.
• Dystonic postures. Type 3 MJD
• Later onset (47 years, mean).
Type 2 MJD • Amyotrophy prominent.
• Most common type. • Slow progression.

Table 41 Classification of autosomal dominant cerebellar ataxias

Name Gene locus Type of Pathology Phenotype
and protein mutation
SCA 1 6p22-p23 CAG repeats Purkinje cells Ataxia, dysarthria
(ADCA type 1) Ataxin 1* 41–81 Pontine nuclei Ophthalmoparesis
(normal 25–36) Inferior olivary nuclei Optic atrophy
Dysphagia, Amyotrophy
Pyramidal signs
Extrapyramidal signs
SCA 2 12q22-24 CAG repeats Purkinje cells Ataxia, dysarthria
(ADCA type 1) Ataxin 2* 35–59 Basis pontis Slow saccades
(normal 15–24) Inferior olivary nuclei Ophthalmoplegia
Peripheral neuropathy
Minimal pyramidal and extrapyramidal signs
Dementia (rarely)
SCA 3 14q24.3-q31 CAG repeats Substantia nigra Ataxia,
(Machado– Ataxin 3* 62–82 Subthalamic nuclei Ophthalmoparesis
Joseph (normal 13–36) Pontine nuclei Variable pyramidal, extrapyramidal and
disease) Dentate nuclei amyotrophic signs
(ADCA type 1) Clarke’s columns Cranial nerve deficits
Spinocerebellar tracts Exophthalmos
Anterior horn cells
Posterior root ganglia
SCA 4 16q24-ter Unknown Unknown Ataxia (late onset)
(ADCA type 1) Eye movements normal
Pyramidal signs
Sensory axonal neuropathy
SCA 5 Chromosome 11, Unknown Unknown Ataxia (late onset)
(ADCA type III) centromeric region Dysarthria
Pyramidal signs in young-onset patients
Benign course relatively
SCA 6 19q13 CAG Cerebellar atrophy Slowly progressive ataxia
(ADCA type III) α1A Ca channel 21–27 repeats Relative sparing of Dysarthria, nystagmus
Ataxin 6* (normal 4–16) brainstem Limited vertical and horizontal gaze
Hyporeflexia
Loss of proprioception
SCA 7 3p14-21.1 CAG Unknown Ataxia
(ADCA type II) Ataxin 7* 37–130 repeats Dysarthria
(normal 7–35) Pigmentary retinal degeneration
Macular dystrophy
Blindness
SCA 8 13q21 CTG Ataxia, dysarthria nystagmus, spasticity,
(ADCA type III) (untranslated) expansion diminished vibration sense
(untranslated)
SCA 12 CAG
Dentatorubro- 12p12-ter CAG repeats Dentate nucleus Ataxia
pallido-luysian Atrophin 1* 49–85 Red nucleus Choreoathetosis
atrophy (normal 7–255) Dystonia
(DRPLA) Myoclonus
Epileptic seizures
Dementia
ADCA: autosomal dominant cerebellar ataxia; SCA: spinocerebellar atrophy subtype; q: long arm of chromosome; *Function of protein is unknown.
440 Degenerative Diseases of the Nervous System

DIFFERENTIAL DIAGNOSIS • Other spinocerebellar degenerations (see Friedreich’s

• Structural cerebellar, brainstem or spinal cord lesion ataxia, p.441).
(tumor, arteriovenous malformation). • Progressive supranuclear palsy (dementia and supra-
• Alcoholic cerebellar degeneration. nuclear ophthalmoplegia).
• Multiple sclerosis.
• Hypothyroidism. INVESTIGATIONS
• Neurosyphilis. • Blood DNA analysis using PCR for gene mutations,
• Subacute combined degeneration of the spinal cord commonly CAG repeat expansions, on chromosomes
(sensory, not cerebellar, ataxia). 3,6,11,12,14,16,19.
• Wilson’s disease. • Cranial CT or, preferably, MRI scan of the brain and
• Mitochondrial cytopathy. craniocervical junction: pronounced cerebellar atrophy,
• Paraneoplastic cerebellar degeneration: usually a subacute particularly affecting the superior vermis (558–560).
ataxic syndrome. • Full blood count and film.
• Iatrogenic cadaveric human growth hormone-induced • Urea and electrolytes, plasma cortisol, very long chain
Creutzfeldt–Jakob disease: a drug history of hormonal fatty acids (in males, adrenoleukodystrophy).
therapy should be taken from all young well-muscled, or • Thyroid function tests.
previously well-muscled, patients and top athletes with • Liver function tests (alcoholic cerebellar degeneration).
cerebellar signs. • VDRL, TPHA.
• Idiopathic late-onset cerebellar ataxia: age of onset 25–70 • Vitamin B12 and vitamin E.
years (onset after 55 years: often a relatively pure midline • Plasma lactate and pyruvate, mitochondrial DNA analysis
cerebellar syndrome with marked gait ataxia, mild (mitochondrial cytopathy).
appendicular ataxia). • Plasma copper, ceruloplasmin (Wilson’s disease).

558 559

560

558–560 T1W midline sagittal (558) and T2W axial (559, 560) MRI of the brain in a patient with autosomal dominantly inherited
cerebellar ataxia due to a mutation of the gene for spinocerebellar ataxia 1 on chromosome 6 causing expansion of the trinucleotide
CAG repeat. Scans show pronounced atrophy of the medulla, pons and cerebellum, particularly affecting the superior vermis.
 Friedreich’s Ataxia
• Alpha fetoprotein (ataxia telangiectasia).
• Antipurkinje cell antibodies (paraneoplastic syndrome).
• EKG, and if abnormal, echocardiograph.
• Nerve conduction studies and EMG.
• Visual evoked potentials and somatosensory evoked
potentials.
DIAGNOSIS
Clinical syndrome of cerebellar ataxia, positive family
history, and positive DNA analysis.
TREATMENT
Symptomatic rather than curative:
• Cholinergic agents: physostigmine, lecithin, and choline
chloride.
• GABAergic drugs: baclofen and sodium valproate.
• Serotonergic compounds:
– L-5-hydroxytryptophan combined with a peripheral
decarboxylase inhibitor.
– Buspirone hydrochloride, a serotonin (5-hydroxy-
tryptamine1A) agonist, 20 mg/day in four divided doses
and increased by 5–10 mg/day up to 60 mg/day. Adverse
effects include transient light-headedness and nausea.
PROGNOSIS
Gradually progressive.
561
562
561, 562 Normal cerebellar cortex, H&E stain, with plentiful
Purkinje cells (561, arrowheads), and higher magnification view of
the cerebellar cortex of a patient with Freidreich’s ataxia showing
Purkinje cell loss (562).
441
FRIEDREICH’S ATAXIA
DEFINITION
An autosomal recessively inherited disease caused by a large
increase in the number of trinucleotide GAA repeats within the
first intron of the FRDA gene (X25) on the proximal long arm
of chromosome 9. This results in decreased expression of the
target protein frataxin, and dysfunction of the central and
peripheral nervous systems and the heart. Clinically, Friedreich’s
ataxia is characterized by the onset before age 25 years of
progressive limb and gait ataxia, cerebellar dysarthria, depressed
deep tendon reflexes, pyramidal signs, distal vibration and
proprioceptive sensory loss, axonal sensory neuropathy and
often skeletal deformities and hypertrophic cardiomyopathy.
EPIDEMIOLOGY
• Prevalence: 2 per 100 000; the most common form of
hereditary ataxia.
• Carrier frequency: 1 in 120 in European populations.
• Age: adolescence and early adult life. Onset usually
occurs at 8–15 years.
PATHOLOGY
Nervous system
• Dorsal root ganglia: degeneration/loss of large sensory
neurons.
• Dying back of axons in:
– Large myelinated sensory nerve fibers in peripheral
nerves.
– Posterior columns of the spinal cord.
– Nucleus gracilis and cuneatus, and the medial lemniscus.
– Dorsal and ventral spinocerebellar tracts.
• Corticospinal tracts: demyelination, with increasing
involvement caudally.
• Cerebellum:
– Loss of Purkinje cells (561, 562).
– Degeneration of dentate nucleus.
– Axonal loss and demyelination of superior cerebellar
peduncles.
Heart
Degeneration leading to hypertrophy and diffuse fibrosis.
Pancreas
Degeneration, giving rise to:
• Diabetes mellitus in about 10% of patients.
• Carbohydrate intolerance in an additional 20%.
• A reduced insulin response to arginine stimulation in all
patients.
ETIOLOGY AND PATHOPHYSIOLOGY
Inheritance
Autosomal recessive.
Gene mutation
Friedrich’s ataxia is due to a mutation in the FRDA gene
(X25), which is located on the proximal long arm of
chromosome 9 (9q13-q21.1). It has five exons spread over
40 kb that encode a novel 210-amino acid protein, named
‘frataxin’. More than 95% of patients with classic
Friedreich’s ataxia are homozygous for the increase in GAA
repeats, but a few have a combination of an increase in GAA
repeats in one allele and a point mutation in the other allele,
442 Degenerative Diseases of the Nervous System
confirming that Friedreich’s ataxia is a loss-of-function
disorder. Larger GAA expansions correlate with earlier age
of onset and shorter times to loss of ambulation. Friedrich’s
ataxia is the only known example of a triplet repeat
expansion causing an autosomal recessive disease.
Gene expression
The expression of the FRDA gene (X25) is not ubiquitous
but is restricted to the sites of degeneration. The mechanism
by which the intronic triplet repeat mutations leads to
cellular degeneration remains unclear. Frataxin appears to
be a nuclear-encoded mitochondrial protein important for
normal production of cellular energy. Reduced frataxin (loss
of function) in spinal cord, heart, and pancreas has been
postulated as the primary cause of neuronal degeneration,
cardiomyopathy and increased risk of diabetes, perhaps by
resulting in abnormal accumulation of iron in mitochondria.
CLINICAL FEATURES
The clinical spectrum is broader than previously recognized.
HISTORY
Symptoms of incoordination and ataxia of the lower limbs
begin in the early ‘teen’ years and progress to involve the
upper limbs and cranial musculature, so that by the age of
25 years almost all patients have some well established
neurologic signs.
PHYSICAL EXAMINATION
General
• Kyphoscoliosis (may affect posture and pulmonary function).
• Foot deformity (pes cavus and extension of the meta-
tarsophalangeal joints in about 90% of patients).
• Hypertrophic cardiomyopathy.
Cranial nerves
• Reduced visual acuity.
• Optic atrophy.
• Eye movements:
– Square wave jerks at fixation.
– Saccadic intrusion upon ocular pursuit (jerky pursuit).
– Gaze-evoked nystagmus.
– Reduced gain of vestibulo-ocular reflex.
• Speech: slurred, slow, staccato, and explosive (ataxic dysarthria).
Limbs
• Wasting of the intrinsic hand and distal lower leg muscles.
• Weakness (pyramidal) of the legs (paraparesis).
• Ataxia of the limbs, speech and eye movements:
– Bilateral intention tremor.
– Dysmetria (overshoot).
– Dysdiadochokinesia (poor coordination of rapid alternating
movements).
• Absent deep tendon reflexes (although they may be
retained) due to axonal degeneration of afferent fibers. This
is reflected neurophysiologically by absence of SNAPs and
loss of the H-reflex.
• Extensor plantar responses.
• Impaired touch, pain and temperature sensations in the feet
and distal lower limbs is unusual but found in a small
fraction of patients.
• Impaired vibration sense in the feet and hands.
• Impaired joint position sense in the distal lower limbs and
hands.
Gait
Spastic, ataxic (cerebellar and sensory) gait.
DIFFERENTIAL DIAGNOSIS
Inherited ataxias with known metabolic defects
Ataxia with isolated vitamin E (α-tocopherol) deficiency
• Inherited: autosomal recessive: frame-shift mutations in
the gene encoding α-tocopherol-transfer protein (α-
TTP) on chromosome 8q (13.1-13.3).
• Acquired fat malabsorption syndromes:
– Abeta- and hypobeta-lipoproteinemia (Bassen–Korns-
weig syndrome).
– Cholestatic liver disease.
– Cystic fibrosis.
– Short bowel syndrome.
– Onset in second to sixth decade of life.
Progressive ataxia, dysarthria areflexia, extensor plantar
responses, and proprioceptive loss ± ophthalmoplegia,
dystonic posturing of hands/feet, bradykinesia, tongue
fasciculations and pigmentary retinal degeneration. Low
serum vitamin E (11.7 µmol/l [<5 µg/ml]).
Low serum lipid concentrations, particularly cholesterol.
Oral vitamin E (800–3500 mg/day [800–3500 IU])
may cause improvement or retard progression.
Hexosaminidase A deficiency (GM2 gangliosidosis)
• Onset in adolescence or early adult life (see p.172).
• Ataxia, tremor, supranuclear ophthalmoplegia, facial grimac-
ing, dystonia and proximal neurogenic muscle weakness.
Cholestanolosis
• Autosomal recessive inheritance.
• Defective bile salt metabolism.
• Onset in second decade of life.
• Ataxia, dementia, spasticity, peripheral neuropathy,
cataract, tendon xanthomata.
• Chenodeoxycholic acid (chenodiol) treatment may
improve neurological function.
Leukodystrophies
• Metachromatic leukodystrophy (arylsulfatase A deficiency).
• Late-onset globoid cell leukodystrophy.
• Adrenoleukomyeloneuropathy: a phenotypic variant of
adrenoleukodystrophy.
Other
• Mitochondrial cytopathy.
• Wilson’s disease.
• Ceroid lipofuscinosis.
• Sialidosis.
• Ataxia telangiectasia.
• Niemann–Pick disease type C (juvenile dystonic lipidosis):
– Ataxia, supranuclear gaze palsy and psychosis.
– Sphingomyelinase activity is normal.
– Foamy storage cells in bone marrow.
Autosomal dominant cerebellar ataxias (see p.437)
Early onset ataxias of unknown etiology
Early onset cerebellar ataxia with retained tendon reflexes
• About one-quarter as common as Friedreich’s ataxia.
• Optic atrophy, severe skeletal deformity, and cardiac
involvement do not occur.
• Deep tendon reflexes are normal or increased.
 Friedreich’s Ataxia 443

• Gait may have a spastic component. Subacute combined degeneration of the spinal cord
• Prognosis is worse than Friedreich’s ataxia. • Ataxia is predominantly sensory rather than cerebellar.
• Associated features include: • Low serum vitamin B12 level.
– Hypogonadism. • Antibodies to intrinsic factor and gastric parietal cell may
– Myoclonus. be present.
– Pigmentary retinopathy.
– Optic atrophy ± mental retardation (including Behr’s INVESTIGATIONS
syndrome). Diagnosis
– Cataract and mental retardation (Marinesco–Sjogren • EKG and echocardiography: many have obstructive
syndrome). hypertrophic cardiomyopathy.
– Childhood deafness. • Pulmonary function tests: may deteriorate due to
– Congenital deafness; extrapyramidal features. kyphoscoliosis.
• Nerve conduction studies:
Congenital deformities (exclude with MRI scan of – Absent sensory nerve action potentials.
the cranio-cervical junction) – Prolonged sensory conduction velocities.
• Arnold–Chiari malformation. – Loss of H-reflex indicative of afferent axonal neuropathy.
• Platybasia. • Somatosensory evoked potentials: absence or abnormalities
• Odontoid compression. of cortical responses to peroneal or tibial nerve stimulation.
• Electronystagmography: fixational instability with square
Multiple sclerosis wave jerks.
• Relapsing and remitting course is usually in young-onset • MRI scan of brain and craniocervical junction: non-
cases. specific atrophy of the cerebellum (563, 564), the
• Bladder involvement is common. cervicomedullary junction and upper cervical spinal cord
• Sensory loss is usually patchy. may be present.
• CSF usually shows elevated protein and IgG and • Molecular DNA analysis for point mutation in X25, or
oligoclonal bands. unstable GAA trinucleotide expansion in the first X25
• MRI brain usually shows multiple lesions in intron, on the proximal long arm of chromosome 9
periventricular white matter, corpus callosum and (9q13-q21.1): useful for diagnosis, determination of
adjacent to the temporal horn of the lateral ventricles. prognosis and genetic counselling.

Structural spinal cord lesion Differential diagnosis

Spinal cord tumor or arteriovenous malformation • Full blood count and film.
• Pain, particularly nerve root pain, is common. • Glucose.
• Progressive spasticity below the level of the lesion. • Lipids.
• Progressive urgency of micturition. • RPR or VDRL, TPHA.
• Sensory level. • Thyroid function tests.
• MRI (± spinal angiography) of spinal cord discloses a • Vitamins B12 and E.
focal lesion. • Copper, ceruloplasmin.
• Cortisol and long chain fatty acids (L C26:C22, C24:C22
Syphilitic pachymeningitis ratio) if spastic paraparesis, axonal neuropathy, male
• Rare. (adrenoleukodystrophy).
• CSF pleocytosis, raised protein and positive VDRL, • Alpha fetoprotein (ataxia telangiectasia).
TPHA, FTA. • DNA analysis for SCA mutations (see p.439).

563, 564 T1W midline 563 564

sagittal (563) and T2W axial
(564) MRI of the brain in a
patient with Freidreich’s
ataxia. Note the marked
cerebellar atrophy (arrows),
but that the rest of the brain
including the brainstem is
normal. (Compare with 553,
multiple systems atrophy.)
444 Degenerative Diseases of the Nervous System
Differential diagnosis (continued)
• Hexosaminidase: if vertical gaze palsy, dystonia,
neurogenic weakness.
• Arylsulfatase A (metachromatic leukodystrophy).
• Galactocerebrosidase: if dementia, psychiatric problems,
optic atrophy, demyelinating neuropathy, radiologic
evidence of white matter disease.
• Plasma lactate and pyruvate, muscle biopsy and blood for
mitochondrial DNA analysis: if short stature, myoclonus,
retinopathy, dementia, stroke-like episodes, and
fatiguable weakness.
• Cholestanol: if cataract, tendinous swellings.
• Gonadotrophins: if hypogonadism.
• Ammonia/amino acids: if fluctuating course, mental
retardation.
• Antipurkinje cell antibodies: if subacute course (para-
neoplastic).
• Bone marrow examination for sea blue histiocytes
(Niemann–Pick disease type C): if vertical gaze palsy,
epileptic seizures, extrapyramidal signs, dementia.
DIAGNOSIS
• Progressive limb and gait ataxia developing before the
age of 25 years.
• Absent deep tendon reflexes.
• Electrophysiologic evidence of axonal sensory neuropathy.
• Point mutation in X25, or unstable GAA trinucleotide
expansion in the first X25 intron, on the proximal long
arm of chromosome 9 (9q13-q21.1).
TREATMENT
No specific treatment is available to slow the progression of
disease.
Symptomatic treatment
• Spasticity (e.g. baclofen, botulinum toxin).
• Ataxia (e.g. clonazepam).
• Physiotherapy.
• Occupational therapy.
• Podiatry.
• Speech therapy.
• Social work.
Cardiologic consultation
• Hypertrophic cardiomyopathy.
• Pulmonary function.
Orthopedic spinal surgery (Harrington rod)
For scoliosis.
Genetic testing
Testing of members of the family of an affected person with
vitamin E deficiency may identify couples heterozygous for
the α-TTP mutation, which in turn will lead to the early
identification of any homozygous children, so that vitamin
E therapy can be initiated before the onset of ataxia.
PROGNOSIS
• Progressive deterioration.
• Most patients are unable to walk independently and
safely >5–10 years after the onset of symptoms, so almost
all are confined to a wheelchair by their late 20s.
• Death usually occurs 10–25 years after symptoms onset (in
40s and 50s), usually due to cardio-pulmonary complications.
ATAXIA TELANGIECTASIA
(LOUIS–BAR SYNDROME)
DEFINITION
A rare autosomal recessive disorder characterized by onset
of ataxia in early childhood and subsequent progressive
neuromotor degeneration, usually resulting in dependence
on a wheelchair by 10 years of age.
EPIDEMIOLOGY
• Incidence: rare.
• Age: early childhood.
• Gender: M=F.
PATHOLOGY
Nervous system
• Cerebellar cortex: severe degeneration: extensive loss of
Purkinje cells.
• Brain and spinal cord white matter: vascular
abnormalities, like the mucocutaneous ones, are scattered
diffusely in a few cases.
• Substantia nigra and locus ceruleus: loss of pigmented
cells may be present, and cytoplasmic inclusions (Lewy
bodies) may be present in the cells that remain.
• Anterior horn cells: loss at all levels of the spinal cord.
• Posterior columns: loss of myelinated fibers.
• Spinocerebellar tracts: loss of myelinated fibers.
• Sympathetic ganglia cells: degeneration.
• Dorsal nerve root ganglion neurons: intranuclear
inclusions and bizarre nuclear formations may be found
in the satellite cells (amphicytes).
• Posterior nerve roots: degeneration.
• Peripheral nerves: loss of myelinated fibers.
Thymus
Hypoplasia.
Lymph nodes
Loss of follicles.
ETIOLOGY AND PATHOPHYSIOLOGY
• Autosomal recessive inheritance.
• Defective gene: ATM, mapped to chromosome 11q22-
23, which encodes a protein belonging to the
superfamily of phosphatidylinositol-3´ kinases.
• Breaks in chromosome 14 and translocations.
• Decreased synthesis of immunoglobulins.
• Defective repair of DNA.
• ATM homozygotes are hypersensitive to ionizing
radiation and radiomimetic drugs.
CLINICAL FEATURES
1–2 years of age
Onset with the acquisition of walking; ataxic-dyskinetic
syndrome: awkward, unsteady gait.
4–5 years of age
• Telangiectases: subpapillary venous plexuses, most
evident in the outer parts of the bulbar conjunctivae
(565, 566), over the ears, on exposed parts of the neck
(567, 568), on the bridge of the nose and cheeks in a
butterfly pattern, and in the flexor creases of the forearms
(569, 570).
 Ataxia Telangiectasia (Louis–Bar Syndrome) 445

565 566

565, 566 Conjunctival telangiectases, most evident in the outer parts of the bulbar conjunctivae, in a young man with ataxia telangiectasia.

567 568

567, 568 Telangiectases on exposed parts of the neck and back.

569 570

569, 570 Telangiectases in the flexor crease of the right forearm.

• Ocular pursuit: jerky due to interruption by saccadic

intrusions.
• Saccades: slow and long latency.
• Apraxia for voluntary horizontal gaze (the head, not the
eyes, turn on attempting to look to the side).
• Loss of optokinetic nystagmus.
• Limb ataxia and dysarthric speech.
• Choreoathetosis.
• Grimacing.
446 Degenerative Diseases of the Nervous System
9–10 years of age
• Mild intellectual decline.
• Mild polyneuropathy: hyporeflexia.
• Growth retardation.
10–20 years of age
• Progressive decline.
• Premature ageing.
• Recurrent pulmonary and sinus infections due to
immunologic abnormalities.
• Death due to intercurrent bronchopulmonary infection
or neoplasia, usually lymphoma, less often glioma.
DIFFERENTIAL DIAGNOSIS
• Metachromatic leukodystrophy: reduced aryl sulfatase A
in urine.
• Neuroaxonal dystrophy (degeneration): characteristic
spheroids within axons upon electron microscopy of skin
and conjunctival nerves.
• Niemann–Pick disease: reduced sphingomyelinase in
leukocytes and cultured fibroblasts.
• GM1 gangliosidosis: deficiency of β-galactosidase activity
in leukocytes and cultured fibroblasts.
• Neuronal ceroid lipofuscinosis: inclusions (translucent
vacuoles) in lymphocytes and azurophilic granules in
neutrophils.
• Abeta-lipoproteinemia (Basses–Kornzweig acanthocyto-
sis): thorny red blood cells (acanthocytes), reduced
serum low density lipoproteins.
• Friedreich’s ataxia.
INVESTIGATIONS
• Lymphopenia.
• Immunoglobulins: IgA, IgE and isotypes, IgG2, IgG4:
reduced or absent.
• Failure of delayed hypersensitivity reactions.
• Abnormal humoral and cell-mediated immunity.
• Alpha fetoprotein: elevated serum levels in almost all patients.
• CT or MRI brain scan may demonstrate cerebellar
atrophy, and occasionally intracranial vascular malform-
ations may be present.
DIAGNOSIS
• Clinical features consistent with diagnosis.
• Abnormal humoral and cell-mediated immunity.
• Raised serum levels of alpha fetoprotein.
TREATMENT
• Supportive.
• Prophylaxis of recurrent infections due to immune defect.
PROGNOSIS
• Poor.
• Median age at death is 20 years.

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 Chapter Fifteen 449

Acquired Metabolic
Diseases of the
Nervous System
HYPOXIC ENCEPHALOPATHY 571

DEFINITION
Brain dysfunction caused by a lack of oxygen to the brain as
a result of failure of the circulation or respiration.

EPIDEMIOLOGY
• Incidence: uncommon.
• Age: middle-aged and elderly.
• Gender: either sex.

PATHOLOGY
Acute, global brain hypoxia (571–573)
• Laminar cortical necrosis (571): extensive, multifocal or
diffuse, and almost invariably involving the hippocampus. 572
• Scattered small areas of infarction or neuronal loss may
be present in the deep forebrain nuclei, hypothalamus or
brainstem. Sometimes, relatively selective thalamic
necrosis occurs.
• Most, if not all, of the gray matter of the cerebral,
cerebellar and brainstem structures, and even the spinal
cord is severely damaged if the hypoxia is severe enough
and prolonged.

573

571 Section of the cerebral cortex showing laminar necrosis due to

cerebral hypoxia (arrow). (Courtesy of Professor BA Kakulas, Royal Perth
Hospital,Western Australia.)

572 Hypoxic neurons in the brain (arrows): swollen, more eosinophilic,

indistinct outline, faint-staining nuclei, and loss of Nissl substance.

573 Hypoxic, eosinophilic purkinje cells in the cerebellum (arrows).

450 Acquired Metabolic Diseases of the Nervous System
Delayed post-anoxic encephalopathy
• Demyelination throughout the subcortical white matter
of the cerebral hemispheres.
• Necrosis of the globus pallidus.
N.B. The above features can occur in any patient with
hypoxia and are not predictors of delayed anoxic
encephalopathy.
ETIOLOGY
Reduced oxygen saturation of hemoglobin
Suffocation
• Aspiration of blood or vomitus.
• Compression of the trachea by hemorrhage or a surgical
pack.
• Obstruction of the trachea by a foreign body.
• Drowning.
• Status asthmaticus.
• Strangulation.
• Altitude sickness.
Carbon monoxide poisoning (574)
Carbon monoxide binds to hemoglobin 200 times more
avidly than oxygen:
• Car exhaust fumes.
• Fumes from incomplete combustion of fossil fuels,
particularly in poorly ventilated heating systems.
• Household gas where natural gas is not used.
• Metabolic conversion of methylene chloride that is found
in paint strippers.
Respiratory paralysis
• Guillain–Barré syndrome.
• Poliomyelitis.
• Diffuse CNS disease (trauma, vascular disease, meta-
bolic/toxic encephalopathy, including drug overdose).
Reduced cerebral perfusion
Shock
• Cardiac arrest during inhalation or spinal anesthesia.
• Myocardial infarction.
• Massive systemic hemorrhage.
• Septicemia.
Delayed post-anoxic demyelination
Relative arylsulfatase A predisposes susceptible individuals
to delayed post-hypoxic leukoencephalopathy and implicates
lactic acidosis in its pathogenesis.
PATHOPHYSIOLOGY
• Although the brain only weighs 1300–1400 g (46–49 oz)
(2% of total adult body weight), it consumes about 20%
of the total oxygen consumption of the body at rest.
• If the brain is deprived of any oxygen for longer than
about 5 minutes, some brain cells become permanently
damaged.
• The persistence and severity of the neurologic damage
reflect the site of ischemia, the duration and severity of
the anoxic insult and the metabolic demands of the cells
(e.g. hypothermia lowers metabolism and prolongs the
tolerable period of hypoxia).
• The brain cells which are most vulnerable to hypoxia are
neurons, followed in order of decreasing sensitivity by
oligodendroglia, astrocytes, and endothelial cells.
• The most vulnerable neurons to mild hypoxia are the
pyramidal neurons in the CA1 and CA4 zones of the hip-
pocampus, followed by neurons in the cerebellum, striatum
and neocortex. Consequently, cerebral anoxia manifests itself
as clinical features of dysfunction of these neurons (i.e.
amnesia, bradykinesia, rigidity, dystonia, choreoathetosis,
and bilateral corticospinal tract involvement).
CLINICAL FEATURES
Mild hypoxia (e.g. mountaineering, chronic low level
carbon monoxide poisoning)
• Inattentiveness, irritability, fatigue, headache, nausea and
mild confusion.
• Poor judgement.
• Motor incoordination.
No lasting clinical effects other than slight decline in visual
and verbal long term memory and mild aphasic errors in some
people. Degrees of hypoxia that at no time abolish consciousness
rarely, if ever, cause permanent damage to the nervous system.
Moderate hypoxia
After a short period of coma, consciousness is regained and
some patients pass quickly through an acute post-hypoxic
phase characterized by variable degrees of confusion, visual
agnosia, or any one of several types of movement disorder (e.g.
action or intention myoclonus, extrapyramidal rigidity, choreo-
athetosis) and proceed to make a complete recovery. Others,
however, are left with permanent neurologic sequelae of
various combinations of one of the post-hypoxic syndromes:
• Persistent coma or stupor (see below).
• Visual agnosia.
• Dementia with or without extrapyramidal signs.
• Extrapyramidal (parkinsonian) syndrome with or without
cognitive impairment.
• Choreoathetosis.
• Cerebellar ataxia.
• Action or intention myoclonus.
• Korsakoff amnesic state.
• Seizures may or may not persist.
574
574 Cross section of the brain in the coronal plane at post mortem
showing a diffuse pink coloration due to vasodilatation induced by
cerebral anoxia in a patient who died from carbon monoxide
poisoning. (Courtesy of Professor BA Kakulas, Royal Perth Hospital,
Western Australia.)
 Hypoxic Encephalopathy
Severe but not sustained hypoxia
Initially patients are comatose with eyes slightly divergent
and motionless, pupils reactive, limbs inert and flaccid or
rigid, and tendon reflexes that are diminished.
Within a few minutes of restoring cardiac action and
breathing, generalized convulsions and muscle twitches
(myoclonus) may occur. Coma and decerebrate postures
persist, or the latter occur in response to painful stimuli, and
bilateral extensor plantar responses can be elicited.
After about 1 week or more, the eyes open, initially in
response to pain and later spontaneously, the eyelids blink
in response to any threat to the eye, and the eyes rove
around inattentively. The patient is unaware of the
surroundings and may manifest chewing movements and
grinding of teeth, and groan and grunt. Swallowing is
possible. Body posture may be decorticate or decerebrate.
Primitive reflexes such as pouting and sucking reflexes, grasp
reflex, and withdrawal reflexes to pain are present. Plantar
responses are extensor. The individual may survive in this
vegetative state (mute, unresponsive, and unaware of the
environment) for weeks, months or years (see p.52).
Vegetative state
• No awareness of self or environment and an inability to
interact with others.
• No sustained, reproducible, purposeful, or voluntary
behavioral responses to visual, auditory, tactile, or
noxious stimuli.
• No language comprehension or expression.
• Intermittent wakefulness manifested by sleep–wake
cycles.
• Sufficiently preserved hypothalamic and brainstem
autonomic functions to permit survival with medical and
nursing care.
• Bowel and bladder incontinence.
• Variable preserved cranial nerve (pupillary, oculocephalic,
corneal, vestibulo-ocular, gag), and spinal reflexes.
Severe and sustained hypoxia (e.g. cardiac arrest)
Brain death (see p.51)
A clinical diagnosis of irreversible loss of function of the
brain when the cause is known, characterized by:
• Coma: unaware and unresponsiveness to pain in all
extremities.
• Absence of brainstem reflexes:
– Pupils: midposition (4 mm [0.2 in]) to dilated (9 mm
[0.4 in]); no response to bright light.
– Ocular movement: no oculocephalic reflex; no deviation
of the eyes within 1 minute of irrigating each ear with
50 ml cold water (wait at least 5 minutes between testing
on each side).
– Facial sensation and motor response: no corneal reflex;
no jaw reflex; no grimacing to deep pressure on nail bed,
supraorbital ridge, or temperomandibular joint.
– Pharyngeal and tracheal reflexes: no response after
stimulation of posterior pharynx with tongue blade; no
cough response to bronchial suctioning.
• Apnea.
Cardiac action and blood pressure can be maintained but
natural respiration cannot be sustained. The EEG shows no
electric activity.
451
SPECIAL FORMS
Delayed post-anoxic encephalopathy
• Encephalopathy usually manifesting 1–4 weeks after
acute anoxic exposure, though the interval may be as
short as 1 day and as late as 7 weeks.
• Epidemiology: rare; middle-aged and elderly are usually
affected.
• Etiology: most commonly reported with carbon
monoxide exposure.
• Pathogenesis: uncertain. Pseudo-deficiency of arylsulfa-
tase A, and reversible alteration of CSF γ-aminobutyric
acid (GABA) and dopamine concentrations following
recovery, may have pathogenic implications.
• Pathology: characteristic subcortical white matter
demyelination with necrosis of globus pallidus.
• Clinical: most patients have severe anoxia with deep
coma when found but regain consciousness within
24 hours and resume full activity in 4–5 days. One to
four weeks later, the clinical triad develops of mental
deterioration (apathy, confusion, irritability, and occa-
sionally agitation or mania), sphincteric incontinence and
gait disturbances consequent to frontal lobe and basal
ganglia dysfunction. Examination reveals dementia,
pseudo-bulbar palsy and parkinsonism, and other frontal
lobe signs of grasp reflex, glabella tap and retropulsion,
and extrapyramidal signs of short steppage gait, masked
face and rigidity.
• Differential diagnosis: many cases are mistakenly
diagnosed as suffering from psychiatric disturbances.
• Imaging: CT and MRI show bilaterally symmetric
extensive hemispheric subcortical demyelination.
Symmetric lesions in the region of the globus pallidus
suggest a poor outcome.
• Treatment and prognosis: no specific therapy known but
the majority (50–75%) recover spontaneously. Some
patients experience persisting late sequelae including
memory disturbances and parkinsonism; in others the
neurologic syndrome progresses with weakness, shuffling
gait, diffuse rigidity and spasticity, incontinence, coma
and death after 1–2 weeks; and rarely, the hypoxic
episode is followed by a slow deterioration over weeks to
months until the patient is mute, rigid, and helpless.
DIFFERENTIAL DIAGNOSIS
• Anesthesia.
• Drug intoxication.
• Hypothermia.
• Psychiatric disturbance.
INVESTIGATIONS
Blood
Carboxyhemoglobin level (<10% is not symptomatic).
EEG
May be normal or show a spectrum of diffuse generalized
polymorphic theta or delta activity which may be of very low
voltage and not attenuated by sensory stimulation. The
EEG may become isoelectric. Epileptiform activity is
unusual.
452 Acquired Metabolic Diseases of the Nervous System

CT brain HEPATIC ENCEPHALOPATHY (HE)

• May show diffuse white matter low density, low density
in the globus pallidus, and parenchymal atrophy.
• Carbon monoxide poisoning produces a similar picture
but with more basal ganglia involvement, seen as
symmetric low density.
MRI brain
• Increased signal throughout the white matter on T2W
imaging and PDW imaging.
• Carbon monoxide poisoning produces a similar picture
but with more basal ganglia involvement, seen as
symmetric increased signal in the globus pallidus (575).
DEFINITION
A clinical neuropsychiatric syndrome characterized by
abnormal mental status occurring in patients with severe
acute, subacute, or chronic hepatocellular insufficiency.
CLASSIFICATION
Porto-systemic encephalopathy
Encephalopathy associated with increased porto-systemic
shunting in the absence of unequivocal evidence of
hepatocellular insufficiency.

DIAGNOSIS Subclinical hepatic encephalopathy

Hypoxic encephalopathy
A history of a hypoxic episode with evidence of a cardiac
arrest, sustained blood pressure below 9.3 kPa (70 mmHg)
systolic, reduced oxygenation of arterial blood, or carbon
monoxide poisoning (cherry red color of skin) and the
typical clinical sequence of events as outlined above aids the
diagnosis.
Carbon monoxide poisoning
The diagnosis is made by measuring the blood
carboxyhemoglobin level (<10% is not symptomatic) in
patients with any of the above symptoms from chronic
headache to coma, if unexplained.
TREATMENT
• Prevention of a critical degree of hypoxic injury.
• Carbon monoxide poisoning: hyperbaric oxygen may
restore consciousness more rapidly and completely than
normobaric oxygen.
• Treat seizures as appropriate, if they occur (see Epilepsy,
pp.65, 74).
Abnormal brain function, as detected by psychometric or
electrophysiologic tests, but a normal ‘routine’ neurologic
examination, in a patient with chronic liver disease (e.g.
cirrhosis). The abnormal brain function is reversible with
treatment for hepatic encephalopathy.
Fulminant hepatic failure and subfulminant
(or late-onset) hepatic failure
Acute liver failure complicated by hepatic encephalopathy
within one to several weeks of the development of jaundice
or the first evidence of liver disease.
EPIDEMIOLOGY
• Prevalence: increasingly common disorder in most major
hospitals since the advent of many new hepatotoxic drugs
and the increased consumption of alcohol by patients
with pre-existing hepatic dysfunction. The prevalence of
subclinical HE in cirrhosis patients ranges from 30–84%.
• Age: usually middle-aged and elderly.
• Gender: M=F.

PROGNOSIS
• Degrees of hypoxia that at no time abolish consciousness 575
rarely, if ever, cause permanent damage to the nervous
system.
• Hypoxic patients who demonstrate intact brainstem
function (as indicated by normal pupillary light and
ciliospinal responses and intact reflex (doll’s-head) eye
movements with the oculocephalic maneuver and
oculovestibular reflexes) have a good prognosis for
recovery of consciousness and perhaps all of their
faculties. On the other hand, absence of brainstem
reflexes, particularly absence of pupillary response to
light, implies a hopeless prognosis.
• The presence of deep coma with fixed dilated pupils and
paralysis of eye movement for 24–48 hours, along with
absence of motor responses to painful stimuli and
marked slowing of the EEG, usually signify irreversible
brain damage (in the absence of intoxication).

575 PDW axial MRI through the basal ganglia showing increased signal
(arrows) typical of carbon monoxide poisoning. (Courtesy of Dr R Sellar,
Department of Neuroradiology,Western General Hospital, Edinburgh, UK.)
 Hepatic Encephalopathy (HE) 453

PATHOLOGY Drugs and toxins

Porto-systemic encephalopathy associated with
chronic liver disease
• Large Alzheimer type 2 astrocytes (astrocytes containing
characteristic glycogen inclusions with periodic-acid
Schiff [PAS] staining) are the cardinal neuropathologic
feature of porto-systemic encephalopathy.
• Astrocytic rather than neuronal changes: diffuse increase
in the number and size of the protoplasmic astrocytes in
the deep layers of the cerebral cortex, lenticular nucleus,
thalamus, substantia nigra, cerebellar cortex, and red,
dentate, and pontine nuclei, with little or no visible
alteration in the nerve cells or other parenchymal
elements. The degree of this glial abnormality is roughly
proportional to the intensity and duration of the
neurologic disorder.
• Reduced number of pallidal D2 post-synaptic receptors
by about 50%.
• Increased 5-hydroxytryptophan receptors in the
hippocampus.
Acute fulminant liver failure
• Cytotoxic brain edema (blood–brain barrier intact),
raised intracranial pressure, herniation.
• Loss of non-NMDA receptors in the brain.
• Acetaminophen (paracetamol) overdose.
• Poisoning with carbon tetrachloride, natural products
such as certain mushrooms or medicinal herbs, and the
recreational drug methylenedioxymethamphetamine
(‘ecstasy’).
• Hypersensitivity reactions to drugs (e.g. halothane,
antidepressants, antithyroid drugs, non-steroidal anti-
inflammatory drugs, and antituberculous drugs).
Ischemia
• Cardiogenic shock.
• Acute occlusion of suprahepatic veins.
Miscellaneous
• Wilson’s disease, sometimes associated with hemolytic
anemia.
• Reye’s syndrome.
• Acute fatty liver of pregnancy.
PATHOGENESIS
Unclear but it is hepatic insufficiency and not the cause of
the liver disease which is important in causing the
neuropsychiatric clinical features.

ETIOLOGY
• Acute hepatic encephalopathy in a patient with liver
disease (e.g. cirrhosis) is usually associated with a clearly
identifiable precipitating factor and usually resolves when
the precipitating factor is removed or corrected. Failure Table 42 Precipitating factors for hepatic encephalopathy
to find a precipitating factor may imply a decrease in
overall hepatocellular function. Precipitant Possible mechanism
• Chronic hepatic encephalopathy usually occurs in a
patient with cirrhosis and substantial porto-systemic Dietary protein excess Increased ammonia
shunting, who has hepatic encephalopathy that is Constipation (anorexia, production
persistent or episodic, with or without complete fluid restriction)
resolution of encephalopathy between episodes. Gastrointestinal hemorrhage
Infection
Porto-systemic venous shunting associated with Uremia
chronic liver disease Hypokalemia
• Predisposing factors: hypoxia, hypokalemia, metabolic
alkalosis, electrolyte depletion, excessive diuresis, and use Systemic alkalosis Increased diffusion of ammonia
of sedative-hypnotic drugs. across blood–brain barrier
• Precipitating factors (see Table 42).
Dehydration Reduced metabolism of toxins
Acute liver failure Hypotension because of hepatic hypoxia
Infection Hypoxemia
• Hepatitis viruses: most commonly hepatitis B virus, but Anemia
also hepatitis D and E viruses, and rarely hepatitis A, C
and G viruses. Benzodiazepine use Activation of central GABA-
• Non-hepatotropic viruses: herpes virus, varicella-zoster benzodiazepine receptors
virus, Epstein–Barr virus, cytomegalovirus, paramyxo-
virus, and others. Other psychoactive Compounding of CNS
drug use depressant effect

Porto-systemic shunts Reduced hepatic metabolism of

toxins because of diversion of
portal blood

Progressive hepatic Reduced hepatic metabolism of

parenchymal damage toxins because of reduced
Development of hepatoma functional reserve
454 Acquired Metabolic Diseases of the Nervous System
Possible mechanisms
• Accumulation in brain extracellular fluid of
unmetabolized gut-derived neurotoxins (e.g. ammonia,
see below) as a result of poor hepatic function and porto-
systemic shunting.
• Functional disturbance of the blood–brain barrier.
• Alteration in neurotransmission:
– Decreased neuroexcitation (glutamate, aspartate,
dopamine, catecholamines).
– Increased neuroinhibition (GABA, endogenous
benzodiazepines, serotonin).
– Activation of central GABA-benzodiazepine receptors by
ligands of endogenous origin.
– Production of false neurotransmitters.
• Reduced energy metabolism in the brain:
– Disturbed activity of Na+/K+-ATPase.
– Decreased activity of urea-cycle enzymes (due to zinc
deficiency).
• Deposition of manganese in the basal ganglia.
Neurotoxins
Ammonia
• In patients with hepatic failure, ammonia (which is
produced in the gut by the action of colonic bacteria and
mucosal enzymes on dietary protein) is not completely
metabolized to urea through the urea cycle so it enters
the systemic circulation and the brain.
• Ammonia uptake in the brain is increased, where it is
normally detoxified in the brain by astrocytes.
• Ammonia has a direct post-synaptic effect on excitatory
and inhibitory post-synaptic potentials.
• Expression of the astrocyte glutamate transporter gene,
GLT-1, is reduced in acute liver failure resulting in
reduced uptake of glutamate into synaptosomes
(astrocytes in particular) and a rise in glutamate in the
extracellular fluid.
• Excessive ammonia reacts, in the presence of glutamine
synthetase, with the excess glutamic acid (glutamate) in
the extracellular fluid to form glutamine.
• Ammonia also affects cerebral energy metabolism by
inhibiting alpha ketoglutarate dehydrogenase and
combining with alpha ketoglutarate in the citric acid
cycle to form glutamic acid, which then combines with
more ammonia to form more glutamine. The effect of
ammonia on glutamine function also has an effect on
tryptophan uptake by the brain.
Manganese
Excess (2–7 fold) manganese is deposited in the pallidum in
patients dying in hepatic coma.
CLINICAL FEATURES
The nature and severity of the symptoms depend on the
acuteness and extent of the liver failure and on the
development of metabolic or infectious complications.
Consequently, the clinical manifestations range from subtle
abnormalities detectable only on psychometric testing to
deep coma.
Abnormal mental status
• Mild restlessness, irritability and perhaps dysarthria are
seen initially. In some patients the syndrome does not
evolve beyond the stage of mild mental dullness and
confusion, with asterixis and EEG changes. These
relatively mild forms must be differentiated from other
acute confusional states. In other patients with an
extensive porto-systemic collateral circulation, a disorder
of mood, personality and intellect may be protracted over
many months or even years, and be associated with
dietary protein intake.
• Confusion, clouding of the sensorium, drowsiness,
constructional apraxia, ataxia, bradykinesia, rigidity, and
asterixis follow, and then coma with extensor plantar
responses bilaterally.
Asterixis
Elicited by having the patient extend his or her arms, with
dorsiflexion of the wrist, and watching for the characteristic
‘flap’ due to an inability to maintain the posture; a form of
negative myoclonus. If the patient is comatose, the flap
response can be elicited by pressing on the finger tips,
causing dorsiflexion of the hand. If the patient can only
grasp the examiner’s fingers, asterixis can be demonstrated
by the involuntary clenching and unclenching of the fist.
Signs of advanced liver disease
Jaundice, fetor hepaticus, hepatomegaly (or small liver size),
and ascites (576).
Signs of comorbidities
Comorbidities such as alcoholism, electrolyte disturbance,
hypoglycemia, renal failure, hypotension due to
gastrointestinal bleeding (e.g. boundary zone infarction),
infection, and hemostatic failure may complicate or mask
the clinical features of hepatic encephalopathy, and
development of metabolic or infectious complications.
DIFFERENTIAL DIAGNOSIS
Metabolic encephalopathy
• Hypoglycemia or hyperglycemia.
• Electrolyte imbalance: hypernatremia, hyponatremia.
• Hypoxia.
• Hypercapnia: carbon dioxide narcosis.
• Uremia: renal failure.
• Ketoacidosis.
• Wilson’s disease.
• Liver transplantation may be complicated within the first
few weeks by an encephalopathy (headache, confusion,
seizures, cortical blindness, coma) due to electrolyte
imbalance, hypocalcemia, hypomagnesemia, cyclosporin,
air embolism, intracerebral hemorrhage and hypotension.
Opportunistic infections may occur later.
• Hyperammonemia: other causes include ornithine
transcarbamylase deficiency, amino and organic acidurias,
arginosuccinic aciduria, citrullinemia, argininemia,
carbamylphosphate synthetase deficiency, lysinuric
protein intolerance, Reye’s syndrome, sodium valproate,
systemic carnitine deficiency, asparaginase toxicity.
 Hepatic Encephalopathy (HE) 455

Toxic encephalopathy INVESTIGATIONS

• Alcohol: Blood
– Acute intoxication. • Liver function tests: hyperbilirubinemia, high
– Withdrawal syndrome: delirium tremens (rapid postural aminotransferase levels.
and action tremor, cortical excitation rather than cortical • Plasma ammonia: elevated usually but not consistently.
inhibition). Hyperammonemia is not invariable because blood
– Wernicke–Korsakoff syndrome. ammonia levels depend on both the rate of production
• Sedative/hypnotic/psychoactive drug intoxication. and metabolism.
• Salicylates. • Coagulation factors: very low values.
• Heavy metals. • Viral serology.

Intracranial lesions Differential diagnosis

• Intracranial hemorrhage: subdural hematoma. • Urea and electrolytes.
• Meningo-encephalitis: e.g. herpes simplex encephalitis. • Glucose: hypoglycemia.
• Creutzfeldt–Jakob disease. • Alcohol: acute intoxication.
• Brain infarction. • Erythrocyte transketolase activity: Wernicke–Korsakoff
• Brain abscess. syndrome.
• Brain tumor. • Toxicology: salicylates, heavy metals, psychoactive drugs.
• Head trauma.
• Epilepsy (e.g. non-convulsive status epilepticus) or EEG
postictal encephalopathy. • Initially the EEG shows non-specific generalized slowing
of the background rhythm.
Neuropsychiatric disorders • Later, it becomes dominated by trains of high amplitude,
Dementia/pseudodepression: in some patients with an bisynchronous, slow waves of delta frequency (1.5–3 Hz)
extensive porto-systemic collateral circulation, a disorder of or frontal-dominant, triphasic waves with a phase lag
mood, personality and intellect may be protracted over from front to back, before flattening in late coma (577).
many months or even years, and be associated with dietary These abnormalities are characteristic of, but not specific
protein intake. for, the disorder, since other metabolic encephalopathies
can cause similar abnormalities.

CT brain
To exclude a structural intracranial lesion if suspected (e.g.
hemorrhage).

576 577

576 Abdomen of a man with hepatic encephalopathy and portal
hypertension showing diminished body hair and dilated superficial
abdominal veins (arrow) shunting blood from the portal to the systemic
circulation. Ascites was also present.
577 EEG, 8 channels, showing trains of medium to high amplitude
bisynchronous, frontal-dominant, triphasic waves with a frequency of
1.5–2.5 Hz and phase lag from front to back.Triphasic waves are often
seen in patients with an acute deterioration in conscious state due to
metabolic disorders such as hepatic or renal failure, or cerebral anoxia.
Atypical triphasic waves may rarely be seen in herpes simplex
encephalitis, drug withdrawal, Creutzfeldt–Jakob disease, or following
head trauma.
456 Acquired Metabolic Diseases of the Nervous System
MRI brain
• Increased signal in the basal ganglia (particularly pallidum
but midbrain may also be affected) on T1WI (578, 579).
• The substances which may cause an increased signal on
T1WI include manganese, melanin, calcium, and blood.
The differential diagnosis of increased signal in the basal
ganglia on T1WI includes hyper-, hypo-, pseudohypo- and
pseudopseudohypoparathyroidism (calcium), hyper-
alimentation, Hallevorden–Spatz disease, carbon
monoxide poisoning, hemorrhage and neurofibromatosis.
CSF
Usually normal apart from elevated levels of glutamine, the
end product of cerebral ammonia metabolism.
Abdominal ultrasound
Size and echostructure of liver.
Liver biopsy (transjugular route)
DIAGNOSIS (Table 43)
There are two components to making the diagnosis:
• To determine that encephalopathy (subclinical or overt)
is present.
• To establish hepatocellular insufficiency and increased
portal-systemic shunting.
The diagnosis is based on the history, physical
examination and laboratory findings.
TREATMENT
Treatment is determined by the underlying cause.
Hepatic encephalopathy due to the rare condition of
acute liver failure is rapid in onset and progression, almost
always complicated by cerebral edema in the later stages, and
has a poor prognosis. Orthotopic liver transplantation should
therefore be considered in these patients and meanwhile
those who are grade 3 or 4 should be electively sedated with
fentanyl, paralysed with atracurium, and ventilated to protect
the airway and facilitate the management of cerebral edema
578 579
by preventing surges in intracranial pressure related to
psychomotor agitation. The cerebral edema is treated with
mannitol given in repeated bolus injections of 0.5 g/kg body
weight over a period of 10 minutes, and acetylcysteine can
be given by continuous infusion to improve cerebral blood
flow and metabolic rate for oxygen in grade 4 patients.
Hepatic encephalopathy due to the much more common
chronic liver disease can be managed quite differently
because it is usually due to a clinically apparent precipitating
event (or combination of events), or to the spontaneous
development of porto-systemic shunting, and because
cerebral edema is much less frequent.
General
• Nasogastric tube.
• Central venous line.
• Indwelling urinary catheter.
• Monitor intracranial pressure (extradural monitor) if
encephalopathy reaches grades 3 or 4.
• Avoid maneuvers that increase intracranial pressure (such
as sensorial stimuli).
• Control restlessness.
• Hydrate carefully.
• Elevate patient’s head 20–30°.
• Avoid (or use with extreme caution) drugs such as
sedatives, phenytoin, phenobarbitone (phenobarbital),
valproate, and dantrolene because drug metabolism and
protein binding are frequently disturbed in liver disease.
• Avoid/be careful with benzodiazepines because plasma
half-life of benzodiazepines is increased four- to fivefold
in hepatic failure, so substantial toxicity may ensue (e.g.
when used for endoscopy or nocturnal sedation).
• Avoid hypoglycemia (monitor blood glucose).
Specific
• Remove the underlying cause:
– N-acetylcysteine for early paracetamol overdose.
– Forced diuresis and activated charcoal for mushroom
poisoning.
– Acyclovir for herpes virus infection.
– Surgery for acute hepatic-vein occlusion.
578, 579 T1W axial
(578) and T1W sagittal
(579) MRI of the brain
in a patient with hepatic
encephalopathy. Note
the increased signal in
the basal ganglia
(arrows). (Courtesy
of Dr R Gibson, Depart-
ment of Neuroradiology,
Western General
Hospital, Edinburgh, UK.)
 Central Pontine Myelinosis 457

• Lower blood ammonia levels: CENTRAL PONTINE MYELINOLYSIS

– Reduce ammonia production (restrict intake of dietary
protein and inhibit urease-producing colonic bacteria).
Low protein diet (20 g a day initially, increasing gradually DEFINITION
later). A disorder characterized by rapidly developing quadriparesis
Vegetable, rather than animal, protein diet. and a large, symmetric, demyelinating lesion of the greater
Carbohydrate enemas. part of the basis pontis. It may also affect extrapontine brain
Oral non-absorbable disaccharides: lactulose or lactisol areas.
(lactose 100 g daily in lactase deficiency): 30–60 g/day
to produce 2–4 soft stools daily. EPIDEMIOLOGY
Oral antibiotics: neomycin 6 g daily, metronidazole • Prevalence: up to 0.25% of autopsies.
800 mg daily, or rifaximin 1200 mg daily. • Age: any age; reported in children (particularly those
Oral Enterococcus faecium. with severe burns) as well as adults.
– Increase ammonia metabolism: sodium benzoate 10 g • Gender: M=F.
daily; ornithine aspartate 9 g tds; phenylacetate.
• For patients who have previously been treated with PATHOLOGY
benzodiazepines (e.g. for treatment of behavioral Demyelination occurs in the centre of the pons (580) and
disturbance caused by hepatic encephalopathy), the occasionally other parts of the brainstem.
administration of a benzodiazepine antagonist, such as
flumazenil, may improve conscious level.
• Consider pharmacologic manipulation of glutaminergic
and monoaminergic systems (experimental).
• If intracranial pressure exceeds 2.7–4 kPa
(20–30 mmHg), apply hyperventilation (paCO2
3.3–4 kPa [25–30 mmHg]), then mannitol 0.5 g/kg in
bolus; then hemodialysis or venovenous hemofiltration;
then barbiturate coma. 580
• Orthotopic liver transplantation: acute liver failure;
severe, refractory hepatic encephalopathy.

CLINICAL COURSE AND PROGNOSIS

• The encephalopathy usually evolves over a period of days
to weeks and, if untreated, often terminates fatally.
Sometimes the symptoms spontaneously regress
completely or partially and may fluctuate in severity for
several weeks or months.
• Most manifestations are reversible with medical treatment.
• Some patients have progressive debilitating neurologic
syndromes such as dementia, spastic paraparesis,
cerebellar degeneration, and extrapyramidal movement
disorders that are associated with structural abnormalities
of the CNS and were hitherto regarded as irreversible, 580 Transverse section of the pons showing demyelination of
but now may gradually improve after successful corticospinal tract fibers in the center of the basis pontis (arrows)
orthotopic liver transplantation. with preserved neurons in the pontine nuclei and no evidence of
inflammation.

Table 43 Grading system based on clinical and EEG features

Grade Conscious level Personality and intellect Neurologic signs EEG abnormalities
0 Normal Normal None None
Subclinical Normal Normal Only on psychometric testing None
1 Inverted sleep Forgetfulness, mild confusion, Tremor, apraxia, incoordination, Triphasic waves
pattern, restlessness agitation, irritability impaired handwriting
2 Lethargy, slow Disorientation in time, Asterixis, dysarthria, ataxia, Triphasic waves
responses amnesia, disinhibited, hypoactive reflexes
inappropriate behavior
3 Somnolent but Disorientated in place, Asterixis, rigidity, hyperactive Triphasic waves
rousable, confusion aggressive behavior reflexes, Babinski signs
4 Coma None Decerebration Delta activity
458 Acquired Metabolic Diseases of the Nervous System
Macroscopic
• Grayish discoloration and fine granularity in the centre
of the basis pontis.
• The lesion may be only a few millimetres in diameter or
it may occupy almost the entire basis pontis.
• The lesion may extend posteriorly to involve the medial
lemnisci and, in most advanced cases, other tegmental
structures as well; superiorly to encroach on the
midbrain; inferiorly to the pontomedullary junction; and
anteriorly, but there is always a rim of intact myelin
between the lesion and the surface of the pons.
• Particularly extensive pontine lesions may be associated
with identical myelinolytic foci symmetrically distributed
in the thalamus, subthalamic nucleus, striatum, internal
capsule, amygdaloid nuclei, lateral geniculate body, white
matter of the cerebellar foliae, and deep layers of the
cerebral cortex and subjacent white matter (‘extrapontine
myelinolysis’).
Microscopic
• Destruction of medullated sheaths throughout the lesion,
with relative sparing of the axis cylinders and intactness
of the nerve cells of the pontine nuclei. These changes
always begin and are most severe in the geometric centre
of the lesion, where they may proceed to frank necrosis
of tissue.
• Reactive phagocytes and glial cells are present through-
out the demyelinative focus, but no oligodendrocytes or
signs of inflammation are present.
ETIOLOGY AND PATHOPHYSIOLOGY
• Sporadic.
• Specific regions of the brain, such as the centres of the
basis pontis, have a special susceptibility to some acute
metabolic fault (possibly to rapid correction or to over-
correction of hyponatremia, and possibly hyper-
osmolality), analogous perhaps to the selective vul-
nerability of the corpus callosum and anterior com-
missure in Marchiafava–Bignami disease.
• Myelinolysis is more likely to occur after the treatment
of chronic rather than acute hyponatremia and is more
likely to occur with a rapid rate of correction.
• The exact pathogenesis has not been determined.
Risk factors
• Hyponatremia.
• Over-rapid correction of severe hyponatremia
(<130 mmol/l [<130 mEq/l]) to normal or higher than
normal levels of serum sodium.
• Extreme serum hyperosmolality.
• Nutritional deficiency.
• Serious, often life-threatening, medical illness.
CLINICAL FEATURES
Predisposing illness
Patients are usually already very ill:
• Vomiting or comatose chronic alcoholics.
• Cachectic patients from a variety of causes.
• Malnourished patients.
• Chronic renal failure treated by dialysis.
• Hepatic failure.
• Advanced lymphoma.
• Carcinoma.
• Severe bacterial infection.
• Dehydration and electrolyte disturbances particularly
hyponatremia.
• Acute hemorrhagic pancreatitis.
• Pellagra.
Variable clinical illness
• Subacute onset over several days, usually after correction
of hyponatremia, of:
– Mental changes ranging from mild confusion to coma.
– Pseudobulbar palsy.
– Flaccid or spastic quadriparesis.
– Extensor plantar responses bilaterally.
– Locked-in syndrome (see p.55): a de-efferented state
whereby the patient cannot speak or move the limbs but
can often move the eyes (particularly in the vertical
plane) and blink, in order to try and communicate.
Awareness and consciousness is preserved because the
brainstem tegmentum, including the reticular formation,
are spared.
– Conjugate eye movements may be limited and
nystagmus may be present.
– Pupillary reflexes, eye movements, corneal reflexes, and
facial sensation are spared.
• Absent or transient mild neurologic symptoms and signs
may be all that are seen if the pontine lesion is small,
extending only 2–3 mm on either side of the median
raphe and involving only a small portion of the
corticopontine or pontocerebellar fibers.
• Coma may be present due to underlying metabolic or
other associated disease which obscures the presence of
central pontine myelinolysis.
Variants
• Confusion, stupor, and cerebellar ataxia, without
corticospinal tract signs, due to brainstem tegmentum
and cerebellar lesions.
• ‘Locked-in’ syndrome due to large symmetric lesions of
the frontal cortex and underlying white matter.
DIFFERENTIAL DIAGNOSIS
Stroke due to brainstem infarction
• Sudden onset or step-like progression.
• History of vascular risk factors (atheroma) or neck
trauma (dissection).
• Asymmetry of long tract signs.
• Caused by basilar artery occlusion.
• More extensive involvement of tegmental structures of
pons as well as midbrain and thalamus.
Multiple sclerosis
Massive pontine demyelination in acute or chronic relapsing
MS may rarely produce a pure basis pontis syndrome but
other features of this disease provide the clue to the correct
diagnosis (see p.340).
Post-infectious encephalomyelitis (see p.292)
Hyponatremic encephalopathy
A generalized encephalopathy without localizing motor
signs. Usually there is a distinct interval between the
occurrence of a generalized hyponatremic encephalopathy
initially which improves with elevation of the sodium level
and then, about 2–3 days after hyponatremia is corrected,
the neurologic syndrome of myelinolysis evolves. However,
 Further Reading 459

sometimes the hyponatremic encephalopathy does not TREATMENT

improve before focal myelinolytic symptoms emerge and it
can be difficult to recognize that two separate disease
processes are occurring sequentially.
Psychiatric illness
The common initial symptoms of myelinolysis (mutism,
dysarthria, lethargy and affective changes) may be mistaken
for psychiatric/psychologic illness.
INVESTIGATIONS
• Full blood count: infection.
• Urea and electrolytes: hyponatremia, renal failure.
• Liver function tests: chronic alcoholism, liver failure.
• Amylase: pancreatitis.
• CT brain scan: there may be low density throughout the
pons, basal ganglia, hemispheric white matter, without
mass effect or enhancement.
• MRI brain scan: more sensitive than CT. Increased signal
is visible in the pons with a thin rim of normal signal
around the margins of the pons and possible sparing of
the corticospinal tracts which leaves two rounded normal
signal areas within the high signal of the pons. There may
also be increased signal in the thalami, putamen, caudate
nuclei, amygdala, and hemispheric white matter.
• Brainstem auditory evoked potentials.
DIAGNOSIS
• Clinical: gravely ill patient with a general medical disease
who develops a quadriplegia, pseudobulbar palsy and
locked-in syndrome over a few days.
• Radiologic: lesion in the center of the basis pontis
consistent with demyelination.
• Supportive (be aware that ‘locked-in’ patients can see,
hear and feel everything [including pain and itch] but are
incredibly frustrated that they cannot move).
• Active treatment of the underlying medical illness.
• Prevention of complications of immobility: pneumonia,
deep vein thrombosis, contractures, urinary tract
infection.
• Rehabilitation: physiotherapy, swallowing and speech
therapy, occupational therapy, psychologic support and
therapy.
PREVENTION
• Optimal management of hyponatremia patients involves
weighing the risk for illness and death from untreated
hyponatremia against the risk for myelinolysis due to
correction of hyponatremia.
• Chronic hyponatremia should be corrected by no more
than 10 mmol/l (10 mEq/l) in any 24-hour period.
CLINICAL COURSE AND PROGNOSIS
• Outcome varies: some die; many make a gradual but
partial recovery with residual sequelae that include bulbar
dysfunction, spastic quadriparesis, movement disorders,
behavioral changes, and alterations in cognition, while
others recover completely.
• Some patients remain in a state of mutism and paralysis
with relatively intact sensation and comprehension, i.e.
the ‘locked-in’ syndrome (see p.515).

FURTHER READING HEPATIC ENCEPHALOPATHY (HE) CENTRAL PONTINE MYELINOLYSIS

HYPOXIC ENCEPHALOPATHY
Chalela JA, Wolf RL, Maldjian JA, et al. (2001)
MRI identification of early white matter injury
in anoxic-ischaemic encephalopathy. Neurolo-
gy, 56: 481–485.
Gottfried JA, Mayer SA, Shungu DC, et al.
(1997) Delayed posthypoxic demyelination.
Association with arylsulfatase A deficiency and
lactic acidosis on proton MR spectroscopy.
Neurology, 49: 1400–1404.
Snyder BD, Tabbaa MA (1988) Assessment and
treatment of neurological dysfunction after
cardiac arrest. Stroke, 19: 269–273.
Jones EA, Weissenborn K (1997) Neurology and
the liver. J. Neurol. Neurosurg. Psychiatry, 63:
279–293.
Jalan R, Hayes PC (1997) Hepatic encephalopa-
thy and ascites. Lancet, 350: 1309–1315.
Mas A, Rodes J (1997) Fulminant hepatic failure.
Lancet, 349: 1081–1085.
Lui HF, Jalan R, Hayes PC (1998) Hepatic en-
cephalopathy: pathogenesis, diagnosis and
management. Proc. R. Coll. Physicians Edin.,
28: 111–118.
Riordan SM, Williams R (1997) Treatment of he-
patic encephalopathy. N. Engl. J. Med., 337:
473–479.
Chalela J, Kattah J (1999) Catatonia due to cen-
tral pontine and extrapontine myelinolysis:
case report. J. Neurol. Neurosurg. Psychiatry,
67: 692–693.
Karp BI, Laureno R (2000) Central pontine and
extrapontine myelinolysis after correction of
hyponatraemia. The Neurologist, 6: 255–266.
Laureno R, Karp BI (1997) Myelinolysis after cor-
rection of hyponatraemia. Ann. Intern. Med.,
126: 57–62.
460 Chapter Sixteen
Nutritional Deficiency
and the
Nervous System
WERNICKE–KORSAKOFF SYNDROME
DEFINITION
Wernicke’s disease (thiamine deficient encephalopathy) is a
disorder characterized by rather abrupt onset of any
combination of nystagmus, gait ataxia, conjugate gaze palsy
and mental confusion in association with nutritional
deficiency, especially due to alcoholism.
Korsakoff’s psychosis is a mental disorder, also associated
with alcoholism and malnutrition, in which retentive
memory is enormously impaired due to a defect in learning
and memory, in an otherwise responsive patient. The
Wernicke–Korsakoff syndrome is a symptom complex
comprising the manifestations of both Wernicke’s disease
and the Korsakoff amnesic state.
EPIDEMIOLOGY
• Prevalence (from autopsy studies): 0.8–2.8% of autopsies;
15% in psychiatric in-patients, 24% in homeless men.
• Age: adults.
• Gender: M>F.
PATHOLOGY
Wernicke’s disease
Macroscopic
Loss of brain tissue (lower brain weight, increased
ventricular volume and pericerebral space) occurs, mainly in
white matter.
Microscopic
• Neuronal loss, proliferative symmetric vasculopathy, and
gliosis occur in the mamillary bodies (medial mamillary
nucleus, diagnostic); thalamus (medial dorsal nucleus);
hypothalamus; around the third ventricle, aqueduct in
the mid brain and floor of the fourth ventricle; brainstem
and sometimes the cerebellum (581–583). There is little
or no specific pathology in the locus ceruleus,
hippocampus and cerebral cortex.
• Acute Wernicke’s disease is characterized by small areas
of petechial hemorrhage and marked vascular endothelial
proliferation in the same sites listed above (i.e. mamillary
bodies and so on).
Korsakoff’s psychosis
Cell loss and gliosis occur in the medial mammillary nucleus
and mediodorsal nucleus of the thalamus (similar to
Wernicke’s disease), but there is greater cell loss in the
anterior principal nucleus of the thalamus in Korsakoff ’s
psychosis.
ETIOLOGY
Thiamine deficiency
• Chronic alcoholism (malnutrition and impaired activity
of thiamine-dependent enzymes).
• Malnutrition.
• Deliberate starvation:
– Anorexia nervosa.
– Hunger strike.
– Obesity treatment (vertical banded gastroplasty).
• Intractable vomiting:
– Gastric carcinoma.
– Pyloric obstruction.
– Hyperemesis gravidarum.
• Prolonged intravenous feeding.
• Renal dialysis.
• Acquired immunodeficiency syndrome.
Magnesium depletion
Magnesium is an essential cofactor in the conversion of
thiamine into active diphosphate and triphosphate esters:
• Diuretics: frusemide (furosemide).
• Alcohol.
• Hyperemesis gravidarum.
• Diarrhea: Crohn’s disease, gluten enteropathy.
PATHOGENESIS
• Absorption of thiamine is impaired by both malnutrition
and alcohol.
• Liver disease that leads to reduced body stores and
impaired metabolism of thiamine often compounds the
situation and may also enhance the toxic effect of alcohol
on the brain. Nevertheless, about a third of substantial
alcohol abusers seem to be resistant to developing the
Wernicke–Korsakoff syndrome.
• Individual differences in thiamine enzyme systems, such
as different levels of affinity between thiamine
pyrophosphate, which acts as coenzyme, and trans-
ketolase, an enzyme concerned with brain glucose
metabolism, may predispose certain individuals to the
Wernicke–Korsakoff syndrome. If so, they are likely to
be extragenetic as there is little evidence of an inborn
transketolase abnormality.
 Wernicke–Korsakoff Syndrome
CLINICAL FEATURES
Wernicke’s disease
Subacute onset over hours to days of one or, more often,
various combinations of:
• Ataxia of stance and gait.
• Ophthalmoplegia: supranuclear horizontal and/or
vertical gaze palsies, internuclear ophthalmoplegia, and
lateral rectus palsies, often causing diplopia.
• Nystagmus: horizontal and/or vertical.
• Mental state disturbance: a global confusional state causing
apathy, inattention, disorientation, minimal spontaneous
speech, forgetfulness, drowsiness, and even coma.
Other features may include:
• Stupor or coma as the initial manifestation.
• Signs of alcohol withdrawal: agitation, hallucinations,
confusion, and autonomic hyperactivity.
• Hypothermia.
• Postural hypotension (autonomic neuropathy).
• Cardiovascular dysfunction (tachycardia, exertional
dyspnea, minor EKG abnormalities).
• Impaired capacity to discriminate between odors (in the
chronic stage of the disease due to a lesion of the medial
dorsal nucleus of the thalamus).
• Pupil abnormalities: miosis and non-reacting pupils can
occur.
• Ptosis.
581
583
583 Axial section through the medulla showing a proliferative
vasculopathy and petechial hemorrhages (arrow) in the floor of the
fourth ventricle of a patient with acute Wernicke’s encephalopathy.
461
• Retinal hemorrhages occur occasionally.
• Papilledema rarely.
• Alcoholic patients: peripheral neuropathy in >80% of
patients, dementia, cerebellar ataxia, macrocytosis and
abnormalities of liver function.
Korsakoff amnestic confabulatory state
(Korsakoff’s psychosis)
A permanent gap in memory characterized by:
• Defect in learning (anterograde amnesia), due to
defective encoding at the time of original learning rather
than exclusively a defect in the retrieval mechanism.
• Loss of short term verbal and non-verbal memory
(retrograde amnesia); immediate memory is preserved
and long term memory appears to be maintained
through multifocal networks.
• Confabulation and confusion
The learning defect can render patients incapable of all
but the most habitual tasks.
DIFFERENTIAL DIAGNOSIS
Wernicke’s disease
• Other causes of confusional states and coma (see p.44).
• Hepatic encephalopathy.
• Brainstem/cerebellar/diencephalic stroke.
582
581, 582 Brain, coronal sections showing petechial
hemorrhages in the mamillary bodies (arrows) and medial
dorsal thalamus (arrowheads) of a patient with acute
Wernicke’s encephalopathy.
462 Nutritional Deficiency and the Nervous System
Korsakoff amnestic confabulatory state
• Third ventricle tumors.
• Temporal lobe infarction or surgical resection.
• Herpes simplex encephalitis.
• Hypoxic encephalopathy.
• Alzheimer’s disease.
INVESTIGATIONS
Blood
Red cell transketolase (reduced markedly) and thiamine
(reduced), and plasma glucose and magnesium levels.
Transketolase is one of the enzymes of the hexose
monophosphate shunt and requires thiamine pyrophosphate
as a cofactor.
CT brain scan
CT may show widening of the third ventricle and
interhemispheric fissures, and other features of long
standing alcohol abuse (generalized cerebral atrophy plus
more pronounced vermian and cerebellar atrophy).
MRI brain scan
MRI may show areas of increased signal in the
periaqueductal gray matter of the midbrain and medial
portions of the thalami, atrophy of the mamillary bodies,
and dilatation of the third ventricle.
DIAGNOSIS
Clinical diagnostic criteria
• Oculomotor abnormalities: ophthalmoplegia and/or
nystagmus.
• Cerebellar dysfunction.
• Altered mental state (e.g. confusion) or mild memory
impairment.
• Dietary deficiencies.
• History of alcohol consumption.
• Red blood cell transketolase assay, with a positive
thiamine pyrophosphate effect of >40%.
• MRI brain: medial thalamic and periaqueductal lesions.
• Clinical response to thiamine.
The diagnosis of Wernicke–Korsakoff syndrome is missed
in about 25% of cases if brains are not examined
microscopically. This is commonly because the history of
symptom onset may be unclear, due to recent alcohol
intoxication or the presence of Korsakoff psychosis. If
clinically suspected, however, the diagnosis can be
confirmed by showing a marked reduction in blood
transketolase activity and a striking restoration toward
normal of the transketolase and the clinical features even
within hours of the administration of thiamine; completely
normal values of transketolase are usually attained within 24
hours. Failure of the ocular palsies to respond to thiamine
within a few days should raise doubts about the diagnosis
of Wernicke disease.
TREATMENT
• Thiamine 100 mg intravenously or Parentrovite forte,
10 ml i.v. (contains 250 mg thiamine), immediately and
then daily for 7 days because intestinal absorption is
usually impaired in alcoholics. The thiamine solution
should be fresh, since it can be inactivated by heat.
Thiamine prevents the progression of the disease and
reverses the brain abnormalities that have not resulted in
fixed structural changes. Hypomagnesemia can
compromise the treatment response and replacement
therapy should be considered.
• Oral vitamin maintenance, providing 10–50 mg thiamine
daily until the patient is no longer at risk (usually for
several months).
• Oral chelated magnesium 500 mg daily (if depleted).
• Balanced diet.
• Alcohol abstinence.
• Psychotherapy and educational efforts: ineffective in
arresting the cognitive decline without abstinence.
• Clonidine and fluvoxamine have been reported to be
effective in improving function, suggesting dysfunction
in noradrenergic and serotonergic systems respectively,
but remain experimental.
PREVENTION
• At risk patients should be given vitamin supplements.
• Comatose patients should be treated with thiamine or
Parentrovite forte, especially if no obvious cause is
recognized.
• At-risk patients should never be given a glucose load
(intravenous dextrose, nasogastric feeding) without
vitamin supplements because this may precipitate
Wernicke’s syndrome.
CLINICAL COURSE
After thiamine treatment, the ophthalmoplegia begins to
improve within hours to days and nystagmus, ataxia and
confusion within days to weeks. The amnesic symptoms may
recover slowly over 1 year or so and incompletely. Recovery
of cognitive function depends on age and continuous
abstinence from alcohol.
PROGNOSIS
• Depends on the stage of the disease and prompt
institution of thiamine treatment.
• Can be fatal if untreated: mortality rate is 10–20%,
mainly due to pulmonary infection, septicemia,
decompensated liver disease, and an irreversible stage of
thiamine deficiency.
• Residual nystagmus and ataxia in 60% of patients.
• Residual chronic memory disorder in 80% of patients.
 Vitamin B12 Deficiency
VITAMIN B12 DEFICIENCY
DEFINITION
Vitamin B12 deficiency is a nutritional disorder of the
nervous system that may be characterized by a symmetric,
distal, predominantly sensory peripheral neuropathy due to
axonal degeneration, autonomic neuropathy, subacute
combined degeneration of the spinal cord (or combined
systems disease), optic neuropathy, dementia and other
disturbances of higher mental function.
EPIDEMIOLOGY
• Prevalence:
– Pernicious anemia: 1–3% over age 65 years.
– Serum vitamin B12 levels <150 pmol/l (<200 pg/ml):
7–16% of the elderly population.
– Serum vitamin B12 levels <225 pmol/l (<300 pg/ml)
and elevated levels of metabolites of homocysteine and
methylmalonic acid: 21% over age 65 years.
• Age: mean age at diagnosis is 60 years.
– Caucasians: increases in frequency with increasing age,
peaking after age 65 years.
– Hispanics and Africans: younger age of onset, particularly
among women.
• Gender: F>M (1.5:1).
PHYSIOLOGY
• The total body store of vitamin B12 is 2–5 mg, half of
which is stored in the liver.
• The body needs about 1–6 µg/day (the average diet
contains about 7–30 µg per day).
• Vitamin B12 is released from dietary food protein in the
stomach and passes into the duodenum and jejunum
where it is bound to intrinsic factor, which is produced
by gastric parietal cells (along with HCl). The vitamin
B12-intrinsic factor complex attaches to specific receptors
in the terminal ileal mucosa, where it is internalized and
degraded. Vitamin B12 enters the portal circulation,
where some binds to transcobalamin II. The vitamin B12-
transcobalamin II complex is taken up by cells and
degraded in lysosomes, releasing vitamin B12 for
conversion to methylcobalamin or adenosylcobalamin.
• Methylcobalamin is a cofactor of methionine synthase,
which catalyses the reaction of homocysteine and
methyltetrahydrofolate to produce methionine and
tetrahydrofolate. Methionine is further metabolized to S-
adenosylmethionine, which is necessary for methylation
of myelin sheath products. Tetrahydrofolate is the
precursor required for purine and pyrimidine synthesis.
Adenosylcobalamin catalyses the conversion of L-
methylmalonyl CoA to succinyl CoA in the mitochondria.
• The dietary source of vitamin B12 is from animals only.
It is tightly conserved through the enterohepatic
circulation, so it takes 2–5 years to develop vitamin B12
deficiency from malabsorption, and up to 10–20 years
for dietary deficiency from strict vegetarianism.
463
PATHOPHYSIOLOGY
• Vitamin B12 deficiency leads to a rise in serum levels of
homocysteine and methylmalonic acid.
• The lack of methionine (produced from homocysteine),
leads to a lack of S-adenosylmethionine, which is
required for all methylation reactions, including myelin
phospholipids. It is puzzling, however, that neurologic
complications are rare in folate deficiency, even though
methionine synthase also requires folate as a cosubstrate.
• Accumulation of methylmalonate and propionate may
provide abnormal substrates for fatty acid synthesis,
resulting in abnormal odd-number carbon and branched-
chain fatty acids, which may be incorporated into the
myelin sheath.
• Nitric oxide is a potent oxidizing agent and irreversibly
oxidizes the cobalt core of vitamin B12, rendering
methylcobalamin inactive. This inhibits the conversion
of homocysteine to methionine, thus reducing the supply
of S-adenosylmethionine. In people with normal stores
of vitamin B12, there may sufficient quantities of
unoxidized vitamin B12 to maintain enzyme function for
longer periods but in patients with compromised stores,
even brief exposure to nitrous oxide may be sufficient to
precipitate a vitamin B12 deficiency syndrome.
ETIOLOGY
Vitamin B12 deficiency
• Genetic: defect of methylmalonyl CoA mutase.
• Dietary deficiency (low intake): vegetarianism.
• Malabsorption states:
– Pernicious anemia. Lack of intrinsic factor due to
autoimmune gastric parietal cell dysfunction.
– Gastric achlorhydria.
– Gastric resection.
– Chronic pancreatic disease.
– Competition for intraluminal vitamin B12:
Bacterial overgrowth in ‘blind loops’, anastomoses, and
diverticula.
Cobalamin-metabolizing fish tapeworm (Diphyllobothrium
latum) infestation.
– Terminal ileum disease.
Crohn’s disease.
Resection.
– Nitric oxide exposure (anesthesia)
• Increased requirements: pregnancy.
• Low utilization: enzyme deficiency.
464 Nutritional Deficiency and the Nervous System

PATHOLOGY Neurologic
• Predominantly sensory, distal, symmetric, peripheral • Altered higher mental function: depression, hallucin-
neuropathy is seen, characterized by axonal degeneration ations, frank psychosis (so-called megaloblastic madness),
with or without demyelination. paranoia, violent behavior, personality changes, mental
• Subacute combined degeneration of the spinal cord (or confusion and dementia occur in about 10% of cases.
combined systems disease) occurs with degeneration of • Optic atrophy, with bilateral centrocecal scotomas and
the white matter of the posterior columns and lateral visual failure is rare.
corticospinal tracts (584). • Spastic paraparesis due to corticospinal tract lesions
• Optic neuropathy: white matter degeneration and occurs. Lower limb weakness may also be due to
occasional foci of spongy degeneration in optic nerves accompanying peripheral neuropathy; lower motor
and chiasm. neuron signs (e.g. wasting, weakness, areflexia) only
• Brain: white matter degeneration. become apparent when neuropathy is severe.
• Autonomic neuropathy: degeneration of small unmye- • Reflexes may be increased (with clonus) or decreased
linated axons. depending on the degree of corticospinal tract and
peripheral nerve involvement.
CLINICAL FEATURES • Plantar responses are often extensor because of
About three-quarters of patients present with neurologic corticospinal tract degeneration.
symptoms and about one-quarter with non-neurologic • Incoordination may be marked because of
symptoms that result from defective DNA synthesis in spinocerebellar degeneration (cerebellar ataxia) or
rapidly dividing cells of the bone marrow and gastro- proprioceptive loss (sensory ataxia).
intestinal mucosa. • Loss of vibration and joint position sense in the feet are
seen due to degeneration of the posterior columns, and
HISTORY loss of pain and temperature sensation distally in the
Neurologic symptoms limbs in a ‘glove and stocking’ distribution due to
• Paresthesiae (tingling sensations) and numbness in the peripheral neuropathy.
feet and later the fingers. • Rhomberg’s sign may be positive due to impaired
• Lhermitte’s symptom occasionally. proprioception as a result of degeneration of large
• Impaired memory. diameter fibers in peripheral nerves and posterior
• Anosmia. columns.
• Reduced visual acuity. • Broad-based gait.
• Diminished taste.
• Impaired manual dexterity. N.B. Neuropathy alone is found in about one-quarter of
• Lower limb weakness ( corticospinal tract lesions and patients, myelopathy alone in about 12%, and combined
peripheral neuropathy). myelopathy and neuropathy in about 40%. Paresthesiae,
• Unsteady gait. vibratory loss and ataxia may be caused by both neuropathic
• Impotence. and myelopathic lesions.
• Incontinence of urine or feces.

Non-neurologic symptoms
• Weakness.
• Tiredness.
• Faints (syncope).
• Palpitations.
• Headache.
• Sore tongue.
• Diarrhea. 584
• Bowel disturbances.
• Family history of anemia requiring monthly ‘vitamin
shots’.

Recent exposure to nitric oxide

PHYSICAL EXAMINATION
General
• Pallor of mucous membrane (anemia) (585).
• Lemon-yellow skin.
• Glossitis (smooth red tongue) (586).
• Premature graying of hair.
• Orthostatic hypotension.
584 Axial section of spinal cord showing tissue destruction and
fibrous gliosis in posterior columns (arrowheads) and lateral and
anterior (arrows) corticospinal tracts of a patient with longstanding
subacute combined degeneration of the spinal cord. (Courtesy of
Professor BA Kakulas, Royal Perth Hospital,Western Australia.)
 Vitamin B12 Deficiency 465

DIFFERENTIAL DIAGNOSIS Low serum vitamin B12 level

Myeloneuropathy
• Syphilis.
• Friedreich’s ataxia.
• Adrenomyeloneuropathy.
• Cervical spondylitic myeloradiculopathy.
• Multiple sclerosis and concurrent peripheral neuropathy
(e.g. alcoholic, diabetic).
• Chronic exposure to nitric oxide. Nitric oxide interdicts
vitamin B12 metabolism.
• Acute exposure to nitric oxide in patients with
unsuspected vitamin B12 deficiency (because of normal
vitamin B12 levels); these patients may develop an acute
vitamin B12 deficiency syndrome after a single exposure
to nitric oxide during a surgical procedure.
• Celiac disease with vitamin E deficiency: sensory
neuropathy, areflexia, confusion, dementia, cerebellar
ataxia, myopathy, weight loss, diarrhea, steatorrhea.
Macrocytosis
• Alcoholism.
• Hypothyroidism.
• Liver disease.
• Reticulocytosis.
• Drugs, cytotoxics.
• Pregnancy.
• Myelodysplasia, myeloma, aplastic anemia.
• Inborn errors of cobalamin metabolism causing
homocystinuria and methylmalonic aciduria.
• Vitamin B12 deficiency.
• Abnormalities of vitamin B12 metabolism: folate
deficiency/antagonists.
• Normal individuals with no tissue deficiency of vitamin
B12: second and third trimester of pregnancy.
INVESTIGATIONS
Vitamin B12 deficiency or not?
• Blood:
– Full blood count and blood film: may be normal.
– Anemia or pancytopenia.
– Macrocytosis (raised mean corpuscular volume).
– Neutrophil hypersegmentation (may be a sensitive
marker of vitamin B12 deficiency, even in the absence of
anemia or macrocytosis).
• Serum vitamin B12 level: <150 pmol/l (<200 pg/ml)
(radioassay method) in 90–95%, 150–225 pmol/l
(200–300 pg/ml) in 5–10%, and >225 pmol/l
(>300 pg/ml) in 0.1–1% of patients.
• Serum homocysteine and methylmalonic acid levels
(metabolites of the B12 pathway): raised, but non-
specific: also elevated in chronic renal disease, several
inborn errors of metabolism, hypothyroidism, folate
deficiency and pyridoxine deficiency.
• Bone marrow: megaloblastic (can be masked by
concurrent iron deficiency).

585 586

585 Pale appearance of the skin and mucous membranes of a patient

with pernicious anemia. (Courtesy of Dr AM Chancellor,Tauranga, New
Zealand.)

586 Smooth, atrophic tongue of a patient with pernicious anemia.

(Courtesy of Dr AM Chancellor,Tauranga, New Zealand.)
466 Nutritional Deficiency and the Nervous System

Cause of vitamin B12 deficiency TREATMENT

• Antiparietal cell antibody: sensitive (present in 90% of
people with pernicious anemia [PA]) but not specific
(also present in 5% of 30 year olds, 10% of the
population over age 70, 15% of elderly women, and 60%
of people with simple atrophic gastritis).
• Anti-intrinsic factor antibody:
– Insensitive (present in only 50–60% of people with PA)
but is highly specific for PA.
– If anti-intrinsic factor antibody is positive (and serum
vitamin B12 level <150 pmol/l (<200 pg/ml) or
homocysteine and methylmalonic acid levels are
elevated), the diagnosis of PA is confirmed and a
Schilling test is not necessary.
• Serum gastrin level: indicated if anti-intrinsic factor is
negative (and serum vitamin B12 levels <150 pmol/l
[<200 pg/ml] or homocysteine and methylmalonic acid
levels are elevated), to help establish the presence of
achlorhydria, which is almost invariably associated with
PA.
• Schilling test: to determine (1) if there is vitamin B12
malabsorption in patients with proven B12 deficiency
without a known cause (e.g. diet, gastrectomy, drugs),
and (2) the cause of the B12 malabsorption.
– Conducted with and without intrinsic factor (IF).
– Radioactive B12 alone is given by mouth (part I). If it is
not detected in the urine, the result is abnormal
indicating that radioactive B12 is not absorbed from the
gut. The test is repeated with radioactive B12 bound to
IF (part II). Radioactive B12 is now detected in the urine
of patients with PA, due to a lack of intrinsic factor,
whereas patients with malabsorption of B12 from the
terminal ileum still fail to show any radioactive B12 in the
urine.
• Remove/treat the underlying cause.
• Replenish vitamin B12 stores with intramuscular injections
of cyanocobalamin 100–1000 µg daily for 5 days, then
• Maintain vitamin B12 stores with:
– 100–1000 µg cyanocobalamin intramuscularly each
month, or
– 500–1000 µg cyanocobalamin orally each day, as a
supplement, until the underlying cause is removed.
The rationale for oral supplementation (e.g. 1000 µg/day)
is that 1% of all ingested vitamin B12 (e.g. 10 µg, more than
the average daily requirement [1–6 µg/day]) may be
absorbed by passive diffusion. This means that vitamin B12
requirements may be satisfied with oral therapy, even in
patients with PA, provided the dose is sufficient. So, oral
replacement, and even sublingual therapy, are alternatives for
patients who cannot tolerate intramuscular injections or for
whom they are impractical.
The therapeutic response to B12 should be a reticulocytosis
and normalization of the blood count changes (unless
concomitant deficiencies or diseases are present). The
hemoglobin will rise by 10 g/l per week on average. The bone
marrow changes also resolve rapidly, within 48 hours of
commencing therapy.
PROGNOSIS
The most important factor influencing the neurologic
response to treatment is the duration of symptoms before
treatment is started. If treatment is given early enough, it
may not only prevent progression but also reverse some
neurologic symptoms and signs besides paresthesia in the
feet and optic atrophy.

Myeloneuropathy or not, and type?

• Nerve conduction studies: reduced or absent sensory
potentials (axonal degeneration) and decreased motor
conduction velocities (demyelination).
• Electromyography (EMG): spontaneous fibrillations in
distal muscles if denervated.
• Sural nerve biopsy: axonal degeneration with or without
demyelination.
• MRI of the brain and spine (587–589): may be used to
exclude structural causes of the patient’s symptoms. In
advanced cases, T1W MR images of the spine may show
swelling of the upper cervical spinal cord and decreased
signal in the posterior columns of the spinal cord,
extending up to the brainstem. T2W images may show
increased signal in the posterior columns. T2W MRI
images of the brain may show confluent high density
changes in the white matter of the tempero-parieto-
occipital lobes bilaterally corresponding to gliosis and
edema with vacuolization of axonal sheath myelin.

DIAGNOSIS
Typical neurologic syndrome (subacute combined
degeneration of the spinal cord, neuropathy), macrocytic
anemia, low serum vitamin B12 level, and biochemical
evidence of vitamin B12 deficiency: elevated methylmalonic
acid and homocysteine levels. A normal vitamin B12 assay
does not fully exclude vitamin B12 deficiency.
 Further Reading 467

587 588

589
587–589 T2W axial cervical spine (587),T2W axial brain (588), and
T2W midline sagittal cervical spine (589) MRI in a patient with
pernicious anemia and subacute combined degeneration of the cord.
Note the increased signal throughout the sensory and motor long
tracts in the brainstem and the posterior columns of the cord
(arrows).

FURTHER READING Thomas PK (1998) Subacute combined degener- Treatment

WERNICKE–KORSAKOFF SYNDROME
McLean J, Manchip S (1999) Wernicke’s en-
cephalopathy induced by magnesium deple-
tion. Lancet, 353: 1768.
Zubaran C, Fernandes JG, Rodnight R (1997)
Wernicke–Korsakoff syndrome. Postgrad. Med.
J., 73: 27–31.
VITAMIN B12 DEFICIENCY
General
Hemmer B, Glocker FX, Schumacher M, et al.
(1998) Subacute combined degeneration: clin-
ical, electrophysiological, and magnetic reso-
nance imaging findings. J. Neurol. Neurosurg.
Psychiatry, 65: 822–827.
ation. J. Neurol. Neurosurg. Psychiatry, 65:
807.
Etiology
Mayall M (1999) Vitamin B12 deficiency and ni-
trous oxide. Lancet, 353: 1529.
Rosener M, Dichgans J (1996) Severe combined
degeneration of the spinal cord after nitrous
oxide anaesthesia in a vegetarian. J. Neurol.
Neurosurg. Psychiatry, 60: 354.
Diagnosis
Green R, Kinsella LJ (1995) Current concepts in
the diagnosis of cobalamin deficiency. Neurol-
ogy, 45: 1435–1440.
Delpre G, Stark P, Niv Y (1999) Sublingual ther-
apy for cobalamin deficiency as an alternative
to oral and parenteral cobalamin supplemen-
tation. Lancet, 354: 740–741.
Elia M (1998) Oral or parenteral therapy for vita-
min B12 deficiency? Lancet, 352: 1721–1722.
Kuzminski AM, Del Giacco EJ, Allen RH, et al.
(1998) Effective treatment of cobalamin defi-
ciency with oral cobalamin. Blood, 98:
1191–1198.
468 Chapter Seventeen

Disorders of the
CSF Circulation
HYDROCEPHALUS • The primary function of the CSF is to provide
buoyancy and allow the brain to float, protecting it
from repetitive trauma whenever the head moves.
DEFINITION Movement of CSF through the foramen magnum
Hydrocephalus is defined as an increase in volume of the compensates for the changes that occur in cerebral
CSF in association with dilatation of the cerebral ventricles. blood volume with each heart beat.

EPIDEMIOLOGY ETIOLOGY
• Incidence: Overproduction of CSF
– Neonatal hydrocephalus: 1/1000 births. Rare, if ever (choroid plexus papilloma usually obstructs).
– Adult hydrocephalus: depends on the incidence of preci-
pitating causes (e.g. meningitis, subarachnoid hemorr- Obstruction to CSF outflow within the ventricles
hage); 1–2% of patients presenting to dementia clinics. (obstructive hydrocephalus)
– In the UK: 3000 shunt operations annually (1500 new, Congenital
1500 recurrent). • Aqueduct stenosis, with or without gliosis, ‘forking’ (in
• Prevalence (lifetime): 0.1 (95% CI: 0.01–0.3) per 1000. which the aqueduct is replaced by a number of small,
• Age: any age. inefficient channels), septum formation, or atresia. May
• Gender: either sex. be caused by mumps and possibly other intra-uterine
infections.
PHYSIOLOGY OF CSF CIRCULATION • Dandy–Walker syndrome (atresia of the foramina of
• CSF contains little protein; bicarbonate is its only buffer. Luschka and Magendie associated with failure of
• The total volume of CSF in the cranial and spinal cavity development of the vermis of the cerebellum).
of the adult is about 150 ml, of which about 30 ml is in • Hind brain abnormalities, spina bifida.
the ventricular system. • Vein of Galen aneurysm.
• About 70% of CSF is actively secreted by the cells of the
choroid plexus of the lateral, third and fourth ventricles Space-occupying lesions
and the remaining 30% comes from the brain’s capillary • Acquired aqueduct stenosis.
bed and from metabolic water production. • Colloid and arachnoid cysts.
• CSF is produced at a rate of 0.35 ml/min (500 ml/day), • Thalamic glioma.
which is equivalent to a turnover of total CSF every 6 • Intraventricular tumors.
hours. • Tentorial herniation.
• The CSF flows slowly through the ventricular system and • Posterior fossa tumor, hemorrhage, infarct.
the foramina of Luschka and Magendie into the • Colloid cyst or tumor of the third ventricle.
subarachnoid space and then up and over the cerebral • Basilar artery dolichoectasia.
convexities. Some of the fluid flows into the central canal
of the spinal cord. Ventricular hemorrhage
• Circulation of the CSF is achieved by arterial pulsation • Prematurity.
in the brain and choroid plexus, and by changes in • Aneurysm, arteriovenous malformation.
posture, exercise and coughing, creating a pressure
differential between the newly formed CSF and its site Defective flow in the subarachnoid space
of drainage (a hydrostatic gradient). (communicating hydrocephalus)
• The CSF drains passively from the subarachnoid space into • Meningitis:
the venous system (principally the superior sagittal sinus) – Pyogenic.
via the arachnoid granulations in the cranial and spinal – Tuberculous.
compartments (open channels that connect the – Fungal.
subarachnoid side to the venous side of the arachnoid villi). – Neoplastic.
• Subarachnoid hemorrhage.
• Hyperviscosity of CSF due to high CSF protein (e.g.
spinal neurofibroma).
 Hydrocephalus
Defective absorption of CSF at the arachnoid
granulations
• Congenital deficiency of arachnoid granulations (rare).
• Raised cerebral venous sinus pressure due to venous sinus
thrombosis (controversial).
Idiopathic
Particularly in the elderly (see Normal pressure
hydrocephalus, p.473).
Loss of brain tissue (hydrocephalus ex-vacuo)
Accumulation of CSF in the ventricular system and cerebral
sulci due to loss of brain tissue as a result of atrophy,
infarction and so on.
PATHOPHYSIOLOGY
Obstruction to CSF flow raises intraventricular pressure
which reverses the direction of flow of CSF from the
ventricles through the ependyma and into the
periventricular brain parenchyma causing periventricular
edema. It also reduces periventricular cerebral blood flow
which, if not treated, results in periventricular demyelination
and gliosis.
CLINICAL FEATURES
Infancy/early childhood
• Asymptomatic, or symptoms of irritability, poor appetite,
vomiting, and poor head control.
• Rapid head enlargement (crossing percentile lines) with
distortion of the normal proportions of the cranial cavity.
• Prominent scalp veins.
• Open, enlarged, tense fontanelle.
• Delayed fusion of sutures.
• ‘Cracked-pot’ tympanitic sound produced by percussion
of the thinned skull (late).
• Brilliant transillumination of the skull (late sign).
• Delayed motor skills and milestones but alert.
• Papilledema (unusual in infants).
• Upward gaze and horizontal gaze paresis (‘setting sun’
eyes) occur, due to pressure of dilated third ventricle on
the posterior commissure in the tectum of the midbrain.
• Paralysis or spasm of convergence.
• Spastic paraparesis with lower limb hyperreflexia and
extensor plantar responses: the corticospinal tracts
emanating from the parasagittal region of the motor
cortex and destined for the legs have a long course
around the lateral ventricles and tend to be most
compressed and stretched by enlarged lateral ventricles.
N.B. Head circumference measurement should be
compared with normal values on a standard head-size chart.
Serial measurements which show a crossing of percentiles
are important signs.
Transillumination of the skull with a torch held against
the baby’s head in a dark room reveals increased redness
around the torch light in the presence of an excessive
amount of fluid beneath the torch light.
469
Older children and adults (skull sutures
have begun to fuse)
Raised intracranial pressure causing
• Headache, often worse in the early morning.
• Nausea and vomiting.
• Blurred vision, occasionally.
• Diplopia, due to VIth nerve palsy may occur.
• Papilledema sometimes; its absence does not exclude
raised intracranial pressure.
• Optic atrophy with progressive visual loss and poor
pupillary reaction to light: a late complication of chronic
papilledema due to raised intracranial pressure.
• Upgaze paresis.
• Increasing unsteadiness of gait occurs, culminating in
frequent falls due to a combination of ataxia, spasticity
and dyspraxia of gait.
• Urgency of micturition and eventual incontinence.
• Personality change and behavioral disturbance.
• Dementia.
• Eventually, depressed consciousness.
Symptoms and signs of the primary obstructive lesion
For example, cerebellar signs of a posterior fossa tumor.
Elderly
Normal pressure hydrocephalus (NPH) syndrome
This is characterized clinically by Hakim’s triad of gait
apraxia, urinary incontinence and progressive dementia.
Difficulty initiating movement, such as getting out of a
chair, is characteristic (see p.473).
DIFFERENTIAL DIAGNOSIS
Infancy/early childhood
Enlarged head
• Achondroplasia.
• Rickets.
• Subdural hematoma.
• Megalencephaly (brain of excessive size and weight).
Transillumination of the head
Localized brain cysts.
Elderly
• Alzheimer’s disease.
• Vascular (multi-infarct) dementia.
• Binswanger’s disease.
• Parkinson’s disease.
• Progressive supranuclear palsy.
• Multiple sclerosis.
INVESTIGATIONS
Imaging
The role of imaging is to:
• Exclude other causes of the patient’s symptoms.
• Try to decide whether the hydrocephalus is obstructive
(communicating or non-communicating) or non-
obstructive.
• Follow-up patients being managed conservatively to
check for the need for a shunt in future and in those who
have been shunted to check for shunt failure.
470 Disorders of the CSF Circulation

If obstructive non-communicating hydrocephalus is Other imaging methods

diagnosed, it may be possible to identify the cause such as
a third ventricular colloid cyst, posterior fossa tumor or
aqueduct stenosis (590, 591). Communicating hydro-
cephalus can be identified when all the ventricles appear
large but the basal cisterns are still patent (592–597). Non-
communicating hydrocephalus is present when the lateral ±
the third ventricle are much larger than the fourth ventricle.
Meningitis and subarachnoid hemorrhage may cause either
communicating or non-communicating hydrocephalus.
CT and MRI brain scan
In general, CT scan is satisfactory. In obstructive
hydrocephalus it shows ventricular dilatation above the site
of obstruction and possibly the causative lesion (e.g. tumor).
If there is no obstruction to CSF flow then all ventricles will
be dilated. The cortical sulci are usually compressed due to
the rise in intracranial pressure. MRI is required, however,
in particular circumstances such as the diagnosis of aqueduct
stenosis, posterior fossa lesions, and malignant meningitis,
to name but a few. For example, MRI of aqueduct stenosis
shows disproportionate dilatation of the lateral and third
ventricles and a small fourth ventricle. On midline sagittal
MRI the aqueduct appears small. Bands or webs may be
visible in the aqueduct causing obstruction. Normally the
CSF flows through the aqueduct fast enough to result in a
flow void on MRI, so the absence of a flow void (on
carefully chosen sequences) is good corroborative evidence
of aqueduct stenosis.
Usually, the temporal horns of the lateral ventricles are the
first to dilate (this is a useful sign after subarachnoid hemorr-
hage as an early warning of possible complicating hydro-
cephalus). Note that the fourth ventricle is the last to dilate,
so may appear small in communicating hydrocephalus simply
because it has not yet had time to dilate. Therefore it can be
very difficult to decide which sort of hydrocephalus is present
on any imaging modality in some cases.
Periventricular white matter lucencies on CT and high
signal on T2WI are common due to transependymal
seepage of CSF usually sited around the angles of the lateral
ventricles when due to hydrocephalus.
• Transfontanelle ultrasonography/echo-encephalography
are safe, non-invasive methods of imaging and moni-
toring lateral ventricular size in infants and young
children.
• Skull x-ray: children <10 years: large head and widened
skull sutures; older children and adults (closed skull
sutures): erosion of the dorsum sellae and clinoid
processes (raised ICP).
• Radioactive cisternography, which is performed by
injecting a radiopharmaceutic into the lumbar sub-
arachnoid space, shows prolonged retention of the
radioactive material within the ventricular system and
impaired movement of radioactive material over the
cerebral convexities.
CSF
CSF pressure is usually elevated, but may be normal in so-
called NPH (see p.473). The appearance, cell count, protein
and glucose are commonly normal, but may be abnormal in
the presence of an underlying causal lesion (e.g. tumor,
meningitis).
Intracranial pressure monitoring
A saline-filled catheter or catheter-tipped transducer inserted
into the lateral ventricle, brain or subdural space records a
pulsatile pressure of 0–1.3 kPa (0–10 mmHg) relative to the
foramen of Monro when the patient is lying flat. As a mass
or the ventricles enlarge within the skull, the mean
intracranial pressure rises and spontaneous periodic waves
become more pronounced, particularly during rapid eye
movement sleep.
Non-invasive techniques include tympanic membrane
displacement and transcranial doppler studies of the
pulsatility index.

590 591 590, 591 CT brain

scan at the level of the
lateral ventricles (590)
and T1W midline
sagittal MR (591) in a
patient with aqueduct
stenosis. Note the
large ventricles
(obviously longstanding
because there is no
periventricular edema)
with typical shape
(590), the narrowed
inferior aqueduct
(591) (arrowhead)
and the small fourth
ventricle (arrow).
 Hydrocephalus 471

592 593

592–594 Communicating
hydrocephalus. Cranial CT
scans showing dilatation of
the fourth ventricle
(arrowhead) and temporal
horns of the lateral ventricles
(592, arrows), and lateral
ventricles (593, arrows); and
narrowing of the cortical sulci
at the vertex of the brain
(594, arrows).

594 595
595 MRI brain scan,T1W
image, sagittal plane,
showing dilated ventricular
system without focal
obstructive lesion.

596 MRI brain scan,T2W 596 597

image, axial plane, showing
dilated lateral ventricles.

597 CT brain scan showing

marked dilatation of the
lateral ventricles in a patient
with communicating
hydrocephalus of unknown
cause.
472 Disorders of the CSF Circulation
Cognitive function testing
• Mini-mental state examination and other mental
screening tests are often insensitive to slight ‘subcortical’
cognitive impairment.
• Psychometric tests are usually needed, particularly to detect
frontal lobe dysfunction.
TREATMENT
Indication
Neurologically symptomatic, progressive ventriculomegaly.
The presence of ventriculomegaly in the absence of any
supporting clinical features does not mean there is active
hydrocephalus.
Treat underlying cause, if possible
Surgically excise the primary lesion if possible (i.e. papilloma of
choroid plexus, or third ventricular or posterior fossa tumor).
Symptomatic treatment
Reduce CSF production
Carbonic anhydrase inhibitors (with or without
corticosteroids or diuretics).
Facilitate CSF drainage (ventricular decompression with
diversion of CSF flow)
• Transient hydrocephalus (e.g. after subarachnoid
hemorrhage): ventricular or lumbar catheter for
temporary CSF diversion.
• Non-communicating hydrocephalus with patent
subarachnoid space: transventricular, endoscopic third
ventriculostomy, with puncture of the floor of the third
ventricle and drainage of CSF into the basal cisterns.
• Intraventricular or large arachnoid cysts: endoscopic
communication of cyst with normal CSF pathways.
• Infantile hydrocephalus: ventriculoperitoneal or
ventriculoatrial shunt (benefits about 80% of cases): CSF
is drained from the frontal horn of the lateral ventricle
(where there is no choroid to block the catheter) via a
ventricular catheter (a pressure valve with reservoir
mechanism and a distal catheter made of non-reactive
tubing) into the peritoneal or atrial cavity.
• Communicating hydrocephalus (some patients):
lumboperitoneal shunt: drains fluid from the lumbar
subarachnoid space to the peritoneal cavity. These shunts
usually work well for a few months only and, where they
are successful, may be associated with symptomatic
secondary descent of the cerebellar tonsils. Insertion of
a separate ventricular access device at the time of shunt-
ing facilitates investigation should complications arise.
• Normal pressure hydrocephalus (see p.473):
– Removal of 50 ml of CSF may result in improvement in
gait and predict a favorable response to a shunting
procedure.
– Repeated lumbar punctures (LP), removing 15–20 ml
CSF, may give rise to transient improvement in the early
stages of the disease.
– Ventriculoperitoneal shunt may produce dramatic
improvement in some cases. Improvement in post
operative cognitive function is more likely if there was a
known cause, and short history.
Shunt complications
• Shunt failure: 80% of shunts fail within 12 years. The
highest risk of underdrainage is in the first year (30%),
usually due to gradual occlusion of the ventricular
catheters by choroid plexus. A CT brain scan is the best
investigation for suspected underdrainage to compare
with earlier scans.
• Shunt occlusion/blockage causing raised intracranial
pressure.
• Overdrainage: particularly in tall patients. May produce
slit ventricle syndrome, subdural hematomas, encysted
fourth ventricles or post-shunt craniosynostosis.
• Infection of the valve: 70% occur within 1 month of
insertion, often due to contamination at the time of
insertion with Staphylococcus epidermidis. Commonly
presents as intermittent pyrexia with malaise and signs of
shunt obstruction. Occasionally there is cellulitis along
the shunt tract or signs of meningitis. Diagnose by
aspirating CSF from the shunt reservoir. Intrathecal
vancomycin may eradicate the infection but often the
entire shunt system has to be removed, followed by a
period of external ventricular drainage before a new
system can be re-inserted. The morbidity/mortality rate
is 30–40% and survivors risk neurologic deficit.
• Subdural hematoma.
• Low pressure headache.
• Epileptic seizures.
• Shunt nephritis (an immunologically mediated disorder
due to secondary Staphylococcus albus infection).
• Pulmonary thromboembolism with ventriculoatrial shunts.
PROGNOSIS
• Depends on the underlying condition.
• Untreated cases of infantile hydrocephalus develop
necrosis of the scalp with leakage of CSF, infection, and
death. A minority survive to childhood with arrested
hydrocephalus characterized by enlargement of the head,
some degree of intellectual handicap, limb spasticity, and
impaired bladder function.
• 70% of infants with treated non-tumoral hydrocephalus
maintain a normal IQ and attend a normal school.
Children with infantile hydrocephalus should therefore
undergo a shunting procedure (because they will
benefit).
 Normal Pressure Hydrocephalus (NPH)
NORMAL PRESSURE
HYDROCEPHALUS (NPH)
DEFINITION
A chronic hydrodynamic hydrocephalus that occurs in adults
and is associated with a delay in the circulation or absorption
of CSF and progressive neurologic deficit comprising
Hakin’s triad of gait apraxia, urinary incontinence, and
progressive dementia. First described in 1965.
EPIDEMIOLOGY
• Prevalence: about 1 per 20 000 population. About 0–6%
of cases of dementia.
• Age: middle-aged and elderly.
• Gender: M=F.
PATHOLOGY
• Impaired CSF flow within the ventricles or in the
subarachnoid space (arachnoid villi) due to a variety of
possible causes (see below).
• There is no pressure gradient between the ventricles and
the cerebral convexity.
ETIOLOGY AND PATHOPHYSIOLOGY
Uncertain. The following are hypotheses:
Impairment of CSF flow within the ventricles or the
subarachnoid space
• Non-communicating NPH: partial obstruction to CSF
flow (e.g. aqueduct stenosis).
• Communicating NPH: impairment of CSF flow distal to
the fourth ventricle, most often at the level of the basal
cisterns (‘cisternal block’) or arachnoid villi.
Causes
• Idiopathic (at least 30%, probably about 50%).
• Subarachnoid hemorrhage.
• Meningitis.
• Head trauma.
• Intracranial surgery.
• Paget’s disease of the skull.
• Mucopolysaccharidosis of the meninges.
N.B. Idiopathic cases have traditionally been attributed
to defective CSF absorption through the arachnoid villi, but
evidence is lacking. More recently, the theory of a vascular
leukoencephalopathy has been proposed, with the concept
that white matter lesions reduce periventricular tissue
strength and elastic properties and thus predispose the
ventricles to dilate under CSF pulse pressure. Systemic
hypertension is frequently associated with NPH and is
thought to lead to ventricular enlargement because of
decreased CSF absorption due to increased superior sagittal
sinus venous pressure and because of increased
intraventricular pulse pressure from the choroid plexus.
Other possibilities include congenital hydrocephalus
becoming symptomatic in elderly persons and increasing age.
Episodes of slightly raised CSF pressure
473
CLINICAL FEATURES
Classic triad of:
• Slowly progressive gait disorder.
• Impairment of mental function.
• Urinary incontinence.
Gait disturbance
The first, and in some cases only, apparent symptom and
sign:
• Difficulty in initiating walking: feet feel ‘glued to the
floor’, also referred to as a ‘magnetic gait’ or gait apraxia.
• Postural instability.
• A short-stepped shuffling gait in more advances stages,
often described as ‘gait apraxia’ but this term is perhaps
inappropriate in NPH because patients with NPH may
execute nearly intact walking movements when minimally
supported or when lying down.
• Hyperreflexia (mainly in the lower limbs) and extensor
plantar responses may be present but spasticity is not a
feature (tone is usually normal) and objective motor
weakness is seldom present (despite complaints of
weakness and tiredness).
Causes
• Stretching or destruction of the paraventricular
corticospinal fibers.
• Disconnection of basal ganglia from the frontal cortex.
• Uninhibited antigravity reflexes and co-contraction of
agonists and antagonists during walking.
Progressive mental impairment
‘Subcortical’ dementia
• Forgetfulness.
• Inertia.
• Inattention.
• Decreased speed of processing complex information.
• Impaired ability to manipulate acquired knowledge.
• Delayed recall is severely impaired but delayed recog-
nition is only relatively mildly affected or even normal.
Cause
• Compromise of the functional integrity of the frontal
lobes and its connections.
• Unlikely to be caused by enlarged temporal horns and
hippocampal dysfunction.
Urinary urgency and incontinence
• Urgency of micturition: almost always present.
• Urinary incontinence: a late sign.
Cause
Damaged periventricular pathways to the sacral bladder
center, resulting in decreased inhibition of bladder contrac-
tions and hyperreflexia and instability of the bladder
detrusor muscle, without concomitant defective sphincter
control. Urinary incontinence is not due to a so-called
‘incontinence sans gene’ except in the most severe forms,
when bladder hyperreflexia is associated with lack of concern
for micturition, due to severe frontal lobe dysfunction.
Clinical features are probably due to hydrocephalic
compression and stretching of the periventricular arterioles
and venules, leading to a state of ‘misery perfusion’
characterized by diminished periventricular blood flow that
is sufficient to result in axonal dysfunction but not enough
474 Disorders of the CSF Circulation
initially to cause irreversible loss of cellular integrity.
Prolonged periventricular ischemia eventually results in
myelin degeneration and irreversible axonal loss, possibly
explaining why some patients with NPH do not improve
after a shunt. Narrowed periventricular arterioles due to
hyaline vessel wall degeneration in hypertensive patients
might be a predisposing factor, and explain the high
prevalence of vascular risk factors in NPH.
DIFFERENTIAL DIAGNOSIS
Alzheimer’s disease
• May cause a parkinsonian syndrome, and disorder of gait
and balance but usually late in its course when dementia is
severe.
• Cardinal features are memory deficits (particularly encoding
deficits and impaired recognition) with or without aphasia,
apraxia, and agnosia.
• MRI reveals atrophy of the hippocampal body as measured
by a reduction in its mean cross-sectional volume.
Multi-infarct vascular dementia
• Vascular risk factors are prevalent.
• Stepwise decline in function.
• CT or MRI brain scan shows multiple infarcts or
strategically located infarcts or hemorrhages.
Subcortical arteriosclerotic encephalopathy (SAE)
• One cause of vascular dementia.
• The clinical picture may be similar to NPH but often
hypertension and other vascular risk factors are present.
• Periventricular lucencies on cranial CT scan are usually
diffuse (around frontal and occipital horns) but in both SAE
and NPH periventricular lucencies may be selectively located
around the frontal horns.
Obstructive hydrocephalus
• Headache.
• Papilledema may be present.
• CT or MRI brain scan evidence of a lesion obstructing CSF
outflow and dilated ventricles rostral to the obstruction and
normal sized ventricles caudal to it.
Multiple systems atrophy
A combination of parkinsonism, autonomic dysfunction,
cerebellar ataxia and corticospinal tract signs.
Parkinson’s disease
• Usually manifests with asymmetric resting tremor, rigidity,
bradykinesia, postural instability and shuffling gait.
• Symmetric involvement of the legs, early abnormalities of
bladder and sexual function, and a lack of response to
levodopa are uncommon (but common in NPH).
Vitamin B12 deficiency
May cause cognitive decline, gait instability and recurrent falls
but usually there are optic atrophy and signs of a distal symmetri-
c sensory neuropathy as well as corticospinal tract signs.
Cervical myelopathy
May cause leg (and arm) spasticity and bladder and bowel
dysfunction but usually there is leg weakness and a motor
and sensory level.
Cauda equina syndrome
• Can produce gait instability, and bowel, bladder and
sexual dysfunction, but usually there are lower motor
neuron signs in the lower limbs (muscle wasting and
weakness, and hyporeflexia or areflexia) and sensory loss
(usually in a radicular distribution) in the lower limbs.
• Parkinsonism is not present.
INVESTIGATIONS
Neuroimaging with CT and MRI brain scan
• Imaging shows a communicating (non-obstructive)
hydrocephalus with large ventricles, particularly the
temporal horns, out of proportion to any degree of
cortical atrophy (598–600).
• Frontal and occipital periventricular hypodensity,
consistent with transependymal CSF absorption, may
occur but are uncommon in NPH.
• Accentuation of the flow void in the aqueduct of Sylvius
is seen on MRI. N.B.T2W MRI images may show a
‘CSF flow voiding sign’, which consists of a decreased
MRI signal, mainly in the aqueduct, which correlates
with the velocity of pulsatile CSF flow. An increased
aqueduct CSF flow velocity may be associated with
shunt-responsive communicating NPH but there is no
good correlation between a pronounced CSF flow
voiding sign and NPH, and successful shunts do not
necessarily reduce this sign.
• Upward bowing of the corpus callosum and ballooning
of the third ventricular recess are also seen on sagittal
MRI.
• Unfortunately in practice it is very often difficult on
imaging to sort out the elderly atrophic brain from the
dilated ventricles of NPH.
• MRI can be used to measure the mean cross-sectional
volume of the hippocampal body in patients with
substantial global cognitive impairment to help dif-
ferentiate Alzheimer’s disease (in which the hippocampal
body is atrophic) from NPH (in which it is not).
• An isotope study using indium 111-DTPA introduced
into the CSF via an LP may help; in NPH and
communicating hydrocephalus the isotope is said to
reflux into the ventricles and does not accumulate over
the convexities by 24–48 hours after the LP.
Lumbar puncture (LP)
• To confirm the CSF pressure is normal.
• To remove up to 30–50 ml of CSF (enough fluid to
decrease the opening pressure by about 50%) to see if a
transient or, in rare cases, prolonged clinical improve-
ment occurs. This can be assessed in various ways, such
as measuring pre-LP and post-LP gait pattern and time
to walk 10 m (33 ft), and measuring psychometric
function. The ‘CSF tap test’ is easy, rapid and inexpensive
but its predictive accuracy is limited by the high rate of
false negative results.
• Continuous external lumbar drainage of about
150–200 ml daily for 2–5 days may more accurately
predict the outcome of a shunt, even in cases of
‘negative’ CSF tap test. This test is technically simple but
complications such as radicular inflammation and
meningitis may occur and experience with it is small. In
addition, it may not allow for the detection of delayed
improvement after several weeks or months unless
prolonged follow-up takes place.
 Normal Pressure Hydrocephalus (NPH) 475

Cisternography Intracranial pressure monitoring and

CT cisternography, in which the isotope indium 111-DTPA
is introduced into the CSF via an LP, can be used to assess
CSF circulation and may help differentiate Alzheimer’s disease
from NPH; in NPH and communicating hydrocephalus the
isotope is said to reflux into the ventricles (i.e. ‘reversed CSF
flow’) and does not accumulate over the convexities by 24–48
hours after the LP. This is a popular but unreliable predictive
test; the results do not seem to add to the diagnostic accuracy
of combined clinical and CT criteria.
Neuropsychologic assessment
• Mini-mental state examination and other brief mental
screening tests may not be sensitive enough to detect
slight cognitive impairment of the ‘subcortical’ type.
These are the very patients who may have the best
surgical prognosis.
• Psychometric tests that include tests of frontal lobe
function, such as the trail making test and the Stroop
test, will reveal abnormalities even in the early stages of
the syndrome, and serial measures at intervals can be very
sensitive to a subtle decline, such as in cases where shunt
dysfunction is suspected. The test profile may not
differentiate NPH from other subcortical dementias but
it can distinguish them from Alzheimer’s disease by the
absence of cortical dysfunction and the presence of a
‘frontal’ pattern of mental deficit.
hydrodynamic tests
• Continuous intracranial pressure monitoring: may show
physiologic CSF pressure oscillations with a frequency of
0.5–2 per minute (B waves). It has been suggested that
the occurrence of B waves is much increased in shunt-
responsive NPH, sometimes exceeding 50% of the
observation time, but there can be technical problems
with this test and the results remain questionable.
• Lumbar CSF infusion tests: measure the resistance of
CSF outflow (Rout) by lumbar or ventricular infusion of
artificial CSF, and conductance of CSF (Cout, the
reciprocal of Rout), by measuring CSF reabsorption
through constant lumboventricular or ventriculo-
ventricular CSF infusions at different CSF pressures; tests
have produced variable results.
598

Cerebral blood flow (CBF) and metabolism measures

• Single photon emission computed tomography
(SPECT).
• Transcranial doppler (TCD) of the middle cerebral artery.
• Positron emission tomography (PET).

These methods may show decreased CBF and

metabolism, most pronounced in the frontal and
periventricular areas. However, there is no good correlation
between changes in CBF and outcome after CSF diversion.
Perhaps the techniques for measuring CBF are not sensitive
enough to detect subtle changes in the frontal
periventricular areas.

598–600 Plain CT 599 600

brain scan, axial slices,
showing dilatation of
the temporal horns
(598), the third
ventricle (599) and
the lateral ventricles
(600) with
periventricular lucency
and less prominent
dilatation of the
cortical sulci in a
patient with normal
pressure
hydrocephalus.
476 Disorders of the CSF Circulation
In most studies of the accuracy of ancillary tests for
predicting the outcome after shunting there has been a lack of
assessment of the pre-test probability of shunt responsiveness
based on well established clinical, CT and MRI data.
EMG
• EMG may be helpful in cases in which gait impairment
is associated with prominent peripheral nerve or lower
motor neuron signs (e.g. wasting, fasciculations and
weakness of muscles, normal or reduced muscle tone,
loss of reflexes, and altered sensation in a radicular or
peripheral nerve distribution).
Blood tests to be considered
• Vitamin B12.
• Folate.
• Vitamin E.
• Thyroid function tests.
• Liver function tests.
• Rapid plasma reagin (RPR).
• Fasting blood glucose.
• Serum protein electrophoresis.
DIAGNOSIS
A clinical diagnosis primarily, supported by CT or MRI of the
brain and LP.
TREATMENT
Medical
• No effective medical treatment is available.
• Acetazolamide, diuretics and corticosteroids are ineffective,
despite having a role in idiopathic intracranial hypertension
(pseudotumor cerebri), particularly when loss of vision has
not occurred. Steroids are most helpful in reducing
increased ICP from vasogenic edema (that is, tumors).
• CSF evacuation through repeated LP can dramatically
reverse the NPH syndrome, but the success rate is also
highly variable.
Surgical
Techniques
Ventriculoperitoneal or lumboperitoneal CSF diversion/shunt
surgery; ventriculoatrial shunting may be more difficult and
more prone to complications such as arrhythmia and
pulmonary hypertension.
Timing
Best done during the first 2 years after onset of symptoms and
signs.
Responsiveness
• Substantial improvement in about 30% of patients with
idiopathic NPH, and in 50–70% where the etiology is
known.
• Gait disturbance is the most likely symptom to improve after
shunting.
• Surgical mortality and severe residual morbidity rate is
5–15%.
• Post surgical complications are 30–40%.
Predictors of shunt responsiveness
• Short history.
• Known cause of hydrocephalus.
• Gait disorder is the initial and predominant feature.
• Mild or moderate mental impairment, and not dementia.
• Hydrodynamic hydrocephalus suggested by cranial CT or
MRI (e.g. a CSF flow void on MRI).
• Positive CSF tap test: improvement in gait or psychometric
function after draining 30–50 ml of CSF.
• 50–70% of patients with these features will do well after
surgery.
Predictors of shunt non-responsiveness
• Dementia for >2 years.
• Onset of dementia before gait abnormality.
• Alcohol abuse.
• Aphasia.
• Substantial cortical atrophy and white matter involvement
suggested by cranial CT or MRI.
Complications/morbidity
• Surgical mortality and severe residual morbidity rate: 5–15%.
• Post surgical complications are 30–40%, mostly due to intra-
cranial hemorrhage and extracranial infection, which fre-
quently necessitate shunt removal and revision (see p.472).
Less common complications include seizures and ischemic
stroke.
Predictors of shunt complications/morbidity
• Elderly.
• Initial symptoms are mental impairment of urinary
incontinence.
• The complication rate exceeds 25% in these patients.
Summary of management
Management remains very difficult because of difficulties with
diagnostic criteria and limited evaluation of therapeutic
techniques by means of randomized trials. As a result,
knowledge about prognosis, response to shunting, and
predictors of a favorable and unfavorable response to shunting
is minimal. In turn, practice remains haphazard and ranges
from therapeutic nihilism to shunting nearly every patient with
suspected NPH. Most patients appear to have a real but limited
chance of improvement after a shunt based on clinical and brain
imaging features. The ratio of substantial benefit and serious
harm may be deceptively low. Consequently, caution and
reserve are required before labelling idiopathic communicating
NPH as a reversible dementia.
Following clinical assessment, cranial CT or MRI scan, and
a CSF tap test, if there is any doubt about what to do next, we
would recommend continuous external lumbar drainage for
4–5 days and shunting only those patients with considerable
clinical improvement who are fit and willing to accept the
potential risks of shunt surgery.
A randomized controlled trial comparing the effect of
shunting plus best medical therapy with best medical therapy
alone on long term outcome (death, cognitive function, gait,
urodynamics and handicap) is required.
PROGNOSIS
The natural history is usually progressive deterioration. CSF
shunting carries a success rate ranging from 25–80%, depending
on patient selection and surgical skill and care.
 Idiopathic Intracranial Hypertension (IIH) 477

IDIOPATHIC INTRACRANIAL Unconfirmed

HYPERTENSION (IIH) (BENIGN • Systemic diseases:
INTRACRANIAL HYPERTENSION, – Chronic renal failure.
PSEUDOTUMOR CEREBRI) – Systemic lupus erythematosus.
• Endocrine diseases:
– Adrenal insufficiency (Addison’s disease).
DEFINITION – Cushing’s disease.
A syndrome characterized by intracranial hypertension and – Hypoparathyroidism.
papilledema, normal sized cerebral ventricles, a normal CSF – Hypothyroidism.
composition, and no focal neurologic signs or evidence of • Thrombophilia (prothrombotic abnormalities):
a space-occupying lesion, an underlying infective process or – Polycythemia.
obstruction to CSF flow. – Thrombocytosis.
– Antiphospholipid antibodies.
EPIDEMIOLOGY – Hyperfibrinogenemia.
Incidence: – Antithrombin III deficiency.
– 0.9 per 100 000 per year. • Medication:
– 1.6 per 100 000 females per year. – Tetracycline.
– 3.3 per 100 000 women aged 15–44 years. – Minocycline.
– 7.9 per 100 000 overweight women. – Trimethoprim-sulfamethoxazole.
– 20 per 100 000 in overweight women aged 15–44 years. – Cimetidine.
• Age: adults 15–45 years of age predominantly; – Nalidixic acid.
adolescents, children, and infants with open fontanelles – Nitrofurantoin.
may also be affected. – Corticosteroids.
• Gender: F>M = 8:1 among adults; F=M in childhood – Tamoxifen.
and adolescence. – Lithium.
– Danazol.
PATHOLOGY – Levothyroxine.
Edema of the brain is present with ventricles of normal size. – Isotretinoin.
There is no obvious obstruction to CSF flow nor – Nasal fluticasone propionate (for hay fever)
abnormality of its content and no intracranial mass. Cerebral
vein thrombosis may be present, and may be secondary to CLINICAL FEATURES
compression of cerebral veins by the raised intracranial • Child or young woman of reproductive age usually.
pressure, rather than the primary cause of the raised • Obese (70%) or recent weight gain.
intracranial pressure. • Alert and generally well.
• Menstrual irregularities may be present.
ETIOLOGY AND PATHOGENESIS • A history of systemic or endocrine disease, or recent
Uncertain. Two fundamental defects of obscure origin: medication use (see above) may be present.
• Reduced CSF absorption at the level of the arachnoid
villi. Symptoms
• Increased brain intraparenchymal water: vasogenic brain • Headache (94%):
edema. – No specific site; usually generalized.
– Aching and throbbing.
Intracranial venous pressure is increased, probably due – Mild/dull.
to the raised intracranial pressure rather than venous sinus – Worse in the morning and may awaken the patient from sleep.
thrombosis being the underlying cause. Although some of – Aggravated by head movement, sitting up or standing, alco-
the risk factors for IIH (see below) are also possible risk hol, exertion, coughing, straining, sneezing and vomiting.
factors for cerebral vein thrombosis (e.g. thrombophilia), it – Relieved by lying down, and by aspirin or paracetamol
is possible that they are confounding factors, due to (in contrast to psychogenic headache).
misdiagnosis of true cases of venous sinus thrombosis as – Associated with nausea, vomiting and eventually papill-
IIH. Irrespective, IIH is probably a heterogeneous entity. edema.
In some patients there may be just one cause, such as • Transient visual obscurations or blurring of vision occurs,
venous sinus thrombosis, or severe obesity, and others may precipitated by activities, such as stooping over, straining,
have multiple risk factors which combine to precipitate IIH. and coughing, which further increase the intracranial
pressure sufficient to compromise the retinal and optic
Risk factors nerve circulation (68%).
Confirmed • Pulsatile intracranial noises (58%).
• Female gender. • Double vision (38%).
• Reproductive age group. • Visual loss (30%).
• Menstrual irregularity. • Retrobulbar pain on eye movement (22%).
• Obesity. • Minor symptoms may include: neck tenderness and
• Recent weight gain. stiffness, tinnitus, paresthesiae in the limbs distally, joint
pains, low back pain and intermittent ataxia.
• Irritability, drowsiness and apathy may be warning signals
of IIH in children.
478 Disorders of the CSF Circulation
Signs
• Papilledema (601–605) is seen, with its resultant con-
centric constriction of the visual fields (30%), enlarged
physiologic blind spots, and perhaps inferior nasal field
defects (15%), arcuate defects, cecocentral scotomas, and
vision loss: usually bilateral but may be unilateral or
highly asymmetric.
• VIth cranial nerve paresis may occur as a false localizing
sign of raised intracranial pressure.
• Other focal neurologic signs such as VIIth cranial nerve
palsy and long tract involvement have been attributed to
IIH, but they are distinctly atypical.
• Patients are alert with no other focal neurologic signs (in
contrast to patients with raised intracranial pressure,
sufficient to cause papilledema, due to an expanding
lesion).
DIFFERENTIAL DIAGNOSIS
• Venous sinus thrombosis: a distinctive diagnostic
category:
– Transverse, lateral or superior sagittal sinus thrombosis.
– Jugular vein obstruction.
– Superior vena cava obstruction.
– Right heart failure.
• Occult mass lesion: gliomatosis cerebri (widely
disseminated glioma).
• Papilledema: normal CT/MRI, abnormal CSF:
– Guillain–Barré syndrome.
– Cryptococcal meningitis.
– Carcinomatous meningitis.
– Chronic brucellosis.
– Cysticercosis.
– Neurosarcoidosis.
– Poliomyelitis.
• Pseudopapilledema: anomalous elevation of the optic
nerve head:
– Hyperopia.
– Optic nerve drusen: can also cause transient visual
obscurations and a progressive optic neuropathy rarely.
• Headache:
– Tension headache.
– Mixed migraine/tension headache.
INVESTIGATIONS
CT and MRI scan of the brain
The ventricles are either normal size or small with a slit-like
third ventricle and diminished basal cisterns (606, 607).
This may be difficult to recognize in individual cases,
therefore the main reason for imaging is to (1) exclude
other causes of the patient’s symptoms such as tumor
masses, and (2) to exclude cerebral venous sinus thrombosis
(see p.257 for imaging of venous sinus thrombosis).
Common associated features are an ‘empty sella syndrome’
(55% of scans), a prominent cisterna magna, and thickened
optic nerve sheaths.
CSF
• Opening pressure: elevated, >25 cm (>250 mm) of
water.
• Cell count: normal.
• Protein: normal or low.
• Glucose: normal.
MRI/MRA (magnetic resonance angiography) or
digital subtraction angiography
To exclude venous sinus thrombosis.
Other
• Serial visual field perimetry: monitor.
• Serial stereoscopic ocular fundus photographs or indirect
ophthalmoscopy.
• Fluorescein angiography: usually leaks diffusely with
papilledema but leaves discrete spots of late focal
fluorescein with drusen.
Blood tests
• Full blood count.
• Urea and electrolytes.
• Calcium.
• Thyroid function tests.
• Antinuclear and antiphospholipid antibody.
• Fibrinogen.
• Factor V Leiden gene mutation.
Snellen acuity, confrontational visual fields, direct
ophthalmoscopic assessment of the degree of papilledema,
and visual evoked responses are insensitive and less useful in
the follow-up of visual loss.
DIAGNOSIS
Modified Dandy’s diagnostic criteria
• Symptoms and signs of increased intracranial pressure
(e.g. papilledema).
• No localizing focal neurologic signs, in an awake and
alert patient, other than occasional abducens nerve
paresis.
• Normal neuroimaging studies (enhanced CT or MRI
brain scan) except for small ventricles or empty sella.
• Documented increased opening pressure (250 mm of
water or more) but a normal composition of the CSF.
• Primary structural or systemic causes of elevated
intracranial venous sinus pressure excluded (e.g. venous
sinus thrombosis, hyperviscosity syndromes and right
heart failure).
• Benign clinical course apart from visual deterioration.
601
601 Normal optic disk.
 Idiopathic Intracranial Hypertension (IIH) 479

602 603

602 Early mild papilledema. (601–605, courtesy of Mr M Wade, 603 Severe papilledema. Note the pinkish congested disc, indistinct
Department of Medical Illustrations, Royal Perth Hospital,Western disc margin, elevation of the optic nerve head, filling-in of the optic cup,
Australia.) and distension of the retinal veins.

604 605

604, 605 Right (604) and left (605) optic fundus of a patient with bilateral papilledema due to idiopathic intracranial hypertension.

606 607

606, 607 CT brain scan (606) and T2W axial MRI (607) in a patient with idiopathic intracranial hypertension.
Note the small third and lateral ventricles but otherwise normal appearing brain.
480 Disorders of the CSF Circulation

COMPLICATIONS Pharmacologic
Visual loss • Acetazolamide (Diamox), a carbonic anhydrase inhibitor
• 15–50% of patients. which inhibits CSF production: start with oral dose of
• May occur early or late. 250 mg four times a day and increase to 500 mg four
• May be sudden or gradually progressive. times daily unless adverse effects develop (paresthesias,
• May be asymptomatic. drowsiness, nausea, malaise, metabolic acidosis, altered
• Visual loss is probably due to a nerve conduction defect taste, and renal calculi).
related to the status of axoplasmic flow found in • Other diuretics: chlorthalidone 100 mg oral, daily; fruse-
papilledema. It is avoidable with appropriate monitoring mide (furosemide), glycerol (but may cause weight gain).
and treatment. • Corticosteroids: prednisone 40–60 mg/day for 10–14
days, and taper over the next 2 weeks.
PROGNOSIS • Anticoagulation if a secondary venous sinus thrombosis
• Not well known. is present.
• Often self-limiting; many people recover spontaneously
in a few weeks and most people experience spontaneous Surgical
resolution in 6–18 months, but it is a chronic process in If vision loss is severe initially or progresses in spite of
some. medical treatment:
• Optic nerve sheath decompression by fenestration is the
TREATMENT treatment of choice as it is reasonably safe with very few
Early detection and prevention of vision loss complications.
Medical • Lumboperitoneal shunting (the insertion of a shunt from
• Avoid or correct predisposing factors (see above): weight the spinal subarachnoid space to the peritoneum) has a
reduction if obese. higher risk of complications and failure.
• Serial LPs: if symptoms persist after initial LP perform
3–4 LPs within the first 2–4 weeks; further LPs are
unlikely to help.

FURTHER READING IDIOPATHIC INTRACRANIAL Radhakrishnan K, Ahlskog E, Garrity JA, Kurland

NORMAL PRESSURE HYDROCEPHALUS
(NPH)
Chen IH, Huang CI, Liu HC, Chen KK (1994)
Effectiveness of shunting in patients with nor-
mal pressure hydrocephalus predicted by tem-
porary, controlled-resistance, continuous lum-
bar drainage: a pilot study. J. Neurol. Neuro-
surg. Psychiatry, 57: 1430–1432.
Evidente VH, Gwinn KA (1997) 73-year-old man
with gait disturbance and imbalance. Mayo
Clin. Proc., 72: 165–168.
Graff-Radford NR (1999) Normal pressure hy-
drocephalus. The Neurologist, 5: 194–204.
Pleasure SJ (1999) Ventricular volume and trans-
mural pressure gradient in normal pressure hy-
drocephalus. Arch. Neurol., 56: 1199–1200.
Vanneste JAL (1994) Three decades of normal
pressure hydrocephalus: are we wiser now? J.
Neurol. Neurosurg. Psychiatry, 57: 1021–1025.
HYPERTENSION (IIH) LT (1994) Idiopathic intracranial hypertension.
Bond DW, Charlton CPJ (2001) Benign intracra- Mayo Clin. Proc., 69: 169–180.
nial hypertension secondary to nasal fluticasone Walker RWH (2001) Idiopathic intracranial hy-
propionate. BMJ, 322: 897. pertension: any light on the mechanism of the
Brazis PW, Lee AG (1998) Elevated intracranial raised pressure? J. Neurol. Neurosurg. Psychia-
pressure and pseudotumor cerebri. Curr. Opin. try, 71: 1–7.
Ophthalmol., 9: VI:27–32.
Digre KB, Corbett JJ (2001) Idiopathic intracra-
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reappraisal. The Neurologist, 7: 2–67.
Go KG (2000) Pseudotumour cerebri. Incidence,
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ogy, 45: 2224–2228.
 Chapter Eighteen
Cranial
Neuropathies
OLFACTORY (IST CRANIAL NERVE)
NEUROPATHY
DEFINITION
Disorder of the Ist cranial, or olfactory, nerve resulting in a
disturbance of smell sensation (anosmia).
ANATOMY
• Nerve fibers subserving the sense of smell have their cells
of origin in the mucous membrane of the upper and
posterior parts of the nasal cavity.
• The olfactory mucosa contains three types of cells:
– Olfactory or receptor cells.
– Sustentacular or supporting cells.
– Basal cells, which are stem cells and the source of both
olfactory (receptor) cells and sustentacular cells during
regeneration.
• The olfactory or receptor cells are bipolar neurons that
each have a peripheral process (the olfactory rod), from
which project 10–30 fine hairs, or cilia, and several
central processes (or olfactory filia) which are fine
unmyelinated fibers that converge to form small fascicles
enwrapped by Schwann cells and pass through openings
in the cribriform plate of the ethmoid bone into the
olfactory bulb. Collectively, the central processes of the
olfactory receptor cells constitute the Ist cranial, or
olfactory, nerve.
• In the olfactory bulb, the axons of the receptor cells
synapse with mitral cells, the dendrites of which form
brush-like terminals or olfactory glomeruli.
• The axons of the mitral cells enter the olfactory tract,
which courses along the olfactory groove of the
cribriform plate to the brain.
• The olfactory tract divides into medial and lateral
olfactory striae. The medial striae contains fibers from
the anterior olfactory nucleus which pass to the opposite
side via the anterior commissure. Fibers in the lateral
striae originate in the olfactory bulb, give off collaterals
to the anterior perforated substance, and terminate in the
medial and cortical nuclei of the amygdaloid complex
and the prepiriform area (the lateral olfactory gyrus). The
latter represents the primary olfactory cortex, which
occupies a restricted area on the anterior end of the
hippocampal gyrus and uncus (area 34 of Brodmann).
481
• Thus, olfactory impulses reach the cerebral cortex
without relay through the thalamus; a unique feature
among the sensory systems.
• From the prepiriform cortex, fibers project to the
neighboring entorhinal cortex (area 28 of Brodmann),
the medial dorsal nucleus of the thalamus, and the
hypothalamus.
• Olfactory stimuli and emotional stimuli are thus strongly
linked, as a result of their common roots in the limbic
system. Yet, the ability to recall an odor is nowhere near
as good as the ability to recall sounds and sights.
PHYSIOLOGY
• During quiet breathing, little of the air entering the
nostril reaches the olfactory mucosa; sniffing carries the
air into the olfactory crypt.
• To be perceived as an odor, an inhaled substance must
be volatile – i.e. spread in the air as very small particles,
and soluble in water or lipid.
• Intensity of olfactory sensation is determined by the
frequency of firing of afferent neurons.
• Quality of odor is probably determined by ‘cross fiber’
activation, since the individual receptor cells are
responsive to a wide range of odors and exhibit different
types of responses to stimulants.
ETIOLOGY
Nasal
Odorants do not reach the olfactory receptors
Nasal obstruction or inflammation (rhinitis) is by far the
most common cause.
Olfactory neuroepithelial
Destruction of receptors or their axon filaments
Congenital absence or hypoplasia of primary receptor
neurons:
• Kallman syndrome (congenital anosmia and hypogon-
adotropic hypogonadism).
• Albino.
482 Cranial Neuropathies

Disruption of the delicate filaments of the receptor cells as • Bilateral anosmia:

they pass through the cribriform plate: – Nasal obstruction or inflammation (rhinitis).
• Head injury, particularly if severe enough to cause skull – Hysteria.
fracture (608). Less common with closed head injury.
The damage may be unilateral or bilateral. Qualitative abnormalities of olfaction
• Cranial surgery. Distortions or illusions of smell (dysosmia or parosmia)
• Subarachnoid hemorrhage. • Local nasopharyngeal conditions (e.g. empyema of the
• Chronic meningitis. nasal sinuses).
• Depression.
Central
Olfactory pathway lesions Olfactory hallucinations or delusions
• Inferior frontal tumor compressing the olfactory tracts • Temporal lobe disease: complex partial seizures, anterior
(e.g. olfactory groove meningioma). temporal lobectomy.
• Large aneurysm of the anterior cerebral or anterior • Psychiatric disease: schizophrenia, depression.
communicating artery.
• Anterior meningoencephalocele (CSF rhinorrhea may be Loss of olfactory discrimination
present in certain head positions). • Alcoholics with Korsakoff ’s psychosis (degeneration of
• Meningitis. neurons in the higher order olfactory systems of the
• Refsum’s disease (hereditary ataxic neuropathy). medial temporal and thalamic regions).
• Sarcoidosis. • Temporal lobe disease: complex partial seizures, anterior
temporal lobectomy.
Parkinson’s disease
Reduced odor recognition
Multiple sclerosis • Alzheimer’s disease.
• Huntington’s disease.
Idiopathic
Usually bilateral but can be unilateral. INVESTIGATIONS
Determined by the clinical findings:
CLINICAL FEATURES • CT or MRI brain scan.
• Smell should be tested with an aromatic odor, such as an • CSF examination.
orange or cordial bottle top, and not with an acrid odor, • EEG.
such as ammonia.
• Associated signs, such as unilateral optic atrophy and TREATMENT
contralateral papilledema (Foster–Kennedy syndrome) Remove the underlying cause, if possible.
may be present in conditions such as olfactory groove
meningioma which extends posteriorly to involve the PROGNOSIS
ipsilateral optic nerve and also causes raised intracranial Depends on the cause. Anosmia due to head injury causing
pressure and papilledema. skull fracture is usually permanent. Anosmia due to closed
head injury recovers in about one-quarter of patients.
Quantitative abnormalities of olfaction
Bilateral loss or reduction of the sense of smell
(anosmia, hyposmia) 608 608 Ventral
Commonly, but not always, recognized by the patient. It surface of the
may present as impaired taste. Indeed, the patient with frontal lobes of
bilateral anosmia is usually convinced that the sense of taste the brain at
has been lost as well (ageusia), because taste depends largely autopsy showing
on the volatile particles in foods and beverages, which reach disruption of the
the olfactory receptors through the nasopharynx, and the olfactory nerves
perception of flavor is a combination of smell and taste. bilaterally
However, these patients are able to distinguish the (arrows) due to
elementary taste sensations (sweet, sour, bitter and salty). traumatic brain
injury.
Unilateral loss or reduction of the sense of smell
(anosmia, hyposmia)
Seldom, if ever, recognized by the patient.

DIFFERENTIAL DIAGNOSIS
Quantitative abnormalities of olfaction
Loss or reduction of the sense of smell (anosmia, hyposmia)
• Unilateral anosmia. Hysteria: anosmia, if unilateral, may
be on the same side as other symptoms such as anesthesia,
blindness or deafness. Hysterical anosmics don’t usually
complain of loss of taste whereas true anosmics do, but
actually show normal taste sensation on testing.
 Optic (IInd Cranial Nerve) Neuropathy
OPTIC (IIND CRANIAL NERVE)
NEUROPATHY
DEFINITION
Disorder of the optic (IInd cranial) nerve.
EPIDEMIOLOGY
Quite common.
ANATOMY
Nerve fibers from retinal nerve cells lying on the choroid at
the back of the eye come straight forward and then angle
sharply to run across the surface of the retina towards the
optic nerve head (optic disc) where they enter the optic nerve.
The macula, situated to the temporal side of the optic nerve
head, is the most critical part of the retina because it is
responsible for central vision. It consists of a very densely
packed mass of cells. These nerve cells are particularly sensitive
to a variety of toxins and, if damaged, lead to a centrocecal
scotoma. Fibers from the macula form the papillomacular
bundle as they shift sideways en mass and enter the temporal
half of the optic disc. As they pass backwards along the optic
nerve, they gradually becoming more central.
At the optic chiasm the fibers in the lateral half of the
optic nerve, coming from the lateral (temporal) half of the
retina, pass straight back into the optic tract on the same
side. The fibers in the medial half of the optic nerve, coming
from the medial (nasal) half of the retina cross (decussate)
in the chiasm and pass back into the optic tract on the
opposite side. However, before doing so, the fibers from the
inferior nasal retina (receiving visual information from the
upper temporal field), having crossed the anterior inferior
optic chiasm, then loop forwards into the posterior part of
the opposite optic nerve before turning back to pass in the
lateral chiasm and optic tract. Consequently, pressure in the
posterior optic nerve can cause not only an ipsilateral blind
eye but also a small defect in the upper temporal field of the
opposite eye (the anterior chiasmal syndrome). The function
of the chiasm is to bring the information from the halves of
each retina that look to the right and the halves of each
retina that look to the left together in the same optic tract.
In the optic tract the fibers serving the identical point of
each of the two retinae have to come together. The fibers in
the anterior part of the optic tract rotate inwards through 90°,
which brings the fibers in the lower and upper fields together
in the medial and lateral halves of the tract respectively. In the
posterior part of the optic tract the fibers fan out towards the
six layers of the geniculate body, allowing the adjacent fibers
from each retina to interdigitate. The macula fibers occupy a
large central wedge of the geniculate body, with the lower
fields being represented medially and the upper fields laterally.
483
Fibers from the lateral geniculate body sweep into the
hemisphere in two fan-shaped projections, which later come
together at the occipital cortex.
The lower fibers of the optic radiation (subserving the
contralateral upper visual field) sweep forward into the
anterior temporal lobe as Meyer’s loop. The upper fibers of
the optic radiation (subserving the contralateral lower visual
field) follow a more direct route back into the parietal lobe.
All fibers then sweep back in the deep white matter of the
occipital lobe and terminate in the calcarine (visual) cortex
astride the calcarine fissure.
The cells subserving the upper visual fields (i.e. lower
retinae) lie in the lower half of the calcarine cortex, and those
subserving the lower fields (i.e. upper retinae) are in the upper
half of the cortex. The cells subserving the peripheral
(temporal) visual fields are represented anteriorly (hence the
finding of a temporal crescent visual field defect with an
anterior striate cortex lesion), and those subserving macular
vision are concentrated at the extreme tip of the occipital
lobe. The longitudinal extent of the calcarine cortex is impor-
tant in permitting striking localized visual field defects that
may occur as a result of lesions (usually vascular) in this area.
ETIOLOGY AND PATHOPHYSIOLOGY
Optic nerve lesion
Optic nerve: unilateral
Sudden monocular visual failure:
• Ischemia: ischemic optic neuropathy (see p.487).
• Demyelination: optic neuritis (see p.488).
• Cavernous sinus thrombosis.
• Carotico-cavernous fistula.
Progressive monocular visual failure:
• Optic neuritis.
• Tumor of the orbit or optic nerve: optic nerve
astrocytoma, optic sheath meningioma.
• Dysthyroid eye disease.
• Paget’s disease of the skull: obstruction of foramina
leading to optic atrophy.
• Anterior communicating artery aneurysm: compression
of optic nerve.
• Irradiation.
• Tolosa–Hunt syndrome.
• Meningovascular syphilis.
• Subacute and chronic meningitis.
Optic nerve (bilateral) or optic chiasm
Sudden binocular visual failure:
• Bilateral ischemic optic neuropathy.
• Pituitary apoplexy.
• Raised intracranial pressure causing bilateral severe
papilledema.
484 Cranial Neuropathies
Progressive binocular visual failure:
• Bilateral optic neuritis.
• Leber’s hereditary optic atrophy.
• Adrenoleukodystrophy.
• Metachromatic leukodystrophy.
• Compression/infiltration: pituitary adenoma; cranio-
pharyngioma; meningioma of tuberculum sellae, olfac-
tory groove, or sphenoid wing; epidermoid/dermoid
tumor; carotid siphon or ophthalmic artery aneurysm,
chordoma of the clivus; nasopharyngeal carcinoma;
metastatic carcinoma; sarcoid granuloma.
• Nutritional deficiency: vitamins B1 and B12 (usually
centrocecal scotoma).
• Toxins: alcohols and glycerols (glycerins; e.g. methyl
alcohol), heavy tobacco consumption, mercury,
clioquinol, iodoquinol, chronic cyanide poisoning.
• Drugs: amiodarone, chloramphenicol, chloroquine,
desferrioxamine (deferoxamine), ethambutol, quinine.
• Systemic disorders: sarcoidosis, dysthyroid eye disease.
• Subacute and chronic meningitis (e.g. tuberculosis,
syphilis, fungal).
• Malignant meningitis.
• Irradiation.
• Primary hypothyroidism (causing pituitary enlargement).
N.B. The chiasm is not affected by ischemia because it
has a very extensive blood supply from many small arteries.
CLINICAL FEATURES
• Visual failure and field defects, which may be monocular
or binocular, sudden or gradual in onset, and transient
or persistent.
• The diagnosis and localization of the etiologic lesions
requires a detailed examination of the visual acuity, visual
fields, pupils, fundi and the first six cranial nerves, along
with the eye itself and for any general neurologic and
medical disorders.
Optic nerve lesion
Visual acuity
• Reduced visual acuity in the visual field of the ipsilateral
eye, which is usually noticed early by the patient.
• Tested with a Snellen chart and, if necessary, with
correction for refractive errors with lenses/spectacles or
a pinhole. Normally the visual acuity is 6/6 in each eye,
or better (i.e. 6/5 or 6/4).
Color vision
• Important for detecting lesions of the pregeniculate optic
pathway, which characteristically compromise ability to
detect a red object. For example, the earliest evidence of
a pituitary lesion may be a bitemporal hemianopia
specifically to a red object. Similarly, an optic tract lesion
may produce an incongruous hemianopic defect to red.
If the patient has impaired visual acuity but can still
detect a red object then a pregeniculate pathway lesion
is unlikely.
• The standard test is Ishihara color plates but those
patterns requiring accurate perception of red are of
particular value in neurology. A red hat pin can
sometimes therefore suffice.
Visual fields
• Tested at the bedside by confrontation testing. Routine
screening is usually performed with a 10 mm (0.4 in)
white hat pin (or fingers); a 10 mm (0.4 in) red hat pin
is useful when a compressive lesion of the optic nerve,
optic chiasm or optic tract is suspected; and smaller pins
(5 mm [0.2 in]) are useful for detecting small scotomata
(small field defects) in the centre of the visual fields.
More sophisticated tests include the Amsler chart,
Tangent (Bjerrum) screen testing and Goldman
perimetry.
• Ipsilateral scotoma: usually central, but sometimes
centrocecal (embracing the blind spot); or:
• Complete monocular blindness.
– An associated upper temporal field defect in the
contralateral eye may be present with retro-orbital optic
nerve lesions that involve some of the nasal crossing
fibers from the other eye in the anterior optic
chiasm/posterior optic nerve.
• Bilateral centrocecal scotoma are suggestive of bilateral
optic neuropathies due to toxins and drugs.
Pupils
• Abnormal (delayed or less intense) direct response to
light (i.e. impaired afferent arc of the reflex) but intact
consensual response (preserved efferent arc). This
commonly manifests as an afferent pupillary defect
(Marcus Gunn pupil) (see p.575).
• A normal response to light occurs with blindness that is
caused by lesions posterior to the lateral geniculate body
(e.g. bilateral occipital lobe disease [cortical blindness]
or hysteria/malingering) because the afferent arc of the
pupillary reflex leaves the optic tract just before the lateral
geniculate body, and goes on its way to the midbrain,
and then to the pupil.
Fundi (609)
• May show features of the underlying cause (e.g. optic
neuritis, see p.489) or the sequelae of the cause (e.g.
optic atrophy, papilledema).
• Atrophy/degeneration of the optic nerve due to
traumatic transection, demyelination, syphilis, Leber’s
hereditary optic atrophy, or a tumor of the nerve usually
causes the optic disc to appear chalk white with sharp,
clean margins (610).
• Atrophy/degeneration of the optic nerve due
to/following papillitis or papilledema usually causes the
optic disc to appear a pallid, yellow-gray color with
irregular and indistinct margins, and partial obscuration
and sometimes sheathing of the vessels.
 Optic (IInd Cranial Nerve) Neuropathy
Optic chiasm lesion
Visual fields
• Initially the crossing fibers tend to be affected first,
resulting in a bitemporal hemianopia that is lower if the
upper chiasm is compressed (e.g. by a craniopharyn-
gioma) and upper if the lower chiasm is compressed (e.g.
by a pituitary adenoma).
• Later, the visual field defect expands to become a
complete bitemporal hemianopia, which may remain
unnoticed by the patient, or only cause vague symptoms
such as difficulty with close work, vertical splitting of
images and double vision.
• The bitemporal hemianopia may be quite asymmetric,
incongruous, or spare the peripheral field (i.e.
scotomatous bitemporal hemianopia), but the midline
vertical division between the normal nasal and abnormal
temporal fields is definite, albeit sometimes subtle and
only detectable with a red target.
• Eventually, involvement of the uncrossed temporal fibers
leads to expansion of the visual field defect across the
midline to also involve the nasal field, and the reduction
in visual acuity is then noticed by the patient, sometimes
rather suddenly.
• An ipsilateral nasal field defect may very occasionally be
seen due to lateral compression of the chiasm (e.g. from
a carotid aneurysm).
Optic tract and lateral geniculate body lesion
• Rare.
• Incongruous homonymous hemianopia.
609
609 Ophthalmoscopic view of a normal optic fundus showing a
healthy optic nerve head, retina, and retinal vessels.
485
Optic radiation lesion
• Congruous homonymous hemianopia involving central
vision results if the whole radiation is involved
(proximally by a small lesion near its origin or distally by
a large lesion such a stroke or tumor).
• Upper temporal homonymous quadrantanopia results if
only the lower fibers are affected: temporal lobe lesions.
• Lower temporal homonymous quadrantanopia results if
only the upper fibers are affected: parietal lobe lesions.
Occipital cortex lesion
Unilateral
Homonymous hemianopia occurs with or without macular
sparing. If the macular is ‘split’ the patient may complain of
seeing ‘half of things’.
Bilateral
• Cortical blindness occurs bilaterally and may be ignored
or denied by the patient.
• Upper or lower altitudinal visual field defect occurs in
both eyes if only the lower or upper calcarine cortex is
involved.
• Tunnel (tubular) vision occurs due to macular sparing if
the occipital pole is spared.
• Bilateral central scotoma occurs if only the occipital poles
are involved.
SPECIAL FORMS
• Anterior ischemic optic neuropathy (see p.487).
• Optic neuritis (see p.489).
• Leber’s hereditary optic neuropathy (see p.491).
• Optic nerve tumor (see p.372).
610
610 Optic atrophy, showing a white optic disc with sharp, clear
margins.
486 Cranial Neuropathies

DIFFERENTIAL DIAGNOSIS • Optic radiation:

Impaired visual acuity in one eye (monocular) – Stroke.
Reduced visual acuity (corrected) indicates a lesion of the – Tumor.
eye (cornea, lens, vitreous, retina), optic nerve, or optic • Occipital lobes:
chiasm. Visual acuity is not commonly affected by lesions of – Bilateral parieto-occipital infarction due to profound
the optic tract, optic radiation and visual cortex in the hypotension/anoxia.
occipital lobe, and, if it is, it is binocular. – Bilateral occipital infarction due to vertebrobasilar
thromboembolism.
Transient – Vertebral angiography.
• Eye: glaucoma. – Head injury.
• Retina: • Other: hysteria and malingering.
– Ischemia (amaurosis fugax).
– Migraine. INVESTIGATIONS
• Orbit: tumor. • Formal visual field testing.
• Optic nerve: demyelination: Uhthoff’s phenomenon. • Visual evoked potentials.
• Posterior optic nerve/anterior optic chiasm: hemorrhage: • MRI or CT scan of the orbits and sinuses, pituitary fossa,
arteriovenous malformation (chiasmal apoplexy). and brain.
• Other: hysteria and malingering. • Fluorescein angiography (611).
• CSF examination.
Persistent • Full blood count and ESR.
• Eye: • Fasting blood glucose.
– Cataract. • Thyroid function tests.
– Vitreous hemorrhage. • Autoantibody screen.
– Glaucoma. • Mitochondrial DNA.
• Retina: • Syphilis serology.
– Infarction: arterial or venous (central or branch artery or • Chest x-ray.
vein). • Cerebral angiography.
– Hemorrhage.
– Macular disease (e.g. senile macular degeneration): visible DIAGNOSIS
with an ophthalmoscope. Clinical, electrophysiologic and radiologic.
– Chorioretinitis: cytomegalovirus, toxoplasma infection.
• Orbit: TREATMENT
– Tumor. Determined by the cause.
– Suppuration, fungal infection (orbit or paranasal sinuses):
mucomycosis. PROGNOSIS
• Optic nerve/anterior optic chiasm (see above). Depends on the cause.
• Central: amblyopia due to a congenital squint.

Impaired visual acuity in both eyes (binocular)

Transient
• Bilateral occipital lobe ischemia: vertebrobasilar transient
ischemic attack.
• Migraine.
• Vertebral angiography.
• Systemic hypotension.
• Head injury.
• Raised intracranial or intraorbital pressure causing
bilateral papilledema; 611
Persistent
• Eye:
– Cataract.
– Glaucoma.
• Retinal:
– Infarction.
– Hemorrhage.
– Diabetic retinopathy.
– Macular disease (e.g. senile macular degeneration): visible
with an ophthalmoscope.
– Toxins: tobacco, alcohol, ethambutol, amiodarone,
isoniazid, chloramphenicol, iodoquinol.
– Retinitis pigmentosa (ultimately leads to optic atrophy).
• Optic nerve and chiasm demyelination, tumor. 611 Fluorescein angiogram of a normal optic fundus, showing no
• Optic tract: middle cranial fossa tumor. leakage of contrast material from the vessels.
 Anterior Ischemic Optic Neuropathy (AION) 487

ANTERIOR ISCHEMIC OPTIC Examination

NEUROPATHY (AION)
DEFINITION
Anterior ischemic optic neuropathy is an acute ischemia of
the anterior portion of the optic nerve.
EPIDEMIOLOGY
• Incidence: 10 per 100 000 per year (non-arteritic).
• Age: 11–91 years, but typically over 50 years of age.
• Gender: M=F.
PATHOLOGY
Acute ischemic infarction of the optic nerve head occurs due
to occlusion of the posterior ciliary arteries that are branches
of the ophthalmic artery and supply the anterior part of the
optic nerve, the choroid and outer retina.
ETIOLOGY AND PATHOPHYSIOLOGY
Posterior ciliary artery territory ischemia
The optic disc is close to an arterial borderzone between the
territories of supply of the two major PCAs and is therefore
liable to selective ischemia when the systemic blood pressure
falls, the intraocular pressure rises or when there is occlusive
disease of local small arteries.
• Systemic hypotension.
• Raised intraocular pressure.
• Thrombotic or embolic occlusion of the PCA:
– Giant cell arteritis (GCA).
– Other connective tissue diseases such as polyarteritis
nodosa.
– Atherosclerosis: patients have an increased prevalence of
hypertension and diabetes and an increased risk of
subsequent cerebrovascular and cardiovascular events.
– Embolism from the proximal carotid circulation, aortic
arch or heart.
Visual acuity: varies from 6/6 to no light perception, so
normal visual acuity does not exclude AION.
Visual fields: usually nerve fiber bundle defects are
characteristic of an optic disc disorder but any visual field
defect can occur. An altitudinal hemi-field defect (loss of
either the upper or, more frequently, the lower half of the
field in one eye) is particularly common, as is inferior nasal
segmental loss and central scotoma. This altitudinal pattern
of field loss is because of the nature of the posterior ciliary
arterial circulation, which is divided into upper and lower
divisions of supply to the optic nerve.
Pupils: relative afferent pupillary defect (see p.575), as
with any unilateral optic neuropathy.
Ophthalmoscopy: the disc may appear normal at first,
but within a few days it becomes pale and swollen, often
with small flame-shaped hemorrhages radiating from the
disc margin (ischemic papillopathy), distended veins and,
occasionally, cotton-wool spots due to ischemic change in
the surrounding retina (612, 613). The swelling may
involve only one segment of the disc or be more marked in
one segment than in another. The disc swelling is attributed
partly to leakage of plasma from damaged blood vessels and
partly to the arrest of axoplasmic transport along damaged
612

Risk factors
• Congenitally small and crowded optic nerve heads (the
so-called ‘disc-at-risk’).
• Increasing age. 612 Fundus photograph showing a swollen optic disc, which is more
• Hypertension. marked in one segment than in another, with small flame-shaped
• Diabetes. hemorrhages radiating from the disc margin.

CLINICAL FEATURES 613

Monocular blindness
History
• Abrupt onset.
• Painless.
• Severe.
• The entire visual field is usually affected but tends to be
more severe in the lower quadrants because the upper
segment of the optic disc is more vulnerable to ischemia.
• It may be exacerbated in early stages by minor postural
change (precarious circulation).
• AION is persistent and non-progressive but can be brief
(and present as transient monocular blindness) and may
progress over several hours or days.
• Preceding amaurosis fugax may have occurred.
• Rarely, blindness is bilateral and simultaneous or develops 613 Fundus photograph showing a swollen optic disc with distended
within a few days (usually due to giant cell arteritis). veins and cotton-wool spots due to ischemic change in the surrounding
retina. (612, 613 courtesy of Mr M Wade, Department of Medical
Illustrations, Royal Perth Hospital,Western Australia.)
488 Cranial Neuropathies

nerve fibers. The disc swelling may be indistinguishable
from that seen with raised intracranial pressure but
sometimes the disc has a pale appearance and, in about half
of the eyes with AION due to giant cell arteritis, the disc
swelling has a chalky white appearance. Later, the swelling
subsides to be succeeded by optic atrophy with attenuation
of the small blood vessels on the disc surface.
DIFFERENTIAL DIAGNOSIS
Sudden and persistent monocular visual failure
• Retinal infarction:
– Central or branch retinal artery occlusion.
– Central or branch retinal vein occlusion.
• Retinal or vitreous hemorrhage.
• Other visible retinal lesions.
• Papilledema due to raised intracranial pressure.
• Cavernous sinus thrombosis.
• Carotico-cavernous fistula.
Sudden and persistent binocular visual failure
• Pituitary apoplexy (see p.268).
• Bilateral occipital infarction causing cortical blindness
(which is sometimes not recognized by the patient) with
normal pupil response to light (since visual afferents
destined for the midbrain leave the optic tract just before
the lateral geniculate body):
– Profound hypotension (bilateral parieto-occipital
infarction).
– Vertebrobasilar thromboembolism.
– Vertebral angiography.
• Head injury.
DIAGNOSIS
Swelling of the optic disc is a necessary sign for the diagnosis
of AION. Having established the diagnosis of AION, the
crucial next step is to differentiate arteritic AION, that is
caused by giant cell arteritis, from non-arteritic AION.
Features suggestive of arteritic AION
• Older age.
• Systemic symptoms: headache, scalp tenderness, jaw
claudication, muscle aches, fatigue and weight loss.
• Premonitory visual symptoms: transient monocular visual
loss or diplopia.
• Early, massive, and progressive visual loss.
• Bilateral visual loss within days or weeks.
• Chalky-white optic disc swelling.
• Concurrent signs of retinal circulation ischemia such as
cotton wool spots or retinal infarction.
• Elevated ESR.
• Absent filling of the choroidal circulation on fluorescein
fundus angiography.
• Hypertension is present in up to half of patients, and
diabetes in up to 40% of patients.
INVESTIGATIONS
• ESR.
• Temporal artery biopsy: likely to remain positive in cases
of GCA even if done up to 14 days after starting steroid
therapy.
• Fluorescein angiography of the ocular fundus.
TREATMENT
Arteritic AION
Immediate high dose steroids to prevent complete blindness
(see GCA, p.234).
Non-arteritic AION
Acute treatment
• No proven effective therapy.
• Optic nerve sheath decompression surgery: making one
or several openings in the dura covering the optic nerve
just behind the eyeball, allowing CSF to escape, thus
reducing the pressure surrounding the optic nerve, has
been shown in a randomized trial of 244 patients to be
ineffective and possibly harmful.
Prevention of subsequent vascular events
• Control of vascular risk factors such as hypertension and
diabetes.
• Long term antiplatelet therapy.
PROGNOSIS
The prognosis for recovery of vision is variable and depends
on factors such as the underlying cause. Many patients (up
to 56%) with non-arteritic AION recover good central
vision (6/18 or 20/60, or better) or are left with arcuate
and sectorial visual field defects corresponding to loss of
bundles of nerve fibers. In other patients, particularly those
with arteritic AION, visual loss may be complete and
permanent.

Features suggestive of non-arteritic AION

• Predominantly in 50s and 60s, but can occur at any age.
• Visual loss is typically altitudinal, especially inferiorly.
• Visual loss commonly progresses over a few days after
onset but few (<10%) worsen over more than 10 days.
• Many (up to 56%) have relatively good visual acuity.
• Recurrences in the same eye are unusual.
• Subsequent involvement of the fellow eye is common,
with an estimated 25th percentile time to bilaterality of
32 months.
 Optic Neuritis 489

OPTIC NEURITIS visual failure progressing over weeks or months and

stopping short of complete blindness in the second or
third decade of life.
DEFINITION • Central scotomas are present and optic atrophy develops.
Optic neuritis is an acute, usually unilateral, inflammatory, Recovery does not occur.
demyelinating optic neuropathy. • Occasionally dementia, ataxia and spastic paraplegia are
present.
TERMINOLOGY
• Papillitis: inflammation of the optic nerve that is Isolated and idiopathic optic neuritis (probably a
sufficiently anterior to cause swelling of the optic disc. forme fruste of MS)
• Retrobulbar neuritis: inflammation of the optic nerve
that is posterior to the optic nerve head so that the direct CLINICAL FEATURES
effects of inflammation are not visible on History (symptoms)
ophthalmoscopy. • Vision becomes blurred, dimmed or is lost in one eye
over hours to days, reaching its worst in a week or so.
EPIDEMIOLOGY • Pain in and behind the eye may precede, and commonly
• Incidence: 1.40 per 100 000 person years (2.28 per accompanies, the visual blurring in about 90% of patients.
100 000 person years for women, 0.53 per 100 000 The eye is commonly painful to move or to touch.
person years for men; age-adjusted). • Bright, brief flashes of light (phosphenes) precipitated by
– Seasonal: highest in spring and lowest in winter. eye movement or unexpected sounds, particularly in the
• Prevalence (lifetime): 0.6 (95% CI: 0.3–1.0) per 1000. dark or when the eyes are closed, may occur in the acute
• Age: peak age of onset is in the 20s and 30s. stage or, more commonly, during recovery.
• Gender: F>M (2–3:1).
Examination (signs)
PATHOLOGY • Visual acuity is impaired.
Inflammatory, demyelinating optic neuropathy. • Color vision is impaired.
Simultaneous bilateral optic neuritis is very rare. • A central or paracentral scotoma, particularly by using a
red target, is present in most patients; most optic nerve
ETIOLOGY AND PATHOPHYSIOLOGY fibers transmit information from the macular which
Multiple sclerosis (MS) processes central vision and is densely innervated.
• The most common and important cause; about 50–60% Consequently, optic nerve lesions tend to affect fibers
of patients with optic neuritis eventually develop multiple that are transmitting information predominantly from
sclerosis (see p.340). the macular. However, the classic central scotoma is not
• Simultaneous bilateral optic neuritis is seldom due to always present and one of a wide variety of other visual
MS. field defects may be present. In addition, visual field
abnormalities in the fellow eye may be detected by visual
A specific infectious or inflammatory disorder field testing which may evolve over subsequent follow-
Viral infections (usually bilateral) up suggesting concurrent bilateral involvement.
• Herpes zoster virus. • A relative afferent pupillary defect (see p.575).
• Measles. • A swollen optic disc on ophthalmoscopy (papillitis) in
• Epstein–Barr virus. about one-third of cases, in whom the inflammatory
• Cytomegalovirus. demyelination is close to the optic nerve head (614).
• HIV. Continued overleaf

Other infections 614

• Syphilis.
• Tuberculosis.
• Histoplasmosis.
• Cryptococcus.

Vaccinations
• Hepatitis B.
• Influenza.

Orbital cellulitis

Meningitis and encephalitis

Neuromyelitis optica (Devic’s disease)

Leber’s hereditary optic atrophy (see p.491) 614 Ocular fundus photograph showing a swollen optic disc
• Rare, variably inherited, males are more often affected (papillitis) due to demyelination close to the optic nerve head.
than females. (Courtesy of Mr M Wade, Department of Medical Illustrations,
• Subacute bilateral (simultaneous or sequential) painless Royal Perth Hospital,Western Australia.)
490 Cranial Neuropathies

Examination (signs) (continued) • Mitochondrial DNA analysis.

• The optic disc appears normal, in the acute phase at least, • MRI of the brain, including orbits: excludes optic nerve
in about two-thirds of patients with more posterior optic compression or infiltration and shows mild to profound
nerve lesions (retrobulbar optic neuritis). changes consistent with brain demyelination in about half
• Later, when symptoms have improved, optic atrophy of patients.
may be present (with pallor of the optic disc, particularly • CSF: often adds little additional information to the MRI
on the temporal side) and sometimes subtle disturbances results. Oligoclonal banding is present in most patients
of color vision, distortion of depth perception (Pulfrich’s who go on to develop clinically definite MS but most of
phenomenon), a paracentral scotoma, and a relative these patients also have an abnormal MRI. In a minority
afferent pupillary defect. of cases, patients with optic neuritis who have oligoclonal
bands in the CSF and a normal MRI will progress to MS
DIFFERENTIAL DIAGNOSIS within the next 2 years.
Progressive monocular visual failure
• Visible ocular lesions (glaucoma, cataract, senile macular DIAGNOSIS
degeneration). Clinical.
• Optic nerve infarction.
• Anterior ischemic optic neuropathy (see p.487). TREATMENT
• Optic nerve inflammation/infection: • Oral prednisone alone has no role in the treatment of
– Perioptic neuritis. acute demyelinating optic neuritis.
– Orbital and nasal suppuration, fungal infection: • Oral high-dose methylprednisolone (500 mg daily for
– Sarcoidosis. 5 days) improves recovery from optic neuritis at 1 and
– Meningitis: subacute and chronic. 3 weeks but has no effect at 8 weeks or on subsequent
• Optic nerve tumor: attack frequency.
– Primary: astrocytoma. • Intravenous methylprednisolone (1000 mg/day) for
– Secondary: nasopharyngeal carcinoma. 3 days followed by oral prednisone (1 mg/kg/day) for
• Optic nerve compression: 11 days is used by many clinicians for acute optic neuritis
– Orbital tumor. patients with brain MRI abnormalities suggestive of
– Dysthyroid eye disease. demyelinating disease and for those with substantial visual
– Tolosa–Hunt syndrome. loss. The rationale is that it hastens recovery of vision but
– Paget’s disease of the skull. it provides no long term benefit at 1 year and it is
– Anterior communicating artery aneurysm uncertain whether it reduces the rate of developing MS.
• Optic nerve irradiation.
PROGNOSIS
Progressive binocular visual failure Eye pain
• Glaucoma. Subsides in about a week.
• Diabetic retinopathy.
• Bilateral severe papilledema. Visual acuity
• Leber’s hereditary optic neuropathy. Commonly improves slowly over a few weeks. Lack of at least
• Nutritional deficiency: vitamin B12, vitamin E. some improvement in visual acuity within the first 3 weeks
• Optic nerve toxins: after onset, or worsening of vision after termination of a
– Alcohol and glycols. course of steroids, should be considered atypical and warrant
– Heavy tobacco consumption. re-assessment of the diagnosis. At 6 months, about 94% of
– Mercury. patients have vision of 6/12 (20/40) or better and 75% have
– Clioquinol. improved to 6/6 (20/20) or better. There is frequently some
– Chronic cyanide poisoning. residual impairment of color vision. Chronic progression with
– Drugs: chloramphenicol, chloroquine, desferrioxamine no improvement, resulting in permanent blindness, is rare and
(deferoxamine), ethambutol. should provoke a search for other causes.
• Optic chiasm compression: At 5 years, about half of patients report their vision to be
– Pituitary adenoma. ‘somewhat worse’ or ‘much’ worse than it had been before
– Craniopharyngioma. the optic neuritis, but only 20% have abnormal results on
– Meningioma of the tuberculum sellae, olfactory groove all of the four tests of visual function (visual acuity, contrast
or sphenoid wing. sensitivity, color vision, and visual field mean deviation).
– Hydrocephalus and dilatation of the third ventricle. The best predictors of visual recovery are baseline visual
– Carotid siphon or ophthalmic artery aneurysm. acuity, and short length of optic nerve signal abnormality
• Optic nerve irradiation. and extracanalicular location on MRI (<17.5 mm of optic
nerve involvement), but even those with no light perception
INVESTIGATIONS can have good recovery of visual acuity.
• Full blood count and ESR.
• Antinuclear antibody. Visual fields
• Syphilis serology. Most visual field defects also return to normal, although
• Chest x-ray. new and different patterns of defects develop in some
• Visual evoked potentials: delayed conduction in the visual patients over the course of follow-up in both eyes. A
pathways. minority of patients (about 13%) develop chiasmal and
 Leber’s Hereditary Optic Neuropathy (LHON)
retrochiasmal visual field defects at some time during the
first year of follow-up, particularly those with an abnormal
brain MRI at the onset of optic neuritis.
Recurrence of optic neuritis
Recurrence in the same or other eye is not unusual; vision
is less likely to recover than after the initial attack.
MS
About 15% of patient will develop clinically definite MS
within the next 2 years, 22% within 5 years, 35% in 10 years,
and about 50–60% of patients with optic neuritis will
eventually develop MS.
MS is less likely to occur
• Following optic neuritis in childhood than in adults.
• With bilateral simultaneous onset.
• With absence of pain.
• With marked disc edema.
• If there are no oligoclonal bands in the CSF.
• If the brain MRI is normal (lack of pain, mild visual
acuity loss, and the presence of optic disc swelling are
also favorable prognostic factors in patients with no brain
MRI lesions).
MS is more likely to occur
• If previous ill-defined non-specific neurologic symptoms
are present.
• If there is an history of previous optic neuritis.
• With increased CSF IgG.
• If the brain MRI is abnormal with three or more lesions
suggestive of demyelinating disease:
– At 3 years follow-up, about 10% of patients with normal
baseline MRI scans develop clinically definite MS,
compared with about 30% of patients with one or two
MRI signal abnormalities and 45% of patients with three
or more MRI lesions.
– At 5 years follow-up, about 16% of patients with normal
baseline MRI scans develop clinically definite MS,
compared with about 51% of patients with three or more
MRI lesions.
• Possibly, if there is a family history of MS.
615
491
LEBER’S HEREDITARY OPTIC
NEUROPATHY (LHON)
DEFINITION
Leber’s hereditary optic neuropathy is a maternally-inherited
optic neuropathy caused by a mitochondrial DNA mutation
and manifesting as an acute or subacute loss of central vision
in both eyes in young adults, predominantly young men.
EPIDEMIOLOGY
• Incidence: rare, but the commonest cause of blindness
in otherwise healthy young men.
• Age: late adolescence and early adulthood. Mean age of
onset: 23 years; rare over the age of 50 years, but
reported up to 70 years of age.
• Gender: M>F (4:1).
ETIOLOGY
• Maternal inheritance.
• Heterogeneous mitochondrial DNA (mtDNA)
mutations: homoplasmic missense point mutations have
been found in at least eight genes that encode subunits
of three biochemical complexes. The most common
‘primary’ mtDNA mutations are at the following
nucleotide positions/base pairs:
– 11 778 (accounts for 31–90% of LHON probands, and
results in substitution of histidine for arginine in subunit
4 of complex 1 of the mitochondrial respiratory chain).
– 3460 (8–15% of probands).
– 14 484 (10–15% of probands).
– 15 257.
• Epigenetic factors: alcohol and tobacco abuse.
CLINICAL FEATURES
• Subacute, bilateral, sequential loss of central vision which
is typically painless but may be associated with a constant
dull pain. The interval between involvement of the two
eyes is rarely more than a few months.
• Abnormal color vision (e.g. Ishihara plates).
• Central or centrocecal visual field defects.
• Fundus:
– Acute phase: normal, or hyperemia and swelling of the
optic disc, peripapillary telangiectasia, and dilatation and
tortuosity of the retinal vasculature, with or without
hemorrhages.
– Chronic phase: optic nerve pallor and loss of nerve fiber
layer develop, loss predominantly in the papillomacular
bundle (615).
• Associated features include dystonia, low amplitude
postural and action tremor of the upper limbs,
myelopathy, and cardiac conduction abnormalities.
Brainstem (midbrain) involvement has also been
described.
• Family history of visual loss is present in about one-half
of patients.
615 Optic fundus, showing optic atrophy, of a man with progressive loss
of central vision in one eye followed a few months later by involvement
of the fellow eye, who was found to have pathogenic mutation of
mitochrondrial DNA at base pair 11 778. Acute stage: hyperemia of the
optic disc with peripapillary microangiopathy but without fluorescein
leakage; chronic: progression to optic atrophy is usual.
492 Cranial Neuropathies
DIFFERENTIAL DIAGNOSIS
• MS: a high proportion of women with a mtDNA
mutation at base pair 11778 develop an illness
indistinguishable from MS.
• Other hereditary optic neuropathies:
– Autosomal dominant optic neuropathy (Kjer’s disease):
symmetric insidious onset of visual loss in the first decade
of life.
– Blue-yellow dyschromatopsia:
Centrocecal scotomas.
Wedges of temporal disc atrophy.
Abnormal gene in telomeric portion of long arm of
chromosome 3.
• Ischemic optic neuropathy.
• Neurosyphilis.
INVESTIGATIONS
• Goldmann perimetry: central or centrocecal scotoma.
• Visual evoked potentials to pattern reversal: show a delay
(>100 ms) and reduced amplitude.
• Fluorescein angiography.
• Venous blood mtDNA analysis, using the polymerase
chain reaction (PCR) for a point mutation: the major ones
are at nucleotide positions 11 778, 3460, and 14 484.
• Full blood count: normal.
• ESR: normal.
• VDRL/RPR, TPHA: negative.
• ECG: usually normal, but may show a conduction
abnormality.
• CT or MRI scan of the head and orbits: normal or high
signal within the optic nerve on MRI short time
inversion recovery (STIR) sequence. A symmetric area
of increased signal intensity on T2W images in the dorsal
midbrain has been reported.
• CSF: normal, or oligoclonal bands in some patients.
DIAGNOSIS
Typical clinical features (e.g. positive family history in half
of cases, visual loss, ophthalmoscopic findings of circum-
papillary telangiectasic microangiography, swelling of the
nerve fiber layer around the optic disc [pseudoedema]),
absence of staining of fluorescein angiography, and venous
blood analysis by PCR showing a mtDNA point mutation
at nucleotide positions 11 778, 3460, or 14 484, or possibly
4160 and 15 257.
TREATMENT
No effective medical (e.g. acetazolamide, prednisolone, and
intravenous dextran) or surgical (e.g. optic nerve sheath
decompression) treatment.
PROGNOSIS
• Visual acuity typically deteriorates permanently to levels
of 6/60 or worse, although spontaneous recovery of
vision can occur even years later.
• The probability of visual recovery varies widely,
depending on the mutation and age of onset.
• Good visual outcome correlates strongly with younger
age at onset.
• The presence of a ‘primary’ LHON mutation does not
guarantee that a patient will lose vision; patients with the
14 484 mutation have a substantially greater chance of
spontaneous recovery of vision (up to 50%) and better
final visual acuities.
PAPILLEDEMA
DEFINITION
Papilledema is edema of the optic papilla or disc. Not a
disease but a sign of an underlying condition.
ETIOLOGY
Raised intracranial pressure (bilateral papilledema)
Brain parenchymal disorders
• Mass lesion: abscess, infarct, hematoma, tumor.
• Cerebral edema: tumor, post head injury, post brain
anoxia, idiopathic intracranial hypertension (benign
intracranial hypertension), lead poisoning, steroid
withdrawal, vitamin A intoxication.
CSF disorders
• CSF circulatory block: aqueduct stenosis, intraventricular
tumor, ventricular outflow block.
• Impaired CSF absorption due to raised CSF protein or
altered blood products: post subarachnoid hemorrhage,
post meningitis, Guillain–Barré syndrome, hypertrophic
polyneuritis, spinal cord tumor.
Malignant hypertension
Circulatory disorders
• Lateral venous sinus thrombosis.
• Jugular vein thrombosis.
• Superior vena cava obstruction.
• Hyperviscosity syndrome: polycythemia rubra vera,
multiple myeloma, macroglobulinemia.
Metabolic disorders
• Hypercapnia.
• Hypocalcemia (in children in particular).
Raised intranerve pressure (unilateral papilledema)
Optic nerve disorder
• Orbital or optic nerve tumor.
• Optic neuritis (see p.489).
• Ischemic optic neuropathy (see p.487).
• Malignant thyrotoxic exophthalmos.
Circulatory disorders
• Central retinal vein occlusion.
• Cavernous sinus thrombosis.
• Carotico-cavernous fistula.
PATHOPHYSIOLOGY
• Disc swelling indicates abnormal elevation of the optic
disc, generally due to blocked axoplasmic flow.
• It usually requires at least 2–4 hours to develop, even
with acute increases in intracranial pressure, and so its
absence does not exclude increased intracranial pressure
of less than several hours duration. Peripapillary
hemorrhages may be seen more acutely.
 Papilledema
CLINICAL HISTORY
• Visual obscurations: brief, painless, monocular or
binocular blurring or complete loss of vision (‘gray-outs’),
precipitated by postural changes such as bending quickly
and standing or exercise, and resolving within seconds.
They are due to temporary optic nerve ischemia as a
result of further obstruction to venous outflow from the
orbit caused by raised intracranial or intraorbital pressure
(resisting venous outflow) and a small drop in systemic
blood pressure (reducing arterial inflow).
• Associated symptoms of the underlying cause (e.g.
headache).
PHYSICAL EXAMINATION
Visual acuity
• Normal, initially at least, if the papilledema is due to
raised intracranial or intraorbital pressure.
• Visual acuity becomes impaired later as raised pressure
papilledema increases and spreads towards the macular
or because of macular hemorrhage or optic atrophy in
severe cases.
Visual fields
Enlarged blind spot, and sometimes constricted visual field,
particularly infero-nasally.
Ophthalmoscopy of the ocular fundus
• Filling in of the optic cup in the optic nerve head.
• Pink, hyperemic optic disc (616).
• Blurred disc margin.
• Swelling and elevation of the optic disc.
• Engorged, non-pulsatile retinal veins; the presence of
spontaneous venous pulsations indicate the CSF pressure
is <200 mm of water at the time of the observation.
616
616 Ocular fundus photograph showing early papilledema in a patient
with idiopathic intracranial hypertension. Note the hyperemic optic disc,
blurred disc margin, and engorged retinal veins. (616, 617 courtesy of
Mr M Wade, Department of Medical Illustrations, Royal Perth Hospital,
Western Australia.)
493
• Flame retinal perivenous hemorrhages on or around the
disc.
• Obscuration of vessels at the edge of the disc.
• Opacity of the peripapillary nerve fiber layer.
• Circular retinal folds around the disc and choroidal folds
may be seen.
• Cotton wool spots – small round white blobs known as
cytoid bodies, indicate very severe axonal damage.
• Chronic papilledema (e.g. in malignant hypertension or
idiopathic intracranial hypertension) may be complicated
by secondary changes in the macular area: the so-called
macular star is edema radiating out from the macular and
seriously interfering with vision (617).
Other
Check the blood pressure, look for proptosis and determine
if the proptosis is pulsatile.
SPECIAL FORMS
The Foster–Kennedy syndrome
A rare combination of papilledema in one eye and optic
atrophy in the other eye due a frontal tumor which is large
enough to compress one optic nerve (and cause ipsilateral
optic atrophy) and increase the intracranial pressure to cause
papilledema in the contralateral eye. The differential
diagnosis is acute anterior ischemic optic neuropathy or
optic neuritis in one eye and optic atrophy due to previous
optic neuritis in the other eye. The distinction can often be
made by the presence of impaired visual acuity in both eyes
in the latter circumstance.
617
617 Ocular fundus photograph showing severe chronic papilledema in
a patient with idiopathic intracranial hypertension. Note the swollen,
hyperemic optic disc with obliteration of the optic cup, blurred disc
margin, engorged retinal veins, obscuration of vessels at the edge of the
disc, retinal hemorrhages around the disc and macular star (edema
radiating out from the macular).
494 Cranial Neuropathies
DIFFERENTIAL DIAGNOSIS
Unilateral optic disc swelling with normal
vision (papilledema)
• Normal optic disc: the nasal side of the normal disc often
looks a little blurred, and retinal venous pulsation is
absent in about 25% of normal people.
• Papillophlebitis (the ‘big blind spot syndrome’): a
benign, self-limiting condition.
• Idiopathic intracranial hypertension.
• Congenital disc anomalies:
– Deep optic cup.
– High myopia (normal corrected vision).
– Myelinated nerve fibers.
– Optic nerve drusen (618, 619): refractile mass in the
optic nerve head which may produce arcuate nerve
bundle-type visual field defects and show auto-
fluorescence with fluorescein angiography.
– Prepapillary vascular loops.
– Tilted discs.
– Megalopapilla.
Optic disc swelling with abnormal vision
(anterior optic neuropathy)
• Optic neuritis (papillitis) (see p.489).
• Anterior ischemic optic neuropathy (see p.487).
• Optic disc infiltration:
– Granuloma: e.g. sarcoidosis.
– Tumor: e.g. leukemia, astrocytoma, lymphoma, metastases.
• Optic disc neovascularization.
• Hereditary optic neuropathy (Leber’s).
INVESTIGATIONS
Fluorescein angiography (619) shows leakage of dye from
the disc. Further investigations depend on clinical clues to
the underlying cause (e.g. CT or MRI scan of brain and
orbits, screen for a procoagulant state).
PROGNOSIS
• The course of papilledema is best followed by serial visual
field testing and fundus photography. Papilledema may
take 6–10 weeks to resolve after intracranial pressure
returns to normal.
• Chronic, untreated papilledema can cause loss of visual
function and blindness. The optic disc becomes gray or
pale (secondary optic atrophy).
618 619
HORNER’S SYNDROME
DEFINITION
Horner’s syndrome presents as unilateral ptosis, miosis and
anhidrosis due to damage to the ipsilateral oculosympathetic
pathway.
EPIDEMIOLOGY
Prevalence (lifetime): 0.2 (95% CI: 0.04–0.4) per 1,000.
ANATOMY AND PATHOPHYSIOLOGY
Cervical sympathetic pathway
Begins in the posterolateral part of the hypothalamus, but
there is a considerable degree of cortical control. There are
three neurons:
First neuron
Descends from the hypothalamus, through the dorsolateral
brainstem and cervical spinal cord, to synapse in the
intermediomedial and intermediolateral cells (the ciliospinal
centre of Budge) in the lateral gray matter of the
cervicothoracic spinal cord at levels C8 and T1. These cells
give rise to preganglionic fibers.
Second neuron
Preganglionic fibers leave the upper thoracic spinal cord,
most via the white rami of the T1–T2 ventral nerve roots
(which lie close to the apex of the lung where they cross in
the pleural covering and loop around the subclavian artery),
and proceed through the stellate ganglion to synapse in the
superior cervical ganglion.
Third neuron
Postganglionic fibers ascend in the cervical sympathetic
trunk (in close proximity to the internal carotid artery),
enter the base of the skull on the surface of the internal
carotid artery, traverse the cavernous sinus where they join
the first (ophthalmic) division of the trigeminal nerve. They
are carried in the nasociliary branch of the ophthalmic nerve
through the superior orbital fissure into the orbit.
Vasomotor fibers in the nasociliary branch of the trigeminal
nerve traverse the ciliary ganglion without synapsing to
supply the blood vessels of the eye. Pupillodilator fibers on
the nasociliary branch of the trigeminal nerve continue, by
618 Ocular fundus
photograph showing optic disc
drusen, which may be
mistaken for papilledema.
Drusen is a hyaline mass that
develops during life and may
cause a central scotoma or, if it
damages nerve fiber bundles in
the optic nerve head, an
arcuate scotoma.
619 Fluorescein angiography
showing auto-fluorescence in
optic disc drusen.
 Horner’s Syndrome 495

passing around the eye, as the long ciliary nerves to CLINICAL FEATURES
innervate the pupil. History
Fibers carried in the third cranial (oculomotor) nerve Asymptomatic unless the patient or others notice the ptosis
innervate the superior and inferior tarsus muscles of Müller or small pupil.
and orbitalis. These muscles assist eye opening by
attachment to the tarsal plates, opposing the action of Examination
orbicularis. When paralysed, the upper lid is ptosed and the Horner’s syndrome
lower lid pulls up – so-called ‘upside down’ ptosis, or ptosis • Ptosis of the upper lid (sympathetic fibers supply the smooth
of the lower lid – narrowing the palpebral fissure and muscle of the upper eyelids) that is partial and not complete
producing an apparent enophthalmos. (as it is in a IIIrd nerve palsy), and slight elevation (‘upward
ptosis’) of the lower lid (paresis of Müller’s muscles)
ETIOLOGY resulting in narrowing of the palpebral fissure (620).
• Damage to the cervical sympathetic pathway. Isolated ‘upside down ptosis’ of the lower lid may occur.
• A cause is found in about 60% of cases. • Pupillary constriction (miosis) occurs. The anisocoria in-
• Hypertension and diabetes mellitus are frequently creases in darkness. Occasionally pupillary involvement
present in the undiagnosed group suggesting ischemia can only be demonstrated on pharmacologic testing (see
of the oculosympathetic pathway. below).
• Anhidrosis (impaired sweating) on the ipsilateral side of
Congenital: 3% the face may occur if the lesion is proximal to the carotid
bifurcation (since sympathetic fibers to the face course
Acquired: 57% with the external carotid artery). Anhidrosis of the
Brainstem medial side of the forehead may occur if the lesion is
• Stroke: lateral medullary syndrome (5%). distal to the carotid bifurcation. Anhidrosis occurs in 5%,
• Tumor. usually with preganglionic lesions. Vascular dilatation in
the face and conjunctiva is transient.
Spinal cord • Iris heterochromia may be seen in congenital Horner’s
• Tumor. syndrome; Horner’s syndrome developing in utero or
• Cervical disc extrusion (3%). infancy interferes with pigmentation of the iris so the
• Syringomyelia. eyes are of different colors (620).
• Meningitis. • Enophthalmos is apparent and not real; it is not a feature
of oculosympathetic palsy.
Apex of lung
• Coronary artery bypass surgery (0.2–7.7%). N.B. Bilateral Horner’s syndrome from a central
• Tumor. (brainstem or cervical spinal cord) lesion can be easily
• Pneumothorax. missed because the ptosis is symmetric and the pupils are
symmetrically equal and react to light, but are small.
Neck
• Trauma.
• Carotid artery dissection, thrombosis.
• Thyroid tumors, surgery.
• Cervical rib.

Cavernous sinus and orbit

• Cluster headache (migrainous neuralgia) (12%).
• Raeder’s paratrigeminal syndrome.

620

620 Facial photograph showing a left Horner’s syndrome. Note the

narrowing of the palpebral fissure due to mild incomplete ptosis of the
upper lid and slight elevation of the lower lid.The pupil is small and
constricts to light and accommodation.
496 Cranial Neuropathies

Associated features Central preganglionic or peripheral

• Chest: open heart surgery scar.
• Neck: wasting of small muscles of hand due to ipsilateral
T1 radiculopathy; thyroidectomy scar.
• Cavernous sinus and orbit lesions: the pupil is often
semidilated or fixed and dilated because the lesion also
damages parasympathetic fibers running with the IIIrd
cranial nerve to the constrictor fibers of the pupil.
Raeder’s syndrome also includes hemicrania with or
without cranial nerve III, IV, V, and VI dysfunction.
DIFFERENTIAL DIAGNOSIS
Small pupil (miosis)
• Congenital.
• Trauma to the iris (usually irregular).
• Pontine lesion.
• Argyll Robertson pupil.
• Pilocarpine and other constricting eyedrops such as
carbachol, metacholine, physostigmine, neostigmine,
isoflurophate, ecothiophate (echothiopate), demecarium,
aceclidine.
• Organophosphorus poisoning.
• Opiates, barbiturates, chloral hydrate, cholinergics,
lignocaine, marijuana, phenothiazines (bilateral).
• Autonomic neuropathy.
• Old age (normal).
• Physiologic anisocoria: about 25% of the normal
population have pupils of unequal size; the difference is
<1 mm in about 20% and >1 mm in up to 5%. The
asymmetry remains constant in the light and dark.
Ptosis
• Congenital.
• Midbrain lesion.
• Neurosyphilis (see p.312).
• IIIrd cranial (oculomotor) nerve palsy (see p.499).
• Myasthenia gravis: ptosis may be variable and asymmetric
(see p.657).
• Myopathies: myotonic dystrophy, ocular dystrophies,
mitochondrial cytopathy (chronic progressive external
ophthalmoplegia), polymyositis, dysthyroidism.
• Levator dehiscence–disinsertion syndrome due to ageing,
inflammation, trauma, surgery or ocular allergy.
• Trauma to the orbit.
• Pseudoptosis due to eyelid inflammation (allergy,
blepharitis, conjunctivitis), hemangioma, enophthalmos,
Duane’s orbital retraction syndrome, trachoma, ptosis
adiposis, plexiform neuroma, amyloid infiltration and
chronic Bell’s palsy.
post-ganglionic lesion?
• Wait until at least 12 hours have elapsed after the cocaine
test.
• Hydroxyamphetamine 1–2% or pholedrine eyedrops:
apply one drop to the affected eye, repeat after a few
minutes, and determine the change in pupillary size after
30 minutes. Hydroxyamphetamine releases noradrenaline
from nerve endings and dilates pupils with an intact third
order neuron. So, normal pupils dilate as do small pupils
caused by a preganglionic (central) oculosympathetic
palsy. Small pupils due to a postganglionic oculosympa-
thetic lesion fail to dilate with hydroxyamphetamine.
The site of the lesion can be deduced further by eliciting
relevant associated clinical features.
INVESTIGATIONS
Determined by the site of the lesion in the oculosympathetic
pathway (which is determined by the presence and absence
of coexistant focal neurologic symptoms and signs, and the
results of eyedrop tests (see above).
Preganglionic Horner’s syndrome
• MRI brain and cervical spinal cord.
• CSF examination.
• Chest x-ray.
• Chest CT scan.
Postganglionic Horner’s syndrome
• Carotid artery imaging (ultrasound, magnetic resonance
angiography, catheter contrast angiography).
• MRI neck.
• MRI head.
TREATMENT
Depends on the cause.
PROGNOSIS
Depends on the cause. Generally benign in isolated, new
onset postganglionic Horner’s syndrome.

DIAGNOSIS
Horner’s syndrome or not?
Horner’s syndrome is characterized by:
• Normal pupil reaction to light in both eyes.
• Anisocoria is greater in darkness than in light.
• ‘Dilatation lag’ of the smaller pupil following sudden
darkness.
• Cocaine 2–10% eyedrops: small pupil fails to dilate.
Cocaine dilates normal pupils by preventing the reuptake
of noradrenaline from sympathetic nerve endings.
Horner’s syndrome, due to disruption of the sympathetic
pathway at any level prevents the release of noradrenaline
from the terminal nerve endings and the pupil fails to
dilate in response to cocaine.
 Holmes–Adie Syndrome
HOLMES–ADIE SYNDROME
DEFINITION
The syndrome is a combination of a Holmes–Adie (tonic)
pupil and absent or depressed deep tendon reflexes.
EPIDEMIOLOGY
• Incidence: uncommon.
• Age: adolescents or young adults.
• Gender: females mainly.
ANATOMY AND PHYSIOLOGY OF THE
PUPIL SIZE AND REACTIONS
• Pupil size is controlled by a circle of constrictor fibers
innervated by the parasympathetic nervous system and a
ring of radially arranged dilator fibers controlled by the
sympathetic nervous system (see p 575).
• The resting size of the pupil is governed by the light
intensity falling on the eye and depends on the integrity
of the parasympathetic nervous system.
• Changes in pupil size do not usually affect vision, and are
usually asymptomatic. However, a fully dilated pupil on
one side will not focus close up, and will cause blurring
on attempted reading.
Parasympathetic pathways
• Light falling on the retina of one eye is conveyed in the
optic nerve to the optic chiasm. The impulses then
decussate and are conveyed in both optic tracts to both
lateral geniculate bodies.
• About 10% of the fibers to the geniculate bodies are para-
sympathetic fibers that subserve the light reflex and are
relayed in the periaqueductal gray matter to both Edinger–
Westphal nuclei (see pp.500, 575) in the high midbrain.
• The parasympathetic fibers join the IIIrd cranial
(oculomotor) nerve, and are carried in a superficial and
dorsal position on the nerve (which may explain the
variable abnormalities of the pupil in IIIrd cranial nerve
palsies [see p.499]), to the orbit.
• The final relay of the parasympathetic pathway is in the
ciliary ganglion, which lies in the posterior orbit on the
branch of the IIIrd nerve to the inferior oblique muscle.
• The postganglionic fibers then enter the eye via 8–10
short ciliary nerves which subdivide into 16–20 branches
that pass around the eye to reach the sphincter pupillae;
about 3% of the fibers innervate the sphincter pupillae
and 97% the ciliary body, which is a muscle that alters the
shape of the lens for focusing.
• The Edinger–Westphal nuclei are also stimulated by
activity in the adjacent IIIrd nerve subnuclei which
control the medial rectus muscles. Consequently,
activation of the medial recti not only leads to
convergence of the eyes but also activation of the
Edinger–Westphal nuclei which, in turn, leads to
pupillary constriction as a result of simultaneous
contraction of the sphincter pupillae and the ciliary
muscle. This is the basis of the accommodation reflex,
which is a much more powerful stimulus to
pupilloconstriction than the light reflex.
Sympathetic pathways
See Horner’s syndrome (p.494).
497
PATHOLOGY
Rare post mortem examinations reveal ciliary ganglion cell
loss.
ETIOLOGY AND PATHOPHYSIOLOGY
Adie’s tonic pupil
The tonic pupil is believed to result from damage to the
ciliary ganglion or the postganglionic cholinergic para-
sympathetic fibers projecting from the ganglion to the iris
sphincter. There is denervation of the postganglionic supply
to the sphincter pupillae and the ciliary muscle. This may
follow infection such as herpes zoster or trauma, but is
usually idiopathic. It may be part of a mild polyneuropathy.
Hyporeflexia
Degeneration in the dorsal root ganglia and dorsal columns
occurs, which leads to impaired synaptic transmission in the
spinal monosynaptic reflex arc, accounting for the absent
reflexes.
CLINICAL FEATURES
History
• The syndrome is usually asymptomatic, other than some
photosensitivity to bright light.
• Patients may present with sudden onset of blurred vision.
Examination
• One pupil is larger than the other (621), but in about
20% of cases both pupils are dilated.
• The pupil reacts very sluggishly to light but with
prolonged exposure to light it will pass through the full
range of constriction. When the light stimulus is
removed, the pupil dilates very slowly, hence the
alternative name of ‘myotonic pupil’.
Continued overleaf
621
621 Dilated Adie pupil of a young woman who presented having woken
one morning and, on looking in the mirror, noted that the left pupil was
larger than the right. The left pupil reacted extremely sluggishly to
prolonged maximal light stimulation but much better to accommodation
(light-near dissociation), after which it remained tonically constricted and
redilated very slowly.The affected left pupil also constricted promptly to
0.1% solution of pilocarpine, indicating denervation supersensitivity.
(Courtesy of Mr Alan Hamilton, Department of Medical Illustrations, Royal
Perth Hospital,Western Australia.)
498 Cranial Neuropathies

Examination (continued) • Amyloidosis.

• Whenever a pupil reacts poorly to light, the near reflex
should be tested by having the patient fixate on their
own finger tip held immediately in front of their nose.
The tonic Adie pupil constricts with convergence (reacts
to accommodation). Because convergence and pupil
constriction depend on adequate close vision, reading
glasses may need to be worn or the patient simply asked
to look at the tip of their nose.
• Knee and ankle jerks may be depressed or absent.
SPECIAL FORMS
Ross’ syndrome
• The triad of Adie’s tonic pupil, hyporeflexia, and
segmental anhidrosis constitutes Ross’ syndrome.
• Orthostatic hypotension, reduced heart rate responses to
Valsalva maneuver, and other autonomic disturbances
may occur in patients with Ross’ or Holmes–Adie
syndrome.
• Ross’ syndrome results from injury to sympathetic and
parasympathetic ganglion cells or to their postganglionic
projections.
DIFFERENTIAL DIAGNOSIS
Large pupil (mydriasis)
Unilateral
• Parasympathetic nervous system lesion (i.e. IIIrd cranial
nerve lesion).
• Trauma to the iris (usually irregular).
• Myotonic pupil.
INVESTIGATIONS
Determined by suspected and likely differential diagnoses
(above).
DIAGNOSIS
• Dilated pupil(s) ± depressed knee and ankle reflexes.
• Poor light reaction of the dilated pupil.
• More anisocoria in light than in darkness.
• Test for cholinergic denervation supersensitivity with
pilocarpine 0.1% (i.e. low dose) or methacholine 2.5%
eye drops: causes Adie’s pupil (but not the normal pupil,
third nerve palsy pupil, or Argyll Robertson pupil) to
constrict because of denervation supersensitivity of
receptors. With 1% pilocarpine, both Adie’s pupil and the
pupil of a third nerve palsy will dilate. On slit lamp
examination, the margin of the iris may be seen to
undulate.
TREATMENT
No specific treatment.
PROGNOSIS
Eventually the pupil may become small and irregular, very
much like an Argyll Robertson pupil (see p.576).

Bilateral
• Autonomic neuropathy.
• Parinaud’s syndrome.
• Anxiety (bilateral and symmetric).
• Mydriatic and cycloplegic eyedrops that dilate the pupil
(mydriatic) and paralyze the ciliary muscle (cycloplegic)
respectively (i.e. antimuscarinic agents), such as atropine,
homatropine, cocaine, cyclopentolate, adrenaline,
phenylephrine, hydroxyamphetamine, oxyphenonium,
scopolamine, tropicamide.
• Mydriatic agents (sympathomimetic or muscarinic
agents) such as anticholinergics (atropine, belladonna,
scopolamine, propantheline, jimsonweed, nightshade
[belladonna]), tricyclic antidepressants, trihexyphenidyl,
benztropine, antihistamines (diphenhydramine, chlor-
pheniramine), phenothiazines, glutethimide, ampheta-
mines, cocaine, ephedrine, adrenaline, ethanol, botu-
linum toxin, snake venom, barracuda poisoning,
tyramine, hemicholinium, thiopental, lysergic acid
diethylamide, fenfluramine (patients on reserpine).
• Hypocalcemia.
• Hypermagnesemia.
• Brain death.
• Normal in infants (bilateral).

Light-near dissociation
• Severe anterior visual system dysfunction (e.g. severe
glaucoma, bilateral optic neuropathy).
• Neurosyphilis (Argyll Robertson pupils): associated with
miosis, irregular pupils, poor dilatation, and usually
relatively normal vision.
• Rostral dorsal midbrain lesion (Parinaud’s syndrome).
• Aberrant IIIrd cranial nerve regeneration.
• Diabetes (out of proportion to any retinopathy).
 IIIrd, IVth, and VIth Cranial Nerve (Ocular Motor) Neuropathies
IIIRD, IVTH, AND VITH CRANIAL NERVE
(OCULAR MOTOR) NEUROPATHIES
DEFINITION
Ocular motor neuropathies are defined as disorders of the
IIIrd (oculomotor), IVth (trochlear), and VIth (abducens)
cranial nerves which carry lower motor neuron fibers from
the midbrain and pons, through the meninges, cavernous
sinus, and supraorbital fissure into the orbit to supply the
extraocular muscles and elevators of the upper eyelid.
These disorders, along with disorders of the extraocular
muscles that are innervated by these nerves, cause
dysconjugate eye movements and thus binocular diplopia
(unless either eye is closed, blind or amblyopic).
ANATOMY
Supranuclear pathways for voluntary vertical and
horizontal conjugate gaze
Rapid eye movements (saccades)
Saccades are generated in area 8 of the contralateral frontal
cortex. Direct, and probably more importantly indirect,
projections descend through the corona radiata and anterior
limb of the internal capsule. At the level of the rostral
diencephalon, two bundles separate:
• A dorsal ‘transthalamic’ bundle, which is predominantly
uncrossed, courses through the thalamus to terminate
diffusely in the midbrain pretectum, superior colliculus,
and periaqueductal gray matter. An offshoot of these
fibers projects to the rostral part of the oculomotor
(IIIrd cranial nerve) nucleus and to the ipsilateral rostral
interstitial nucleus of the medial longitudinal fasciculus
(riMLF) and interstitial nucleus of Cajal (iC) in the
midbrain, which are involved in vertical eye movements.
• A more ventral ‘capsular-peduncular’ bundle descends
through the posterior limb of the internal capsule and
most medial part of the basis pedunculi (cerebral
peduncle), to partially decussate in the rostral pons and
terminate mainly in the paramedian pontine reticular
formation (PPRF), which in turn, projects to the VIth
cranial nerve (abducens) nucleus.
The final common pathway for horizontal saccadic (and
pursuit, see below) eye movements involves the low lateral
pontine centres for horizontal gaze (on the right and left),
which comprise the PPRF, abducens and vestibular nuclei,
and MLF. The PPRF functions as a relay station for the
horizontal and probably for the vertical saccade pathways.
The abducens nucleus contains two groups of neurons,
abducens motor neurons, which project to the ipsilateral
lateral rectus and abducens internuclear neurons, which
project via the contralateral MLF to the medial rectus
neurons of the (contralateral) IIIrd cranial nerve
(oculomotor) nucleus. The MLFs are fasciculi (pathways)
in the medial pontine and mesencephalic tegmentum,
connecting the ocular motor nuclei of the IIIrd and VIth
cranial nerves.
499
Two other pathways for vertical saccadic (and pursuit,
see below) eye movements involve ascending pathways from
the pontine centres to the mesencephalic reticular
formation: the central tegmental tract, which terminates in
the pretectum, in the nucleus of the posterior commissure
(mediating upgaze); and a bundle that passes around the
nucleus of Cajal and Darkschewitz to the rostral interstitial
nucleus of the MLF (mediating downgaze).
Conjugate horizontal gaze is accomplished by activation
of the contralateral frontal eye field, followed by activation
of the ipsilateral PPRF, and then simultaneous innervation
of the ipsilateral lateral rectus and contralateral medial
rectus, the latter through fibers that run in the medial
portion of the contralateral MLF.
Conjugate vertical gaze is accomplished by activation of
the frontal eye fields, followed by activation of the dorsal
‘transthalamic’ bundles and pontine centres, which project
to the rostral midbrain and innervate the oculomotor (IIIrd
cranial nerve) nucleus, riMLF, iC, and posterior commis-
sure. Saccades are modulated by the posterior vermis of the
cerebellum.
Smooth pursuit eye movements
• The object to be followed is located by a voluntary eye
movement (saccade).
• The eyes ‘lock in’ on the object and then only move in
response to movement of the object.
• Focus is maintained on the macular part of the retina by
pathways from the retina, optic nerve, optic tract and
optic radiation to the primary visual cortex (area 17),
from where visual information is relayed to the ipsilateral
parieto-occipital cortex, mainly area 7 of the parietal
cortex and area 19 of the ipsilateral visual cortex, as well
as other regions of the adjacent anterior occipital and
superior temporal lobes.
• From the ipsilateral parieto-occipital cortex, corticotectal
and corticotegmental fibers descend to the superior
colliculus and rostral midbrain (vertical pursuit) and the
ipsilateral dorsolateral pontine nuclei (horizontal pursuit),
which project to the flocculus and dorsal vermis of the
cerebellum.
• Movements are modulated by the ipsilateral vestibulo-
cerebellum (flocculus and nodulus).
• There is also a large forward projection that gives the
frontal eye fields information as to where to direct
voluntary gaze. Thus a direct relay from the eye to the
visual cortex and ipsilateral parieto-occipital cortex
controls ocular pursuit.
• Paralysis of both voluntary saccadic gaze and pursuit gaze
usually indicates damage at the subthalamic level, where
both pathways come together (the Roth–Bielschowsky
syndrome).
500 Cranial Neuropathies
Nuclear and infranuclear pathways for voluntary
vertical and horizontal conjugate gaze
IIIrd (oculomotor) cranial nerve
• Nuclei:
– Nuclei consist of several paired groups of nerve cells in
the midbrain, adjacent to the midline and central to the
aqueduct of Sylvius, at the level of the superior colliculi.
– The groups of nerve cells innervate the levator of the
eyelid, superior and inferior recti, inferior oblique, and
medial rectus. The medial and inferior recti and inferior
oblique have strictly homolateral representation in the
oculomotor nuclei, the superior rectus receives only
crossed fibers, and the levator palpebrae superioris has
bilateral innervation in this dorsal–ventral order.
– The parasympathetic portion of the oculomotor nucleus
(the so-called Edinger–Westphal nucleus) is central and
dorsal in the midbrain, and innervates the pupillary
sphincters and the ciliary bodies (muscles of accommoda-
tion).
• Midbrain. The IIIrd nerve fibers course ventrally in the
midbrain, traversing the MLF, red nucleus, substantia
nigra, and medial part of the cerebral peduncle.
• Interpeduncular cistern. The IIIrd nerves emerge from
the midbrain between the cerebral peduncles, and then
splay out as they pass anteriorly, lying between the
posterior cerebral arteries and the superior cerebellar
arteries. They then run parallel to the posterior
communicating arteries, until they enter the cavernous
sinus.
• Cavernous sinus. The nerves lie between the two layers
of dura that form the lateral wall of the cavernous sinus.
• Orbit. The nerve enters the orbit through the superior
orbital fissure and divides into two main branches:
– The upper branch supplies the eyelid and superior rectus
muscle.
– The lower branch supplies the medial rectus, inferior
rectus, and inferior oblique and, via the ciliary ganglion,
the pupil.
IVth (trochlear) cranial nerve
• Nuclei. The nuclei lie in the dorsal midbrain, just caudal
to those of the oculomotor nuclei and at the level of the
inferior colliculi.
• Midbrain. The fibers decussate (cross over) a short
distance from their origin, around the periaqueductal
gray and in the superior medullary velum, before
emerging on the dorsal surface of the brainstem, just
caudal to the inferior colliculi. The right trochlear nerve
thus originates in the left trochlear nucleus and vice versa.
• Cavernous sinus. After encircling the brainstem, the
nerve passes forwards on the opposite side to enter the
cavernous sinus.
• Orbit:
– The nerve enters the roof of the orbit through the
superior orbital fissure and in doing so crosses the IIIrd
nerve.
– In the orbit it passes around a trochlea (pulley) in the
anteromedial orbital roof just under the inner end of the
eyebrow.
VIth (abducens) cranial nerve
• Nuclei. A paired group of cells in the floor of the fourth
ventricle, adjacent to the midline, at the level of the lower
pons.
• Pons:
– The VIth nerve courses ventrally and medially, traversing
the corticospinal tracts to emerge from the low pons
adjacent to the pontomedullary junction in the midline,
deep in the posterior fossa.
– The intrapontine portion of the facial nerve loops around
the VIth nerve nucleus before it turns anterolaterally to
make its exit.
• Pre-pontine. The nerve ascends on the front of the pons
and then angles sharply forwards over the tip of the
petrous bone, and into the canal under the petroclinoid
ligament (Dorello’s canal) to enter the back of the
cavernous sinus.
• Cavernous sinus. The nerve lies free in the sinus.
• Orbit. The nerve enters the orbit through the superior
orbital fissure, and passes laterally to reach the lateral
rectus muscle.
Extra-ocular muscles
• The lateral rectus muscle of one eye and the medial
rectus muscle of the other work as a yoked pair to
produce horizontal (lateral) eye movements.
• The superior and inferior rectus muscles of each eye work
together (one relaxes as the other contracts) in producing
vertical eye movements. Their effect is maximal when the
eye is abducted, that is, looking outwards, as in this
position the line of pull of the muscles is along the
vertical axis of the eye.
• The superior and inferior oblique muscles each work
together in producing vertical eye movements,
particularly when the eye is adducted, that is, looking
inwards, because in this position their line of pull is along
the vertical axis of the eye.
ETIOLOGY AND PATHOPHYSIOLOGY
Midbrain (IIIrd and IVth cranial nerves) and pons
(VIth cranial nerve)
• Stroke (see p.192).
• Migraine (ophthalmoplegic: IIIrd cranial nerve only).
• Encephalitis (e.g. Listeria) (see p.292).
• Wernicke’s encephalopathy (see p.460).
• MS (see p.340).
• Tumor (see p.357).
Meninges
• Posterior communicating artery aneurysm (IIIrd cranial
nerve only) (622).
• Basilar artery aneurysm or ectasia.
• Infective meningitis: acute and chronic (see pp.273, 279).
• Malignant meningitis.
• Meningovascular syphilis.
• Tumor: chordoma, nasopharyngeal carcinoma.
• Diabetes.
• Sarcoidosis.
• Inflammatory neuropathies: Guillain–Barré syndrome
(Miller Fisher syndrome).
• Infectious neuropathies: herpes zoster, HIV infection,
borrelia (Lyme disease).
• Ischemic neuropathies (at the level of meninges and
along the course of the nerve).
 IIIrd, IVth, and VIth Cranial Nerve (Ocular Motor) Neuropathies 501

Petrous bone apex (VIth cranial nerve only) CLINICAL FEATURES

• Raised intracranial pressure. Assessment of diplopia
• Infection: middle ear. The eyes are normally positioned so the image falls on
• Tumor: nasopharyngeal carcinoma, chondrosarcoma exactly the same spot on the retina of each eye. The
(623). symmetric and synchronous movement of the eyes is termed
conjugate movement or gaze (‘conjugate’ means ‘yoked’ or
Cavernous sinus ‘joined together’). The slightest displacement of either eye
• Pituitary adenoma/apoplexy (see p.268). causes diplopia. Most nerve lesions causing extra ocular
• Meningioma sphenoid wing (see p.374). muscle weakness produce obvious dysconjugate gaze, but
• Nasopharyngeal carcinoma. occasionally, mild lesions or other diseases may cause
• Metastases. diplopia in which the degree of weakness is too slight to be
• Carotid siphon aneurysm expansion or rupture. observed (i.e. the eyes appear to move conjugately but the
• Carotico-cavernous fistula. patient still complains of diplopia). This may be due to
• Cavernous sinus thrombosis. monocular diplopia (due to refractive errors, vitreous
lesions, retinal lesions in the affected eye, or hysteria) or
Superior orbital fissure binocular diplopia (due to a misalignment of the visual
• Sphenoid wing meningioma (see p.374). axes). In this situation the cover test is useful.
• Optic sheath meningioma. The fundamental principle of the cover test is that when
• Metastases. the patient looks in the direction of action of the weak
• Orbital pseudotumor. muscle, the misalignment of the visual axes increases (i.e.
• Tolosa–Hunt syndrome. the disparity in eye movements is greater), and the degree
of separation of the two images increases. The true image
Orbit remains on the macula of the ‘good eye’ but the false image
• Tumor. moves progressively further away from the macula of the
• Cellulitis. lagging eye. The false image is therefore always projected as
the outer image of the two. If the examiner asks the patient
to follow an object until double vision is maximal, and then
determines which eye must be covered to obliterate the
outer (false) image, the affected eye is identified. The weak
muscle can then be deduced from the direction of gaze of
the affected eye.

622 623

622 CT brain scan, three slices in the axial plane, of a patient with a left ocular motor
(IIIrd cranial) nerve palsy due to a ruptured aneurysm of the left posterior
communicating artery.The lower slice, on the left, shows the malalignment of the visual
axes due to the left ocular motor (IIIrd cranial) nerve palsy (the left eye is abducted due
to unopposed action of the left lateral rectus).The middle slice shows some blood in the
pre-pontine cistern and left medial temporal lobe of the brain (arrows).The higher slice,
on the right, shows subarachnoid blood in the suprasellar cistern, the left ambient cistern,
and left quadrigeminal cistern (arrows).

623 PDW axial MRI showing a large mass arising on the right side of the skull base at
the petrous apex, projecting posteriorly into the posterior fossa and anteriorly into the
temporal fossa. Note that the internal carotid artery is elevated by the mass (arrows).
This feature is typical of chondrosarcomas.The calcification (which is frequent) is better
visualized on CT scan. The patient had presented with a painful VIth nerve palsy, which is
also said to be typical, and other cranial nerve palsies had developed later.
502 Cranial Neuropathies
IIIrd cranial nerve (oculomotor nerve) lesion
Diplopia
• Due to weakness of all extraocular muscles except the
lateral rectus and superior oblique (624).
• In the primary position of gaze, the eye is looking ‘down
and out’ due to unopposed action of the lateral rectus
(which abducts the eye ‘out’) and the superior oblique
(which rotates the eye ‘out’ [i.e. intorsion] when the eye
is abducted and the patient attempts to look down).
Ptosis
• Due to damage to the parasympathetic fibers, which run
with the IIIrd nerve, to the levator palpebrae superiorus.
• If complete, covers the eye and so abolishes the diplopia.
Dilated pupil with impaired response to light
and accommodation
• Due to damage to the parasympathetic pupilloconstrictor
nerve fibers, which run along the outside of the IIIrd
nerve. This is almost always the case when the IIIrd
nerve is compressed by a structural (‘surgical’) lesion
such as a posterior communicating artery aneurysm.
• N.B. The pupil is usually spared (i.e. normal) if the IIIrd
nerve palsy is caused by ischemia to the nerve as result of
occlusion of the vasa nervorum (e.g. diabetes, arteritis)
which supplies the inner fibers of the nerve.
• The pupil may not be fully dilated, and appear to be
fixed, in the case of a IIIrd nerve palsy combined with a
Horner’s syndrome, as may occur with a cavernous sinus
lesion.
IVth cranial nerve (trochlear nerve) lesion
Diplopia
• Due to weakness of the superior oblique muscle.
• In the primary position of gaze, there is oblique
separation of the images, due to unopposed action of the
inferior oblique which rotates the eye (i.e. extorsion).
The diplopia can be abolished by tilting the head to the
side contralateral to the lesion.
• The diplopia is maximal, and thus exacerbated, when
looking down and inwards (e.g. as when descending
stairs, or looking at one’s feet or nose), which is the
primary action of the superior oblique.
624
624 Ptosis of the left eyelid with the left eye looking down and out
due to a left oculomotor (IIIrd cranial) nerve palsy, with sparing of the
pupil, in a patient with diabetes mellitus.
VIth cranial nerve (abducens nerve) lesion
Diplopia
• Due to weakness of lateral rectus muscle (625).
• In the primary position of gaze, there is unopposed
action of the medial rectus, and the eye is adducted.
• On attempted lateral gaze to the side of the lesion (i.e.
abduction of the eye), the diplopia is maximal.
DIFFERENTIAL DIAGNOSIS
Ophthalmoplegia
Latent strabismus
• Congenital strabismus (squint) causes dysconjugate gaze
but no diplopia because of longstanding suppression of
vision and amblyopia in one eye.
• A latent strabismus (squint) may break down in adult life,
and lead to intermittent diplopia, under conditions of an
intercurrent illness, fatigue, or drowsiness; or following
the development of uncorrected impaired vision in either
eye, which makes it difficult for the patient with a
lifelong squint to maintain binocular vision.
• A history of a childhood squint or previous orthoptic
exercises is often present.
• The examination reveals normal monocular eye
movements.
• Cover test:
– Cover one of the patient’s eyes and ask the patient to fix
gaze on an object held 40 cm (16 in) away.
– Uncover the eye, and the uncovered eye will be seen
immediately to be deviated inwards or outwards before
quickly returning to align with the fixating eye.
– This unmasks a latent deviation requiring positive muscle
action to keep it compensated. Fatigue allows the eye to
drift, resulting in intermittent diplopia, such as in the
evenings watching TV.
Congenital oculomotor apraxia
Seen in children who have difficulty with horizontal eye
movements and need to blink to produce them.
Impaired conjugate vertical gaze (supranuclear
vertical gaze palsy)
• Midbrain stroke (626).
• Progressive supranuclear palsy.
• Huntington’s disease, Parkinson’s disease and some other
parkinsonian syndromes.
• Hydrocephalus.
• Parinaud’s syndrome (e.g. pineal tumor).
• Wernicke’s encephalopathy.
• Autosomal dominant and idiopathic cerebellar ataxias.
• Vitamin E deficiency.
• Whipple’s disease.
• Hexosaminidase deficiency (GM2 gangliosidoses).
• Niemann–Pick disease.
• Miller Fisher syndrome (probably nuclear/infranuclear).
• Elderly people (particularly upgaze and convergence).
Impaired conjugate horizontal gaze (supranuclear
horizontal gaze palsy)
• Contralateral frontal lobe (eyefield 8) lesion: e.g. stroke,
tumor, abscess.
• Ipsilateral low pontine (abducens nuclear complex/pon-
tine lateral gaze centre) lesion: e.g. stroke, tumor,
demyelination (627, 628).
 IIIrd, IVth, and VIth Cranial Nerve (Ocular Motor) Neuropathies 503

625 626

625 The nine cardinal positions of gaze showing features of a right
abducens (VIth cranial) nerve palsy (due to trauma). Note the inability
to abduct the right eye on attempted lateral gaze to the right due to
weakness of the right lateral rectus muscle. In the primary position of
gaze (looking straight ahead) the right eye is deviated inwards, causing
diplopia, due to the unopposed action of the right medial rectus.
626 Bilateral ptosis, supranuclear vertical gaze pareses (particularly up
gaze), and skew deviation (left eye lower [hypotropia]) due to a rostral
midbrain ischemic stroke. (624–629 courtesy of Mr M Wade,
Department of Medical Illustrations, Royal Perth Hospital,Western
Australia.)

627 628

627, 628 Impaired and dysconjugate lateral gaze to the left due to a left low pontine ischemic stroke affecting the pontine lateral gaze centre.

Internuclear ophthalmoplegia (629) 629

Damage to the MLF, which connects the IIIrd nerve
nucleus above with the opposite VIth nerve nucleus below,
causes the medial rectus ipsilateral to the MLF lesion to fail
to contract synchronously with the contralateral lateral
rectus on attempted lateral gaze to the contralateral side (i.e.
away from the side of the lesion). A unilateral lesion of the
MLF therefore results in incomplete or slow adduction of
the ipsilateral eye but normal abduction of the contralateral
eye when looking away from the lesion. Usually there is
nystagmus in the abducting eye (ataxic nystagmus); the
mechanism is uncertain, but may represent a form of gaze-
paretic nystagmus. The impaired adduction of the ipsilateral
eye is not due to a medial rectus palsy because convergence
and monocular movements are reasonably normal.
Unilateral lesions may be caused by demyelination, 629 Slow and incomplete adduction of the right eye (with horizontal
infarction (paramedian pontine), and tumor; but bilateral nystagmus in the abducting left eye) on lateral gaze to the left due to a
lesions are almost pathognomonic of demyelination (MS). right internuclear ophthalmoplegia in a patient with multiple sclerosis.
504 Cranial Neuropathies
One-and-a-half syndrome
• Paralysis of conjugate deviation of the eyes on horizontal
gaze to one side (the side of the lesion) and an
internuclear ophthalmoplegia on horizontal gaze to the
other side (away from the lesion); i.e. the eye ipsilateral
to the lesion does not abduct or adduct and the
contralateral eye can only abduct, often with associated
ataxic nystagmus.
• Due to a unilateral lesion (usually infarction, demyelina-
tion, or tumor) of the MLF and pontine centre for
horizontal gaze in the low pontine tegmentum.
Neuromuscular junction disorders
Myasthenia gravis: usually but not always bilateral.
Muscle disorders
• Ocular myopathies: usually bilateral.
• Mitochondrial cytopathies (Kearns–Sayre syndrome).
• Ocular muscular dystrophies.
• Facioscapulohumeral dystrophy.
• Myotonic dystrophy.
• Orbital myositis: unilateral or bilateral.
• Orbital tumor: usually unilateral.
• Orbital trauma.
• Dysthyroid eye disease: usually but not always bilateral.
• GCA (ischemia of the orbital muscles or their nerve
supply).
Ptosis
• Congenital.
• Senile (usually bilateral).
• IIIrd cranial nerve (oculomotor nerve) lesion (see
below).
• Horner’s syndrome (partial ptosis only) (see p.494).
Cerebral hemisphere (‘cerebral ptosis’)
Stroke – often non-dominant and right hemisphere.
Midbrain
Syphilis (tabes dorsalis).
Neuromuscular junction
• Myasthenia gravis.
• Lambert–Eaton myasthenic syndrome.
Muscle
• Mitochondrial cytopathies.
• Ocular muscular dystrophies.
• Myotonic dystrophy.
• Orbital trauma.
Unilateral dilated pupil
• Parasympathetic nervous system lesion (i.e. IIIrd cranial
nerve lesion).
• Trauma to the iris (usually irregular).
• Holmes–Adie syndrome (see p.497).
Pseudo VIth nerve palsy
• Hysterical convergence spasm: the pupils are constricted,
due to voluntary convergence. When the patient is asked
to look horizontally to one side, not only do the eyes still
converge, but the pupils remain constricted. Patients
with VIth nerve palsies are not trying to converge the
eyes, and therefore the pupils are not constricted.
• Duane’s syndrome (630, 631): a congenital anomaly
due to fibrous replacement of the lateral rectus muscle
causing impaired action of the lateral rectus muscle, and
thus impaired abduction of the eye. On attempted
adduction of the eye, the eyeball retracts into the orbit,
and consequently the palpebral fissure narrows.
Clinical points
The most likely differential diagnoses can be deduced by
accurately localizing the site of the neurologic lesion (from
the neurologic examination) and the tempo of onset (from
the history).
Important physical signs to seek are:
• Anosmia.
• Visual failure (uniocular or binocular).
• Visual field defects.
• Papilledema.
• Optic atrophy.
• Proptosis.
• Pain around the eye/face/head.
• Vth cranial (trigeminal) nerve involvement.
• Fatiguability.
One of the most common scenarios in neuro-
ophthalmologic practice is the acute onset of an isolated
complete lesion of one oculomotor nerve, with or without
pain around the ipsilateral eye, in a middle-aged or elderly
person. If there is no history of trauma, and there are no
other neurologic symptoms or signs, and particularly if the
pupil is spared in a IIIrd nerve lesion, the most likely cause
is ‘ischemic’. Spontaneous recovery usually begins within
2–4 weeks, during which time it is important to check for
and control any diabetes, arteritis, syphilis, and other
vascular risk factors. Recovery is usually complete. However,
if recovery does not ensue, or if at onset there is pain, a
history or evidence of cancer, the pupil is dilated, or there
are other neurologic signs, then it is important to exclude a
compressive lesion (by CT or MRI scan of brain ±
nasopharynx ± cerebral angiography) and meningeal
infection, inflammation or malignancy (CSF examination).
INVESTIGATIONS, DIAGNOSIS,
TREATMENT AND PROGNOSIS
Depend on the likely site of involvement and cause (622,
623, 632).
 Trigeminal (Vth Cranial Nerve) Neuropathy
630
630 Attempted lateral gaze to the left by a patient with Duane’s
syndrome (congenital fibrosis of the left lateral rectus muscle) showing
impaired abduction of the left eye due to impaired action of the left
llateral rectus muscle.
631
631 Lateral gaze to the right by the same patient as in 630 with
Duane’s syndrome showing retraction of the left eyeball into the orbit,
and consequent narrowing of the left palpebral fissure due to fibrosis
(and failure to relax and stretch) of the left laterial rectus muscle.
632
505
TRIGEMINAL (VTH CRANIAL NERVE)
NEUROPATHY
DEFINITION
Disorder of the trigeminal (Vth cranial) nerve.
EPIDEMIOLOGY
Quite common.
ANATOMY
The largest cranial nerve, it arises from the middle of the
pons and passes forwards and laterally across the
subarachnoid space to form a large ganglion which lies over
the tip of the petrous bone, where the nerve divides into
three.
Sensory
Peripheral
First (ophthalmic) division. Innervates the skin of the
ipsilateral scalp (on top of the head), forehead, cornea and
nose via three branches: the lacrimal nerve (lateral eyelid and
brow); the frontal nerve, and its branches the supratrochlear
and suprorbital nerves (forehead to vertex); and the
nasociliary nerve (cornea, upper medial eyelid, upper side
of nose, tip of nose, alar and vestibule, and nasal mucosa).
The first division carries most of the afferent pathway of the
corneal reflex, with perhaps some contribution from the
second division for the lower half of the cornea. It then
enters the orbit and passes through the superior orbital
fissure, lateral wall of the cavernous sinus (below the
abducens nerve) to the trigeminal sensory ganglion.
Second (maxillary) division. Innervates the skin of the
ipsilateral lower half of the cornea and lower eyelid; cheek
and jaw, sparing the skin over the angle of the mandible
(which is innervated by the C2/C3 nerve roots); midlateral
nose and lateral part of the alar, and the mucous membranes
of the cheek and upper lip. It enters the skull through the
foramen rotundum and then passes in the extreme lower
lateral wall of the cavernous sinus to the trigeminal sensory
ganglion.
Third (mandibular) division. Innervates the skin of the
ipsilateral temple, cheek and upper lip, lower oral cavity,
anterior tongue, and gums. It then enters the skull through
the foramen ovale (with the motor fibers) and passes inferior
to the cavernous sinus to the trigeminal sensory ganglion.
Central
There are two central sensory pathways within the brainstem.
632 T1W coronal MRI showing a large mass (chondrosarcoma) arising
on the right side of the skull base at the petrous apex, projecting
posteriorly into the posterior fossa and anteriorly into the temporal
fossa.The calcification (which is frequent) is better visualized on CT scan.
The patient had presented with a painful VIth nerve palsy, which is also
said to be typical, and other cranial nerve palsies had developed later.
506 Cranial Neuropathies

Touch and afferent arc of the corneal reflex: it enters the mid- Petrous temporal bone apex (Gradenigo’s syndrome)
pons, crosses the midline and ascends through the midbrain • Inflammation: osteitis.
to the contralateral thalamus and then to the face area of the • Infection (trigeminal sensory ganglion): herpes zoster
sensory cortex in the inferior anterior parietal lobe. (usually first sensory division) (633, 634).
• Tumor.
Pain and temperature: it enters the mid-pons but does not
enter the trigeminal nucleus. It descends in the lateral part of Cavernous sinus/superior orbital fissure
the brainstem, parallel to the descending nucleus of the Vth Vascular
nerve, and adjacent to the ascending pain pathway from the • Aneurysm of carotid siphon or ophthalmic artery.
contralateral arm, leg and trunk. It then enters the descending • Carotico-cavernous fistula.
nucleus of the Vth nerve in the lower medulla and upper • Cavernous sinus thrombosis.
cervical cord (C1–2) and crosses to the opposite side.
The crossed fibers in the contralateral lower medulla and Inflammation
upper cervical spinal cord become the secondary ascending • Meningitis (acute and chronic).
tract of the trigeminal nerve (the quintothalamic tract), lying • Sarcoidosis.
adjacent to the medial lemniscus. The fibers then ascend in the • Tolosa–Hunt syndrome.
medial part of the brainstem to the midbrain, where they join
the touch pathways from the same side of the body and face, Tumor
and proceed to the contralateral thalamus and then to the face • Schwannoma (635).
area of the sensory cortex in the inferior anterior parietal lobe. • Pituitary adenoma/apoplexy.
• Meningioma sphenoid wing.
Motor • Nasopharyngeal carcinoma.
The nucleus is in the pons. Efferent fibers leave the base of • Metastases.
the skull, in the mandibular branch of the trigeminal nerve, • Malignant meningitis.
through the foramen ovale. A small branch, the nerve to the
medial pterygoid, supplies the medial pterygoid, tensor Orbit
tympani and tensor veli palatini. The main mandibular nerve • Inflammation: cellulitis.
divides into anterior and posterior trunks. The anterior • Tumor.
trunk conveys the bulk of the motor root and supplies the
muscles of mastication: temporalis, masseter and lateral Mandible
pterygoid. The posterior trunk is mainly sensory (see above) • Inflammation.
and divides into the auriculotemporal nerve, lingual nerve, • Tumor: often metastatic.
and inferior alveolar nerve.
Other
ETIOLOGY • Mixed connective tissue disease.
Pons • Systemic sclerosis.
• Stroke. • Polio (motor loss only).
• MS. • Guillain–Barré syndrome and other peripheral
• Tumor. neuropathies (motor ± sensory).
• Herpes zoster (usually first sensory division).
Medulla • Skull trauma.
• Syringobulbia. • Trichloroethylene (organic solvent) toxicity: bifacial
• Tumor. numbness.
• Organic mercury poisoning.
Cerebello-pontine angle • Isolated trigeminal sensory neuropathy.
• Acoustic neuroma.
• Meningioma. CLINICAL FEATURES
• Trigeminal neuroma. Unilateral lesion
• Glossopharyngeal neuroma. Motor loss
• Epidermoid/dermoid tumor. • Difficult to detect.
• Chordoma. • Wasting of the ipsilateral temporalis and masseter muscles
• Nasopharyngeal carcinoma. may be evident (636).
• Metastases. • The open jaw deviates to the side of the lesion, due to
• Basilar artery ectasia or aneurysm. pterygoid muscle weakness.
• Arteriovenous malformation.
Sensory loss
Base of the skull Sensory disturbance in any or all of the three sensory
• Infective meningitis. divisions, ipsilateral or contralateral to the lesion can occur,
• Malignant meningitis. depending on the location of the lesion (see below).
• Sarcoidosis.
• Meningovascular syphilis.
• Chordoma.
• Nasopharyngeal carcinoma.
• Metastases.
 Trigeminal (Vth Cranial Nerve) Neuropathy
Lesion in the brainstem
• Sensory disturbance in all three sensory divisions can
occur, with or without motor loss:
– A lesion in the pons can result in ipsilateral or contra-
lateral facial pain, temperature, touch and corneal reflex
loss, with or without motor loss.
– A lesion in the medulla can cause ipsilateral or contra-
lateral facial pain and temperature loss only.
– Usually symptoms are associated with other brainstem (e.g.
lower cranial nerve and long tract) and cerebellar signs.
633
635
635 MRI examination of the brain, axial plane,T2W image,
showing a large area of increased signal intensity, due to an
intracavernous Schwannoma of the ophthalmic division of
the right trigeminal nerve, extending from the right
cavernous sinus into the retro-orbital space (causing
proptosis), and compressing the medial right temporal lobe.
507
Cerebello-pontine angle and base of skull
• Ipsilateral facial sensory disturbance (pain [and tem-
perature] and touch [and corneal reflex] loss) in all three
sensory divisions and motor loss occurs.
• Symptoms are associated other ipsilateral cranial nerve
(e.g. VI, VII, VIII, IX), brainstem and cerebellar signs.
Petrous temporal bone apex (Gradenigo’s syndrome)
Ipsilateral sensory disturbance in all three sensory divisions
and motor loss occurs, with associated ipsilateral abducens
(VIth cranial) nerve palsy and/or ear pain.
634
633, 634 Skin rash in the distribution of the mandibular branch of the
left trigeminal nerve due to herpes zoster infection.The patient also has
left facial weakness (Ramsay Hunt syndrome) due to involvement of the
left facial (VIIth cranial) nerve. (Courtesy of Dr AM Chancellor,
Neurologist,Tauranga, New Zealand.)
636
636 Wasting of the left temporalis muscle and weakness
of the left side of the face due to infiltration of the left
trigeminal and facial nerves by metastatic breast carcinoma.
(Courtesy of Dr AM Chancellor, Neurologist,Tauranga,
New Zealand.)
508 Cranial Neuropathies

Cavernous sinus/superior orbital fissure lesion • Known causes need to be excluded, such as a skull base
• Sensory disturbance occurs in the first division, and tumor, mixed connective tissue disease, systemic sclerosis,
sometimes the second division if the lesion is posterior and other connective tissue diseases, but sometimes no
and inferior (i.e. not the superior orbital fissure); the cause can be found.
third division is spared. • Recovery sometimes occurs after weeks or months.
• Symptoms are associated with ocular motor (IIIrd, IVth,
and VIth cranial) nerve palsies, optic nerve or chiasm DIFFERENTIAL DIAGNOSIS
compression, and sometimes pain above and within the Pain in and around the eye
orbit. • Glaucoma.
• Proptosis, eyelid and conjunctival edema, episcleral • Iritis.
vasodilatation, and papilledema may be present if there • Optic neuritis.
is venous obstruction (e.g. cavernous sinus thrombosis) • Distal carotid or posterior communicating artery
or a carotico-cavernous fistula (also pulsating exophthal- aneurysm.
mos and orbital bruit). • Dissection of the internal carotid artery.
• The Tolosa–Hunt syndrome is the subacute onset of • Diabetic IIIrd nerve palsy.
severe unilateral orbital pain which may be accompanied • Post-herpetic neuralgia.
by sensory disturbance in first and sometimes the second • Migrainous neuralgia (cluster headache).
division of the trigeminal nerve, and ocular motor (IIIrd, • Ophthalmoplegic migraine.
IVth, and VIth cranial) nerve palsies. The ESR may be • Nasopharyngeal tumors.
raised. It is very rare and the cause is sometimes a chronic • Lesions of the petrous apex, cavernous sinus, superior
inflammation behind and/or within the orbit. It can only orbital fissure, and orbit (see above).
be diagnosed after excluding the other painful
inflammatory and neoplastic causes in the superior orbital Pain in the face
fissure listed above. • As for pain in the eye (see above).
• Trigeminal neuralgia (see p.509).
Orbital lesion • Atypical facial pain.
Sensory disturbance in the first division only. • Cervical spondylosis.
• Cerebello-pontine angle tumor.
Foramen ovale or mandibular lesion • Trigeminal neurofibroma.
Sensory disturbance in the third division only; sometimes • Isolated trigeminal sensory neuropathy.
only unilateral numbness of the chin. • Gradenigo’s syndrome.
N.B. Sometimes the sensory loss may be a very restricted • Nasopharyngeal tumor.
area within the territory of a sensory division of the • Post-herpetic neuralgia.
trigeminal nerve if only a few fibers of a division are affected, • Internal carotid artery dissection.
as in the case of a skull base tumor, for example. • Angina (usually in neck and jaw, rather than face).
• Tabetic lightning-like pains.
Bilateral lesion
Sensory Weak jaw muscles
• Bilateral facial sensory loss occurs, which may not be • Motor neuron disease.
complete (e.g. it may be in an ‘onion skin’ distribution • Myasthenia gravis.
as may occur with syringobulbia [see p.541]). • Myopathy.
• There may be a history of exposure to trichloroethylene
(an organic solvent in glue, paint stripper, and paint) or INVESTIGATIONS
organic mercury (e.g. methyl mercury discharged into These depend on the clinical syndrome and likely location
water and entering fish, or contaminated grain from and etiology:
fungicides). • Direct examination of the nasopharynx and larynx.
• There may be systemic evidence of a connective tissue • MRI or CT scan of brain, base of skull and orbits (636).
disease such as progressive systemic sclerosis, SLE and • CSF examination.
polymyositis (mixed connective tissue disease). • Full blood count and ESR.
• Fasting blood glucose.
Motor • Autoantibody screen, antiribonuclear protein.
More obvious symptoms, with weakness and wasting of the • Chest x-ray.
temporalis and masseter muscles bilaterally, are usually • Carotid angiography if a carotico-cavernous fistula is
evident. If severe, the jaw hangs open. suspected.

SPECIAL FORMS DIAGNOSIS

Isolated trigeminal sensory neuropathy Clinical.
• Uncommon.
• It may begin as a small numb patch on the face which TREATMENT
spreads to the territory of innervation of the whole Determined by the cause.
division of the nerve and then to the adjacent divisions
and even the whole face. PROGNOSIS
• Severe loss of pain sensation in the face may lead to Depends on the cause.
ulcerative lesions around the nose and of the cornea.
 Trigeminal Neuralgia (Tic Douloureux, Paroxysmal Facial Pain)
TRIGEMINAL NEURALGIA (TIC
DOULOUREUX, PAROXYSMAL
FACIAL PAIN)
DEFINITION
A degenerative condition of the trigeminal nerve pathways,
characterized by severe stabbing pains in the distribution of
one or more divisions of the trigeminal nerve. The
condition is known as tic douloureux (a painful spasm)
because of the typical lightning-like jabs of pain.
EPIDEMIOLOGY
• Incidence: 2–8 per 100 000 per year.
• Lifetime prevalence: 0.7% (95% CI: 0.4–1.0%) of general
population; 4% of MS patients.
• Age: usually starts after the age of 40 years, most
commonly in the sixth and seventh decades.
• Gender: F>M (1.6:1).
PATHOLOGY
Focal demyelination and microneuromas are often present
at the site of microvascular compression of the trigeminal
nerve but these features may also be found in asymptomatic
subjects.
ETIOLOGY
Idiopathic
The most common ‘cause’.
Vascular compression of the trigeminal nerve root
Branches of the anterior or superior cerebellar arteries
impinge on the root of the trigeminal nerve where it enters
the mid-pons.
Secondary causes
• A plaque of demyelination (MS) at the root entry zone
in the pons accounts for 2–3% of all cases of trigeminal
neuralgia and up to 8% of younger patients.
• A small tumor arising from the trigeminal nerve itself
(e.g. neuroma) or compressing the trigeminal nerve (e.g.
cerebello-pontine angle neurofibroma, meningioma, or
angioma).
• Rarely, arteriovenous malformations, aneurysms, and
herpes zoster may be implicated.
PATHOPHYSIOLOGY
Uncertain.
Compression hypothesis
Vascular compression of the trigeminal root appears to be
an important contributing factor. At posterior fossa
exploration, many patients are found to have a trigeminal
root that is compressed or even grooved by a blood vessel,
usually the superior cerebellar artery.
It is thought that compression results in partial demye-
lination and axonal damage, rendering the axons hyper-
excitable. Damaged axons that are near each other become
susceptible to chemical coupling. Under these conditions,
normal impulses elicited by light mechanical stimulation can
recruit nearby pain fibers, particularly if they have already
been made hyperexcitable by axonal damage. This results in
synchronous discharge and, therefore, intense pain.
509
CLINICAL FEATURES
History
Pain
• Site: face or mouth. Commonly starts in the dermatome
of the second or third division of the trigeminal nerve;
only 5% start in the first division.
• Trigger factors:
– Talking.
– Chewing.
– Swallowing.
– Shaving.
– Cleaning the teeth.
– Wind blowing on the face.
• Trigger points: areas around the nose, lips or mouth
which, when touched, evoke a paroxysm. When sites are
inside the mouth patients become hesitant about eating,
drinking and brushing their teeth.
• Nature: stabbing/lightning or electric shock-like/pene-
trating jabs of pain or clusters of stabbing pains.
• Duration: brief (seconds) and followed by long pain-free
intervals.
• Episodic pattern: pain may recur many times a day for
weeks or months, and then may remit for months or
years (as for cluster headache).
Complications
Patients may become anxious and withdrawn because of the
pain. Oral hygiene may suffer and weight loss may occur as
patients attempt to avoid triggering the pain: depression,
dehydration, and even suicide can occur in severely afflicted
patients.
PHYSICAL EXAMINATION
Normal in idiopathic trigeminal neuralgia. If abnormal, such
as ipsilateral trigeminal nerve sensory loss, depressed corneal
reflex, or deafness; or if an aching pain persists between the
characteristic stabs, then an underlying cause for the tic-like
pains must be searched for; these include intra-axial lesions
such as MS plaques, and extra-axial lesions that compress
the trigeminal nerve or root such as acoustic neuroma,
trigeminal neuroma and other posterior fossa tumors.
DIFFERENTIAL DIAGNOSIS
• Temperomandibular joint disorders.
• Atypical dental pain.
• Phantom tooth pain.
• MS.
• Glossopharyngeal neuralgia: extremely rare. Pain is of a
similar nature (i.e. severe, unilateral, lancinating, and
episodic) but at a different site: pain arises from the
throat, larynx, pharynx, or pinna of the ear (i.e. in the
distribution of the IXth [glossopharyngeal] nerve).
510 Cranial Neuropathies

INVESTIGATIONS
CT brain scan, or ideally MRI brain scan
CT may not identify intra-axial demyelination or small extra-
axial neurofibromas. Scans should be used particularly if the
patient is young, bilateral pain is present (more common in
MS), or neurologic signs (e.g. deafness) (637).
Surgical
If the pain persists in spite of best medical management, one
of several surgical procedures can be undertaken. These are
either decompressive or denervating (i.e. permanently
damage the trigeminal nerve). However, no clinical trials
have established the efficacy of any surgical procedure.

Tomographic magnetic resonance angiography Decompression

MRA allows the simultaneous visualization of blood vessels
and neural tissue against a dark background of CSF. In a
series of 50 patients with trigeminal neuralgia, neurovascular
contact was demonstrated on the affected side in 51 of 55
symptomatic nerves studies and on the contralateral side in
only four of 45 nerves.
DIAGNOSIS
Clinical.
TREATMENT
Most patients can be managed medically.
Posterior fossa exploration and microvascular decompression
(the Jannetta procedure) consists of separating/removing
and decompressing the offending artery or vein from the
trigeminal nerve root. The majority of patients have im-
mediate relief after microvascular decompression, although
some later have recurrent pain. The advantage of this
procedure is that facial sensation is preserved. The operation
has risks which include cranial hematomas, CSF leakage,
meningitis, ipsilateral facial paresis or hearing loss (1%),
brainstem infarction (0.1%) and death (0.2%). Despite its
risks, microvascular decompression is currently the best first
surgical option, especially late in the course of the disease.

Medical
Carbamazepine 200 mg three times daily, is the drug of
choice for idiopathic trigeminal neuralgia, being effective
initially in about three-quarters of patients. It may control
symptoms by suppressing sodium ion currents in the
trigeminal caudal nucleus or in the gasserian ganglion. A
small dose of 50–100 mg nightly is the usual starting dose
(to avoid drowsiness), escalating in weekly increments until
pain relief is achieved (or adverse effects occur). A slow 637
release preparation can also be used. The dose is continued
for 1 month or so, and can then be tapered slowly, reloading
if the pain recurs. Most responders will experience about
6–12 months of respite before recurrence. Up to one-third
of patients cannot tolerate carbamazepine in the doses
required to alleviate the pain, because of adverse effects such
as rash, nausea, drowsiness, and ataxia. Carbamazepine may
also cause hyponatremia, megaloblastic anemia (folate
interaction), aplastic anemia, agranulocytosis and
hypersensitivity reactions.
Alternatives, which may be as, or more, effective include:
• Phenytoin 200–400 mg nocte, or 100 mg three times
daily. Less effective than carbamazepine but can be given
intravenously for acute relapses of pain, in a similar
regimen to that given for status epilepticus.
• Baclofen, a gamma-aminobutyric acid-B-receptor
agonist, 10–20 mg three times daily.
• Clonazepam.
• Pimozide.
• Oxcarbazine.
• Mexiletine.
• Gabapentin.
• Lamotrigine, which is at least as potent as carbamazepine
in inactivating sodium ion currents, with fewer adverse
effects, and is effective in some cases. Lamotrigine is a
potent antiglutamatergic agent which may depress
excitatory transmission in the trigeminal caudal nucleus.
It may cause initial ataxia, diplopia, nausea, vomiting, and
blurred vision in 15–35% of patients but these are often 637 MRI brain scan,T2W image, axial section through the mid-pons of
dose related. An allergic skin rash is seen in 3–17% of a patient with trigeminal neuralgia due to multiple sclerosis.The MRI
patients. shows multiple areas of high signal, consistent with demyelination
(arrows), in the mid-pons bilaterally (and also in the deep white matter
of the temporal lobes) involving the intra-axial component of the
trigeminal nerves bilaterally.
 Facial (VIIth Cranial Nerve) Neuropathy
Denervation
• Percutaneous stereotactic radiofrequency thermal
rhizotomy of the trigeminal (Gasserian) ganglion. This
is a relatively simple procedure in which a probe is
inserted into the foramen ovale under local anesthesia
without the need for craniotomy. General anesthesia is
required for the very painful process of coagulation. This
procedure is effective in most cases and preserves some
sensation but troublesome dysesthesia develops in about
one-sixth of cases.
• Percutaneous glycerol (glycerin) rhizotomy.
• Balloon compression of the trigeminal ganglion.
• Intracranial nerve section of the appropriate divisions of
the trigeminal nerve.
Percutaneous procedures are less invasive than
microvascular compression and are associated with low rates
of mortality and morbidity but they all create trigeminal
nerve lesions, occasionally producing anesthesia dolorosa or
keratitis.
PROGNOSIS
Commonly the episodes of pain follow a relapsing and
remitting course, with exacerbations lasting weeks to months
and spontaneous remissions that become shorter and less
frequent over the years. Some patients go into spontaneous
remission, and if soon after onset, may last for years.
Ten years after microvascular decompression surgery,
70% of patients are free of pain without medication for tic.
Another 4% have occasional pain that does not require long
term medication.
The frequency of recurrent pain is similar for both micro-
vascular decompression and percutaneous radiofrequency
rhizotomy. Recurrence is more likely and occurs sooner after
milder damage to the trigeminal nerve, produced either
chemically or by compression with a percutaneously
positioned balloon.
Predictors of recurrence after microvascular decom-
pression:
• Female sex.
• Symptoms lasting >8 years before surgery.
• Venous compression of the trigeminal root entry zone.
• Lack of immediate cessation of tic.
511
FACIAL (VIITH CRANIAL NERVE)
NEUROPATHY
DEFINITION
Disorder of the facial (VIIth cranial) nerve.
EPIDEMIOLOGY
• Common.
• Age: any age.
• Gender: M=F.
ANATOMY
The facial nucleus and nerve is mainly a motor nerve
supplying all the muscles concerned with facial expression
on one side.
Motor (facial muscle) innervation
Supranuclear (upper motor neuron)
• Precentral gyrus of the cerebral motor cortex: the
innervation of the facial muscles begins in the most
lateral and inferior aspect of the precentral gyrus, near
the Sylvian fissure. This region is supplied by a branch of
the middle cerebral artery.
• Centrum semiovale. From the motor cortex the axons
pass through the centrum semiovale and converge in the
internal capsule.
• Internal capsule. The fibers to the face are located at the
genu of the internal capsule (the fibers to the arm are
posterior to the facial fibers, and the fibers to the leg are
posterior to the arm fibers).
• Midbrain cerebral peduncles. From the internal capsule
the motor fibers continue down through the cerebral
peduncles where the facial fibers are most medial, the
arm fibers are lateral to them, and the leg fibers are most
lateral.
• Lower pons. The motor fibers continue down to the
lower pons where they innervate the upper part of the
ipsilateral facial nucleus (which controls the upper face
muscles) and also cross to innervate the contralateral
facial nucleus. Because the upper part of the facial
nucleus, that controls the upper facial muscles, receives
innervation from both cerebral hemispheres, a unilateral
hemisphere lesion impairs only the lower facial muscles.
Nuclear and infranuclear (lower motor neuron)
The motor nucleus of the facial nerve lies ventral and lateral
to the abducens nucleus in the lower pons. From the facial
nucleus, all the nerve fibers that innervate the ipsilateral
facial muscles ascend posteriorly and medially to hook
around the abducens nucleus before travelling forward
through the pons (just lateral to the corticospinal tract), the
subarachnoid space, the internal auditory meatus, the
petrous temporal bone, the parotid gland, and the
subcutaneous facial region to the muscles of facial expression
(except the elevators of the eyelids). Therefore, a lesion in
the facial nucleus or proximal part of the nerve, before it
gives off branches in the parotid gland, impairs all the
ipsilateral muscles of facial expression. The facial nerve also
supplies the small stapedius muscle that damps oscillations
of the tympanic membrane in response to loud sounds.
512 Cranial Neuropathies

Sensory (tongue taste) innervation Associated neurologic symptoms

• The sensory component of the facial nerve is small (the • Ipsilateral hemiparesis, hemisensory loss, hemineglect,
nervus intermedius of Wrisberg); it conveys taste hemianopia suggest a supranuclear (upper motor
sensation from the anterior two-thirds of the tongue and neuron) facial palsy.
probably cutaneous sensation from the anterior wall of • Contralateral hemiparesis, ipsilateral limb ataxia, facial
the external auditory canal. numbness and gaze palsy to the side of the facial
• The taste fibers from the anterior two-thirds of the weakness may be signs of an intra-axial low pontine
tongue first traverse the lingual nerve (a branch of the lesion and indicate a nuclear/infranuclear (lower motor
mandibular nerve) and then diverge to join the chorda neuron) facial neuropathy.
tympani (a branch of the VIIth cranial nerve); thence • Ipsilateral sensorineural deafness indicates a lesion in the
they pass through the pars intermedia and geniculate ipsilateral brainstem, cerebello-pontine angle or petrous
ganglion of the VIIth nerve to the rostral part of the temporal bone because of the close proximity of the
nucleus of the tractus solitarius in the medulla. vestibulocochlear nerve (see p.517).
• Secretomotor fibers innervate the lacrimal gland through • Ipsilateral reduced corneal reflex and ataxia are suggestive
the greater superficial petrosal nerve and the sublingual of a cerebello-pontine angle lesion. The corneal reflex
and submaxillary glands through the chorda tympani. can be assessed when ipsilateral paralysis of eyelid closure
is present by asking the patient if a stimulus is felt, and
ETIOLOGY by observing the normal consensual closure of the
Brainstem opposite eyelid and the upward roll of the eyeball when
• Stroke. the cornea is touched on the paralysed side. The last sign
• Pontine glioma. (‘Bell’s phenomenon’) is also apparent when the patient
• MS. attempts to close the eye forcefully and is a normal event,
• Abscess. albeit usually invisible.
• Ptosis is not found with isolated facial nerve lesions and,
Cerebello-pontine angle if present, may indicate a Horner’s syndrome or an
• Acoustic neuroma. oculomotor nerve lesion.
• Meningioma. • Vesicles in the external ear canal and on the palate are
suggestive of herpes zoster infection.
Geniculate ganglion • Altered taste and hyperacusis suggest a lesion of the facial
Herpes zoster (Ramsay Hunt syndrome) (638–640). nerve in the facial canal (e.g. Bell’s palsy). However,
Bell’s palsy should not be diagnosed if deafness, reduced
Facial canal corneal reflex or ptosis are present.
Bell’s palsy (see p.515). • Otitis, trauma, and steadily worsening facial weakness
suggest a lesion of the facial nerve in the petrous
Petrous temporal bone temporal bone.
• Trauma: fracture. • Parotid mass or trauma suggest a lesion of facial nerve
• Infection: Pseudomonas aeruginosa. branches.
• Tumor: metastatic, invasive meningioma. • Peripheral nervous system signs such as sensory
disturbances in the distal extremities suggest a lower
Facial nerve branches motor neuron facial palsy.
• Parotid gland tumor or infection.
• Trauma: facial lacerations. Pre-existing medical conditions which could cause or
• Leprosy. predispose to facial weakness
Risk factors for ischemic stroke and ischemic neuropathy:
Facial mononeuropathy • Increasing age.
• Ischemic: small vessel disease (e.g. vasculitis). • Hypertension.
• Sarcoidosis. • Cigarette smoking.
• Behçet’s syndrome. • Hypercholesterolemia.
• Sjögren’s syndrome. • Diabetes mellitus.
• Syphilis.
• Lyme disease. Ear and parotid gland infections

CLINICAL HISTORY Head trauma with basal skull fracture

Rate of onset of weakness
• Sudden or rapid onset within hours suggests trauma or
a vascular etiology such as stroke or peripheral ischemic
neuropathy if the weakness is unilateral, and
Guillain–Barré syndrome if the weakness is bilateral.
• Subacute or gradual onset over days or weeks is most
likely idiopathic (Bell’s palsy) or the result of an infection
or weakness.
Malignancy
PHYSICAL EXAMINATION
• Drooping of one side of the face with flattening of the
forehead creases, widening of the palpebral fissure,
flattening of the nasolabial fold, lowering of the corner
of the mouth, and impaired smiling and grinning are
observed at rest.
• The eye may be red and dry as a result of impaired
blinking or decreased lacrimation.
 Facial (VIIth Cranial Nerve) Neuropathy
• The patient is unable to elevate the eyebrow, wrinkle the
forehead, and close the eye on the affected side.
• Air escapes between the lips on the affected side when
the cheeks are puffed with air.
• Emotional facial movements are also impaired.
• Corneal reflex is impaired because the lesion affects the
efferent part of this reflex arc.
• Taste may be impaired if the facial nerve is lesioned
proximal to the chorda tympani nerve branch, within the
temporal bone, which carries taste sensation from the
anterior two-thirds of the tongue.
• Speech is usually slurred (flaccid dysarthria).
• Sounds may be exaggerated (hyperacusis) if the facial
nerve is lesioned proximal to the stapedius nerve branch
in the temporal bone, which supplies the ipsilateral
stapedius muscle to dampen loud sounds.
• Associated CNS, cranial nerve, or peripheral nervous
system signs may be present such as hemisensory loss on
the contralateral side or gaze palsy on the same side as
the lower motor neuron facial weakness (suggesting a
low pontine lesion), multiple cranial neuropathies
(suggesting basilar meningitis or vasculitis) or sensory
disturbances in the distal extremities or muscle wasting
(which may indicate an underlying neuropathy).
638
638, 639 Weakness of the left forehead (and lower facial muscles) on
attempts to raise the eyebrows (638) and herpetic skin rash involving
the external ear (639) due to herpes zoster infection (Ramsay Hunt
syndrome) of the left facial nerve.
640 Vesicles on the right side of the palate due to varicella-zoster virus
infection in a patient with a right lower motor neuron facial palsy due to
varicella-zoster virus infection (Ramsay Hunt syndrome).
513
• Otoscopy of the external auditory canal may reveal signs of
infections and tumors in the tympanic cavity which could
be relevant (e.g. vesicles of the external ear suggest herpetic
facial neuropathy [Ramsay Hunt syndrome] [639]).
Examination of the oral cavity may reveal vesicles on the
palate in patients with Ramsay Hunt syndrome (640).
N.B. The distinction between upper and lower motor
neuron facial weakness made on examination is very reliable
if made during acute weakness. However, after a partial
recovery has occurred, lower motor neuron facial weakness
may occasionally resemble upper motor neuron weakness.
SPECIAL FORMS
Ramsay Hunt syndrome (herpes zoster
facial paresis)
• Reactivation of the varicella-zoster virus.
• Otalgia.
• Hearing loss.
• Vesicles in the external ear canal and palate (639, 640),
from which varicella-zoster virus can be easily recovered.
• Seroconversion is common, with an increase in specific
antibody to VZV.
• Worse prognosis than Bell’s palsy.
• Treat with oral antiviral agents: aciclovir (acyclovir),
famcyclovir, valaciclovir (valacyclovir).
639
640
514 Cranial Neuropathies

DIFFERENTIAL DIAGNOSIS INVESTIGATIONS

Upper motor neuron facial weakness
Clinical features
• Normal appearance of the forehead and width of the
palpebral fissure.
• Emotional lower facial movements, such as smiling, are
usually intact despite weakness of voluntary lower facial
movements, because facial innervation for voluntary
movements comes from the pyramidal motor cortex
whereas facial innervation for emotional facial expression
comes from extrapyramidal cerebral regions (e.g.
thalamus).
• Preservation of eyebrow elevation, forehead wrinkling,
and eye closure.
• Corneal reflex is intact because the lesion is above this
reflex arc.
• Associated CNS signs may be present: hemiparesis,
hemisensory loss, hemineglect, hemianopia.
Causes
• Stroke: 85% ischemic, 15% hemorrhagic.
• Brain tumor: primary or metastatic, hemispheric or
brainstem.
• Brain abscess.
MRI brain/temporal bone scan
• Indicated when a brain or temporal bone lesion is
suspected.
• It is more sensitive than CT brain scan of the posterior
fossa, which is limited by bone artifacts.
• Reveals gadolinium-induced enhancement of the facial
nerve in acute cases of Bell’s palsy.
CT brain scan
CT is superior to MRI in demonstrating basal skull
fractures, if suspected.
Blood serology titres
Herpes simplex; herpes zoster; Lyme disease.
CSF
• Indicated if possible meningitis or vasculitis (e.g. fever,
headache, nuchal rigidity, or systemic signs of vasculitis).
• Inconsistently shows mildly elevated cell counts and
protein levels in Bell’s palsy.
Electrodiagnostic studies
May be used to prognosticate recovery.

Lower motor neuron facial weakness DIAGNOSIS

Associated with multiple cranial nerve deficits Clinical.
• Infectious basal meningitis: common bacteria (pneumo-
coccus, meningococcus, Haemophilus influenzae), TREATMENT
Mycobacterium tuberculosis, Lyme borreliosis, syphilis, Determined by the cause.
fungi, HIV.
• Carcinomatous basal meningitis. PROGNOSIS
• Basilar skull tumor. Determined by the cause.

Bilateral lower motor neuron facial weakness

Rapid onset:
• Guillain-Barré syndrome (may be HIV associated).
• Sarcoidosis.
• Vasculitis.
• Botulism.
• Basal meningitis.
• Stroke.
• Lyme disease.

Slow onset or longstanding:

• Congenital hypoplasia of the facial nuclei (Möbius
syndrome).
• Myasthenia gravis.
• Muscular dystrophy and other myopathies (e.g.
facioscapulohumeral muscular dystrophy).
 Acute Idiopathic Facial Paralysis (Bell’s Palsy) 515

ACUTE IDIOPATHIC FACIAL DIFFERENTIAL DIAGNOSIS

PARALYSIS (BELL’S PALSY) Lower motor neuron facial weakness
• Isolated unilateral lower motor neuron facial weakness,
without other neurologic deficits.
DEFINITION • Direct facial nerve infections: herpes viruses (e.g.
A unilateral, lower motor neuron facial paralysis that is reactivation of the varicella-zoster virus [Ramsay Hunt
probably due to acute viral inflammatory demyelination of syndrome]: vesicles in the ear from which varicella-zoster
the facial nerve causing swelling and secondary nerve virus can be easily recovered; seroconversion often, with
ischemia within the facial canal. increase in specific antibody to VZV); Lyme disease.
• Ischemic facial neuropathy due to small vessel disease
EPIDEMIOLOGY (e.g. vasculitis).
The most common cause of facial paralysis. • Sarcoidosis, Behçet’s syndrome, Sjögren’s syndrome,
• Incidence: 20–30 per 100 000 persons per year. syphilis.
• Age: any age. • Middle ear infections: common organisms, Pseudomonas
• Gender: M=F. aeruginosa.
• Middle ear tumors.
PATHOLOGY • Temporal bone fracture.
• Inflammation of the facial nerve is present within the • Temporal bone tumors: metastatic, invasive meningioma.
subarachnoid space, composed largely of lymphocytes • Parotid gland tumors or infections.
with associated demyelination or axonal destruction or • Facial lacerations.
both.
• Studies of autopsy material have shown latent herpes Upper motor neuron facial weakness
simplex virus (HSV) in the geniculate ganglia of humans. • Stroke.
• Brain tumor.
ETIOLOGY AND PATHOPHYSIOLOGY • Brain abscess.
• Uncertain.
• Probably acute viral inflammatory demyelination within INVESTIGATIONS
the facial canal, causing swelling of the nerve within the Not usually necessary, unless there is doubt about the
facial canal and secondary ischemia. diagnosis.
• Viral infection:
– HSV is the strongest association: reactivation of HSV 1 Blood serology titres
genomes. HSV might be present in the geniculate A light preponderance of elevated titres against HSV,
ganglia where it could cause a facial nerve palsy when the compared with controls but increased titres are the
virus travels down the nerve axon, perhaps infecting the exception rather than the rule.
Schwann cells.
– Mumps.
– Epstein–Barr virus. 641
– Cytomegalovirus.
– Coxsackievirus.
– Influenza.
– HIV.
• Autoimmune reaction.

Risk factors
• Diabetes: fivefold increased risk.
• Pregnancy: threefold increased risk.

CLINICAL FEATURES
• A viral prodrome is present in about 60% of patients.
• Pain behind the ear, evolving over about 48 hours before
reaching a plateau.
• Unilateral facial weakness of lower motor neuron type
(see p.511) (641) follows the pain, and may be
associated with excessive tearing due to weakness of the
orbicularis oculi (which normally holds the lacrimal
puncta against the conjunctiva).
• Ipsilateral facial numbness is a common symptom, but
objective sensory testing is normal.
• Taste may be altered.
• Sensitivity to sound (hyperacusis) may be increased, such
as when using a telephone. 641 Weakness of the left facial muscles in a patient with a left Bell’s
palsy who is attempting to close his eyes gently and grimace. He does
not demonstrate a Bell’s phenomenon (upward deviation of the
eyeballs on attempted eye closure).
516 Cranial Neuropathies
CSF
Inconsistently shows mildly elevated cell counts and protein
levels.
MRI brain scan
• Indicated when a brain lesion is suspected (e.g. when
more than an isolated lower motor neuron facial palsy is
present).
• MRI scans are more sensitive than CT brain scan of the
posterior fossa, which is limited by bone artifacts.
• Reveals gadolinium-induced enhancement of the facial
nerve in acute cases of Bell’s palsy.
PCR techniques
• These are used to amplify viral genomic sequences from
endoneurial fluid collected from the facial nerve or tissue
of the posterior auricular muscle innervated by the facial
nerve in patients undergoing decompressive surgery.
• In one study, HSV type 1 genomes were amplified from
the nerve or muscle tissue of 11 of 14 patients with Bell’s
palsy. However, PCR does not distinguish between viral
genomes that are present in a latent state and those that
are present because of reactivated virus in the course of
a productive infection.
Electrodiagnostic studies
Electroneurography may be used to prognosticate recovery,
but not to make the diagnosis.
DIAGNOSIS
A clinical diagnosis of exclusion:
• Lower motor neuron facial weakness (peripheral facial
nerve palsy).
• No other neurologic deficits.
• No apparent cause, other than a herpes simplex virus,
after prolonged follow-up (until the condition has
resolved or fresh clues to a specific cause appear).
TREATMENT
Corticosteroids
Controversial, partly because of the good prognosis of the
untreated condition and the failure of controlled trials to
prove a beneficial effect on long term outcome.
Nevertheless, steroids are used empirically by some
neurologists to:
• Relieve pain that is sometimes an early feature.
• Prevent progression of incomplete to complete paralysis.
• Prevent denervation in cases of complete paralysis.
• Shorten the time to recovery.
• Retard development of abnormal synkinesias.
It is likely that any benefit obtained is due to steroids
used early in the course (within 1 week of onset). The usual
regime is prednisolone, 25 mg per day, orally, for 1 week,
with patient review on completion. Corticosteroids should
not be used when contraindications exist, such as diabetes,
hypertension, peptic ulcer disease, osteoporosis, glaucoma,
or pregnancy.
Acyclovir
May be effective if the underlying cause is herpes virus infec-
tion. More data are needed from a large, randomized con-
trolled and blinded trial with at least 12 months’ follow up.
Other treatments
There is no proven place for adjunctive therapies or surgical
decompression of the facial nerve in Bell’s palsy.
Avoid complications
Exposure keratitis
• Occurs if the cornea is not adequately protected.
• It can be avoided by using artificial tears, instilling
lubricating paraffin ointment, and taping (rather than
padding) the eye closed at night.
• Dark glasses should be worn outdoors.
• Ophthalmic advice should be sought if the patient
reports eye discomfort or the eye becomes irritated
despite the above measures.
• Botulinum toxin injection into the eyelid levator to
weaken it may be considered if conservative measures fail.
• Tarsorrhaphy is rarely necessary in cooperative patients.
PROGNOSIS
60–80% of patients recover completely. In these cases,
recovery usually begins within 8 weeks and is complete by
6–12 months. The most favorable prognostic sign is an
incomplete rather than complete facial palsy. If weakness is
severe or complete, recovery commencing within 3 weeks
is a favorable sign. The longer the delay in return of
movement the poorer the recovery.
Predictors of incomplete recovery are:
• Complete facial weakness.
• Pain other than in or around the ear (i.e. back of head,
cheek, other).
• Systemic hypertension, diabetes or psychiatric illness.
• Older age.
• Hyperacusis.
• Decreased tearing.
Residual deficits include:
• Facial weakness.
• ‘Jaw winking’ and other abnormal facial movements
(synkinesias) caused by aberrant reinnervation of the
muscles of facial expression by regenerating facial nerve
fibers (i.e. a miswiring).
• ‘Crocodile tears’ (rare): an excessive flow of tears when
eating, caused by aberrant reinnervation of the lacrimal
gland by regenerating facial nerve fibers.
Recurrent facial palsy occurs in about 10% of patients. If
this occurs, alternative causes should be excluded, such as
diabetes, sarcoidosis, tumors, or infection.
 Vestibular-cochlear (VIIIth Cranial Nerve) Neuropathy
VESTIBULAR-COCHLEAR (VIIITH
CRANIAL NERVE) NEUROPATHY
DEFINITION
Disorder of the vestibulo-cochlear (VIIIth cranial) nerve.
EPIDEMIOLOGY
Not uncommon.
ANATOMY
The vestibulo-cochlear nerve carries information from two
highly specialized end organs, the vestibular apparatus and
the organ of Corti, both of which lie deep in the temporal
bone where they are suspended in perilymph (which is
basically CSF which is in continuity with the subarachnoid
space). Endolymph is a highly specialized fluid which has a
high protein content and fills the semicircular canals of the
labyrinth and the scala media of the cochlear.
Vestibular apparatus
Semicircular canals
• Situated in the temporal bone on each side of the head.
• Each side contains three fine tubes/canals orientated in
three different planes.
• When the head is in the normal upright position facing
forwards, the lateral canal is tilted up 30° from the plane
of the floor; it is not horizontal.
• When the head is reclined backwards 60° so that it is 30°
from the plane of the floor, the lateral canal lies vertically
(i.e. at 90° from the floor).
• The end of each canal joins the utricle where there is a
swelling called the ampulla.
• The ampulla contains the cupola and the hair cells.
• The hair cells are polarized to respond to movement in
one direction only by the position of the single
kinocilium on each cell.
• In the lateral canal, movement towards the utricle
stimulates the cupola, and in the vertical canals
movement away from the utricle stimulates the cupola.
• The semicircular canals work as three matched pairs in
the three planes.
• Neural activity generated by the canals in transmitted in
the vestibular nerve to the vestibular nucleus on the same
side of the brainstem, and then to the oculomotor nuclei.
Utricle
• Contains an otolith organ which senses tilting of the
head.
• The organ is plate-shaped, tilted up at the anterior end,
and covered with hairs polarized toward the bend.
• Head tilt leads to variation in pressure of the calcium
carbonate crystals on the hairs because of the effect of
gravity.
Saccule
• Contains an otolith organ which senses angular
acceleration of the head.
• The organ is shaped like a shield, with a central ridge
facing forwards.
• Forward movement forces the crystals to slide down the
slope on either side in proportion to the speed and angle
of movement.
517
Auditory apparatus
Cochlear
• A fluid-filled spiral tube, which is divided into three
compartments by a roof membrane (of Reissner) and a
basilar membrane.
• Endolymph fills the closed cavity between the
membranes, and perilymph fills the cavities on either
side.
• At the apex the membrane has a diameter of 0.5 mm and
at the base the membrane diameter is 0.04 mm,
responding to low tones and high tones respectively.
Organ of Corti
• Receptor hair cells which lie on supporting tissue arising
from the basilar membrane in the cochlear spiral.
• The hair processes are embedded in a thin membrane
that bridges across the organ of Corti, known as the
tectorial membrane.
• Sound waves are transmitted by the pump-like effect of
the stapes in the oval window which creates shock waves
that are passed to the round window where the energy
dissipates. The pressure wave is transmitted through the
perilymph, and leads to vibration of the basilar
membrane, depending on the frequency of the sound.
When the basilar membrane oscillates, the tectorial
membrane has a shearing effect across the hair cells,
stimulating the cochlear nerve fibers.
Vestibulo–cochlear nerve
The vestibulo–cochlear nerve emerges from the temporal
bone to enter the posterior fossa through the internal
auditory canal along with the facial nerve. Both nerves pass
through the cerebello–pontine angle to enter the brainstem
at the anterolateral pontomedullary junction.
Brainstem
Vestibular nucleus
Occupies much of the lower lateral pontine tegmentum,
with vertical ramifications over the entire brainstem from
the midbrain down to the cervical spinal cord. Conse-
quently, vestibular symptoms and signs are almost always
present in brainstem disease but are of limited intrinsic
localizing value within the brainstem.
Cochlear nucleus
Receives fibers from the cochlear nerve as they enter the
pons, and transmits auditory information to the superior
olives bilaterally (mainly contralaterally), from where the
fibers ascend in the lateral lemniscus to the inferior colliculus
(midbrain), medial geniculate and temporal cortex (Heschl’s
gyrus).
ETIOLOGY
Brainstem (pontomedullary junction)
• Stroke.
• MS.
• Tumor.
518 Cranial Neuropathies

Cerebello–pontine angle Tinnitus

• Acoustic neuroma (vestibular schwannoma) (642). • May accompany any form or cause of hearing loss.
• Meningioma. • Rarely an isolated symptom of neurologic disease unless
• Trigeminal neuroma. pulsatile and associated with a bruit that is audible to the
• Glossopharyngeal neuroma. examiner (as well as the patient).
• Epidermoid/dermoid tumor.
• Chordoma. Vertigo
• Nasopharyngeal carcinoma. • Vertigo is uncommon, particularly if there is no deafness.
• Metastases. • Associated nystagmus tends to be fairly transient and no
• Basilar artery ectasia or aneurysm. longer than any associated vertigo when caused by a
• Arteriovenous malformation. labyrinthine or a vestibular nerve lesion.

Base of skull Nystagmus

• Infective meningitis. • Horizontal or rotatory nystagmus.
• Malignant meningitis. • Fast phase beats away from the side of the lesion.
• Sarcoidosis. • Maximal on lateral gaze away from the side of the lesion.
• Meningovascular syphilis. • It tends to be fairly transient and no longer than any
• Chordoma. associated vertigo, whereas nystagmus due to a brainstem
• Nasopharyngeal carcinoma. lesion tends to persist.
• Metastases. • ‘Canal paresis’ on caloric testing: irrigating warm and cold
• Paget’s disease of the skull: obstruction of foramina. water in the external auditory canal on the side of the
vestibular nerve (or labyrinthine) lesion, leads to a shorter
Ototoxins duration of nystagmus when compared with irrigating the
• Aminoglycosides. normal ear. False negative results may occur.
• Frusemide.
Unsteadiness
CLINICAL FEATURES • Veering or falling to one side – the side of a unilateral
Deafness vestibular (or cerebellar) lesion.
• The first symptom is usually progressive, unilateral • Wide-based gait.
hearing loss (sensori-neural deafness), often with • Incoordination of finger-nose and heel-knee-shin testing
ipsilateral tinnitus. with the limbs on the side of the vestibular (or cerebellar)
• Involvement of adjacent neurologic structures in the lesion if the eyes are closed; performance is improved
brainstem, cerebello-pontine angle, or inner ear while the patient is watching.
determines the subsequent clinical course:
– Trigeminal nerve: absent corneal reflex and loss of facial Other symptoms
sensation ipsilaterally. Ipsilateral face pain and trigeminal Ototoxins tend to cause imbalance and oscillopsia rather
neuralgia are rare. than vertigo.
– Facial nerve: ipsilateral facial weakness (usually mild) with
taste seldom affected, or rarely, hemifacial spasm. Associated symptoms
– Imbalance is common but vertigo is unusual. Determined by the location of the lesion (e.g. cerebello-
pontine angle).

642 DIFFERENTIAL DIAGNOSIS

Deafness
• Cerebello-pontine angle lesion (see above).
• Acute or chronic meningitis.
• Malignant meningitis.
• Intrinsic brainstem lesion (unusual).
• Cortical lesion (most unusual).

Tinnitus
Pulsatile
• Dural arteriovenous malformation involving the
transverse sinus.
• Arteriovenous malformation in the neck, or head.
• Stenosis of the distal internal carotid artery extra- or
intracranially.
• Carotico-cavernous fistula.
• Giant intracranial aneurysm.
• Glomus jugulare tumor.
• High cardiac output (e.g. pregnancy, thyrotoxicosis,
anemia).
642 Axial section through the pons and cerebellum at autopsy
showing a vestibular schwannoma (arrows).
 Vestibular-cochlear (VIIIth Cranial) Neuropathy
Vertigo
The nature of the vertigo and nystagmus are not as reliable
in localizing the site of the lesion as other associated
neurologic symptoms and signs.
Peripheral vertigo
The clues to localization are not so much the features of the
vertigo but more so other features such as deafness, tinnitus
and pain or fullness in the ear:
• Vestibulo-cochlear nerve lesions.
• Inner ear lesions.
Central vertigo
Brainstem lesions may cause episodic or prolonged vertigo but
hearing is usually normal; there are usually other brainstem
features (e.g. diplopia, dysarthria, pyramidal and cerebellar signs),
and if present, nystagmus persists after the vertigo has resolved.
Nystagmus
• A to-and-fro oscillation of the eyes which may be
pendular or phasic (jerk).
• The direction of the nystagmus may be horizontal,
vertical or rotatory.
• It may be present in the primary position of gaze (i.e.
looking straight ahead) or in one or more of the other
eight cardinal positions of gaze.
• It is usually accentuated (or appears) on horizontal
and/or vertical gaze.
• The nystagmus is described in terms of the direction of
gaze in which it is observed, and the direction of the fast
phase of the abnormal movements (e.g. rotatory
nystagmus on horizontal gaze to the left).
• It is seldom symptomatic (although the underlying cause
may be symptomatic in the form of vertigo, for example),
but a few patients complain of oscillation of the visual
field (oscillopsia).
• The nature of the nystagmus (and vertigo, if present) are
not as reliable in localizing the site of the lesion as other
associated neurologic symptoms and signs.
Pendular
• Congenital nystagmus: rare, horizontal nystagmus equal
in amplitude in both eyes and in all directions of gaze
(horizontal and vertical). Usually vision has been poor
since childhood.
• Albinos and miners who have spent years in dim light
may also have pendular nystagmus.
Phasic
• Symmetric horizontal nystagmus on lateral gaze to the left
and right may occur transiently (i.e. for a few beats) in normal
individuals if the direction of gaze is >30° from the midline,
or if the eyes are convergent. More sustained bilateral
horizontal (± vertical) nystagmus is usually due to drug
toxicity (e.g. alcohol, barbiturates, carbamazepine, phenytoin).
• Vertical nystagmus is always due to a brainstem lesion;
the cause may be drug toxicity (e.g. anticonvulsants) as
well as structural lesions.
• Rotatory nystagmus has no localizing value.
• Positional nystagmus (and vertigo) which fatigues in
seconds is due to benign paroxysmal positional vertigo.
• Positional nystagmus which persists for minutes to hours
or longer is likely to be due to a central (brainstem or
cerebellar) lesion.
519
Associated vertigo
Nystagmus, when associated with vertigo, tends to persist
when due to a brainstem lesion whereas it tends to be fairly
transient and no longer than any associated vertigo when
caused by a labyrinthine or a vestibular nerve lesion.
Brainstem lesion
• Nystagmus may be asymptomatic (i.e. present without
vertigo), ataxic (i.e. part of an internuclear ophthalmo-
plegia), or rotatory with the fast phase beating away from
the side of the lesion.
• Nystagmus tends to persist.
Cerebellar lesion
Horizontal gaze-evoked nystagmus on lateral gaze to the
side of a cerebellar hemisphere lesion. Associated ipsilateral
limb ataxia, imbalance, and dysarthria are present.
Opsoclonus
Rapid, chaotic oscillation of the eyes in all directions of
gaze, with an interval between each saccade.
Opsoclonus–myoclonus–ataxia syndrome
A subacute syndrome seen as a rare complication of
neuroblastoma in childhood, and cancer in adulthood.
INVESTIGATIONS
Caloric test of vestibular function
The most useful test of vestibular function.
Rationale
The cupola can be deflected by convection currents set up
in the semicircular canals if they are heated or cooled. The
lateral canals can be easily stimulated by hot or cold fluid
traversing the external auditory canal.
Procedure and interpretation
• Position the patient’s head so that it is reclined
backwards 60°, and therefore lying 30° from the plane
of the floor. In this position the lateral canal lies vertically
(i.e. at 90° from the floor).
• Examine the external auditory canal and check the
eardrum is not perforated.
• Ask the patient (if conscious) to look at a point straight
ahead.
• Inject warm water at 44°C (111°F) slowly into one ear,
at a rate of about 5 ml per second for about 45 seconds.
• The warm water heats the apex of the canal setting up a
convection current so that fluid flows away from the
warm area towards the utricle. This stimulates the cupola.
Activation of the semicircular canals moves the eyes away
from the stimulated ear to the opposite side.
• If the patient is conscious, they will experience vertigo
and will manifest nystagmus as they try to correct the
tonic deviation of the eyes away from the stimulated ear
by corrective saccades in the opposite direction.
• The normal duration of the nystagmus is about
2 minutes.
• The test can be repeated by injecting water at 30°C
(86°F) slowly into the same ear, and then repeating the
warm and cold water in the other ear. The cold water
cools the apex of the canal and fluid flows towards the
cool area away from the utricle. The cupola is inhibited.
The eyes move toward the stimulated ear.
520 Cranial Neuropathies

Canal paresis IXTH CRANIAL NERVE

A lesion of the semicircular canals or vestibulo-cochlear (GLOSSOPHARYNGEAL)
nerve on one side results in an incomplete or defective NEUROPATHY
response to both hot and cold water in the affected ear (e.g.
nystagmus, characterized by tonic eye movement and
corrective saccades, cannot be induced to the side of the DEFINITION
stimulation), and normal responses from the other ear. Disorder of the glossopharyngeal (IXth cranial) nerve.

Other tests EPIDEMIOLOGY

• Audiometry. Rare, particularly in isolation.
• Brainstem auditory evoked potentials (643): prolonged
interpeak latency, but false positives are common. ANATOMY
• Direct examination of the nasopharynx and larynx. Medulla
• MRI or CT brain scan with high resolution views of the Motor nucleus
posterior fossa and internal auditory canal of the • Situated in the upper part of the nucleus ambiguus in the
temporal bone, before and after i.v. contrast. medulla, and supplies stylopharyngeus (which cannot be
• CSF examination. tested clinically).
• Full blood count and ESR. • The nucleus ambiguus is the main motor nucleus of the
• Fasting blood glucose. IXth, Xth and XIth cranial nerves, and it receives bilateral
• Autoantibody screen. supranuclear innervation from the corticobulbar fibers.
• Chest x-ray.
Sensory nuclei
DIAGNOSIS • The long spoon-shaped nucleus of the tractus solitarius
Clinical. receives taste fibers from the posterior third of the
tongue, soft palate, and palatal arches (via the
TREATMENT glossopharyngeal nerve).
Determined by the cause. • The nucleus of the spinal tract of the trigeminal nerve
receives somatic sensation from the mucous membrane
PROGNOSIS of the soft palate and pharynx.
Depends on the cause.
Inferior salivatory nucleus
Gives rise to autonomic parasympathetic nerves.

Base of skull (jugular foramen)

• The glossopharyngeal nerve emerges from the medulla
in line with the vagus (cranial nerve X) and accessory
(cranial nerve XI) nerves, and enters the internal part of
the jugular foramen lying on the medial side of the
sigmoid sinus.
• The foramen angles forwards and laterally under the
petrous bone, which is excavated by the slight ballooning
643 of the sigmoid sinus as the sinus exits through the skull
2 4 6 msec to become the jugular bulb.
V • The glossopharyngeal, vagus and accessory nerves exit
I II III IV from the jugular foramen in front of the jugular bulb
(644).
VI Outside the skull
A1–Cz
VII
• The glossopharyngeal nerve descends between the
jugular vein and internal carotid artery, which ascends to
enter the carotid canal just anterior to the jugular vein as
it emerges from the jugular foramen. Here, the
glossopharyngeal nerve picks up sympathetic fibers from
the cervical sympathetic chain which has ascended into
the area on the carotid artery. Nearby is the hypoglossal
A1–Cz
(XIIth) cranial nerve, which exits the skull through the
anterior condylar canal posteromedial to the jugular
foramen and comes into close contact with the three
other nerves outside the skull.
• The glossopharyngeal nerve then loops forwards and
medially to reach the soft tissues of the oropharynx,
643 Normal brainstem auditory evoked potential (BAEP) following posterior tongue and palate.
repetitive auditory stimulation of the left ear and duplication of waves
I–VII.The sweep duration is 10 msec.
 IXth Cranial Nerve (Glossopharyngeal) Neuropathy 521

• The final branches are the pharyngeal, tonsillar, and
lingual branches carrying general sensation and taste
from the named areas.
• In its course to the pharynx, it gives off the tympanic
(Jacobson’s) nerve, which conveys the preganglionic
secretomotor fibers for the parotid gland to the otic
ganglion via the tympanic plexus and lesser petrosal
nerve. The otic ganglion lies just below the foramen
ovale, attached to the mandibular nerve but functionally
conveying information from the glossopharyngeal nerve.
Postganglionic parasympathetic fibers supply the parotid
gland, and evoke salivation, by way of the auriculo-
temporal nerves.
• An important branch, the carotid nerve, innervates the
carotid body and carotid sinus conveying, respectively,
chemoreceptor and stretch reflex information centrally
for respiratory and circulatory reflex function.
ETIOLOGY AND PATHOPHYSIOLOGY
Unilateral isolated glossopharyngeal neuropathy
Rare:
• Neuroma of the glossopharyngeal nerve.
• Meningioma.
• Neurofibroma.
• Epidermoid tumor (cholesteatoma).
• Glomus or carotid body tumor (645, 646): arises in
ectopic chemoectodermal tissue that is normally present
in the carotid body, and which may be found in the inner
ear and jugular foramen, around the glossopharyngeal
and vagus nerves. Neoplastic changes in this tissue
produce highly vascular erosive tumors which may
destroy the petrous temporal bone and present as a
vascular nodule in the external auditory canal. These
tumors occur in either gender with a peak incidence in
the third and fourth decades. Depending of the exact site
of the tumor, an external jugular foramen syndrome
(cranial nerves IX, X, XI) and/or a cerebello-pontine
angle syndrome (cranial nerves V, VII, VIII) may result.

Optic foramen Superior orbital fissure 644 645

Foramen
rotundum
Petrous
Foramen temporal
ovale bone
VII and VIII
enter the VI V
internal
auditory
canal

IX, X, XI
in jugular
foramen

XII in
anterior
condylar
canal Lateral sinus

644 Diagrammatic view from above of the inside of the right petrous temporal 646
bone of the skull showing the exit foraminae for the glossopharyngeal (IXth)
and other cranial nerves.

645, 646 T1W MRI post contrast (645) and carotid angiogram (646) of a
right-sided glomus jugulare tumor. Note the mass near the jugular bulb (645,
arrows) and the intense vascularity on angiography (646, arrows).
522 Cranial Neuropathies

Unilateral glossopharyngeal neuropathy patient is then asked to compare these gentle stimuli.
plus other neurologic signs Evaluation of taste sensation over the posterior third of the
• Lateral medullary infarct. tongue has no proven value in clinical diagnosis.
• Other medullary pathology (e.g. tumor, demyelination).
• Glomus or carotid body tumor. Associated clinical features
• Meningioma. These are clues to the site of involvement (e.g. intracranial
• Neurofibroma. vs. extracranial).
• Epidermoid tumor (cholesteatoma). • Long tract signs of brainstem involvement or
• Glomus or carotid body tumor. compression indicate an intracranial lesion.
• An isolated ipsilateral Horner’s syndrome (together with a
Bilateral isolated glossopharyngeal neuropathy glossopharyngeal palsy) is suggestive of a lesion outside the
Extremely rare. skull, as the cervical sympathetic ascends into the area of the
jugular foramen but does not pass through the foramen.
Bilateral glossopharyngeal neuropathy plus other • A palpable mass at the angle of the jaw may represent a
neurologic signs meningioma or neurofibroma that has extended out
• Syringobulbia. through the jugular foramen in a dumb-bell fashion, but
• Arnold–Chiari malformation. it must not be confused with the tip of the transverse
• Infection: process of the atlas which is a normal bony hard mass
– Viral: Epstein–Barr virus; infectious mononucleosis. palpable in this area.
– Mycoplasma infection.
– Chronic granulomatous diseases. Glossopharyngeal neuralgia
– Syphilis. • Attacks are rare and comprise severe, excruciating neuralgic
– Tuberculosis. pain (similar to that of trigeminal neuralgia) in the posterior
– Cryptococcal infection. pharynx, tonsillar fossa, base of the tongue and the ear
• Sarcoidosis. when fluid or food is swallowed or when coughing or
• Vasculitis: yawning, due to a ‘trigger point’ in the throat.
– Polyarteritis nodosa. • Occasionally, bradycardia and syncope occur (associated
– Wegener’s granulomatosis. with swallowing or coughing), perhaps because of cross
– SLE. stimulation, via the carotid nerve, of the carotid sinus.
– Rheumatoid arthritis. • May be associated with MS.
– Sjögren’s syndrome. • May respond to carbamazepine.
• Whipple’s disease.
• Tumor: DIFFERENTIAL DIAGNOSIS
– Chordoma. • Vagus (Xth cranial) nerve palsy.
– Epidermoid cyst. • Pharyngeal and palatal mucosal disease.
– Giant cell tumor. • Functional disorder.
– Primary leptomeningeal gliomatosis.
– Carcinomatous meningitis. INVESTIGATIONS
– Lymphoma. Suspected intracranial lesion
• CT or, preferably, MRI scan (645) of brain and base of skull.
Glossopharyngeal neuralgia • CSF examination.
• Aberrant vessels coursing across the glossopharyngeal
nerve. Suspected extracranial lesion
• Neurofibroma or cholesteatoma adjacent to the nerve • Direct examination of the nasopharynx and larynx.
causing nerve compression. • MRI scan of base of skull and sinuses.
• Intra-axial lesions such as demyelination (MS). • Full blood count and ESR.
• Paranasal sinus x-ray.
CLINICAL FEATURES • Chest x-ray.
Glossopharyngeal nerve palsy • Carotid angiography if a glomus tumor is suspected (646).
Depressed pharyngeal and palatal sensation
From a clinical point of view, the glossopharyngeal nerve is DIAGNOSIS
pure sensory because the only muscle supplied by the nerve Clinical.
(stylopharyngeus) cannot be tested clinically. Contrary to
what many students misconceive, the glossopharyngeal nerve TREATMENT
is not motor to the palate. When the gag reflex is tested the Glossopharyngeal palsy
sensory stimulus is relayed via the glossopharyngeal nerve, Determined by the cause.
but the resulting visible palatal movement is mediated by the
vagus nerve. The gag reflex therefore is too gross for accurate Glossopharyngeal neuralgia
clinical diagnosis of a glossopharyngeal lesion. Carbamazepine, baclofen or microsurgical vascular
The only way of accurately testing the integrity of the decompression if no other lesion is demonstrable.
glossopharyngeal nerve is to test pharyngeal sensation by
carefully touching each side of the palate gently with an PROGNOSIS
orange sick and then, with the patient saying ‘Aah’, Depends on the cause.
touching the posterior pharyngeal wall on each side. The
 Vagus Nerve (Xth Cranial Nerve) Neuropathy 523

VAGUS NERVE (XTH CRANIAL Base of skull (jugular foramen)

NERVE) NEUROPATHY • Multiple rootlets from the extensive nuclear connections in
the brainstem leave the anterolateral medulla and form a
flat cord which enters the jugular foramen.
DEFINITION • The jugular foramen transmits the glossopharyngeal, vagus
Disorder of the vagus (Xth cranial) nerve. and accessory cranial nerves along with the sigmoid sinus.
It is adjacent to the hypoglossal canal which transmits the
EPIDEMIOLOGY hypoglossal cranial nerve. Anteriorly lies the internal carotid
Uncommon. artery with the associated sympathetic nerves which enter
the skull through the foramen lacerum.
ANATOMY • In the jugular foramen, the vagus nerve gives off a
The most widely distributed cranial nerve. meningeal branch supplying the dura of the posterior fossa.
• In the jugular foramen, and immediately below, lie the
Medulla superior and inferior ganglia, which make connections with
Dorsal nucleus of the vagus the accessory and hypoglossal nerves, and pick up fibers
• Motor: general visceral efferent to the smooth muscle of from the sympathetic plexus on the carotid artery.
the bronchi, heart, esophagus, stomach and intestine.
• Sensory: receives general visceral afferents from the Branches
esophagus and upper bowel, with cell bodies in the • The superior ganglion gives off the auricular branch, which
superior and inferior vagal ganglia. is joined by a branch from the glossopharyngeal, and is distri-
buted to the skin of the external ear with the branch of the
Nucleus ambiguus facial nerve. These fibers all ultimately enter the nucleus of
Motor: efferent to striated muscle of the pharynx and intrinsic the descending tract of the trigeminal nerve in the brainstem.
muscles of the larynx. Bilateral supranuclear innervation. • The inferior ganglion gives off the superior laryngeal nerve,
which divides into two branches. The inferior laryngeal
Nucleus of the tractus solitarius nerve supplies sensation of the mucous membrane of the
Sensory: receives fibers from the taste buds of the epiglottis larynx and conveys proprioceptive information from the
and vallecula. Shared with the glossopharyngeal nerve. neuromuscular spindles and stretch receptors of the larynx.
The external laryngeal nerve supplies the cricothyroid and
Spinal nucleus of the trigeminal nerve contributes to the pharyngeal plexus (important for speech).
Sensory: receives general somatic afferent fibers from the • Below the inferior ganglion, the cranial root of the accessory
pharynx and larynx. nerve merges into the vagus nerve, and forms the
pharyngeal branch which distributes its fibers to supply the
pharynx and larynx.
• The recurrent laryngeal nerve on the right loops under the
647 subclavian artery and on the left under the aortic arch. On
both sides it then ascends on the side of the trachea to reach
the larynx, where it supplies all the muscles of the larynx,
except the cricothyroid, and carries sensory fibers from the
mucous membranes and the stretch receptors of the larynx.

ETIOLOGY AND PATHOPHYSIOLOGY

Unilateral
Lower motor neuron
• Medullary stroke (e.g. lateral medullary infarct).
• Syringobulbia.
• Infective mononeuropathies (e.g. viral).
• Diabetes.
• Arteritis.
• Internal carotid artery dissection.
• Neuroma of the vagus nerve.
• Meningioma.
• Epidermoid/dermoid tumor.
• Glomus tumor.
• Chordoma (647).
• Extension of cerebello-pontine angle mass.
• Nasopharyngeal carcinoma.
• Metastasis.
647 T2W axial MRI through the skull base showing a large, high signal • Malignant lymph nodes in the neck.
lesion in the midline arising from the clivus and invading the post nasal • Trauma:
space (arrows). Chordomas typically affect the clivus or C1/2 causing – Accidental injury to recurrent laryngeal nerve (usually the
bone destruction and areas of calcification (in 50%).The intracranial left as it passes around the aorta) during open heart surgery.
component may compress the pons, invade cranial nerves and the sellar – Gunshot or knife wounds.
region. The main differential diagnosis radiologically is chondrosarcoma. – Skull base fracture.
524 Cranial Neuropathies

Upper motor neuron • Wasting and weakness of the ipsilateral tongue (hypoglos-
Stroke. sal nerve).
• Pain in and around the ear if bone erosion or
Bilateral inflammation occur.
Lower motor neuron • Brainstem signs if lesion is within the skull.
• Syringobulbia. • Ipsilateral Horner’s syndrome if lesion is outside the
• Motor neuron disease. skull.
• Polio.
• Multiple systems atrophy. Unilateral upper motor neuron vagus nerve palsy
• Arnold–Chiari malformation. Contralateral palatal weakness: very transient, if at all, in
• Guillain–Barré syndrome. upper motor neuron lesions because of bilateral
• Subacute/chronic infective or malignant meningitis. supranuclear control of the palate.
• Infective neuropathies.
• Diabetes. Bilateral lower motor neuron vagus nerve palsy
• Arteritis. Bilateral palatal and vocal cord weakness.

Upper motor neuron Bulbar palsy

• Motor neuron disease. • Nasal regurgitation.
• Stroke. • Nasal dysarthric speech.
• MS. • Dysphagia.
• Multiple system atrophy. • Choking and aspiration.
• Central pontine myelinolysis. • Absent gag reflex.
• Hoarse voice.
CLINICAL FEATURES • Weak cough.
Unilateral lower motor neuron vagus nerve palsy • Stridor sometimes, particularly during sleep.
Examine the patient’s palatal movement, voice and cough.
Bilateral upper motor neuron vagus nerve palsy
Motor to the ipsilateral palate and vocal cords Pseudobulbar palsy
Ipsilateral palatal weakness: • Emotional lability (common).
• Regurgitation of fluid and foods into nasopharynx and • Brisk jaw jerk (if bilateral lesions above the mid pons).
nose. • Spastic tongue: slow repetitive movements.
• Nasal speech. • Bilateral corticospinal (pyramidal) tract signs in all four
• Asymmetric palatal movement: unopposed action of the limbs.
contralateral vagus nerve allows the palate to be pulled
across to the intact side (i.e. contralateral to, or away DIFFERENTIAL DIAGNOSIS
from, the vagus lesion) when the patient says ‘Aah’ or Bilateral vagus nerve palsy
when the gag reflex is elicited. Lower motor neuron
• Myasthenia gravis.
Ipsilateral vocal cord weakness (usually a recurrent laryngeal • Myopathy (e.g. myotonic dystrophy, polymyositis).
nerve lesion if isolated vocal cord weakness): • Psychogenic vocal cord adductor palsy.
• Hoarseness.
• Loss of voice volume (dysphonia). INVESTIGATIONS
• Weak cough: unable to cough explosively (‘bovine Suspected intracranial lesion
cough’). • MRI scan of brain and base of skull (647).
• Asymmetric vocal cord movement: the paralysed vocal • CSF examination.
cord lies permanently and limply abducted to the
midline. Suspected extracranial lesion
• Direct examination of the nasopharynx and larynx.
Somatosensory from the ipsilateral ear • MRI scan of base of skull and sinuses.
Reduced sensation in the skin over the cranial part of the • Full blood count and ESR.
auricle and posterior wall and floor of the external auditory • Paranasal sinus x-ray.
meatus (auricular branch). Hence the referred pain from • Chest x-ray.
malignant disease or other irritation of the throat to the ear • Carotid angiography if a glomus tumor suspected.
and auditory canal.
DIAGNOSIS
Associated features Clinical.
Jugular foramen syndrome: lesions in or near the jugular
foramen may cause any combination of: TREATMENT
• Diminished ipsilateral palatal sensation (glossopharyngeal Determined by the cause.
nerve).
• Hoarse voice, nasal speech, dysphagia, asymmetric palatal PROGNOSIS
movement to the contralateral side (vagus nerve). Depends on the cause.
• Wasting and weakness of the ipsilateral sternomastoid
and trapezius (accessory nerve).
 Spinal Accessory Nerve (XIth Cranial Nerve) Neuropathy 525

SPINAL ACCESSORY NERVE (XITH Supranuclear innervation

CRANIAL NERVE) NEUROPATHY Probably ipsilateral, because hemispheric lesions (e.g. stroke)
cause weakness of the sternocleidomastoid on the same side
as the lesion (i.e. weakness turning the head to the side of
DEFINITION the hemiparesis); and partial epileptic seizures originating
Disorder of the spinal accessory (XIth cranial) nerve. in the frontal lobe cause the head to turn away from the side
of the lesion and the epileptic focus, indicating that the
EPIDEMIOLOGY ipsilateral sternocleidomastoid is contracting.
Uncommon.
ETIOLOGY AND PATHOPHYSIOLOGY
ANATOMY Intracranial
Cranial part • Arnold–Chiari malformation.
• A detached portion of the vagus nerve. • Syringomyelia.
• It arises predominantly from the lower part of the
nucleus ambiguus and a small component from the Jugular foramen
dorsal efferent nucleus of the vagus. • Neuroma.
• The nerve rootlets emerge from the anterolateral medulla • Meningioma.
in line with the vagus. • Epidermoid/dermoid tumor.
• They are joined by the ascending spinal component, and • Glomus tumor.
then run laterally to enter the jugular foramen. • Chordoma.
• The cranial portion merges with the vagus nerve at the • Extension of cerebello-pontine angle mass.
level of the inferior vagal ganglion and is then distributed • Nasopharyngeal carcinoma.
in the pharyngeal and recurrent laryngeal branches of the • Metastasis.
vagus nerve. • Malignant lymph nodes in the neck.
• These fibers probably supply the muscles of the soft • Trauma:
palate. – Gunshot or knife wounds.
– Skull base fracture.
Spinal part • Infective mononeuropathies (e.g. viral).
• Motor to the sternocleidomastoid and upper part of the • Diabetes.
trapezius. • Arteritis.
• It arises from the anterior horn cells from C1–C5. • Subacute and chronic meningitis.
• The spinal root fibers (C1–C5) emerge from the upper
cervical cord laterally between the anterior and posterior Neck
spinal nerve roots to form a separate nerve trunk, which • Trauma.
ascends into the skull through the foramen magnum. • Malignancy.
• Once inside the skull it exits by way of the jugular
foramen in the same dural sheath as the vagus nerve. CLINICAL FEATURES
• Upon emerging from the jugular foramen, it imme- Unilateral lower motor neuron lesion
diately runs posteriorly to supply the sternocleidomastoid Weakness of the ipsilateral sternocleidomastoid and upper
and upper part of the trapezius. part of the trapezius muscles (648, 649).
• It also receives a major contribution from branches of the
ventral motor roots of C3 and C4 to form a plexus which Acute upper motor neuron lesion
passes through the posterior triangle of the neck (where Weakness of the ipsilateral sternocleidomastoid and upper
it is prone to damage by lymph node biopsy and other part of the contralateral trapezius muscles, so that the
operations) to supply the cervical musculature. patient cannot elevate the shoulder of the paralysed arm nor
turn the head towards the paralysed side.

648 649

648, 649 Wasting and weakness of the trapezius muscle due to section of the left accessory nerve in the process of lymph node on the left
biopsy for tuberculosis. (Courtesy of Dr AM Chancellor, Neurologist,Tauranga, New Zealand.)
526 Cranial Neuropathies

DIFFERENTIAL DIAGNOSIS HYPOGLOSSAL (XIITH CRANIAL

Bilateral weakness of the sternomastoids NERVE) NEUROPATHY
(and neck flexors)
• Motor neuron disease.
• Myasthenia gravis. DEFINITION
• Polymyositis. Disorder of the hypoglossal (XIIth cranial) nerve, which is
• Myotonic dystrophy. the motor nerve to the tongue.
• Acid maltase deficiency.
EPIDEMIOLOGY
INVESTIGATIONS Rare.
Electromyography to confirm denervation of the sterno-
mastoid and trapezius muscles. ANATOMY
• Arises from a nuclear column in the floor of the fourth
Suspected intracranial lesion ventricle, which was derived from the same embryologic
• MRI scan of brain and base of the skull. cell groups as the nuclei of ocular motor cranial nerves
• CSF examination. III, IV and VI.
• Fascicular fibers traverse the full sagittal diameter of the
Suspected extracranial lesion brainstem (medulla), like cranial nerves III and VI, to
• Direct examination of the nasopharynx and larynx. exit from the ventral surface between the pyramid and
• MRI scan of base of skull and sinuses. the olive.
• Full blood count and ESR. • Numerous rootlets combine to form two main fasciculi
• Paranasal sinus x-ray. with their own dural sleeves.
• Chest x-ray. • Leaves the skull through the hypoglossal canal,
• Carotid angiography if a glomus tumor suspected. immediately below the jugular foramen and descends
anteriorly to emerge between the carotid artery and
DIAGNOSIS jugular vein, crosses the inferior vagal ganglion, and
Clinical and EMG. ascends anteriorly on the hyoglossus muscle, distributing
branches to all the muscles of the tongue.
TREATMENT • Receives sympathetic fibers from the superior cervical
Determined by the cause. ganglion, some fibers from the vagus, and from the
motor roots of C1 and C2 via the ansa cervicalis.
PROGNOSIS • Fibers from the hypoglossal nucleus innervate the ipsi-
Depends on the cause. lateral styoglossus, hyoglossus, geniohyoid, and
genioglossus.
• Fibers from the C1 components supply the sternohyoid,
sternothyroid, omohyoid, thyrohyoid, and geniohyoid.
• Supranuclear innervation of the hypoglossal nucleus is
usually bilateral but may be predominantly contralateral.

ETIOLOGY
Unilateral
Lower motor neuron (nuclear/infranuclear)
Medulla:
• Glioma.
• Syringobulbia.
• Arteriovenous malformation.

Meninges:
• Neurofibroma of the hypoglossal nerve (650, 651):
usually female.
• Meningioma.
• Chordoma.

Base of skull:
• Dissecting aneurysm of the internal carotid artery.
• Glomus tumor.
• Nasopharyngeal carcinoma.
• Metastasis.
• Epidermoid/dermoid tumor.

Neck:
• Malignant disease or lymph nodes.
• Resection of malignant disease in the neck.
• Carotid endarterectomy.
 Hypoglossal (XIIth Cranial Nerve) Neuropathy 527

• Central venous catheterization. 650

• Infective mononeuropathies (e.g. viral).
• Diabetes.
• Arteritis.

Upper motor neuron (supranuclear)

Stroke (transient).

Bilateral
Lower motor neuron
• Syringobulbia.
• Motor neuron disease.
• Polio.
• Arnold–Chiari malformation.
• Subacute/chronic infective or malignant meningitis.

Upper motor neuron

• Motor neuron disease.
• Stroke.
• MS.
• Multiple system atrophy.
• Central pontine myelinolysis.

CLINICAL FEATURES 651

Unilateral
Lower motor neuron hypoglossal nerve palsy
• Mild dysarthria.
• Wasting, fasciculation and weakness of one side of the
tongue (ipsilateral to the lesion), with deviation of the
tongue to the opposite side (652). During tongue
protrusion, the weak muscle cannot balance the forward
(and contralateral) push of the normal muscle on the
other side, and the normal muscle forces the tongue
forward and to the opposite side (which is towards the
side of the weak muscle and damaged nerve or nucleus).
• Laryngeal shift to one side on swallowing (contralateral
to the lesion) due to failure of the hyoid to elevate on the
paralysed side.

Upper motor neuron hypoglossal nerve palsy

• Mild dysarthria.
• Mild tongue weakness contralateral to the side of the
UMN lesion.
• Usually transient.

652

650, 651 MRI brain scans. Axial plane T1W image (650) and T2W
image (651) showing a schwannoma of the right hypoglossal nerve
(arrows), adjacent to the right ventral medulla and right vertebral
artery. (Courtesy of Dr AM Chancellor, Neurologist,Tauranga, New
Zealand.)

652 Weakness and wasting of the right side of the tongue due to a
right hypoglossal nerve palsy.The unopposed action of the normally
innervated left genioglossus muscle pushes the tongue toward the side
of the lesion.
528 Cranial Neuropathies

Bilateral fasciculations. Tongue fasciculation is best seen with the

Lower motor neuron hypoglossal nerve palsy tongue resting in the floor of the mouth.
• Difficulty manipulating food in the mouth, chewing, and
swallowing. Bulbar palsy
• Difficulty speaking (flaccid dysarthria). • Motor neuron disease.
• Other signs of a bulbar palsy may be present: • Myasthenia gravis.
– Nasal regurgitation. • Myopathy (e.g. myotonic dystrophy, polymyositis).
– Choking and aspiration.
– Absent gag reflex. INVESTIGATIONS
– Hoarse voice. Suspected intracranial lesion
– Weak cough. • MRI scan of brain and base of skull (651, 652).
– Stridor sometimes, particularly during sleep. • CSF examination.

Upper motor neuron hypoglossal nerve palsy Suspected extracranial lesion

• Severe dysarthria. • Direct examination of the nasopharynx and larynx.
• Spasticity of the tongue: slow movements. • MRI scan of base of skull.
• Other signs of a pseudobulbar palsy may be present: • Full blood count and ESR.
– Emotional lability (common). • Paranasal sinus x-ray.
– Brisk jaw jerk (if bilateral lesions above the mid pons). • Chest x-ray.
– Bilateral corticospinal (pyramidal) tract signs in all four
limbs. DIAGNOSIS
Clinical.
DIFFERENTIAL DIAGNOSIS
Bilateral hypoglossal nerve palsy TREATMENT
Normal tongue Determined by the cause.
The tongue normally flickers slightly when it is held out for
more than a few seconds, which can be mistaken for PROGNOSIS
Depends on the cause.

FURTHER READING
OPTIC (IInd CRANIAL NERVE)
NEUROPATHY
Acheson J (2000) Optic nerve and chiasmal dis-
ease. J. Neurol., 247: 587–596.
Balcer LJ (1996) Optic nerve disorders. Curr.
Opin. Ophthalmol., 8: VI:3–8.
Newman NJ (1996) Optic neuropathy. Neurolo-
gy, 46: 315–322.
Shingleton BJ, O’Donoghue MW (2000) Blurred
vision. N. Engl. J. Med., 343: 556–562.
ANTERIOR ISCHEMIC OPTIC
NEUROPATHY
Hattenhauer MG, Leavitt JA, Hodge DO, Grill R,
Gray DT (1997) Incidence of non-arteritic an-
terior ischaemic optic neuropathy. Am. J. Oph-
thalmol., 123: 103–107.
Ischaemic Optic Neuropathy Decompression Trial
Research Group (1995) Optic nerve decom-
pression surgery for non-arteritic anterior is-
chaemic optic neuropathy (NAION) is not ef-
fective and may be harmful: results of the Is-
chaemic Optic Neuropathy Decompression
Trial. JAMA, 273: 625–632.
OPTIC NEURITIS
Chan JW (2000) Optic neuritis in multiple scle-
rosis: an update. The Neurologist, 6: 205–213.
Jin Y-P, de Pedro-Cuesta J, Söderström M, Link
H (1999) Incidence of optic neuritis in Stock-
holm, Sweden, 1990–1995. Arch. Neurol., 56:
975–980.
Optic Neuritis Study Group (1997) The 5-year
risk of MS after optic neuritis. Experience of
the Optic Neuritis Treatment Trial. Neurolo-
gy, 49: 1404–1413.
Purvin V (1998) Optic neuritis. Curr. Opin. Oph-
thalmol., 9; VI:3–9.
Sellebjerg F, Nielsen HS, Frederiksen JL, Olesen
J (1999) A randomised, controlled trial of oral
high-dose methylprednisolone in acute optic
neuritis. Neurology, 52: 1479–1484.
LEBER’S HEREDITARY OPTIC
NEUROPATHY
Riordan-Eva P, Sanders MD, Govan GG, Sweeney
MG, Da Costa J, Harding AE (1995) The
clinical features of Leber’s hereditary optic
neuropathy defined by the presence of a path-
ogenic mitochondrial DNA mutation. Brain,
118: 319–337.
HORNER’S SYNDROME
Bates AT, Chamberlain S, Champion M, et al.
(1995) Pholedrine: a substitute for hydrox-
yamphetamine as a diagnostic eye drop test in
Horner’s syndrome. J. Neurol. Neurosurg. Psy-
chiatry, 58: 215–217.
Keane JR (1979) Oculosympathetic paresis. Analy-
sis of 100 hospitalised patients. Arch. Neurol.,
36: 13–16.
Kerrison JB, Biousse V, Newman NJ (2000) Iso-
lated Horner’s syndrome and syringomyelia.
J. Neurol. Neurosurg. Psychiatry, 69: 131–132.
HOLMES–ADIE SYNDROME
Martinelli P (2000) Holmes-Adie syndrome.
Lancet, 356: 1760–1761.
IIIRD, IVTH AND VITH CRANIAL NERVE
(OCULAR MOTOR) NEUROPATHIES
Kline LB, Hoyt WF (2001) The Tolosa–Hunt
syndrome. J. Neurol. Neurosurg. Psychiatry,
71: 577–582.
TRIGEMINAL NEURALGIA
Barker FG, Jannetta PJ, Bissonette DJ, et al.
(1996) The long term outcome of microvas-
cular decompression for trigeminal neuralgia.
N. Engl. J. Med., 334: 1077–1083.
FACIAL (VIIth CRANIAL NERVE)
NEUROPATHY
Fiedler CP, Raza SA (1998) Steroids in facial palsy
due to herpes zoster. BMJ, 316: 233–234.
Ross RT, Mathiesen R (1998) Volitional and emo-
tional supranuclear facial weakness. N. Engl. J.
Med., 338: 1515.
ACUTE IDIOPATHIC FACIAL PARALYSIS
Grogan PM, Gronseth GS (2001) Practice para-
meter steroids, acyclovir, and surgery for Bell’s
palsy (an evidence-based review). Neurology,
56: 830–836.
Murakami S, Mizobuchi M, Nakashiro Y, et al.
(1996) Bell’s palsy and herpes simplex virus:
identification of viral DNA in endoneurial fluid
and muscle. Ann. Intern. Med., 124(1 pt 1):
27–30.
Sipe J, Dunn L (2001) Aciclovir for Bell’s palsy
(idiopathic facial paralysis) (Cochrane review).
The Cochrane Library, Issue 3, 2001. Oxford:
update software.
VESTIBULAR-COCHLEAR (VIIIth CRANIAL
NERVE) NEUROPATHY
Fife TD, Tusa RJ, Furman JM, et al. (2000) As-
sessment: vestibular testing techniques in
adults and children. Neurology, 55:
1431–1441.
IXth CRANIAL NERVE
(GLOSSOPHARYNGEAL) NEUROPATHY
Minagar A, Sheremata WA (2000) Glossopharyn-
geal neuralgia and MS. Neurology, 54:
1368–1370.
HYPOGLOSSAL (XIIth CRANIAL NERVE)
NEUROPATHY
Keane JR (1996) Twelfth nerve palsy: analysis of
100 cases. Arch. Neurol., 53: 561–566.
Keane JR (2000) Combined VIth and XIIth cra-
nial nerve palsies. A clival syndrome. Neurolo-
gy, 54: 1540–1541.
 Chapter Nineteen 529

Spinal Cord Diseases

HEREDITARY SPASTIC PARAPARESIS • Neuronal cell bodies of degenerating fibers are preserved.
• Mild loss of anterior horn cells may occur.
• Dorsal root ganglia, posterior roots and peripheral nerves
DEFINITION are normal.
A group of clinically and genetically diverse disorders • There is no evidence of primary demyelination.
characterized by progressive lower limb spasticity and weakness.
ETIOLOGY AND PATHOPHYSIOLOGY
TERMINOLOGY Heterogeneous pattern of inheritance.
Hereditary spastic paraparesis (HSP) is also known as
familial spastic paraparesis and Strumpell–Lorrain syndrome. Pure uncomplicated forms
The term ‘hereditary spastic paraparesis’ is more precise • Autosomal dominant (70%): seven different loci mapped
because it indicates the genetic basis of this group of to chromosomes 2p (SPG4), 14q (SPG3), 15q (SPG6),
disorders; conditions that occur in families (familial) are not 8q24 (SPG8), 10q (SPG9), 12p (SPG10), 19q (SPG12),
necessarily inherited (genetic). 2q (SPG13). A single gene is known for autosomal
dominant HSP; the gene encodes spastin which is
EPIDEMIOLOGY responsible for SPG4 (spastic paraplegia 4).
• Uncommon. • Autosomal recessive (30%) mapped to a locus on
• Age: age at onset can be difficult to date precisely chromosome 8q12-13 (SPG5).
because incipient disease can go unnoticed unless a • X-linked (rare): mapped to a locus on Xq11.
clinical examination is performed. Most patients
experience symptom onset in the second through fourth Complex forms
decades, but there is a wide range of symptom onset • Autosomal dominant: one locus mapped to chromosome
from infancy through to age 85 years. 10q (SPG9), with associated cataract, distal amyotrophy,
motor axonal neuropathy, short stature, gastro-
CLASSIFICATION esophageal reflux, and vomiting.
Genetic • Autosomal recessive: four loci mapped to chromosomes
• Autosomal dominant (70%). 2q, 3q (SPG14), 13q (ARSACS), 15q (SPG11), and 16q
• Autosomal recessive (30%). (SPG7), all with different phenotypes. Two genes have
• X-linked (rare). been identified, paraplegin and sacsin.
• X-linked: two loci mapped to chromosome Xq28 (SPG1)
Clinical and Xq22 (SPG2). Two genes have been identified, L1
Pure (uncomplicated) HSP cell adhesion molecule and proteolipid protein (PLP).
• Most common.
Surprisingly, the five genes identified to date (spastin,
Complicated HSP paraplegin, sacsin, L1 cell adhesion molecule, and PLP) en-
Associated with: code proteins of different families, making understanding and
• Intellectual handicap. diagnosis of HSP difficult. The discovery of new genes should
• Optic neuropathy. hopefully help to clarify the pathophysiology of these disorders.
• Retinal pigmentary degeneration.
• Ophthalmoplegia. 653
• Deafness.
• Extrapyramidal signs.
• Cerebellar symptoms.
• Amyotrophy in the upper limbs.
• Skin disorders (ichthyosis).

PATHOLOGY
• Axonal degeneration occurs in the terminal/distal
portions of the longest descending and ascending tracts
of the spinal cord (653):
– Corticospinal tract fibers (crossed and uncrossed) from
pyramidal neurons in the motor cortex to the legs.
– Fasciculus gracilis (and cuneatus to a lesser extent) fibers
from the dorsal root ganglia neurons. 653 Axial section through the spinal cord showing degeneration (pallor)
– Spinocerebellar fibers to a lesser extent. in the corticospinal tracts, spinocerebellar tracts, and dorsal columns.
530 Spinal Cord Diseases

CLINICAL FEATURES patients should be evaluated thoroughly for concurrent or

History
• Following normal gestation, delivery and early childhood
development, patients develop leg stiffness and gait
disturbance (stumbling and tripping) due to difficulty
dorsiflexing the foot and weakness of hip flexion.
• Paresthesiae below the knees are quite common.
• Urinary urgency progressing to urinary incontinence is
a frequent, although variable, late manifestation.
• A significant minority of patients are asymptomatic and
unaware of signs.
EXAMINATION
Cranial nerves
• Fundi, and extraocular and facial movements are normal
(unless complex HSP: optic neuropathy, retinal pig-
mentary degeneration, ophthalmoplegia).
• Jaw jerk may be brisk in older subjects but there is no
evidence of frank corticobulbar tract dysfunction.
Upper limbs
• Tone and muscle power are normal (unless complex
HSP: amyotrophy).
• Hoffman’s and Tromner’s signs may be observed.
• Deep tendon reflexes may be brisk (2–3+).
• Slight terminal dysmetria is present on finger-to-nose
testing in occasional older affected patients.
Lower limbs
• Pes cavus is generally present and usually prominent in
older affected patients.
• Wasting of muscles may occur but is mild and limited to
the anterior and posterior tibial compartment in
wheelchair-dependent elderly patients.
• Tone is increased in the hamstrings, quadriceps and
ankles. Ankle clonus is present uniformly.
• Weakness is most notable of the iliopsoas, tibialis anterior
and, to a lesser extent, hamstring muscles.
• Deep tendon reflexes are pathologically increased (3–4+).
Crossed adductor reflexes and extensor plantar responses
are present uniformly.
• Sensation to sharp stimuli is decreased below the knees
in occasional patients and vibratory sense is often
diminished mildly in the distal lower limbs.
• Gait: circumduction is present due to difficulty with hip
flexion and ankle dorsiflexion.
alternative neurologic disorders.
DIFFERENTIAL DIAGNOSIS
Inherited ataxias
• Spinocerebellar ataxias (see p.437): prominent ataxia.
• Friedreich’s ataxia.
Inherited leukodystrophies
• Adrenoleukodystrophy (ALD)/adrenomyeloneuropathy
(AMN) (see p.166):
– MRI brain, plasma long-chain fatty acid analysis.
– Childhood-onset ALD: progressive cognitive impairment
and peripheral neuropathy accompany corticospinal tract
signs.
– Adolescent-/adult-onset AMN: cognition is normal,
peripheral neuropathy is variable.
• Metachromatic leukodystrophy (see p.169): autosomal
recessive, psychomotor retardation and peripheral neuro-
pathy are typical in children; MRI brain, arylsulfatase
analysis.
• Krabbe (globoid cell) leukodystrophy (see p.171):
autosomal recessive, peripheral neuropathy may be
absent in adolescent-/adult-onset Krabbe disease; MRI
brain, galactocerebrosidase analysis.
Structural spinal cord abnormality
• Arnold–Chiari malformation (see p.136): ataxia, MRI of
posterior fossa.
• Cervical or lumbar spondylosis: radiculopathy,
radiographs and MRI spine.
• Tethered cord syndrome: MRI conus medullaris.
• Tumor of the spinal cord: pain, loss of sensation,
asymmetric involvement; MRI spinal cord.
• Arteriovenous malformation of the spinal cord: saltatory
progression, spinal sensory level; MRI, spinal arterio-
graphy.
654 655

Other
Icthyosis of the skin in some patients (654, 655).

Clinical variability
The clinical phenotypic expression of ‘pure’ autosomal
dominant spastic paraparesis is highly variable. The age of
symptom onset, rate of symptom progression, and extent of
disability vary within and between HSP kindreds. Phenotype
variation is related, at least in part, to symptom duration.
However, neurologic deficits are limited to corticospinal and
dorsal column tracts subserving the lower limbs, with the
exception of a trace degree of terminal dysmetria. Additional
deficits such as visual disturbance, marked amyotrophy,
fasciculations, dementia, seizures, or peripheral neuropathy
in patients from pure HSP kindreds should not be
attributed to variant presentations of pure HSP but rather, 654, 655 Ichthyosis of the skin in a patient with complicated hereditary
spastic paraparesis.
 Hereditary Spastic Paraparesis
• Granuloma (e.g. tuberculous) involving vertebrae and
spinal cord: back pain, subacute course, spine radio-
graphy and MRI.
Infectious disease
• Tertiary syphilis (hypertrophic pachymeningitis):
VDRL/RPR, TPHA.
• Tropical spastic paraparesis: subacute course, HTLV-I
antibodies.
• AIDS: subacute course, HIV antibodies.
Metabolic disorder
• Subacute combined degeneration of the spinal cord:
peripheral neuropathy, marked dorsal column involve-
ment; serum vitamin B12 concentration.
• Mitochondrial encephalomyopathy: short stature,
retinitis pigmentosa, multiple stroke-like episodes; MRI
brain, serum lactate and pyruvate.
• Abetalipoproteinemia (Bassen–Kornzweig disease):
peripheral neuropathy; lipoprotein electrophoresis.
• Vitamin E deficiency: peripheral neuropathy; serum
vitamin E concentration.
Degenerative disease
• Motor neuron disease (familial/sporadic): fasciculations,
amyotrophy; EMG and nerve conduction studies.
Miscellaneous
• Dopa-responsive dystonia due to tyrosine hydroxylase
gene mutations: diurnal fluctuation, response to low dose
levodopa-carbidopa.
INVESTIGATIONS
• MRI brain and spinal cord.
• Serum vitamin B12, E.
• HTLV-1 antibodies.
• VDRL/RPR, TPHA.
• Plasma long-chain fatty acid analysis.
• DNA analysis.
Electrophysiology
• Nerve conduction studies: normal. Subclinical sensory impair-
ment in peripheral nerves or spinal pathways may be detected.
• Somatosensory evoked potentials (SSEPs), after stimu-
lation of peripheral nerves in the lower limbs, shows
conduction delay in dorsal column fibers.
• Cortical evoked potentials, used to measure neurotrans-
mission in corticospinal tracts, can produce variable results
but generally show greatly reduced corticospinal tract
conduction velocity and amplitude of the evoked potential
in muscles innervated by lumbar spinal segments. However,
the cortical evoked potentials of the arms are normal or
show only mildly reduced conduction velocity. These find-
ings indicate that there are decreased numbers of cor-
ticospinal tract axons reaching the lumbar spinal cord and
that the remaining axons have reduced conduction velocity.
• Autonomic nervous system has not been studied system-
atically in HSP.
DIAGNOSIS
The diagnosis of HSP is straightforward when the family
history indicates inheritance of progressive spastic paraparesis
as an isolated symptom. In these cases, documenting
associated deficits, such as retinitis pigmentosa, extrapyramidal
531
signs, ataxia, amyotrophy and peripheral neuropathy, is the
basis for classifying HSP as pure or complex and helps to
distinguish HSP from other neurologic disorders.
Otherwise, the diagnosis of HSP is a diagnosis of
exclusion, and should only be made after excluding treatable
disorders, (such as vitamin B12 deficiency, dopa-responsive
dystonia, cervical spondylosis) and disorders with a different
prognosis (such as familial ALS).
Definite HSP
• Diagnosed when alternative disorders in the differential
diagnosis have been excluded.
• A family history supports inheritance of an X-linked,
autosomal recessive, or autosomal dominant disorder.
• Progressive gait disturbance is present.
• Spastic paraparesis with grade 4 hyperreflexia and extensor
plantar responses: occasionally, evidence of a spastic para-
paresis will be found in asymptomatic subjects and, unless
serial neurologic examinations have been performed, it is not
possible to know whether these signs have been present from
birth (representing mild spastic cerebral palsy, for example)
or presage a progressive gait disorder. Such subjects should
be classified as probably affected and examined serially.
TREATMENT
Specific
• There is no specific treatment to prevent, retard, or
reverse the progressive disability.
• A trial of low dose levodopa-carbidopa is advised for all
patients with childhood-onset progressive gait dis-
turbance of uncertain etiology (particularly those with
dystonia) because hereditary progressive dystonia with
diurnal variation can resemble HSP and is treatable.
Symptomatic
Similar treatment approaches are used as for chronic
paraplegia from other causes, such as:
• Regular physiotherapy and occupational therapy to
minimize contractures and abnormal postures and
maximize physical function and independence.
• Oral and intrathecal baclofen (or oral dantrolene).
• Regular local botulinum toxin injections into spastic hip
adductors or ankle and toe flexors/invertors (e.g. tibialis
posterior).
• Oxybutynin for bladder dysfunction due to detrusor
hyperreflexia.
Genetic counselling
The availability of genetic markers tightly linked with HSP
loci greatly improves genetic counselling but is applicable
only to counselling informative subjects from kindreds with
linkage to these loci who are at risk of transmitting or
inheriting this disorder.
Genetic counselling must consider that, despite complete
genetic penetrance, there may be substantial variation, even
within the same family, in age of symptom onset, rate of symp-
tom progression, extent of bladder involvement, and functional
disability. In some HSP kindreds, the condition begins in child-
hood and is relatively non-progressive after about age 10 years.
CLINICAL COURSE AND PROGNOSIS
Gait disturbance progresses insidiously without exacerbations,
remissions, or saltatory worsening. The evolution of the
disease is similar in patients with early- and late-onset.
532 Spinal Cord Diseases

SPINAL MUSCULAR ATROPHY (SMA)
DEFINITION
SMAs are a group of common inherited disorders
characterized by degeneration of lower motor neurons,
leading to progressive paralysis with muscular atrophy.
EPIDEMIOLOGY
• Incidence: childhood SMA: 1 per 6000 newborns.
• Age: onset varies from birth to adulthood.
• Gender: depends on inheritance (males only if X-linked).
PATHOLOGY
Neuronal loss occurs in the anterior horn cells and beyond in
the spinal cord and brainstem, with degeneration of lower
motor neurons, typical signs of axonal degeneration (reduction
of myelin and dystrophic axons with shrunken and condensed
axon structures) and neurogenic denervation of muscles (656).
ETIOLOGY AND PATHOPHYSIOLOGY (see Table 44)
Inherited
Childhood SMA
Most pedigrees show an autosomal recessive pattern of
inheritance.
Severe SMA with arthrogryposis (a heterogeneous group of
neuromuscular disorders) and bone fracture
X-linked.
Adult SMA
• Autosomal dominant and recessive forms are described.
• Genetically heterogeneous.
• Some patients demonstrate the survival motor neuron
gene (SMNT) deletion.
• X-linked form (Kennedy syndrome/spinal and bulbar
muscular atrophy).
All forms
• Disease locus mapped to chromosome 5q11.2-q13.3,
suggesting that they are allelic disorders.
• Three inherited or de novo deletions:
– The survival of motor neuron (SMN) gene.
– The neuronal apoptosis inhibitory protein (NAIP).
– P44, a subunit of the basal transcription TFIIH.
CLINICAL FEATURES
• Slowly progressive symmetric muscle weakness (proximal
> distal) and atrophy.
• Absent or markedly decreased deep reflexes.
• Fasciculations of the tongue.
• Tremor of the hands.
SPECIFIC DISORDERS
Type I (infantile: the acute form of WH disease)
• Severe generalized muscle weakness and hypotonia at birth
or within the next 6 months (floppy baby syndrome).
• Death from respiratory failure usually occurs within the
first 2 years.
• A more slowly progressive variant is recognized.
Type II (intermediate)
Children can sit, but cannot stand or walk unaided and
survive beyond 2 years.
Type III (juvenile-onset: Kugelberg–Welander
disease)
• Birth prevalence: 1.2 per 100 000.
• Inheritance: usually autosomal recessive, but dominant
and X-linked forms are described.
• Recessive types are linked to chromosome 5 (5q11.2); at
least 5% of families are not linked.
• Linkage in families with autosomal dominant inheritance
has not yet been established.
• Onset is in childhood or adolescence (3–18 years) with
difficult walking due to hip-girdle weakness.
• Proximal muscle weakness of upper and lower limbs is
present, of varying severity, starting after age 18 months.
• Fasciculations are often seen.
• Bulbar musculature is spared.
• Upper motor neuron signs are rarely present.
• The SMA is slowly progressive.
• Joint contractures often develop during the course of the
disease.
• Spinal and chest deformities are common complications.
• Otherwise, type III has a benign prognosis and is
compatible with a normal life-span.

Table 44 Etiology of SMAs

Disorder Inheritance Locus Gene 656
product

SMA I (Werdnig–Hoffman [WH]) AR 5q11-q13 SMN

SMA II (chronic infantile WH) AR
SMA III (Kugelberg–Welander) AR 5q11-q13 SMN
SMA (distal with UL predominance) AD 7p
Kennedy disease XR Xq13 SBMA
Familial ALS AD 21q22 ALS1
(SOD1)

SMA: spinal muscular atrophy; SMN: survival motor neuron protein;

SBMA: androgen receptor; ALS: amyotrophic lateral sclerosis;
SOD: Cu/Zn superoxide dismutase; AR: autosomal recessive;
656 Muscle biopsy, H&E stain, showing denervation atrophy. Several
AD: autosomal dominant; XR: X-linked recessive; UL: upper limb
fascicles consist of atrophic fibers containing dark pyknotic nuclei,
indicating denervation of muscle.
 Spinal Muscular Atrophy (SMA)
Type IV (adult-onset)
• Rare.
• Age of onset: after 15 years; mean age of onset 35 years.
• Proximal weakness and wasting.
X-linked bulbospinal neuropathy
(Kennedy’s syndrome) (see p.537)
• Onset is in adulthood.
• The gene is localized to Xq21-22, where a tandem repeat
of CAG in the androgen receptor disrupts the gene.
• Features are similar to proximal SMA (symmetric muscle
weakness [proximal > distal] and atrophy, and absent or
markedly decreased deep reflexes) but also perioral
fasciculations/tremor, which usually also involve the
tongue (657), and gynecomastia.
• Electrophysiology tests show evidence of anterior horn cell
disease and axonal degeneration at a more peripheral level.
• Counselling is advocated as for other X-linked
conditions. All daughters of affected males will be carriers
and sons will be unaffected. Carrier daughters will have
a 50% risk of having an affected male. Given the CAG
repeats, this enables gene carriers to be tested and will
allow prenatal diagnosis. There is a reasonably good
correlation between the number of repeats and the
severity of the clinical picture.
DIFFERENTIAL DIAGNOSIS
• Other non-inherited motor neuron diseases (see p.534).
• Limb-girdle muscular dystrophy (see p.674).
• Becker muscular dystrophy (X-linked dystrophinopathy):
– Family history.
– Clinically similar distribution of weakness but large calves
and lordosis, and no fasciculations.
– Serum CK: elevated 10-fold.
– EMG: myopathic.
– Muscle biopsy: dystrophic muscle (not neurogenic
changes) and reduced intensity of dystrophin
immunostaining.
INVESTIGATIONS
• Serum CK: <5 times the upper limit of normal.
• Nerve conduction studies and EMG: denervation with
neither sensory involvement nor marked decrease of
motor nerve conduction velocities.
• Muscle biopsy: evidence of skeletal muscle denervation
with groups of atrophic and hypertrophic fibers and type
grouping (in chronic cases) (656).
• Molecular DNA analysis: homozygous absence/mutation
of the SMNT gene.
DIAGNOSIS
Diagnosis is confirmed by demonstration of a homozygous
absence of the SMNT gene or, in rare cases, of a small
mutation.
Diagnostic criteria
Age at onset
• In SMA type I (severe form) onset ranges from prenatal
period to age of 6 months.
• In SMA type II (intermediate form) onset is before the
age of 18 months.
• In SMA type III (mild form) onset is usually after the age
of 18 months.
533
Muscle weakness
• Muscle weakness of the trunk and limbs (proximal more
than distal; lower limbs weaker than upper).
• Symmetric.
• Absence of weakness of extra-ocular muscles, diaphragm
and the myocardium, or marked facial weakness.
N.B. There are rare congenital-onset cases of SMA
whose clinical picture also includes external ophthalmo-
plegia, facial diplegia, and early respiratory insufficiency.
Wasting is often not conspicuous in SMA type I.
Other associated features
• Fasciculations of tongue and tremor of hands. N.B.
Tremor of the hands is frequently observed in SMA types
II and III.
• Absence of sensory disturbances.
• Absence of CNS dysfunction. N.B. Arthrogryposis of the
major joints is a rare finding in a severe form of SMA
type I. In SMA type I some mild limitation of abduction
of the hips or extension of the knees or elbows is
common.
• Absence of involvement of other neurologic systems or
organs, i.e. hearing or vision.
Electrophysiology
• Abnormal spontaneous activity, e.g. fibrillations, positive
sharp waves and fasciculations by EMG.
• Increased mean duration and amplitude of motor unit
potentials by EMG.
• In SMA types II and III, motor nerve conduction
velocities (MNCVs) >70% of lower limit and normal
sensory nerve action potentials (SNAPs).
N.B. MNCVs are markedly reduced in SMA type I.
There is a rare congenital-onset SMA with death within the
first few weeks of life in which MNCVs are very long and
SNAPs are absent.
657
657 Wasting and fasciculations of the tongue in a man with X-linked
recessive bulbar and spinal neuronopathy (Kennedy’s syndrome).
534 Spinal Cord Diseases
Histopathology of muscle
• Groups of atrophic muscle fibers of both types.
• Hypertrophic fibers of type 1.
• Type grouping (chronic cases).
N.B. In early-onset cases of SMA type I these
characteristic features may not be present. Instead there are
small fibers of both types. In SMA III there may be a
concomitant myopathic pattern.
Laboratory criteria
Biochemistry: CK usually <5 times the upper limit of
normal.
Molecular genetics
The homozygous absence/mutation of the SMNT gene in
the presence of clinical symptoms is diagnostic.
N.B. In cases with absence/mutation of the SMNT gene
further diagnostic procedures such as EMG and muscle
biopsy are no longer needed. The presence of both copies
of SMNT argues strongly against the diagnosis.
TREATMENT
• No specific therapy.
• A multidisciplinary team approach is required involving
the neurologist, GP, physiotherapist, occupational
therapist, speech/swallowing therapist and social worker.
PROGNOSIS
The prognosis depends on the age of onset and subtype:
• In SMA types I and II, there is an arrest of development
of motor milestones. Children with SMA type I are never
able to sit without support. Children with SMA type II
are unable to stand or walk without aid. In SMA type III
the ability to walk is achieved.
• In SMA type I the majority of patients have life
expectancy <2 years. In SMA type II survival into
adolescence or adulthood is common. In SMA type III
life expectancy is most likely normal.
N.B. There will be certain patients who do not clearly fit
any one category.
MOTOR NEURON DISEASES (MND)
DEFINITION
Motor neuron diseases are a heterogeneous group of
inherited and sporadic disorders of upper and lower motor
neurons which lead to progressive weakness of bulbar, limb,
thoracic, and abdominal muscles with relative sparing of
oculomotor muscles and sphincter function.
The term ‘amyotrophic lateral sclerosis’ is used to
describe this condition in North America whereas the term
‘motor neuron diseases’ is used on both sides of the
Atlantic.
EPIDEMIOLOGY
• Incidence: 1.5–2.5 per 100 000 person years, relatively
constant throughout the world but higher (5 per
100 000 per year) in western Pacific (Guam).
• Prevalence: 4–6/100 000 of total population.
• Age: any age but the age-specific incidence rises steeply
with age, reaching a maximum of 1 in 10 000 per year
between 65–85 years.
– Sporadic MND: median age of onset: 65 years.
– Familial MND: mean age of onset: 50 years.
• Gender: M (2.5 per 100 000) >F (1.8 per 100 000):
1.4:1.
PATHOLOGY
Macroscopic
Brain and spinal cord often appear normal; precentral gyrus
and corticospinal tracts may show atrophy (658–662).
Microscopic (663, 664)
• Loss of pyramidal cells of the motor cortex:
chromatolysis, spheroid formation, neuronophagia.
• Degeneration of the corticospinal tracts.
• Degeneration of lower brainstem motor nuclei (not
oculomotor nuclei) in most cases.
• Cytoplasmic eosinophilic inclusions (Bunina bodies) and
ubiquitin immunoreactive inclusion bodies in
degenerating cranial motor nuclei and anterior horn cells.
• Accumulation of neurofilaments (spheroids) in the
proximal axons of spinal motor neurons.
• Muscle shows features of denervation.
Subtypes
• Amyotrophic lateral sclerosis (the classical form of
MND): degeneration of corticospinal tract neurons in
the motor cortex (upper motor neurons) and brainstem
and spinal cord motor neurons (lower motor neurons)
(658–662).
• Progressive bulbar palsy: degeneration of the motor
neurons of cranial nerves IX–XII originating in the
medulla oblongata (the ‘spinal bulb’).
• Progressive muscular atrophy: loss or chromatolysis of
motor neurons of the spinal cord and brainstem.
• Primary lateral sclerosis: complete absence of Betz cells
from layer 5 of the precentral cortex, reduced numbers
of pyramidal cells in layers 3 and 5 of the precentral
cortex with accompanying laminar gliosis and shrinkage
of pyramidal neurons of all sizes.
 Motor Neuron Diseases (MND) 535

658 659

660 661

658–661 Axial section through a normal cervical spinal cord (658). 662
Axial sections though an abnormal spinal cord at the cervical (659),
thoracic (660) and lumbar (661) levels showing degeneration in the
anterior and lateral corticospinal tracts, which is more prominent on the
right than the left.

662 Axial section through the spinal cord of another patient with
motor neuron disease showing degeneration in the anterior (arrows)
and lateral (arrowheads) corticospinal tracts.

663 Normal neurons in the anterior horns of the spinal cord (arrows).

664 Chromatolysis of neurons in motor neuron disease.

663 664
536 Spinal Cord Diseases
ETIOLOGY
Unknown.
Inherited (5–10% of cases)
Familial ALS (upper and lower motor neuron)
• Autosomal dominant:
– Chromosome 21q22.1: Cu/Zn superoxide dismutase
(SOD1) gene mutation (lowers threshold for apoptosis
in motor neurons).
– Chromosome 22q: neurofilament heavy subunit.
• Autosomal recessive (juvenile): chromosome 2q.
Spinal muscular atrophy (SMA) (lower motor neuron)
• Chromosome 5q11.2-13.3 I, II, III: homozygous
deletion of exons 7 and 8.
• X chromosome: X-linked bulbospinal atrophy
(Kennedy’s disease): an androgen receptor defect due to
an abnormal trinucleotide repeat (CAG) in the first exon
of the androgen receptor gene.
Sporadic (90–95% of cases)
• Candidate toxins: sulfur-containing.
• Viruses: enteroviruses (e.g. polio), retroviruses (e.g. HIV,
HTLV-I).
• Autoimmune factors: antiganglioside antibodies.
PATHOGENESIS
What kills motor neurons in MND or, conversely, maintains
their long life in the absence of disease is not known, but
genes controlling the cell cycle, growth factors, and
programmed cell death (apoptosis) may be implicated;
ageing has been considered as nothing more than the
accumulation of disease-carrying mutations with age-
dependent expression.
Three hypotheses have been suggested
• Autoimmune attack on motor neurons by IgG
antibodies against L-type calcium channels.
• Excessive formation of free radicals due to mutations in
genes such as copper-zinc SOD gene, which is an enzyme
that detoxifies the superoxide anion, a free radical formed
as a by-product of aerobic metabolism.
• Excessive activation of inotropic glutamate receptors,
such as N-methyl-D-aspartate (NMDA) and α-amino-3-
hydroxy-5-methyl-4-isoxazole propionic acid/kainate
receptors in motor neurons, causing excitotoxicity and
permitting the influx of sodium and calcium into motor
neurons, activation of many enzymes, breakdown of
proteins and lipids and formation of free radicals.
CLINICAL HISTORY
• Gradual onset.
• Limb weakness: 70% present with progressive asymmetric
weakness of the limbs.
– Often begins in the leg as a foot drop, though symptoms
may start in the hands, with difficulty of fine movements,
or in the shoulder girdle.
– Muscle twitches and cramps may be present, which may
be severe.
– Local pain may herald the onset of weakness and wasting
by several weeks; pain may be severe in the late stages.
– Paresthesia is an occasional symptom but the sensory
examination is normal.
• Bulbar symptoms: 25% present with:
– Slurred speech (dysarthria): spastic (pseudobulbar palsy),
flaccid, nasal speech (bulbar palsy), or a combination of
the two.
– Difficulty swallowing (dysphagia), often with drooling
of saliva.
– Alteration in voice quality (dysphonia).
– Emotional lability (common in pseudobulbar palsy).
• Nocturnal breathlessness due to respiratory failure is a
presenting symptom in 3%.
• Family history: 5–10% have a family history, suggesting
autosomal dominant inheritance of MND; 20% of such
families have mutations of the Cu, Zn SOD1 gene on
chromosome 21.
PHYSICAL EXAMINATION
Signs may be initially confined to the upper or lower motor
neurons or to one anatomic area, such as the lumbar
segment of limbs, bulbar or respiratory musculature.
Lower motor neuron (nuclear or infranuclear) signs
• Muscle wasting (665, 666).
• Fasciculations.
• Muscle weakness.
• Areflexia.
Upper motor neuron (supranuclear) signs
• Increased (spastic) tone: may be marked, particularly in
young patients.
• Clonus.
• Hyperactive deep tendon reflexes, including brisk jaw
jerk in patients with bilateral corticospinal tract lesions
above the mid-pons.
• Weakness in a pyramidal distribution.
• Extensor plantar responses.
Combined upper and lower motor neuron signs
Increased tendon reflexes in a corresponding wasted,
fasciculating and weak myotome.
Bulbar palsy (dysfunction of the muscles of the
pharynx, larynx, and tongue innervated by cranial
nerves IX–XII originating in the medulla oblongata
[the ‘spinal bulb’])
• Flaccid dysarthria: labial sounds are usually affected first;
palatal weakness gives the speech a nasal quality and dif-
ficulty with palatal sounds such as ‘ing’, ‘egg’, and ‘ka’.
• Dysphonia.
• Dysphagia.
• Weakness, wasting and fasciculation of lower facial
muscles and tongue.
• Reduced voluntary and reflex movement of the palate,
and also tongue bilaterally.
• Reduced cough and gag reflexes.
• Absent jaw jerk.
Pseudobulbar palsy (dysfunction of the muscles of
the pharynx, larynx, and tongue due to bilateral
corticobulbar pathway involvement rostral to lower
cranial nerve nuclei)
• Spastic dysarthria: slow and forced speech with difficulty
enunciating labial and lingual sounds.
• Dysphagia: slow and difficult swallowing.
 Motor Neuron Disease (MND) 537

• Reduced voluntary movement of the palate with the
patient saying ‘ah’.
• Normal reflex movement of the palate after touching the
posterior pharyngeal wall with a wooden probe such as
a tongue depressor.
• Brisk/exaggerated jaw jerk and facial reflexes.
• Small, contracted tongue which cannot be fully
protruded.
• Bilateral spastic quadriparesis.
• Associated emotional lability: inappropriate and excessive
laughter or crying.
Ventilatory failure
• Increased respiratory rate.
• Reduced vital capacity, which is worse on lying flat.
• Life expectancy near normal and patients remain
ambulant until just before death.
• Diagnosis: abnormal expansion of the trinucleotide
(CAG) repeat in the first exon of the androgen receptor
gene on the X chromosome.
Spinal muscular atrophy (SMA) (see p.532)
• A group of genetically inherited diseases that usually
present in infancy or childhood and affect only lower
motor neurons.
• Inheritance is usually autosomal recessive.
• Gene locus for SMA types I–III has been mapped to
chromosome 5q. Abnormalities have been found in two
genes at this locus (SMN and NAIP genes).

Other
• Mild cognitive impairment, particularly of frontal lobe
function, and less so memory, may be present. 665
• Signs of comorbidities such as cerebrovascular disease
and spinal degenerative disease, may be present in
20–50% of patients without overt dementia.
• Eye movements are normal, besides impaired smooth
pursuit by saccadic intrusions.
• Bladder and bowel function is usually preserved.

VARIANTS
Amyotrophic lateral sclerosis (the classical form of MND)
A unique combination of upper and lower motor neuron
signs.

Progressive bulbar palsy

About 10% of patients present in this manner and most
progress to classical MND.

Progressive muscular atrophy

About 10% of patients show only lower motor neuron signs.

Primary lateral sclerosis

Progressive symmetric spinobulbar spasticity and weakness
of the limbs, more marked in the legs (spastic quadriparesis),
and sometimes the bulbar musculature, causing a
pseudobulbar palsy. Lower motor neuron signs are absent
and higher cognitive function is preserved.
665 A patient with severe limb weakness due to motor neuron
disease in his own environment. Note the severe wasting of the hands.
(Courtesy of Dr AM Chancellor,Tauranga, New Zealand.)

SPECIAL FORMS
Familial MND 666
• Earlier age at onset: 6–55 years.
• Initial symptoms: arms or legs.
• Variable duration of disease: 3–38 years.

X-linked recessive bulbar and spinal muscular

atrophy (Kennedy’s syndrome) (see p.533)
• Rare.
• X-linked recessive disease affecting men aged 20–50 years.
• Patients present with dysarthria with a wasted fasciculating
tongue, prominent facial fasciculations and postural tremor.
• Proximal muscle wasting, fasciculations and weakness are
also present with hypo- or areflexia.
• Endocrine abnormalities including gynecomastia, reduced
fertility, maturity onset diabetes mellitus can occur.
• Patients have absent sensory action potentials. 666 A patient with ventilatory failure due to motor neuron disease.
• Slowly progressive. Note the severe wasting of the hands. (Courtesy of Dr AM Chancellor,
Tauranga, New Zealand.)
538 Spinal Cord Diseases

Type I SMA (Werdnig–Hoffman disease) dysarthria, pyramidal tract signs, dystonia, dyskinesias,
• Presents at birth or early infancy. supranuclear ophthalmoplegia, white cell/skin fibroblast
• Hypotonia. hexosaminidase A deficiency, electron microscopy of
• Reduced movements. rectal biopsy).
• Proximal muscle wasting and weakness.
• Hyporeflexia. Metabolic and toxic disorder
• Death before 3 years of age. • Thyrotoxicosis.
• Hyperparathyroidism.
Type II SMA • Diabetic ‘amyotrophy’.
• Presents at about 6 months of age. • Lead poisoning.
• More protracted course. • Mercury poisoning.
• Death from respiratory failure before 10 years of age. • Manganese toxicity.

Type III SMA (Kugelberg–Welander disease) Neuromuscular

• Presents at about 10 years of age. • Monomelic amyotrophy.
• Much slower progression than lower motor neuron • Multifocal motor neuropathy with conduction block
forms of MND. (defined electrophysiologically) (see p.593):
• Life expectancy normal. – A disorder of the motor axon rather than the motor
nerve cell body.
DIFFERENTIAL DIAGNOSIS – Patchy, asymmetric, progressive, mainly distal, wasting,
Initially diagnosis is incorrect in about 10% of cases; clues fasciculations and weakness, principally of the upper
are failure to progress, development of atypical features, limbs.
and the results of radiologic and neurophysiologic – Preserved reflexes.
investigations. – EMG: multifocal conduction block.
– High serum titers of anti-GM1 ganglioside antibodies
Brain often detectable.
Pseudobulbar palsy – May respond to immunomodulation with intravenous
• Parasagittal meningioma. human immunoglobulin, plasmapheresis or cyclosphos-
• Pick’s disease. phamide.
• Bilateral corticobulbar vascular lesions (e.g. brainstem • Cramp-fasciculation syndrome due to peripheral nerve
and/or capsular). hyperexcitability:
• Multiple sclerosis. – Normal muscle strength.
– Benign fasciculations.
Bulbar palsy • Myasthenia gravis.
• Myasthenia gravis. • Lambert–Eaton syndrome.
• Posterior fossa tumors or aneurysms involving medulla • Myopathy: inclusion body myositis, scapuloperoneal
or lower cranial nerves. dystrophy.
• Syringobulbia.
• Polyneuritis cranialis: low grade basal meningitis, vasculitis. INVESTIGATIONS
• Full blood count and ESR.
Creutzfeldt–Jakob disease (amyotrophic form) • Serum creatine phosphokinase (may be slightly raised),
calcium, lead levels.
Spinal cord • Thyroid function tests.
• Craniocervical junction abnormality (Chiari malformation). • Serology for syphilis (RPR, TPHA), HIV antibodies,
• Cervical radiculomyelopathy. HTLV-I antibodies.
• Cervical myelopathy and lumbosacral spondylotic • White blood cell/skin fibroblast hexosaminidase A levels.
polyradiculopathy. • Nerve conduction studies:
• Syringomyelia. – Conduction velocity of sensory fibers is normal, and of
• Arteriovenous malformation. motor fibers is normal for nerves of unaffected muscles,
• Vasculitis. and not <70% of average normal value in nerves of
• Infection: poliomyelitis, syphilis, HIV, HTLV-I. affected muscles.
• Intramedullary neoplasia: lymphoma, carcinoma. – EMG: often reveals subclinical chronic partial denerva-
• Paraneoplastic syndrome: encephalomyelitis with anterior tion in clinically unaffected muscles (e.g. increased
horn cell involvement. insertional activity, spontaneous fasciculations and
• Post-radiation myeloplexopathy. fibrillation potentials, positive sharp waves, reduction in
• Hereditary spastic paraparesis with distal amyotrophy number and increase in amplitude and duration of motor
(ethnic origin [Amish, Tunisian, Lebanese], early age of unit action potentials, reduced interference pattern) due
onset, positive family history, slow progression, pes cavus, to anterior horn cell disease.
vibration sense loss, dementia, dystonia). • MRI brain: indicated in patients with bulbar onset to
• Late-onset SMA. exclude a brainstem lesion. MRI may show atrophy of
• Kennedy’s syndrome. the precentral gyrus in primary lateral sclerosis (667), or
• Hexosaminidase A, B deficiency (adult GM2 ganglio- abnormal signal in the corticospinal tracts and cortex
sidosis) (ethnic origin [Ashkenazi Jews], intellectual (thought to be due to iron deposition) (668).
impairment, psychiatric disturbances, ataxia, stutter-
 Motor Neuron Diseases (MND) 539

• MRI cervical spinal cord: particularly recommended if a 667

combination of spastic paraparesis and lower motor neuron
signs in the upper limbs are present to exclude a
compressive lesion in the neck (most commonly cervical
spondylosis). May show atrophy and increased signal in the
anterolateral parts of the spinal cord due to gliosis (669).
• Cerebrospinal fluid: normal.
• Neuropsychologic testing: may reveal frontal lobe
dysfunction.
• Ventilatory muscle strength: forced vital capacity.
• Arterial blood gases: abnormalities occur late and
indicate ventilatory failure.
• Magnetic motor cortex stimulation: prolonged central
motor conduction times: more prolonged in primary
lateral sclerosis.
• Positron emission tomography: diminished glucose [18F]
fluorodeoxyglucose uptake in the pericentral motor
cortex in primary lateral sclerosis.

DIAGNOSIS
No specific diagnostic test.

Diagnostic criteria
Presence of
• Lower motor neuron signs (including EMG features in 668
clinically normal muscles).
• Upper motor neuron signs.
• Progression of the disorder.

Diagnostic categories
• Definite MND: upper motor neuron and lower* motor
neuron signs in three regions**.
• Probable MND: upper motor neuron and lower motor
neuron signs in two regions, with upper motor neuron signs
rostral to lower motor neuron signs (thereby excluding
myelopathy, which is characterized by the reverse).
• Possible MND: upper motor neuron and lower motor
neuron signs in one region, or upper motor neuron signs
in two or three regions (e.g. monomelic MND,
progressive bulbar palsy, and primary lateral sclerosis).
• Suspected MND: lower motor neuron signs in two or
three regions (e.g. progressive muscular atrophy, and
other motor syndromes).

*Clinical or electrophysiologic evidence of chronic partial

denervation of anterior horn cell origin.
**Regions are: head, arms, thorax and trunk, legs.
669

667 MRI brain,T1WI, sagittal section near midline, showing atrophy of

the precentral gyrus (arrow) in a patient with primary lateral sclerosis.

668 PDW axial MRI of the brain at the level of the lateral ventricles
(same patient as in 669). Note the abnormal signal in the
periventricular white matter in the region of the major motor fibers
(arrow). (Courtesy of Dr R Gibson, Dept of Neuroradiology,Western
General Hospital, Edinburgh, UK.)

669 Axial T2W MRI of the cervical spinal cord in a patient with motor
neuron disease. Note the increased signal in the left anterolateral
aspect (arrow) due to gliosis of the motor tract.
540 Spinal Cord Diseases
Absence of
• Sensory signs.
• Sphincter disturbances.
• Visual disturbances.
• Autonomic dysfunction.
• Parkinson’s disease.
• Alzheimer-type dementia.
• MND ‘mimic syndromes’ (see Differential diagnosis,
above).
Supporting features
• Fasciculation in one or more regions.
• Neurogenic change in EMG studies.
• Normal motor and sensory nerve conduction (distal
motor latencies may be increased).
• Absence of conduction block.
TREATMENT
Symptomatic
• Multidisciplinary team approach (neurologist, GP, clinical
nurse, physiotherapist, occupational therapy, speech
therapy and social worker, from which a key worker acts
as the coordinator).
• Physiotherapy: muscle tone and strength, mobility.
• Occupational therapy: activities of daily living, prompt
provision of aids and appliances.
• Speech and swallowing therapy:
– Attention to swallowing techniques and function, cough
and texture of food.
– If there is no bulbar weakness, a poor cough does not
require any specific treatment unless severe enough to
cause retention of sputum (in which case, consider
tracheostomy).
• Dysphagia:
– Dietary and swallowing advice, and food thickeners.
– Percutaneous endoscopic gastrostomy if oral feeding
poses a risk of aspiration.
– Tracheostomy with a cuffed tube, or a laryngeal diversion
procedure are considered, if aspiration is still a problem,
but both of these deprive the patient of speech.
• Dyspepsia: common. Diaphragmatic weakness results in
esophageal reflux. Treat with antacids, H2-blockers or
omeprazole.
• Excess saliva can be treated with anticholinergic medi-
cations (e.g. benzhexol [trihexyphenidyl], hyoscine
[scopolamine]) or antidepressants ([e.g. amitriptyline,
dothiepin]). A home suction device can be used.
Radiotherapy can be given to the parotid gland when
these measures fail.
• Constipation: due to poor diet, reduced fluid intake and
abdominal wall weakness. Encourage fluid intake, and
use laxatives (e.g. lactulose, senna [anthraquinone
laxatives], co-danthramer).
• Nocturnal respiratory failure (e.g. breathlessness on lying
flat at night, hypoxemia, hypercapnia):
– Nasal intermittent positive pressure ventilation or a
negative pressure system such as a cuirass can be used at
night, if good bulbar and limb function are present.
– If assisted ventilation is inappropriate, dyspnea should be
relieved with benzodiazepines and opiates; permanent
tracheostomy and intermittent positive pressure
ventilation are best avoided.
• Muscle cramps: quinine.
• Spasticity: physiotherapy, baclofen, dantrolene, focal
botulinum injections.
• Depression and insomnia: common: antidepressants and
hypnotics can be used when appropriate.
• Referral to a local hospice and/or palliative care as well
as terminal and home care should be given when
appropriate.
Specific
• Riluzole:
– 2-amino-6-(trifluoromethoxy)benzothiazole which
crosses the blood–brain barrier.
– It inhibits glutamate release, inactivates voltage-
dependent sodium channels, and interferes with
intracellular events that follow transmitter binding at
excitatory amino acid receptors.
– May retard the course of MND (improves tracheostomy-
free survival by about 3 months without any effect on
muscle strength and neurological function) but does not
arrest the disease.
– Dose: one 50 mg tablet every 12 hours.
– Well tolerated.
– Adverse effects include weakness, nausea, dizziness,
vertigo, sleepiness, shortness of breath and headache.
– Monitoring of full blood count and liver function tests
is required at monthly intervals for the first 3 months of
treatment and then every 3 months.
– A year’s treatment costs US$7000–8000 per patient and
is best used early in the evolution of the disease if it is to
be used at all.
• Vitamin E may retard onset but not progression (cf.
riluzole which may retard progression but not onset).
• Nerve growth factors (e.g. brain-derived neurotrophic
growth factor, insulin-like growth factor): may have a
role in the future.
CLINICAL COURSE
• Progressive.
• About 2% develop dementia of frontal lobe type.
PROGNOSIS
• Median life expectancy: 2.5–3.5 years; about 2 years for
patients with bulbar onset and 4 years for patients with
onset of limb weakness.
• 25% survive 5 years from onset of symptoms.
• Favorable prognostic factors:
– Early age of onset (some may survive 20 years).
– Progressive muscular atrophy.
– Primary lateral sclerosis: mean disease duration: 15 years
(median: 19 years).
• Poor prognostic factors:
– Bulbar onset.
– Older age.
– Female sex.
• Death is usually from respiratory failure due to
diaphragmatic weakness, and may be precipitated by
aspiration pneumonia.
 Syringomyelia
SYRINGOMYELIA
DEFINITION
A chronic, progressive, degenerative disorder of the spinal
cord, characterized by cavitation (syrinx [from the Greek
syrinx, ‘tube’ or ‘pipe’]) of the central part of the cervical
spinal cord (syringomyelia), sometimes extending caudally
to the thoracic and lumbar cord and rostrally to the brain
stem (syringobulbia), which causes progressive neurologic
symptoms, usually brachial amyotrophy and segmental
dissociated sensory loss, as it expands.
TERMINOLOGY
Hydromyelia refers to dilatation of the central canal of the
spinal cord. It occurs in association with obstruction at the
foramen magnum (Chiari I and II malformations, Paget’s
disease and other lesions associated with basilar invagin-
ation). The dilated canal is lined with ependyma and
communicates with the fourth ventricle via the obex.
Syringomyelia refers to cavities in the central portion of
the spinal cord, unconnected with the central canal. The
cavity may be central or eccentric, is lined with glial cells and
does not communicate with the fourth ventricle. It is
associated with arachnoid cysts, arachnoiditis, meningiomas
and neurofibromas, cord tumors and inflammation, trauma
and spondylotic compression. For our purposes both will be
considered together under the title ‘syringomyelia’.
EPIDEMIOLOGY
• Prevalence: 8.4 per 100 000 population.
• Age: symptoms usually begin about 35–45 years of age,
but occasionally in late childhood or adolescence.
• Gender: M=F.
ANATOMY AND PHYSIOLOGY OF CENTRAL CANAL
The central canal of the spinal cord is fluid-filled and lined
by ependymal cells that have open gap junctions. Normal
products of metabolism and products of disease enter the
central canal from spinal interstitial spaces (the central canal
thus acts like a sink draining CSF) and are carried rostrally
toward the fourth ventricle, with the aid of vascular
pulsations transmitted to this fluid-filled tube. The central
canal of the spinal cord normally undergoes stenosis or
occlusion. This is attributed to common viral infections
causing inflammation of the ependyma.
PATHOLOGY
An abnormal fluid-filled cyst (syrinx) is present, lined by
astrocytic gliotic tissue and a few thick-walled vessels, and
containing clear fluid with a relatively low protein content,
like CSF.
It most commonly occurs in the central gray matter of
lower cervical or upper thoracic segments of the spinal cord,
but can involve the entire length of the spinal cord and may
extend rostrally into the brainstem (syringobulbia) as far as
the thalamus.
Anatomy of the syrinx: axial plane of the spinal cord
• Central: not continuous with the fourth ventricle or
subarachnoid space; the most common type of syrinx.
• Central with expansion into the paracentral parenchyma:
about 40%.
541
• Paracentral parenchymal syrinx: no communication with
the central canal, fourth ventricle, or the subarachnoid
space; almost exclusively caused by spinal cord injury
(trauma, ischemia, viral infection).
Anatomy of the syrinx: communicating or loculated
• Communicating syrinx: free communication between the
cavity and the subarachnoid space, and therefore free
exchange between the syrinx and the CSF; hence, the
fluid is the same as CSF. These syrinxes are mostly
associated with Chiari I and II hindbrain malformations.
• Non-communicating syrinxes: loculated. The syrinx fluid
has a higher protein content than CSF. These are mostly
neoplastic.
ETIOLOGY
Congenital
Hindbrain herniation: the Chiari type I malformation (see
p.136) is present in many cases of syringomyelia that present
in adulthood, and the more severe Chiari types II and III
abnormalities are associated with infantile forms of syringo-
myelia. However, there is a school of thought that the
Chiari I malformation of the cerebellar tonsils is acquired,
not congenital, because of the disappearance of the
abnormal shape and position of the tonsils after simple
decompressive extra-arachnoidal surgery.
Acquired
• Trauma: post-traumatic spinal cord cavitation is a
progressive disorder in which initial spinal cord damage
leads to altered CSF hydrodynamics and arachnoiditis,
resulting in progressive expansion and extension of the
syrinx. Most cases result from motor vehicle accidents
and affect the lower portion of the cervical segment of
the spinal cord.
• Surgery: intradural spinal surgery, such as resection of a
spinal cord tumor, may lead to syringomyelia.
• Inflammation: post-inflammatory syringomyelia may
result from infections (e.g. tubercular, fungal, parasitic)
or from chemical meningitis, and is commonly associated
with arachnoidal scarring.
CLASSIFICATION
• Type I. Syringomyelia with foramen magnum
obstruction and central canal dilatation:
– With type I Chiari malformation.
– With other obstructive lesions of the foramen magnum.
• Type II. Syringomyelia without foramen magnum
obstruction (idiopathic).
• Type III. Syringomyelia with other diseases of the spinal
cord:
– Spinal cord tumors.
– Traumatic myelopathy.
– Spinal arachnoiditis and pachymeningitis.
• Type IV. Pure hydromyelia with or without hydro-
cephalus.
PATHOPHYSIOLOGY
Unknown. There is no consensus on the pathophysiology
of syringomyelia, particularly in Chiari I malformations.
Consequently, there is a great diversity in the surgical
approaches that are being used.
542 Spinal Cord Diseases
Hydrodynamic theory
The normal outflow of CSF from the fourth ventricle is
prevented by a congenital failure of opening of the outlets
of the fourth ventricle. As a result, a pulse wave of CSF
pressure, generated by systolic pulsations of the choroid
plexuses, is transmitted through the fourth ventricle into the
central canal of the spinal cord leading to the formation of a
central cavity that dissects along gray matter and fiber tracts.
This theory is supported by the frequent association of
syringomyelia with congenital malformations at the
craniocervical junction that could interfere with normal flow
of CSF, such as the Arnold–Chiari malformation, and the
Klippel–Feil syndrome (fusion of one or more cervical
vertebrae), and other congenital abnormalities such as spinal
bifida and hydrocephalus.
It has also been proposed that syringomyelia associated
with Chiari I malformation is produced by the action of the
cerebellar tonsils, which partially occlude the subarachnoid
space at the foramen magnum and act as a piston on the
partially enclosed spinal subarachnoid space. This creates
enlarged cervical subarachnoid pressure waves that compress
the spinal cord from without, not from within, and
propagate syrinx fluid caudally with each heartbeat, which
leads to syrinx progression.
Hydrodynamic mechanism within a destructive
cervical cord lesion
A cervical cord lesion, occurring in childhood as part of a
Chiari malformation, results in an enlarging cavity and
diverticulation of the spinal canal via a hydrodynamic
mechanism within a destructive cervical cord lesion.
CLINICAL FEATURES
Dissociated sensory loss and its consequences
• Loss of pain and temperature sensation occurs in one or
two dermatomes in the upper limbs bilaterally, often in
a cape-like distribution across the back and shoulders.
This is due to expansion of the cavity anteriorly (and over
one or two segments) at the level of the dermatomes,
thus compressing the decussating (crossing) pain and
temperature fibers of the lateral spinothalamic tracts. If
the syrinx expands laterally it may cause contralateral pain
and temperature loss below the level of the lesion.
Consequently, patients frequently damage their skin from
burns and injure their joints from trauma because the
pain goes undetected.
• Infection, scars, trophic changes and joint deformities in
the upper limbs give rise to a soft fleshy appearance of
the fingers and Charcot joints.
• Touch and position sense are retained initially
(dissociated sensory loss) but later proprioceptive loss
also occurs in the limbs due to compression of the
posterior columns.
• Pain may occur.
Motor weakness and wasting
Wasting and weakness of upper limb muscles is present,
usually the small muscles of the hand initially, when the
cavity compresses the anterior horn cells sufficient to cause
them to degenerate. Fasciculations may be seen. Later,
lower limb weakness may occur due to compression of the
corticospinal tracts, causing a spastic paraparesis.
Reflex change
Loss of reflexes occurs in the upper limbs due to
interruption of the reflex arc in affected segments of the
cord. Brisk reflexes and increased muscle tone in the legs
occur (leg stiffness is a common symptom) if the lateral
corticospinal tracts become compressed, causing a spastic
paraparesis or quadriparesis, below the level of the syrinx.
Horner’s syndrome
Horner’s syndrome may occur in the presence of
compression of the ipsilateral descending sympathetic fibers.
Associated abnormalities
Brainstem and cerebellum
Type 1 Chiari malformation: present in about 90% of
patients with syringomyelia (about 50% of patients with type
1 Chiari malformation have syringomyelia).
Skull base
Platybasia and basilar invagination.
Vertebral column
• Klippel–Feil anomaly.
• Fusion of vertebrae.
• Thoracic kyphoscoliosis.
SPECIAL FORMS
Syringobulbia
The syrinx extends rostrally into the medulla (usually
beneath the floor of the fourth ventricle) and rarely beyond.
• Pain and temperature sensation is reduced or lost over
one or both sides of the face, (often in an ‘onion-skin’
type distribution) if the syrinx extends into the upper
cervical cord (C1,2) and compresses the spinal
trigeminothalamic tract.
• Touch, proprioception and vibration sensation may be
reduced or lost ipsilateral to compression of the
decussating fibers of the medial lemniscus in some cases
of syringobulbia.
• Wasting and weakness of the tongue, soft palate, pharynx
and vocal cords, causing dysphagia, dysarthria and
dysphonia, may occur if the syrinx extends into the
medulla and compresses the nuclei of the hypoglossal
and vagus nerves (nucleus ambiguus).
• An internuclear ophthalmoplegia may occur with
involvement of the medial longitudinal fasciculus.
 Syringomyelia 543

670–672 MRI 670 INVESTIGATIONS

cervical spine,T1W MRI spine
image, midline sagittal MRI is the imaging modality of choice. MR of the cervical
section (670), and spinal cord will usually demonstrate widening of the spinal
axial lower cervical cord, the full extent of the syrinx within the spinal cord and
(671) and upper the extent of expansion in the axial, sagittal and coronal plane,
thoracic (672) and associated lesions such as tonsillar herniation (670–674).
sections, showing The signal from the syrinx is usually of similar signal to CSF
cerebellar tonsillar on all sequences unless it is loculated and contains
ectopia and a proteinaceous material or blood breakdown products.
relatively low lying
fourth ventricle due Other imaging modalities
to a Chiari 1 • Plain cervical spine x-rays may reveal widening of the
malformation (with spinal canal but this is rather non-specific.
previous posterior • Myelography may demonstrate a widened cord; CT may
decompression), and show widening of the spinal cord and canal.
a syrinx within the • CT myelography may demonstrate the syrinx as a low
cervical and upper density area within the widened cord, but it is more
thoracic cord.The difficult to cover an entire syrinx with axial CT than it is
syrinx is at its widest with sagittal MRI.
in the upper thoracic
cord, where it has a EMG
transverse diameter Nerve conduction studies and EMG show reduced
of about 8 mm (0.3 compound muscle action potential amplitude and features of
in).The syrinx chronic partial denervation (fibrillation potentials and reduced
terminates rostrally interference pattern) in the small muscles of the hand among
at the level of the C2 patients with a moderately extensive cervical syrinx.
vertebral body.

671

673 674

672

673, 674 T2W (673) and T1W (674) midline sagittal MRI of the cervical
spine showing a congenital vertebral anomaly at C1, 2 and 3 (arrows), and
also at C5/6 (arrowhead).There is a small syrinx at the level of C4/5.The
appearance is consistent with a Klippel–Feil anomaly.
544 Spinal Cord Diseases
DIFFERENTIAL DIAGNOSIS
• Intramedullary spinal cord tumor (primary or
secondary): rapid course, raised CSF protein.
• Extramedullary spinal tumor: tends to present with nerve
root pain and a spastic paraparesis due to extramedullary
cord compression. CSF protein is elevated.
• Hematomyelia: usually a history of trauma, sudden onset
and pain in the involved area.
• Cervical spondylosis: sensory loss is usually confined to
the involved nerve roots.
• Motor neuron disease: wasting of the hands but no
sensory loss.
• Multiple mononeuropathy: may be associated with
peculiar sensory deficits. Usually abrupt onset of loss of
function of one, followed by other peripheral or cranial
nerves. Sensory dissociation in the upper trunk is very
uncommon.
• Diabetic neuropathy: another (but rare) cause of Charcot
joints in the shoulders but other clinical features of
diabetes.
• Vasculitic neuropathy (systemic: polyarteritis nodosa,
rheumatoid arthritis, or non-systemic): may present with
distal symmetric polyneuropathy but more commonly a
mononeuropathy multiplex.
• Leprosy: tends to affect pain and temperature sensation
and may cause a syringomyelia-like syndrome. However,
leprosy preferentially affects the intracutaneous nerves
and so the pattern of sensory loss does not follow the
distribution of individual peripheral nerves or nerve
roots. In lepromatous leprosy, sensory loss occurs in areas
with low skin temperature, causing a superficial
resemblance to a glove and stocking distribution, but
other cool areas such as the nose, earlobes, breasts,
abdomen and buttocks may also be affected. In addition
there is usually a history of residence in an area where
leprosy is endemic and there are skin lesions and enlarged
nerves.
• Acute intermittent porphyria: patchy sensory loss
involving the trunk or arms but usually acute onset, all
four limbs are affected before the trunk, abdominal pain,
psychiatric symptoms, or a deficiency of erythrocyte
porphobilinogen deaminase.
• Amyloidosis: loss of sensation to pain and temperature
but autonomic dysfunction is also common.
• Fabry’s disease: an X-linked recessive disorder that
frequently presents with severe burning pain in the hands
and feet.
• Tangier disease: may cause a syringomyelia-like syndrome
(spontaneous pain in the arms, wasting of the hand
muscles, dissociated sensory loss in the upper trunk, and
facial diplegia) due to selective loss of small myelinated
and unmyelinated nerve fibers and small dorsal-root
ganglion cells, but patients have large, lobulated, yellow-
gray tonsils, and they may have hepatosplenomegaly, a
low serum cholesterol level (unless a second lipid
disorder), and nearly absent high-density lipoprotein
(HDL) and apolipoprotein A-I and A-II.
DIAGNOSIS
Diagnosis is clinical and radiologic (MRI).
TREATMENT
Conservative
If a small syrinx is present associated with very slow progres-
sion/deterioration. Carbamazepine, amitriptyline or trans-
cutaneous nerve stimulation can be used if the pain does not
respond to simple analgesics.
Surgical
If increasing neurologic deficit occurs. Spinal deformity,
such as kyphoscoliosis, should be first corrected. A variety
of shunts, shunt materials, and shunt locations are used but
there is no consensus, one reason being our lack of full
understanding of the pathophysiology of syringomyelia, and
lack of randomized trials of treatment strategies.
Syringomyelia associated with Chiari I malformation
The primary goal is to arrest the progression of the neuro-
logic deficits by decompressing the Chiari I malformation
with a suboccipital craniectomy and upper cervical (C1)
laminectomy in combination with a duraplasty. If scarring
occludes the outlet of the fourth ventricle, an opening is
made in the scar to re-establish the outlet of the fourth
ventricle of treatment strategies.
Syringomyelia associated with Chiari II malformation
Chiari II is a congenital malformation associated with
myelomeningocele, hydrocephalus and often lower cranial
nerve abnormalities. In addition to the hindbrain herniation
seen in Chiari I, the posterior fossa in Chiari II is too small
for the cerebellum, and there is upward herniation into the
middle fossa. Consequently, decompression of the posterior
fossa in Chiari II is not effective in most patients, and may
result in shunt malfunction and immediate herniation into
the decompression.
Post-traumatic syringomyelia
Treatment of cysts with shunts should be considered a
treatment of last resort. Shunting can collapse the cyst but
often complications result in re-expansion and the need for
subsequent surgery and reshunting. Placing shunts in the
spinal cord can also add to the neurologic deficit.
Decompression by means of a dural graft with a bypass
for CSF may be helpful.
PROGNOSIS
Usually slowly progressive and ultimately severely disabling
but some patients experience a stepwise deterioration, and
others ‘plateau’ and do not progress.
 Cervical Spondylotic Myelopathy and Radiculopathy 545

CERVICAL SPONDYLOTIC ETIOLOGY AND PATHOPHYSIOLOGY

MYELOPATHY AND RADICULOPATHY
DEFINITION
A condition in which the spinal cord (myelopathy) and/or
nerve roots (radiculopathy) are damaged, either directly by
traumatic compression and abnormal movement, or
indirectly by ischemia due to arterial compression, venous
stasis, or other consequences of the proliferative bony
changes that characterize spondylosis.
EPIDEMIOLOGY
Most people older than 50 years have cervical spondylosis.
Most have no symptoms apart from reduced mobility of the
cervical spine.
• Incidence: 83 per 100 000 per year (cervical radiculopathy),
2 (95% CI: 0.5–6) per 100 000 per year (chronic spondy-
lotic myelopathy).
• Prevalence (lifetime): 0.4 (95% CI: 0.2–0.7) per 1000
(spondylotic and compressive myelopathy).
• Age: middle-aged and elderly; peak incidence in the age
group 50–54 years.
• Gender: M>F.
Predisposing factors
• Narrowing of the spinal canal in the sagittal
(anteroposterior) plane: <11–12 mm (<0.4–0.5 in)
results in deformation of the cord, the degree of which
correlates with the clinical severity of myelopathy. The
salient static measurement is however, the cross sectional
area of the cord. Reduction in cross sectional area of the
cord by 30% or more to a value of about 60 mm2 or less,
results in symptoms and signs.
• In patients with cervical spondylotic myelopathy caused
by an ossified posterior longitudinal ligament, the
dentate ligaments fix the cord against the anterior part
of the canal. Sectioning of the dentate ligaments may
spread the tension in the cord over a greater segment.
• Hypertrophic facet and uncovertebral joints occupy space
in the root canal.
• Neck motion: predisposes to spur formation and activates
symptoms and signs of cervical spondylotic myelopathy
(e.g. patients with athetoid cerebral palsy).
• Deflexion (i.e. extension) of the neck.

PATHOLOGY
Macroscopic
Spondylosis of the vertebral column
• Transverse bars occur which may extend across the
posterior aspect of the vertebrae and compress the spinal
cord. The lateral end of the transverse bars may encroach
on an intervertebral foramen and compress the nerve root. 675
• Localized bosses occur centrally or laterally, which may
compress the spinal cord.
• Intervertebral disc protrusions are commonly associated
with the bars and bosses.
• Frequently these lesions are found at more than one
vertebral level.

Spinal cord/root compression

• Indentation, flattening and distortion of the spinal cord
occurs corresponding to the spondylotic protrusions (675).
• The C6 or C7 nerve roots are affected in two-thirds of
cases of cervical radiculopathy.

Microscopic
• Demyelination of the lateral columns, ischemic change and
nerve cell damage and loss in the central gray matter, and
cavitation at the site of the compression are all present.
• Degeneration of the dorsal columns occurs rostral to the
lesions.
• Degeneration of the lateral columns occurs caudal to the
lesions.

675 Autopsy specimen of the cervical spine in the sagittal plane

showing a degenerate cervical intervertebral disc (oblique arrow),
compressing the cervical spinal cord causing a necrosis of the cervical
spinal cord at that level (horizontal arrow).
546 Spinal Cord Diseases

Causes Cervical radiculopathy (see Acute ‘slipped disc’,

• A bulging or herniated disc (676). p.550)
• Degenerated yellow ligaments. • Neck and arm pain in some (677, 678).
• A fixed subluxation due to disc degeneration. • Paresthesiae, pain and cutaneous sensory loss in a
• Microtrauma. radicular distribution.
• Wasting and weakness of proximal arm muscles or in the
Mechanism hands.
Direct • Fasciculations in a segmental distribution in the hands
Traumatic compression and abnormal movement. Acute and arms.
trauma is likely to exacerbate any pre-existing myelopathy
in a chronically distorted, narrowly confined, cord. DIFFERENTIAL DIAGNOSIS
Mechanical compression theory: the spinal cord is com- Cervical spine/spinal cord pathology
pressed by a spondylotic bar anteriorly and the ligamenta • Discogenic or degenerative cervical spine stenosis.
flava posteriorly, particularly during extension of the neck, • Vertebral body fracture: trauma, metabolic bone disease,
when the ligamenta flava bulge into the spinal canal, tumor.
decreasing its anteroposterior depth while the antero- • Tumor:
posterior dimension of the spinal cord itself increases. – Tumor of vertebral column or epidural space (or both):
People with congenitally narrow spinal canals are more Metastases.
vulnerable. Plasmacytoma or multiple myeloma.
Dentate tension theory: the anterior spondylotic bar Primary bone tumor.
displaces the spinal cord posteriorly and stretches the dentate Primary intradural tumor of spinal cord.
ligaments, which attach the lateral pia to the lateral dura. The • Infection:
attachment to the dura is fixed because the dural root sleeves – Intervertebral discitis or osteomyelitis.
are anchored in the neural foramina. Consequently, the – Epidural or subdural abscess.
spinal cord is pulled laterally by the dentate ligaments. The – Herpes zoster or other viral-based radiculopathy.
spondylotic bar may also increase dentate tension by • Vascular lesion:
interfering locally with dural stretch during neck flexion, the – Acute epidural hematoma.
resultant increase in dural stress being transmitted to the – Spinal cord infarction.
spinal cord via the dentate ligaments. – Arteriovenous malformation of the spinal cord.
– Spinal dural arteriovenous fistula.
Indirect • Amyotrophic lateral sclerosis.
The role of ischemia is uncertain. There is no correlation • Multiple sclerosis.
with atherosclerosis of major vessels or with obstruction of • Syringomyelia.
blood flow in the anterior spinal artery. Distortion and com- • Diabetic radiculoneuropathy.
pression of small vessels in the cord may have a pathogenetic • Acute inflammatory demyelinating polyradiculopathy
influence. The influence of venous stasis is uncertain. (Guillain–Barré syndrome).

CLINICAL FEATURES Brain pathology

Cervical spondylosis without foraminal or spinal canal
stenosis does not result in cervical spondylotic radiculopathy
or myelopathy.
Cervical spondylotic myelopathy
• Neck pain in some.
• Numb, clumsy hands:
– Amyotrophic hand: localized wasting and weakness of
the hand without remarkable sensory loss or gait
disturbance. Correlates with a reduced cross-sectional
area of the spinal cord at the C7–T1 segments. Similar
to hands of patients with spinal muscular atrophy.
– Myelopathic hand: spastic dysfunction and deficient pain
sensation due to reduction in spinal cord diameter at
higher spinal levels.
• Spastic paraparesis: the sine qua non for the diagnosis.
• Loss of proprioception and vibratory sensation in the legs.
• Poorly defined cutaneous sensory loss in the legs.
• Parasagittal meningioma.
• Bilateral anterior cerebral artery territory infarction.
• Bilateral corticospinal tract infarction (e.g. internal
capsule and pons).
• Primary lateral sclerosis.
• Hydrocephalus.
INVESTIGATIONS
Plain films of the cervical spine
Useful because they demonstrate narrowing of the spinal
canal, osteophytes arising from the posterior surfaces of
degenerate discs and at the neurocentral joints, and the
alignment of the vertebral bodies. Flexion and extension
views may be done to look for instability with movement.
They do not, however, give any information on the degree
of cord or root compression or the soft tissue abnormalities
around the spine.
Plain CT (679)
CT has a limited role; it images osteophytes and calcified discs,
and accurately measures the dimensions of the bony spinal
canal, but the cervical cord and roots cannot be assessed.
 Cervical Spondylotic Myelopathy and Radiculopathy 547

676 Illustration showing the effect of a cervical spondylitic 676

bar, osteophyte or degenerate intervertebral disc at the
C5/6 level, compressing the cervical spinal cord (causing a
Spinal cord
cervical myelopathy) and/or left C6 nerve root (causing a compressed by
left C6 radiculopathy). spondylitic bar

Spine of C6 vertebra

Osteophyte

C6 root damaged by
lateral osteophyte

Degenerate
intervertebral disc

Vertebral artery

677 678
C3
C4 C3
C5 T2 C4
T3 C5
T4 T2
T2 T3
T5 T4
C6 T3 T5 T2
T6
T6 C6
T1 T7 T3
T7 T1
T8 T8
C6 T9
T9 C6
T10
T10
C7 T11
T11 C7
C8 T12
T12 L1 C8
L1

677, 678 Distribution of the cervical and thoracic dermatomes on 679

the anterior aspect of the upper limb, chest and abdomen (677), and
the posterior aspect of the upper limb and back (678).

679 CT scan of the cervical spine, axial plane at C5/6 showing very
advanced spondylotic change with anterior and posterior lipping
osteophytes and a large osteophyte arising from the posterior aspect
of the C5 disc (circle) causing markedly severe central spinal canal
stenosis.
548 Spinal Cord Diseases
MRI cervical spine
The imaging modality of choice (680–684).
• Sagittal T1W and T2W images show the cord and level
of any compression.
• Axial views at those levels further define the degree of
cord and root involvement.
• Disc protrusions are seen in about 20% of neurologically
asymptomatic people aged 45–54 years, and in about
57% of asymptomatic people older than 64 years.
• Spinal cord impingement (a concave defect in the spinal
cord adjacent to a site of disk bulging, without obliteration
of the subarachnoid space posterior to the cord) is seen in
about one-sixth of neurologically asymptomatic people
under 65 years and one-quarter over 65 years.
• Cord compression (with obliteration of the posterior
subarachnoid space) may also be neurologically
asymptomatic but usually the percentage reduction in
cord area in asymptomatic people is well below 30%
(usually below 15%). Thinning of the cord opposite a disc
protrusion is indicative of compression, worse if there is
increased signal in the cord at that point on T2WI.
Increased signal intensity on T2W images of a compressed
cord reflect myelomalacia, demyelination, gliosis or
microcavities. An intense signal correlates with clinical
deficit and probably reflects inflammation or edema.
• Nerve root compression can occur without significant
cord compression in which case axial views targeted to
the level of the patient’s symptoms (plus the level
immediately above and below) are required. Absence of
the fat signal from within the root canal, in addition to
obvious abnormal mass (e.g. disc or bone) and
displacement or obliteration of the nerve is good
evidence on imaging of compression.
Computer assisted myelography (CAM)
• Useful if MRI quality is suboptimal, the MRI study
inconclusive, or the patients is unable to have MRI.
• Useful for delineating the bone and soft tissue abnormali-
ties but it is an invasive procedure.
• It has a low complication rate, mostly due to cervical
spine hyperextension or lateral C1–C2 puncture.
DIAGNOSIS
• Diagnosis is based on clinical symptoms and signs of
spinal cord (± nerve root) compression (i.e. spastic
paraparesis) with unequivocal MRI or CAM evidence of
spinal cord compression that correlates precisely with the
clinical findings.
• Key clinical features are:
– A spastic paraparesis.
– Numb, clumsy hands.
– Sudden quadriplegia or paraplegia after a minor fall in an
elderly patient.
• Diseases such as motor neuron disease and multiple
sclerosis must be ruled out by a thorough neurologic
clinical assessment, plain cervical spine radiographs in
flexion and extension, in combination with MRI and if
necessary CAM.
TREATMENT
Patients without major neurologic deficits or signs of
worsening are probably best treated conservatively and
observed closely over time. A restraining collar may help
limit the mobility of the cervical spine, and particularly
flexion of the neck which increases dural tension.
Improvement has been reported in nearly half of patients
treated with a cervical collar but the studies have been
uncontrolled.
Surgical decompression is considered in patients who are
moderately or severely disabled on initial assessment and
who, on close follow-up, have progressive impairment of
function without sustained remission. Measurement of
cervical mobility on functional radiographs may help to
select patients who are more likely to deteriorate and thus
more likely to benefit from surgery, such as those with spinal
hypermobility possibly. (N.B. Male patients with symptoms
and signs of prostate enlargement should first be treated for
that problem to avoid major post operative micturition
disturbances). Less suitable cases for surgery are those with
advanced neurologic changes (e.g. existing severe
myelopathic features and evidence of severe cord atrophy),
associated neuropathies (i.e. due to diabetes and
alcoholism), and those too elderly to engage actively in a
post operative rehabilitation programme.
The aim of surgical therapy is to arrest the progression
of myelopathy by elimination of mechanical compression of
the dura-enclosed spinal cord, but the risks and benefits of
surgical therapy in a large proportion of patients are
uncertain and a randomized controlled trial is sorely needed.
Surgical techniques include laminectomy (which would
seem unhelpful if the problem is not one of compression by
the posterior elements of the spine) with or without
facetectomy (which releases the tethering of the dural sac
by the dural root sleeves in the foramina, removing the fixed
point against which the dentate ligaments can be stretched);
opening the dura and sectioning the dentate ligaments (but
extensive adhesion may form and involve the spinal cord),
and, perhaps preferably, removal of the spondylotic bar
through an anterior or posterior approach that remains
extradural. This removes the source of posterior pressure on
the spinal cord and the source of interference with
stretching of the dura during cervical flexion. Fixation of
680 680 MRI of the cervical
and upper dorsal spine,
sagittal T2WI, of the same
patient in 679 who had
severe Parkinson’s disease
and had fallen forwards
and landed on his face. He
was so bradykinetic that
he failed to move his arms
forwards to cushion the fall
and consequently fell on
his face, suffering a sudden
hyperextension injury to
the cervical spine. In the
presence of severe cervical
spondylosis he
compressed the cervical
spinal cord and presented
with quadriplegia of
sudden onset. He had a
motor level at C6/7 and a
sensory level at T5 on the
left and T8 on the right.
 Cervical Spondylotic Myelopathy and Radiculopathy 549

the vertebrae bordering the spondylotic bar with a bone PROGNOSIS

graft may also help in reducing spinal mobility. This form of
surgery fails in about 25% of cases however, possibly because
post operative adhesions between the anterior dura and the
anterior wall of the spinal canal may cause increased tension
in the dura during neck flexion.
The natural history is not well known because most patients
undergo some form of surgical treatment. Spontaneous
regression and complete remission is unusual. About one-
third of patients experience a recurrence during a median
time of follow-up of 5 years.

681 682

681, 682 T1W sagittal (681) and T2W axial (682) MRI of a C5/6
disc herniation. Note that the disc (arrows) protrudes posteriorly and
to the left, displacing the cord posteriorly and to the right and
obliterating the left C6 nerve root.

683 684

683, 684 T2W sagittal (683) and T2W axial (684) MRI of the
cervical spine in a patient with severe cervical spondylosis. Note the
marked narrowing of the spinal canal at multiple levels. On the axial
view the cord appears ribbon-like. Also note the increased signal within
the cord indicating gliosis.
550 Spinal Cord Diseases
ACUTE ‘SLIPPED DISC’
DEFINITION
Acute extrusion of the nucleus pulposus of an intervertebral
disc.
EPIDEMIOLOGY
• Common.
• Incidence – acute cervical myelopathy related to disc:
2 (95% CI: 0.2–6) per 100 000 per year.
• Age: young adults or middle-aged.
PATHOLOGY
• The prolapse is usually posterolateral rather than central.
• The lumbar discs are most often affected (L4/5 or
L5/S1), cervical discs occasionally (C7 root involved in
70% of cases of cervical disc protrusion, C6 root in 20%
of cases, C5 and C8 roots in the remaining 10%), and
thoracic discs rarely.
ETIOLOGY AND PATHOPHYSIOLOGY
• Acute slipped disc may be spontaneous or precipitated
by sudden spine movement (e.g. sudden hyperextension
of the neck, diving, forceful chiropractic manipulations),
lifting and straining.
• A prolapsed cervical disc compresses the nerve root and
spinal cord at that level (e.g. a laterally situated disc
protrusion between the sixth and seventh cervical
vertebrae compresses the seventh cervical root) (676),
whereas a prolapsed disc in the lumbar region (e.g. at
L4/5), where nerve roots are angulated, usually
compresses the root passing to the foramen below (e.g.
the L5 root) (685).
• Nerve root compression usually involves only one nerve
root on one side (perhaps two) but a central lumbar disc
prolapse may compress most of the cauda equina,
causing multiple lumbosacral root lesions and sphincter
disturbance.
• Spinal cord compression by central cervical or thoracic
discs (at or above the level of the conus medullaris, which
is at the level of the L1/2 intervertebral disc) causes
upper motor neuron signs.
CLINICAL FEATURES
• Acute pain, tenderness and paraspinal muscle spasm at the
level of the prolapse. N.B. Central cervical disc
herniations, compressing the spinal cord, may be painless.
• Nerve root (radicular) pain, which is sharp, burning or
‘electric’, and severe; combined with sensory disturbance;
in the dermatomal distribution of the compressed nerve
(677, 678, Table 45, 686).
• Pain: exacerbated by coughing, sneezing, straining, mov-
ing (bending and stooping), straight leg raising (low
lumbar and sacral root compression), and femoral stretch
test (upper lumbar roots); relieved by rest and particular
postures.
• Muscle wasting and weakness and depressed tendon
reflex in myotomal distribution (see Tables 46, 47).
HISTORY
• Neck/back pain: location (radicular), onset (usually acute,
?precipitating factors), timing (?nocturnal), nature (sharp),
intensity (severe), radiation (dermatomal), duration
(seconds-minutes-hours), associated symptoms (e.g. limb
weakness or sensory disturbance, bladder or bowel dysfunc-
tion, weight loss, fever), exacerbating factors (e.g. cough,
sneeze, strain) and relieving factors and body positions.
• History of trauma, weight loss, malignancy, other
systemic illness.
• Medication/drug history (cf. ?analgesic abuse).
• Explore secondary gain phenomenon such as litigation,
worker’s compensation issues, psychiatric problems,
narcotic abuse.
EXAMINATION
• Gait: examine a few steps while walking ‘normally’, on
toes, on heels, heel-to-toe; hopping on either leg, arising
from a squat, Rhomberg’s sign.
• Spinal tenderness or spasm.
• Limited range of motion of the spine.
• Aggravation of pain with movement of the spine
(particularly hyperextension of the neck and downward
pressure on the head in the hyperextended position with
cervical disc protrusion).
• Straight-leg raising (Lasegue’s sign).
• Limb muscle bulk, tone, power, deep tendon reflexes,
sensation (including perianal sensation and anal tone if a
cauda equina syndrome is suspected).
• Signs of systemic disease, infection or malignancy.
DIFFERENTIAL DIAGNOSIS
Painless cervical myelopathy (see p.545)
• Subacute degeneration of spinal cord.
• Motor neuron disease.
Back pain with or without radiculomyelopathy
• Discogenic or degenerative spinal stenosis:
– Herniated intervertebral disc.
– Degenerative spondylosis:
Central canal stenosis.
Lateral recess stenosis.
– Synovial cyst of facet joint.
• Metabolic bone disease: osteoporotic compression fracture.
• Spinal trauma.
• Spinal tumor:
– Primary intradural tumor of spinal cord, medullary cone
or cauda equina.
– Tumor of vertebral column or epidural space (or both):
Metastases.
Plasmacytoma or multiple myeloma.
Primary bone tumor.
– Extraspinal retroperitoneal malignant lesion.
• Vascular lesion:
– Acute epidural hematoma.
– Spinal cord infarction.
– Arteriovenous malformation of the spinal cord.
– Spinal dural arteriovenous fistula.
• Infection:
– Intervertebral discitis or osteomyelitis.
– Epidural or subdural abscess.
– Urinary tract infection.
– Herpes zoster or other viral-based radiculopathy.
• Intra-abdominal or intrapelvic pathology:
– Abdominal aortic aneurysm.
– Posterior perforating duodenal ulcer.
– Pancreatic disease.
– Endometriosis.
 Acute ‘Slipped Disc’ 551

• Degenerative hip disease. 685

• Diabetic radiculoneuropathy. Dura mater Subarachnoid Dura mater Subarachnoid
• Acute inflammatory demyelinating polyradiculopathy space space
(Guillain–Barré syndrome).
• Congenital:
– Tethered cord.
– Intraspinal lipoma.

Radiculopathy
Mononeuropathy: e.g. ulnar nerve palsy may be mistaken L5 L5
for compression of the eighth cervical root by a disc L4 L4
protrusion at C7–T1.

L5 L5

S1 S1

685 Illustration showing the effect of a lumbar disc prolapse at L4/5

which is central (illustration on the left), compressing many or all of the
nerve roots below L4, particularly the most anterior roots (L5, S1, S2); 686
and lateral (illustration on the right), compressing the L5 nerve root L1
T10
(and sometimes the S1 nerve root) and displacing the root pouch on
the side of the prolapse. T11 S4
S5 L2
S3
T12
Table 45 Nerve root (radicular) pain and sensory L1
disturbance in the dermatomal distribution of the
S3
compressed nerve (677, 678 and see p.545)
S2
C5: lateral shoulder and upper arm S4
L2
C6: lateral forearm, thumb and index finger
C7: middle finger
C8: ring and little fingers and medial forearm
L3
T1: medial forearm and upper arm
L4: pain radiates down the leg to the thigh, knee, medial lower leg
and medial malleolus and sometimes the groin L3
S2
L5: lateral lower leg; lateral malleolus and dorsum of the foot
S1: heel, lateral border and sole of the foot L4
S2: back of leg
S3,4,5: perineal and perianal region (686).
Pain: sharp,‘electric’, and severe, and exacerbated by coughing, S1
L5
sneezing, straining, moving (bending and stooping), straight leg raising
L4
(low lumbar and sacral root compression), and femoral stretch test
(upper lumbar roots). Relieved by rest and particular postures

S1

Table 46 Innervation of spinal segments and muscles S1 L5

L5
Spinal Muscle Action
segment
686 Distribution of the lumbar and sacral dermatomes in the lower
C5, C6 Deltoid Shoulder abduction abdomen, buttocks and legs.
C5, C6 Biceps Elbow flexion
C6, C7 Extensor carpi radialis Wrist extension
C7, C8 Triceps Elbow extension Table 47 MRC grading scale for evaluation of
C8,T1 Flexor digitorum profundus Hand grasp muscle strength
C8,T1 Hand intrinsics Finger abduction
L1, L2, L3 Iliopsoas Hip flexion MRC grade Muscle strength
L2, L3, L4 Quadriceps Knee extension 5 Normal strength
L4, L5, S1, S2 Hamstrings Knee flexion 4 Active power against both resistance and gravity
L4, L5 Tibialis anterior Ankle dorsiflexion 3 Active power against gravity but not resistance
L5, S1 Extensor hallucis longus Great-toe extension 2 Active movement only with gravity eliminated
S1, S2 Gastrocnemius Ankle plantar flexion 1 Flicker or trace of contraction
S2, S3, S4 Bladder and anal sphincter Voluntary rectal tone 0 No movement or contraction
552 Spinal Cord Diseases
INVESTIGATIONS
Screen for non-discogenic causes of back pain
• Plain radiography of the relevant part of the spine
(anteroposterior and lateral projections).
• Full blood count.
• ESR.
• Urea and electrolytes, glucose, calcium, phosphate and
liver function tests.
• Urinalysis.
• Prostatic specific antigen (in men older than 50 years of age).
Electromyography
EMG can help confirm the clinical impression of the absence
or presence, site and severity of a radiculopathy and may reveal
an unsuspected polyradiculopathy or peripheral neuropathy.
Imaging of lumbar spondylosis
• Plain films may demonstrate narrowing of individual disc
spaces and the spinal canal, either congenital or
secondary to degenerative joint disease, but are rather
non-specific and do not show the contribution from any
soft tissue component.
• CT is very good and can be set up to cover the whole
lumbar spine, by imaging through each disc space and
the mid point of each vertebral body. Thus osteophytes,
disc herniations, ligament hypertrophy, facet joint
hypertrophy, lateral recess stenosis and exit canal
narrowing can be demonstrated at all the lumbar levels.
When disease is suspected at a specific level, then images
of the corresponding disc space plus the one above and
below are usually obtained. If there has been previous
disc surgery the examination should be done before and
after intravenous contrast.
687, 688 T2W 687
sagittal (687) and
T1W axial (688) MRI
of an L5/S1 disc
(arrows) herniation.
• Myelography will demonstrate canal narrowing, nerve
root displacement, thickening and cut off, disc hernia-
tions and the number of levels involved, but is invasive.
• Myelography with water-soluble contrast medium followed
by CT (myelogram-CT) images the subarachnoid space
and may reveal cauda equina tumors and other intradural
lesions that can mimic lumbar disc herniation.
• MRI is excellent for imaging the lumbar spine and shows
the features of disc herniation, canal stenosis and so on
(687–691). As with CT, a pre- and post-contrast exam
is required if there has been previous surgery. T1W and
T2W midline sagittal followed by T1W axial images are
routine. Absolute contraindications include the presence
of a pacemaker or ferromagnetic implant (e.g. intracranial
vascular clip); relative contraindications include claustro-
phobia, obesity and the need for advanced life support.
DIAGNOSIS
Diagnosis is based on findings of nerve root pain, objective
neurologic signs of spinal cord and/or nerve root compression,
and clear-cut evidence of a herniated disc on MRI or
myelogram-CT that correlates precisely with the clinical findings.
TREATMENT
Conservative
• Reassure patients that they most likely have a benign,
self-limited condition and that symptoms should rapidly
resolve without active treatment. Hospitalization is
usually not needed.
• Simple analgesia: aspirin, non-steroidal anti-inflammatory
drugs, paracetamol (acetaminophen); narcotic analgesics
are usually unnecessary.
• Muscle relaxants (e.g. cyclobenzaprine hydrochloride or
methocarbamol) for a short term in selected patients
with pronounced paraspinal muscle spasm.
• Bed rest: short term (2–3 days), on a firm mattress or board.
• Immobilization of the involved spine: avoid movements
of the involved spine and strain on the spine; for cervical
disc protrusions use a neck collar that is rigid enough to
prevent neck movement, particularly if flexion and
extension are painful (a soft collar may be more tolerable
at night); for lumbar disc prolapses, use a firm lumbar
corset. Use a chair with adequate back support, and
change positions frequently. Control body weight.
688
 Acute ‘Slipped Disc’ 553

• Begin a physiotherapy programme: aerobic exercise as
tolerated but avoiding heavy lifting and repetitive bend-
ing and twisting of the back. Traction, manipulation,
ultrasound therapy, transcutaneous electric stimulation,
and application of heat and cold can be effective.
• Lumbar epidural corticosteroid injections may be of
benefit in selected patients.
• Reassess the few patients who have not experienced
improvement within 6 weeks.
Surgical decompression
• Emergency:
– Acute cord compression.
– Acute bladder disturbance due to cauda equina
compression by a central lumbar disc prolapse.
• Urgent: severe or progressive loss of motor function due
to a monoradiculopathy; trivial root signs such as absent
tendon reflex are not an indication for surgery.
• Elective: continuing nerve root pain with a mild to
moderate neurologic deficit which has not responded to
about 6 weeks of conservative treatment.
Lumbar discectomy with magnified vision is the ‘gold
standard’ operation for lumbar disc disease; various closed
or percutaneous procedures, such as chemonucleolysis,
percutaneous automated discectomy, and endoscopic
discectomy are being trialled. Chymopapain is more
effective than placebo for lumbar disc prolapse, but
discectomy may lead to better clinical outcomes with fewer
second procedures than chymopapain.
Surgical complications include great vessel and cauda
equina injury and deep spinal infection but are uncommon.
PROGNOSIS
• Acute neck and low back pain, in the absence of tumor
and other serious underlying disease, usually resolves
rapidly within 4–6 weeks.
• Lumbar discectomy is successful in 80–90% of patients,
if properly selected.
• Patients with severe cauda equina syndrome due to
massive midline disc herniation have a guarded prognosis
for neurologic recovery, even with prompt disc removal
and neural decompression.

689, 690 T1W 689 691

axial pre- (689) and
post contrast (690)
MRI of the lumbar
spine in a patient
with fibrosis
following previous
lumbar disc surgery.
Note the enhancing
tissue around the
right hand side of
the spinal theca
(arrow).

691 T2W sagittal

MRI of thoracic
discs (arrows).

690
554 Spinal Cord Diseases

SPINAL EPIDURAL HEMATOMA MRI spine

MRI is the primary method of diagnosis (693). The
findings depend on the timing of the MR scan after the
DEFINITION onset of the hemorrhage. At about 36 hours after onset,
Hemorrhage in the spinal epidural space. T1W MRI of the spine usually shows an isointense
collection in the epidural space, usually anterior, with or
EPIDEMIOLOGY without cord or nerve root compression. An underlying
• Uncommon. spinal vascular malformation may be seen.
• Age: any age.
• Gender: M=F. CT spine
CT may also show an epidural mass, which does not tend
PATHOLOGY to enhance with contrast.
• Blood in the spinal epidural space.
• Direct compression of the spinal cord or roots by the Chest x-ray
mass effect of the hematoma. Hilar lymphadenopathy, pulmonary nodules or interstitial
• Spinal cord/nerve root pressure necrosis. lung disease may be seen in patients with arteritis causing
spinal epidural hemorrhage.
ETIOLOGY AND PATHOPHYSIOLOGY
• Trauma. Spinal angiography
• Spinal extradural arteriovenous malformation (692). May identify the source of the hemorrhage and even
• Vertebral body hemangioma. distinguish between the several types of vascular
• Epidural metastases. malformations and hemangioblastomas, and localize them
• Arteritis. accurately to the vertebral bodies, epidural or subdural
• Hypertension. space, or spinal cord.
• Bleeding diathesis due to a coagulopathy.
• Anticoagulant therapy.
• Cocaine injection.
• Epidural anesthesia.
• Lumbar puncture in patients with a bleeding diathesis.
• Idiopathic.

CLINICAL FEATURES 692 693

Sudden and severe neck or back pain, followed in minutes
to hours by progressive motor, sensory and sphincteric
disturbances referable to radicular spinal cord or cauda
equina origin. Other clinical features are determined by the
underlying cause (e.g. vasculitis causing associated skin rash
[693–695]).

DIFFERENTIAL DIAGNOSIS
• Hemorrhage into the spinal cord (hematomyelia) or
spinal subarachnoid space (693).
• Intervertebral disc prolapse.
• Vertebral body collapse (spinal angulation: tuberculosis,
tumor).
• Trauma.
• Spinal cord infarction.
• Epidural abscess.

INVESTIGATIONS
Blood
• Full blood count.
• ESR.
• Coagulation profile.
• Serum chemistry profile. 692 Autopsy specimen of spinal cord showing an epidural spinal
• VDRL/RPR and TPHA. arteriovenous malformation (a common cause of spinal epidural
• Antinuclear antibody titer. hematoma), containing dark clotted blood. (Courtesy of Professor BA
• Urine test for cocaine/amphetamine metabolites. Kakulas, Royal Perth Hospital,Western Australia.)

693 MRI cervical and upper thoracic spine,T1W image, sagittal plane,
showing a linear streak of high intensity due to hemorrhage in the
spinal subarachnoid space in a patient with arteritis due to
Churg–Strauss syndrome (allergic angiitis and granulomatosis).
 Spinal Epidural Abscess 555

CSF SPINAL EPIDURAL ABSCESS

Blood and xanthochromia are present in the spinal fluid, if
there has been subarachnoid hemorrhage or hemorrhage
into the spinal cord (hematomyelia).
DIAGNOSIS
MRI spine or spinal angiography in a patient with
appropriate clinical syndrome.
TREATMENT
• Prompt neurosurgical decompressive laminectomy,
particularly if acute onset and neurologic function is
deteriorating.
• Microsurgical resection or embolization of the cause (e.g.
if a vascular malformation is present).
PROGNOSIS
Depends on the site, duration and degree of spinal cord and
nerve root compression, and the underlying cause of the
hematoma.
DEFINITION
Pus or infected granulation tissue in the spinal epidural
space.
EPIDEMIOLOGY
• Rare.
• Age: any age; children or adults.
• Gender: either sex.
PATHOLOGY
• An abscess containing pus or infected granulation tissue in
any part of the spinal epidural space, most commonly the
dorsal aspect of the thoracic spinal cord, where the loose
attachment of the dura permits rapid spread of infection.
• Direct compression of the spinal cord or roots by the
mass effect of the abscess.
• Spinal cord infarction secondary to pressure and
thrombophlebitis of the local venous channels.

ETIOLOGY
• Staphylococcus aureus: most common.
• Streptococci.
• Brucella (a Gram-negative coccobacillus which may infect
694 people in close contact with infected animals and
carcasses [camels, cows, goats, sheep] or after drinking
infected milk).
• Salmonella.
• Fungus.
• Tuberculosis (696) (complications include nerve root
and/or spinal cord compression, arteritis and spinal cord
infarction, spinal arachnoiditis, and spinal cord
tuberculoma).
• Anaerobic organisms.

696

695 694, 695 Hands (694) and shin

(695) of the patient with
Churg–Strauss syndrome (693)
showing the typical skin rash.

696 Spine of a patient with a

tuberculous spinal epidural
abscess due to localized spinal
meningitis (Pott’s disease of the
spine) with vertebral body
collapse and destruction of the
adjacent intervertebral discs.
556 Spinal Cord Diseases
PATHOPHYSIOLOGY
Seeding of the spinal epidural space or a vertebral body with
micro-organisms occurs under the following circumstances:
• Septicemia complicating a chronic medical illness (e.g.
diabetes, infective endocarditis, immunocompromise) with
seeding of the spinal epidural space or of a vertebral body.
• Vertebral osteomyelitis.
• Infected intervertebral disc.
• Penetrating or non-penetrating back injury at the time
of furunculosis or other skin or wound infection.
• Local spinal surgery: laminectomy.
• Spinal or epidural anesthesia.
• Lumbar puncture.
CLINICAL FEATURES
• Subacute onset.
• Systemic upset: fever, headache, malaise.
• Back pain and tenderness to palpation/percussion: local
and severe.
• Neck/spine rigidity.
• Nerve root pain.
• Nerve root and/or spinal cord compression/infarction:
progressive paraparesis, sensory loss and sphincter
paralysis (urinary and fecal retention).
DIFFERENTIAL DIAGNOSIS
• Epidural hematoma (see p.554).
• Acute intervertebral disc prolapse (see p.550).
• Subdural abscess: spinal imaging often reveals a less sharp
margin and a greater vertical extent of the abscess than
an epidural abscess.
• Transverse myelitis (see p.561).
• Spinal cord abscess.
• Spinal cord infarction (see p.558).
697 698
INVESTIGATIONS
Blood
• Neutrophil leukocytosis.
• Raised ESR.
• Serology may be positive for infectious organisms such
as brucella.
MRI spine
The imaging method of choice (697–699). The findings
are similar to those of epidural tumors (see p.567). Bone
involvement varies as the abscess can simply sit as a cuff in
the spinal canal with minimal bone involvement, though
more commonly bone involvement is substantial. The cord
appears normal width or narrowed, with the CSF obliterated
around it at the level of the lesion, but visible above and
below, and a mass around the outside plus or minus bone
destruction. MRI not only demonstrates the extent of the
symptomatic lesion, but also other lesions that may be at
other levels and may be asymptomatic.
Spine x-ray
Bone changes of osteomyelitis.
Myelography (with or without CT)
Shows spinal cord compression. It may only show up to the
lower level of the lesion, as if the block is complete, the
contrast will not pass it to outline the cord above.
CSF
• Cells: mild pleocytosis: <100 white cells/mm3, both
polymorphonuclear leukocytes and lymphocytes; frank
pus if the needle penetrates the abscess.
• Protein: quite high: 1–4 g/l (100–400 mg/dl).
• Glucose: normal.
• Culture: often sterile.
DIAGNOSIS
The definitive pre-surgical diagnosis can only be made with
an MRI scan, indicating the extent and localization of the
lesion, in combination with clinical, serologic, microbiologic
and/or pathologic information.
699
697–699 MRI lumbar spine,T1W (697) and dual echo T2W (698)
images in the sagittal plane from T11 to S3, and axial T1W (699)
images at the L3/4 disc level showing at the L3/4 disc level an anterior
epidural soft tissue mass which causes severe canal stenosis.The soft
tissue mass (arrows) is of intermediate signal intensity on T1W images
with increased signal on T2W images and minimal contrast
enhancement.The differential diagnosis includes epidural abscess,
tumor or hemorrhage.
 Spinal Arachnoiditis
TREATMENT
• Surgical decompression by laminectomy and drainage as
soon as possible if the spinal cord is compressed.
• Antibiotics appropriate for the infecting organism must
be given (e.g. for brucellosis: doxycycline, 200 mg orally,
once daily, plus rifampicin (rifampin), 900 mg orally,
once daily for at least 6 weeks, or tetracycline, 500 mg
orally, four times daily for 6 weeks plus streptomycin, 1g
daily i.m. for 3 weeks).
PROGNOSIS
• A fibrous or granulomatous reaction may develop at the
site of apparently successful surgical drainage and give
rise to a slowly progressive, then stabilizing syndrome of
incomplete cord compression.
• If allowed to smoulder due to delayed diagnosis or
inadequate therapy, a chronic adhesive meningomyelitis
may evolve.
SPINAL ARACHNOIDITIS
DEFINITION
A non-infectious or post infectious aseptic inflammatory
process of the leptomeninges which may or may not be
associated with other disease of the spine or spinal cord and
results in a progressive overgrowth of fibrous tissue in the
subarachnoid space.
EPIDEMIOLOGY
• Uncommon.
• Age: any age; most commonly 40–60 years of age; rarely
younger than 20 years.
• Gender: M=F.
ETIOLOGY
• Myelography using oil based contrast media (pantopaque,
Myodil [iophendylate]). These substances had to be
removed from the CSF space by aspiration through the
lumbar puncture needle once the procedure had finished.
Due to the oily nature it was impossible to remove all of
it. The contrast excited an inflammatory reaction leading
to arachnoiditis. One occasionally still sees plain x-rays of
the spine with little radiopaque droplets overlying the
spinal canal indicating a previous Myodil myelogram.
Modern water-soluble contrast media rarely, if ever, cause
arachnoiditis.
• Intrathecal administration of penicillin and other
antibiotics, spinal anesthetics (a detergent that had
contaminated vials of procainamide), and repeated corti-
costeroid injections.
• Repeated spinal surgery (e.g. for lumbar discs).
• Subarachnoid hemorrhage.
• Meningeal infection:
– Viral: lymphocytic choriomeningitis.
– Bacterial: acute: meningococcal, gonococcal, listeria;
subacute or chronic: tuberculosis, syphilis, cryptococcus.
– Worms: cysticercosis.
• Ankylosing spondylitis.
557
PATHOGENESIS
• The arachnoid is an avascular membrane which lies
between the vascular pia and the vascular dura. It has a
limited capacity to participate in an inflammatory response.
• In response to injury or irritation, a reactive inflammatory
response begins in the vascular pia and dura and progresses
to a chronic stage with fibrous thickening of the arachnoid
and adhesions between the pia and the dura.
PATHOLOGY
• Opacification and thickening of the arachnoidal
membranes.
• Adhesions between the arachnoid and dura due to
proliferation of connective tissue in response to an
antecedent arachnoidal inflammation.
• Obliteration of the subarachnoid space.
• Strangulation of nerve roots and the spinal cord by
thickened connective tissue, causing compression and
progressive vascular occlusion and ischemia of the spinal
roots and cord, and obstruction of CSF flow at the
foramen magnum, possibly causing hydrocephalus and
syringomyelia.
• Variable destruction of the peripherally placed fibers of
the spinal cord.
• Secondary degeneration of the dorsal and lateral columns
of the spinal cord.
• Usually diffuse, with a predilection for the thoracic
segments.
• Occasionally confined to relatively circumscribed sections
of the cord or subarachnoid space, giving rise to
loculated collections of fluid (meningitis serosa
circumscripta).
CLINICAL FEATURES
Asymptomatic
Myeloradiculopathy
• Onset: concurrent with acute arachnoidal inflammation
or delayed for weeks, months or even years.
• Dorsal sensory nerve root compression:
– Spine and/or radicular pain in the distribution of one or
more sensory nerve roots, initially on one side and then
bilaterally. Persistent and burning, stinging or aching.
– Depressed deep tendon reflexes.
• Ventral motor nerve root compression: muscle wasting
and weakness (particularly with cauda equina
involvement).
Spinal cord compression
Spastic ataxic paraparesis, slowly progressive (may follow
months or years after radicular symptoms).
Signs of the underlying cause
Previous disc surgery, Myodil (iophendylate), infection,
subarachnoid hemorrhage, malignancy.
558 Spinal Cord Diseases

DIFFERENTIAL DIAGNOSIS SPINAL CORD INFARCTION

• Spinal cord tumor (see p.567).
• Cervical and lumbar spondylotic myeloradiculopathy (see
p.545). DEFINITION
• Subacute/chronic meningitis (see p.279). Infarction of the spinal cord caused by arterial occlusion, or
less often, venous occlusion.
INVESTIGATIONS
• Can be imaged with myelography (700), CT or MRI: EPIDEMIOLOGY
• Non-ionic water-soluble myelography: shows various • Rare.
specific features including truncated or absent nerve root • Age: any age; mean 55 years.
sleeves, clumping of the nerve roots, adherence of the • Gender: M>F (2:1).
roots to the thecal membranes, and obliteration of the
thecal sac. PATHOLOGY
• CT myelography: also demonstrates these features, but • Infarction of the anterior two-thirds of the spinal cord
on axial imaging it is often easiest to appreciate that the with occlusion of the anterior spinal artery or a spinal
nerve roots are abnormally bunched together as the radicular artery.
other signs may be more subtle. The meninges may or • Infarction of one dorsal column with unilateral posterior
may not enhance. spinal artery occlusion.
• MRI: shows similar features to CT, with the most easily • Ischemic or hemorrhagic infarction with venous
appreciated sign again being bunching of the nerve occlusion.
roots. The meninges may or may not enhance.
• CSF: moderate lymphocytic pleocytosis, elevated protein PATHOPHYSIOLOGY
(sometimes extremely so); CSF may be normal or have Blood supply to the spinal cord
only a slightly raised protein in localized lumbar Anterior spinal artery
arachnoiditis. The gray and inner white matter of the anterior two-thirds
of the spinal cord (anterior and lateral columns on either
DIAGNOSIS sides) receives its blood supply via the left and right
Diagnosis is based on clinical features of a sulcocommissural arterial branches of the anterior spinal
myeloradiculopathy with characteristic CSF, and imaging
findings of obliteration of the nerve root sheaths, smooth
outline of the theca, and eventually attenuation and 700
obliteration of the thecal sac.

TREATMENT
• No effective treatment for chronic adhesive lumbar
arachnoiditis.
• Corticosteroids seem ineffective in controlling the
inflammatory reaction and preventing progression of the
disease.
• Surgery may be helpful for the rare case of localized ‘cyst’
formation and cord compression.
• Posterior rhizotomy may help relieve severe radicular
pain.

Prevention
• Avoid oil-based and ionic water-soluble contrast media
for myelography.
• Use caution in the selection and preparation of spinal
anesthetic agents.

PROGNOSIS
Variable: partial or complete recovery within a year or two,
no change, gradual progression and sometimes fatal.

700 Lumbar myelogram showing narrowing of the spinal theca, with

nerve root cut-off typical of arachnoiditis.
 Spinal Cord Infarction 559

artery, which originates in its most rostral portion from the ETIOLOGY
union of paired branches of the vertebral arteries (proximal Hypoxia
to their union to form the basilar artery) at the ventral • Respiratory or cardiac arrest.
surface of the medulla oblongata and passes down the • Anemia.
anterior surface of the cord in the midline, narrowing near
the upper fourth thoracic segment. Low spinal cord perfusion
Along its discontinuous course below T4, it receives • Prolonged, severe hypotension.
segmental input from six to nine intercostal radicular arteries
arising from the aorta. The major radicular artery, the great Aorta, vertebral or radicular branch artery occlusion
ventral radicular artery or artery of Adamkiewicz, arises Embolism
usually on the left, variably from T9–T12, or less commonly • Embolism from the heart.
anywhere from T5–L2, and supplies the lumbar cord and • Atherothromboembolism from the aorta or origin of the
conus medullaris. At the lumbosacral level, radicular arteries intercostal and lumbar arteries.
are derived from larger regional vessels, the largest of which • Air embolism: nitrogen bubbles lodge in spinal veins
enters the intervertebral foramen at L2 to form the (decompression sickness).
lowermost portion of the anterior spinal artery (the terminal • Fibrocartilaginous embolism from intervertebral disc
artery) which runs along the filum terminale. rupture.
• Therapeutic renal artery embolization.
Posterior spinal arteries
The posterior one-third of the spinal cord (posterior white Aortic, vertebral and radicular artery disease
columns and part of the posterior gray columns) receives its • Atherosclerosis and atherothrombosis.
blood supply from the posterior spinal arteries which are • Dissection or rupture (701, 702).
paired and considerably smaller than the anterior spinal • Thoracic or abdominal aortic aneurysm.
artery. They receive branches from the posterolateral plexus • Aortic instrumentation (radiologic or surgical).
at various levels. • Intra-aortic balloon pump counterpulsation.
The surface of the spinal cord is richly interwoven with • Arteritis (syphilis, sarcoidosis, tuberculosis, polyarteritis
circumflex anastamoses arising from the anterior and nodosa and other connective tissue disease, drugs:
posterior spinal arteries. A relative hypovascularity exists in cocaine, amphetamine).
the mid thoracic region from about T4–T8, which is the • Thoracoplasty.
most vulnerable part of the spinal cord to ischemia. • Pneumonectomy.
Venous drainage occurs via the median posterior and the • Porto-caval shunt placement.
anterior spinal veins. The lack of venous valves may permit • Radicular artery ligation.
abdominal infectious processes to spread to the spinal cord. • Arteriovenous malformation of the spinal arteries (703).

701 702 703

701, 702 Sagittal section of the spine at autopsy showing vertebral artery thrombosis (702) secondary to 703 Autopsy specimen of a
vertebral artery dissection, which also caused brainstem and anterior upper cervical spinal cord infarction at spinal cord arteriovenous
the craniocervical junction (701). malformation.
560 Spinal Cord Diseases
Venous thrombophlebitis
• Intra-abdominal and renal sepsis.
Hematologic
• Sickle cell disease.
• Procoagulant states: thrombocytosis, metastatic cancer.
Spinal cord
• Trauma to the spine.
• Acute compression of the spinal cord:
– Vertebral body and disc disease.
– Extradural masses: hematoma, abscess, tumor, fat.
– Subdural masses.
• Infection within the spine.
• Intrathecal lignocaine or phenol injection (spinal artery
thrombosis).
CLINICAL FEATURES
Anterior spinal artery syndrome
• Sudden onset.
• Flaccid paraparesis and weakness of myotomes below the
level of the lesion.
• Areflexia below the level of the lesion.
• Babinski responses.
• Loss of pain and temperature sensation below the level
of the lesion; proprioception intact.
• Autonomic dysfunction:
– Sphincter flaccidity.
– Atonic urinary bladder.
– Paralytic ileus.
• Radicular or back pain may herald these findings
sometimes. May mimic angina pectoris.
• May progress over a few days.
• Later: spasticity, clonus and exaggerated deep tendon
reflexes below the lesion:
– Mixed or lower motor neuron deficits may occur if
infarction involves anterior horn cells (e.g. flaccidity),
nerve roots or cauda equina.
– Detrusor hyperreflexia and striated sphincter dyssynergia.
– Sexual dysfunction.
– Orthostatic hypotension (if lesions are superior to the
origin of the greater splanchnic nerve at T4–T9).
– Impaired thermoregulation due to impaired vasomotor
and sudomotor tone below the level of the lesion.
– Spinal dysautonomia: a paroxysmal, generalized hyper-
sympathetic state in which disinhibited sympathetic
neurons of the intermediolateral cell column may mount
an exaggerated response to mildly noxious stimuli such
as a distended bladder.
Sulcocommissural artery syndrome
Ipsilateral paralysis and contralateral loss of pain and
temperature sensation below the level of the lesion.
Posterior spinal artery syndrome
• Rare.
• Impaired discrimination of direction of scratch on the
skin of the legs.
• Impaired vibration and proprioception cannot be
attributed to isolated destruction of the dorsal columns
but rather indicate involvement of additional regions of
the spinal cord such as the dorsal horns.
Spinal venous infarction syndrome
• Subacute onset.
• Variable patterns of deficits.
Spinal TIAs
• Painless paraparesis or quadriparesis without loss of
consciousness.
• Sporadic, or precipitated by postural changes in patients
with foramenal stenosis during cervical or lumbar
extension, which maximally compromises the intervertebral
foramina through which pass spinal radicular arteries.
DIFFERENTIAL DIAGNOSIS
Acute cord compression
• Intervertebral disc prolapse.
• Vertebral body collapse/fracture (spinal angulation:
tuberculosis, tumor).
• Trauma.
• Epidural hemorrhage.
Intramedullary
• Hemorrhage.
• Demyelination (myelitis).
INVESTIGATIONS
CT/MRI spine
To be performed urgently to rule out spinal cord compres-
sion by vertebral fractures or hematomata (CT). When
repeated after several days, MRI is more likely to reveal focal
cord swelling, and may reveal increased signal in the cord on
T2WI (704, 705), and gadolinium enhancement of the
lesion on T1WI, a similar appearance to that of transverse
myelitis. Hemorrhage may be identified by the typical
changes (see hemorrhagic brain lesions section). If per-
formed months or years later, MRI shows focal cord atrophy.
CSF
• Cells: normal or moderate leukocytosis (<100 mono-
nuclear cells/cm3).
• Protein: mild elevation (<1 g/l [100 mg/dl]).
Other
• Myelography: prone and supine, if arteriovenous
malformation is suspected.
• Spinal arteriography: if myelogram suggests AVM.
• Somatosensory evoked potentials: abnormal only if the
double perfused posterior columns are infarcted.
• EMG: abnormal only if infarction involves anterior horn
cells or nerve roots.
TREATMENT
• Treat the underlying cause, if possible.
• Symptomatic control of pain, paresthesia, depression and
autonomic and bladder dysfunction.
• Avoid complications of immobility: regular turning to
avoid pressure sores, graduated compression stockings
and aspirin or subcutaneous heparin to prevent deep
venous thrombosis, and regular bladder emptying.
• Rehabilitation: physiotherapy, occupational therapy,
psychologic support, social work.
 Acute Transverse Myelitis 561

PROGNOSIS ACUTE TRANSVERSE MYELITIS

• Death: about 20%.
• No improvement: about 25%.
• Minimal improvement: about 10%. DEFINITION
• Moderate improvement: about 25%. An acute loss of sensory, motor and bladder function due
• Marked improvement: about 20%. to inflammation of a transverse (± rostral-caudal) segment
of the spinal cord.
Prognostic factors
• Recovery is impeded by autonomic dysfunction, pain, EPIDEMIOLOGY
paresthesia, depression. • Incidence: 0.1–0.5 per 100 000 population per year.
• Favorable ambulatory outcome correlates with • Age: any age (18 months–82 years), most commonly
improving neurologic examinations in the acute phase young to middle-aged adults.
and relatively preserved strength in hip abductors and • Gender: M=F.
knee extensors.
• Poor prognosis if extensive deficits are present without PATHOLOGY
initial improvement. Ranges from severe necrosis of white and gray matter over many
cord segments to predominant demyelination of white matter.
704
ETIOLOGY AND PATHOPHYSIOLOGY
Infections
• Tuberculosis.
• Syphilis.
• Borrelia (Lyme disease).
• Mycoplasma pneumoniae.
• Enteroviral infection.
• Herpes simplex types 1 and 2.
• Herpes zoster.
• Epstein–Barr virus (EBV).
• Cytomegalovirus (CMV).
• Human herpes virus-6.
• HIV.
• Measles.
• Rubella.

Immune-mediated
• Post infectious: non-specific (e.g. upper respiratory
infection) or specific (e.g. post-mycoplasma or post-
varicella).
• Post vaccination.
• Multiple sclerosis (MS).
• Connective tissue disease (e.g. systemic lupus
erythematosus [SLE]).

705 Granulomatous inflammation

Sarcoidosis.

Radiation
• Early radiation myelopathy may occur 10–16 weeks after
radiation exposure. The symptoms usually resolve
2–9 months later.
• Delayed radiation myelopathy is rare and is also
suggested only when there is a previous history of
radiation. The delay between radiation and acute
myelopathy can exceed 10 years.

N.B. In most cases, no definite cause is found although

one may subsequently declare itself with time (such as MS).

704, 705 T2W sagittal (704) and T2W axial (705) MRI of the PATHOGENESIS
cervical spine in a patient with sudden onset of right-sided neck pain • Immune-mediated.
followed by a lateral medullary syndrome, showing an infarct in the • Active infection of the spinal cord.
upper cervical cord/lower medulla.The right vertebral artery was
partially occluded, thought to be dissected. Note the increased signal in
the upper right side of the cord (arrows).
562 Spinal Cord Diseases
CLINICAL HISTORY
Antecedents
• Upper respiratory tract illness in 30–60% of patients.
• Vaccination.
• Recent surgery.
• Adenocarcinoma.
Onset
• Paresthesiae: usually ascending from the feet.
• Pain: typically interscapular; a Lhermitte’s symptom may
be present.
• Leg weakness: usually bilateral.
• Sphincter disturbance: urinary retention.
Evolution
Smooth or stepwise progression to a nadir, usually over
several days to weeks, but sometimes rapidly progresses to
a maximum within 1 hour (in 15% of cases) and within
24 hours (in 45% of cases).
PHYSICAL EXAMINATION
Bilateral, fairly symmetric cervical or thoracic
myelopathy
• Paraparesis: usually flaccid and of variable severity
(pyramidal tracts).
• Deep tendon reflexes: usually depressed or absent.
• Sensory level: usually thoracic; can be dissociated sensory
loss (e.g. loss of pain and temperature [spinothalamic]
but not proprioception [dorsal columns]) or loss of
sensation to all modalities (light touch, pain,
temperature, and proprioception). The upper extent of
the lesion is typically several segments above the level of
the sensory loss.
• Loss of sphincter tone in nearly all patients.
• Altered sexual and other autonomic function.
• Postural hypotension occurs rarely.
• Ventilatory compromise (upper cervical myelopathy).
Clues to the underlying cause
• Skin rash: erythema chronicum migrans: Lyme disease;
vesicles and pustules: herpes virus infections.
• Palatal petechiae: EBV infection.
• Lymphadenopathy and hepatosplenomegaly: EBV, CMV,
hepatitis, rubella.
• Myringitis: Mycoplasma pneumoniae infection.
• Oligoarticular arthritis: Lyme disease.
DIFFERENTIAL DIAGNOSIS
Enlarging parasagittal cerebral lesion
• Encephalomyelitis.
• Bilateral anterior cerebral artery territory infarction.
• Parasagittal meningioma.
• Hydrocephalus.
• Focal cerebral edema.
Spinal cord compression
• Extradural abscess (see p.555).
• Extradural hematoma (see p.554).
• Extradural tumor (see p.567).
Acute ascending necrotizing myelitis
• Lymphoma.
• Carcinoma.
• Thrombophlebitis.
Spinal cord infarction (see p.558)
Arteriovenous malformation.
Rapidly evolving myeloradiculopathy
Lyme disease (see p.316).
Rapidly evolving polyradiculopathy
Guillain–Barré syndrome (segmental form).
INVESTIGATIONS
The aim is to exclude treatable causes of a myelopathy (e.g.
spinal epidural abscess, haematoma or tumor) and identify
the underlying cause.
MRI of the spine
• The imaging modality of choice.
• The spinal cord may be focally swollen with single or
multiple areas of increased signal within the cord on
T2W (706, 707) and proton density images, and
hypointense signal on T1W images which may enhance
with gadolinium. The vertebral canal and vertebral
bodies are normal.
• This appearance is non-specific and occurs in MS, other
inflammatory causes and vasculitis.
MRI of the brain
• Normal, unless associated encephalomyelitis, MS or
vasculitis.
• Should be considered if these diagnoses (e.g. MS) are
possible.
Myelography
Myelography is useful if MRI cannot be tolerated because the
patient is claustrophobic or obese, or has a contraindication
to MRI. In the past, MRI did not always reveal angiomas,
and supine myelography followed by spinal angiography was
the recommended investigation. However, most angiomas
are now detectable using modern MRI technology, with
phased array receiver coils, high resolution fast spin echo and
dynamic scanning after a bolus of gadolinium.
CSF
• Cell count: normal (>50% of cases) or increased (usually
>30 lymphocytes/ml, but can be polymorphonuclear).
• Protein: normal or, more often, raised; if very high and
xanthochromia is present, suspect severe cord swelling
with block.
• Glucose: normal.
• Oligoclonal bands: sometimes present.
• Acid fast bacilli: not seen.
• Viral and syphilis serology.
• Polymerase chain reaction to amplify DNA from human
herpes virus 6 and other infectious agents.
N.B. There is no correlation between CSF analysis and
the extent of neurologic impairment.
Blood
• Full blood count.
• ESR.
• Urea, creatinine, electrolytes, glucose, and liver function
tests.
• Antinuclear antibody screen (antinuclear antibody, anti-
dsDNA, anticardiolipin antibody, rheumatoid factor).
 Acute Transverse Myelitis 563

• VDRL, TPHA, FTA. • Acute lupus myelopathy is generally treated with high
• Hepatitis B surface antigen tests. dose methylprednisolone and pulse dose cyclophos-
• Mantoux tests. phamide.
• Serology: herpes simplex, herpes zoster, HIV, • Zoster myelitis: intravenous aciclovir (acyclovir).
mycoplasma, Lyme disease, EBV, CMV, rubella. • Neurosyphilis: penicillin.
• Tibial somatosensory evoked potentials: usually • Tuberculous myelopathy: antituberculous therapy.
unrecordable bilaterally. • HTLV-1 or radiation myelopathy: no satisfactory therapy
• Cortical and spinal motor stimulation: normal motor at present.
response in upper limbs, absent motor response in the
lower limbs. PROGNOSIS
• Visual evoked potentials. Recovery of neurologic function
• Extremely variable: about two-thirds recover to variable
DIAGNOSIS degrees and one-third remain paraplegic.
• Acute or subacute painful spinal cord syndrome (usually • May also be protracted.
thoracic), with disturbance of motor, sensory and
sphincter function. Predictors of a poor outcome
• Spinal segmental level of sensory disturbance with a well • Pain.
defined upper limit. • Catastrophic onset of symptoms.
• No evidence of spinal cord compression. • High ‘deficit score’ at onset.
• Abnormal spinal cord imaging.
TREATMENT • Abnormal somatosensory evoked potentials.
General nursing and comprehensive rehabilitation
programme N.B. CSF findings are not predictors of outcome.
• Bladder care: intermittent catheterization.
• Bowel care: bulk laxatives. Recurrence of transverse myelitis (relapsing
• Elastic stockings. isolated transverse myelitis)
• Physiotherapy. • Rare.
• Analgesia: tricyclic antidepressants, carbamazepine • Distinct from MS and infrequently a harbinger of MS.
(usually ineffective), transcutaneous electric nerve • Causes include: SLE, antiphospholipid antibody syn-
stimulation (TENS), and guanethidine blocks. drome, isolated angiitis of the CNS, HIV, herpes simplex
• Intensive care, including mechanical ventilation, may be infections, and spinal arteriovenous malformations.
required with lesions involving the upper cervical cord.
MS
Specific • Develops in about 1–10% of cases.
• Short course of high-dose steroids: intravenous • Predictors of MS:
methylprednisolone, usually 1 g/day for 3 days or – More subacute onset.
500 mg/day for 5 days (anecdotal reports of benefit, no – Partial or asymmetric lesion.
controlled trials). – Oligoclonal bands in CSF.
• Recurring spinal cord dysfunction in MS manifests most
often as a partial cord syndrome, generally of subacute
706, 707 T2W 706 or chronic onset and with associated evidence of
sagittal (706) and dissemination at onset or in the early follow-up period.
T2W axial (707)
MRI of the cord in
a patient with
transverse myelitis.
Note the increased
signal in the cord at
C3–C6 levels with
swelling. 707
564 Spinal Cord Diseases
HUMAN IMMUNODEFICIENCY VIRUS
(HIV) MYELOPATHY
DEFINITION
Involvement of the spinal cord by HIV-1, a lentivirus, which
is a family of viruses known to cause chronic neurologic
disease in their animal hosts, as a result of primary infection
and opportunistic infections in immunosuppressed patients.
EPIDEMIOLOGY
Incidence and prevalence
• Unknown.
• About one-third of AIDS patients show varying degrees
of vacuolar myelopathy and about 10% of AIDS patients
will show clinical features of a myelopathy. For unknown
reasons, HIV myelopathy is very uncommon in HIV-
infected children.
• The most common cause of myelopathy in AIDS is
vacuolar myelopathy, which is detected in as many as 40%
of autopsies.
PATHOLOGY
There are two separate pathologic entities (see below), but
in some cases multinucleated cell myelitis with evidence of
productive local HIV infection may coexist with the
vacuolar changes.
Vacuolar myelopathy
• Multiple vacuoles are present in the myelin sheaths of the
white matter of the posterior and lateral columns of the
spinal cord, particularly the cervical and high thoracic
cord. Vacuolization of myelin sheaths is due to the
accumulation of foamy macrophages and microglia, with
relative preservation of axons.
• Infrequent lipid-laden macrophages.
• Separation of the myelin lamellae seen on electron micro-
scopy; the changes are not confined to a particular tract.
Multinucleated giant cell myelitis
Multinucleated giant cell infiltrates that do not seem to have
a predilection for any particular part of the cord.
PATHOGENESIS
Vacuolar myelopathy
There is no evidence that the pathogenesis of vacuolar
myelopathy is related to a direct effect of HIV infection as
the disorder has been described in immunocompromised
non-AIDS patients. This suggests that it is a consequence
of an as yet undefined opportunistic infection. The myelin
damage may be the result of indirect mechanisms such as
the release of toxic cytokines, particularly tumor necrosis
factor, or another metabolic or toxic insult.
Multinucleated giant cell myelitis
Related at least in part to the direct effects of the infiltrating
cells as immunohistochemical studies have demonstrated
various HIV antigens. The precise mechanisms of spinal
cord damage are likely to be similar to those that operate in
HIV encephalopathy (see p.301).
CLINICAL FEATURES
• Painless, often slowly progressive, spastic ataxic
paraparesis without a definite sensory level.
• Variable sensory disturbance in the feet and legs
(predominantly of proprioception and vibration sense).
A marked sensory ‘level’ is unusual and should suggest
other diagnoses such as a spinal mass.
• Dysesthesiae may occur, but are often due to a
concomitant polyneuropathy.
• Urinary hesitancy is common but urinary retention and
loss of sphincter control does not occur usually until late
in the illness.
• Often there are features of coexistent HIV
encephalopathy (see p.301).
DIFFERENTIAL DIAGNOSIS
• Vitamin B12 deficiency: presents over weeks or months
as a subacute spinal cord syndrome with intense
paresthesia and a combination of pyramidal and dorsal
column signs.
• Infection of the spinal cord:
– HTLV-1 associated myelopathy (‘tropical spastic
paraparesis’) in adults from endemic regions or with
other risk factors (e.g. Afro-Caribbeans). Lifetime
prevalence: 0.04 (95% CI: 0–0.2) per 1000. A
progressive spastic paraplegia develops over a number of
years; however, sphincter disturbance is the rule and
considerable neuropathic lower limb pain is common.
– Toxoplasmosis.
– Varicella-zoster granulomatous myelitis.
– Herpetic necrotizing myelitis.
– CMV.
– Tuberculosis.
– Schistosomiasis.
– Syphilis.
• MS and other demyelinating disease of the spinal cord.
• Sarcoidosis.
• Spondylotic myelopathy.
• Lymphoma or other neoplastic mass lesions of the spine
(e.g. astrocytoma, ependymoma, lipoma, hemangioma,
metastases).
• Dural arteriovenous malformation: the most common
type of spinal angioma. Usually affects the thoracolumbar
segments and tends to present in middle-aged men as a
chronic progressive myelopathy with symptoms that may
fluctuate or be aggravated by exercise. A combination of
upper and lower motor neuron signs may be present.
• Hereditary spastic paraparesis: usually a family history of
autosomal dominant inheritance, but may be autosomal
recessive.
• Adrenomyeloneuropathy: X-linked inherited disorder
that affects males and some heterozygous females with a
progressive myelopathy. A peripheral neuropathy and
adrenal insufficiency may be present.
• Radiation myelopathy: steadily progressive spastic para-
plegia months to years after radiotherapy. Pathologically
there is necrosis of the irradiated cord segments with
obliterative changes in blood vessels in the same region.
• Lathyrism: endemic in parts of India and presents as a
subacute or chronic spastic paraparesis in people who
regularly ingest chickling pea vetch over several months.
It is thought to be caused by a toxin in the chickling pea.
 Radiation-induced Encephalo-myelo-radiculopathy
INVESTIGATIONS
• MRI of the spine or myelogram appears normal or shows
mild cord atrophy only but helps to exclude other
possible causes.
• Full blood count and film (?vitamin B12 deficiency).
• Serum vitamin B12.
• Serology for HIV, herpes virus.
• Blood CD4 lymphocyte count.
• CSF: non-specific changes of elevated WBC, elevated
protein and IgG. There is no correlation between levels
of HIV-1 RNA viral load in the CSF and the presence or
severity of AIDS myelopathy. HIV can be cultured from
CSF.
DIAGNOSIS
• Negative MRI examination of the spine and brain.
• Positive HIV antibody test.
• Blood CD4 lymphocyte (T helper cell) count <200 ×
106/l (normal 800–1200 × 106/l).
• Culture of HIV in CSF may be positive.
• HIV may be demonstrable by immunochemistry in
spinal cord tissue at autopsy.
TREATMENT
• No clinical trials of therapy have been performed in this
disorder.
• Anecdotal data suggest that vacuolar myelopathy does
not respond to antiretroviral therapy (see p.301) but
multinucleated cell myelitis may.
• Other treatment is symptomatic and supportive, and
includes antispasticity agents (e.g. baclofen), manage-
ment of sphincter dysfunction, physiotherapy, occupa-
tional therapy and provision and education in the use of
walking aids.
• Counselling is frequently required for patient and carers
early in the illness.
• Medical power-of-attorney should be recommended to
patients early in the illness.
• Regular respite care is beneficial to patient and carers
during the illness and palliative care facility is usually
required to manage late complications of dementia.
CLINICAL COURSE/PROGNOSIS
HIV myelopathy has a variable course:
• Patients may remain ambulatory with only modest leg
weakness.
• Occasionally a more fulminant course occurs, with
progression to paraplegia over a few months.
• High plasma HIV RNA values and rapidly declining
CD4 lymphocyte number and percentage predict
progression to AIDS and death.
565
RADIATION-INDUCED ENCEPHALO-
MYELO-RADICULOPATHY
DEFINITION
An iatrogenic disease of the nervous system arising as a
complication of radiation therapy.
EPIDEMIOLOGY
• Incidence: decreasing.
• Age: any age.
• Gender: either sex.
PATHOLOGY
Mild-moderate disease
Spongy appearance, demyelination, depletion of
oligodendrocytes and partial preservation of axons.
Severe disease
• Coagulation necrosis, typical of infarction, of focal or
multifocal regions of the white matter and, less so, gray
matter of the brain or spinal cord.
• Softening and liquefaction, with cyst formation, may
occur in some areas.
• Arterioles: hyaline thickening and fibrinoid necrosis of
the vessel wall, with thrombosis.
• Secondary degeneration of the ascending and descending
tracts.
ETIOLOGY
Radiation
• Tissue-dependent: the brain and spinal cord appear more
sensitive than the peripheral nerves to irradiation
damage.
• Dose- (total and fractional) dependent: a daily dose
>2 Gy (>200 rads), weekly dose >9 Gy (>900 rads), total
dose >60 Gy (>6000 rads) (40 Gy in 25 fractions for
spinal cord) is associated with an increased risk of
radiation injury.
• Time-dependent: a total given over a period of
<30–70 days is associated with an increased risk of
radiation injury.
• Risk factors: hyperthermia treatment for cancer
predisposes to radiation myelopathy.
PATHOPHYSIOLOGY
• Irreversible radiation damage to small intracranial blood
vessels.
• The relative contribution of irradiation and concurrent
chemotherapy can be difficult to determine in some
patients.
CLINICAL SYNDROMES AND FEATURES
Multifocal and diffuse encephalopathy
• Subacute onset.
• Focal or multifocal neurologic dysfunction.
• Partial or generalized seizures.
• Impaired mental function: progressive dementia (which
may be accompanied by gait ataxia and sphincter and
motor dysfunction).
• Pituitary dysfunction.
• Raised intracranial pressure eventually.
• History of whole-brain irradiation (e.g. for tumor or
acute lymphoblastic leukemia).
566 Spinal Cord Diseases

Multiple cranial neuropathies MRI

Usually follows radiation therapy of nasopharyngeal tumors.
Mild ‘early’ transient sensory myelopathy
• Occurs several (3–6) months after irradiation.
• Paresthesiae in the limbs, evoked or exacerbated by neck
flexion (Lhermitte symptom/sign).
• Resolves spontaneously in most cases after a few months.
Acute myelopathy
Developing over hours to days, due to spinal cord
infarction.
• Previous radiotherapy involving a section of the spine can
be recognized on T1WI as diffuse increased signal in the
bone marrow of several adjacent vertebral bodies
(decreased on conventional T2WI).
• The spinal cord may also be atrophic at that level.
• Increased signal in the cord on T2WI may be due to
radiation myelitis (708) or residual tumor (if that was the
original reason for the therapy).
CSF
Normal except for slightly elevated protein.

Delayed chronic progressive myelopathy DIAGNOSIS

• Incidence: about 2–3% of treated patients (but difficult
to estimate because many patients die of their malignant
disease before the cord lesion matures).
• Latent period: 14 months post-irradiation on average;
usual range 4 months–19 years.
• Onset: insidious, but exceptionally it may be subacute,
within a few hours.
• Sensory symptoms: paresthesiae and dysesthesiae of one
or both feet (and hands, if cervical cord involved) or a
Lhermitte symptom /sign.
• Motor symptoms, such as weakness of one or both legs,
usually follow the sensory loss, and may complete a
Brown–Sequard syndrome or transverse myelopathy.
• Autonomic dysfunction may occur.
• Local pain is notably absent (in contrast to spinal
metastases).
Motor lumbosacral radiculopathy (lower motor
neuron syndrome)
Sensorimotor lumbosacral plexopathy
Usually following irradiation for pelvic neoplasia.
Histologic.
TREATMENT
Symptomatic
• Corticosteroids (dexamethasone) may reduce the edema
surrounding the lesion in some patients, with concurrent
regression of symptoms, but the effects are often
temporary.
• Surgical debulking may also be temporarily effective but
results are indifferent.
• Antithrombotic therapy (e.g. aspirin, warfarin) remains
to be evaluated.
Prevention
Radiation injury to the nervous system is preventable if the
total and fractional dose of radiation is delivered according
to established guidelines.
PROGNOSIS
Radiation-induced encephalo-myelo-radiculopathy usually
has a progressive clinical course, but periods of apparent
arrest for several years may occur.

DIFFERENTIAL DIAGNOSIS
Diffuse brain injury (radiation encephalopathy) 708 708 T2W sagittal
• Normal pressure hydrocephalus. MRI of the whole
• Leukodystrophy. cord showing an
• Alzheimer’s disease. area of increased
signal in the upper
Focal brain injury (radiation encephalopathy) thoracic cord
• Brain tumor. (arrow).The patient
• Stroke. had received
radiation for
Mild ‘early’ transient sensory myelopathy lymphoma and then
• Cervical spondylotic myelopathy. developed long tract
• MS. signs.The increased
signal is the result of
Delayed chronic progressive myelopathy radiation myelitis.
• Spinal tumor recurrence or metastases: usually local pain The bone marrow
and evidence of a mass lesion. changes of radiation
• MS. are not visible on
this T2W image.
INVESTIGATIONS
CT brain scan
Low density, contrast-enhancing lesion(s).
 Spinal Cord Tumors 567

SPINAL CORD TUMORS Primary source:

• Breast (often multiple extradural deposits).
• Bronchus (usually single spinal lesion).
DEFINITION • Prostate.
Tumors of the spinal cord. • Melanoma.
• Multiple myeloma.
EPIDEMIOLOGY • Lymphoma.
• Incidence: 10 (95% CI: 5–18) per 100 000 per year. • Renal cell carcinoma.
Primary spinal cord tumors represent about 15% of • Gastrointestinal carcinoma.
primary CNS tumors. Metastases to the spine are far
more common. Intradural but extramedullary (rare)
• Age: Leptomeningeal metastases of carcinoma or lymphoma
– Young and middle-aged adults predominantly. causing malignant meningitis.
– Intramedullary tumors are more common in children.
– Extramedullary tumors are more common in adults. Intramedullary (very rare)
• Gender: M=F. Carcinoma of the bronchus is the main source.
Metastases tend to arise in the thoracic region and
PATHOLOGY usually spread from the vertebral body into the anterior and
Primary tumors of the spine anterolateral parts of the dural space. They are most unusual
Extradural: common (45–55%) in the cervical spine except when due to local spread from
• Neuroblastoma. adjacent regions such as nasopharyngeal carcinoma.
• Lymphoma and leukemia.
• Myeloma/plasmacytoma. Associations
• Primary bone tumors. Syringomyelia is frequently associated with intramedullary
• Hemangioma of bone. tumors.
• Sarcoma.
CLINICAL FEATURES
Intradural but extramedullary (outside the spinal cord The spinal cord and its nerve roots are contained within the
but beneath the dura, i.e. in the leptomeninges or roots): rigid vertebral canal and are therefore vulnerable to
common (40–50%) compression, particularly in those individuals with
• Meningioma (anywhere along the cord). constitutionally narrow vertebral canals. The clinical features
• Neurofibroma (commonly thoracic). depend on the site and extent to the spinal cord lesion as
• Sarcoma (F>M). well as the rate of growth.
• Vascular tumors. Compression of the spinal cord and nerve roots at a
• Chordoma (commonly sacral region). given level may give rise to:
• Epidermoid. • Segmental pain or sensory disturbance at the level of the
• Dermoid (often sacral region). lesion due to dorsal root irritation. The pain is
• Malignant meningitis. exacerbated by sneezing, coughing, and straining.
Cervical cord compression may cause Lhermitte’s
Intramedullary (inside the spinal cord): uncommon (5%) symptom/sign of a sudden, unpleasant, electric shock-
• Ependymoma (many arise from filum terminale): 60%. like sensation down the back and into the legs, and
• Astrocytoma (mostly cervical): 25%. occasionally the arms, after flexing the neck. It is due to
• Oligodendroglioma. dysfunction of the cervical spinal cord from a number of
• Hemangioblastoma: may cause hematomyelia. causes (e.g. compression, MS, subacute combined
• Lipoma. degeneration of the cord, acute radiation myelopathy)
• Epidermoid. and may also occur in some sensory neuropathies
• Dermoid. (cisplatin, pyridoxine abuse).
• Teratoma. • A segmental lower motor neuron lesion at the level of
compression.
Secondary tumors (metastases) of the spine • Upper motor neuron signs, including bladder
Most spinal tumors are metastases, rather than primary dysfunction, below the level of the lesion. The upper
benign or malignant tumors. motor neuron deficit is hardly ever unilateral but may be
asymmetric.
Extradural (most common site of metastases) • Sensory loss to some or all modalities (usually joint
• 85% are bony metastases in the vertebral column which position sense) below the level of the lesion with a
involve the spinal canal directly or via the intervertebral distinct upper level; the sensory symptoms and signs tend
foramina. to begin in the feet and ascend to just below the
• The minority arise from hematogenous dissemination to anatomic level of the lesion. Sensory loss may be mild or
the extradural space. even absent depending on whether and which ascending
spinal cord pathways are involved.
• Autonomic changes below the level of the lesion, and
even an ipsilateral Horner’s syndrome with severe cervical
cord compression.
568 Spinal Cord Diseases
Three typical clinical syndromes
Myelopathy (sensori-motor spinal tract syndrome)
• Gradual onset.
• Progressive course.
• Symmetric or, more commonly asymmetric, motor
and/or sensory deficits at and below the level of the
lesion, together with bladder and bowel dysfunction.
Myelo-radiculopathy
• Segmental pain and sensory change in the distribution of
one or more sensory nerves.
• Segmental cramps, fasciculations, wasting, weakness,
reflex loss in the distribution of one or more motor
nerves.
• Spinal pain and tenderness.
• Associated myelopathy: asymmetric spastic para- or
quadriparesis, sensory level below which pain and
temperature perception and joint position sense is
reduced, and detrusor hyperreflexia.
Central cord (syringomyelic) syndrome
• Segmental dissociated sensory loss and amyotrophy.
• Early incontinence.
• Later corticospinal weakness.
Extramedullary tumors
• Tumors usually involve a few segments with root com-
pression (usually dorsal) and progressive compression of
the cord to cause an incomplete or complete transection
syndrome.
• Pain and local tenderness is the initial symptom of
extradural metastases in about 95% of adults. It is a good
localizing sign of the level of the lesion. Spinal pain at
night is highly suggestive of a tumor.
• Muscular weakness, wasting and sensory loss is present
in the distribution of the affected roots.
• There is a variable pattern of spastic paraparesis and
sensory loss below the lesion, as well as bladder (less
commonly bowel) dysfunction, if the cord is compressed.
• Vascular spinal cord syndromes may occur, and are
suggestive of metastases (and abscesses) because they
tend to occlude spinal vessels.
Intramedullary tumors
Tumors may extend over multiple levels and give rise to a
clinical picture similar to syringomyelia (see p.541). Asym-
metric location within the cord results in asymmetric clinical
signs.
Other features suggestive of the cause
• Skin lesions, e.g. café-au-lait spots of neurofibromatosis;
pigmented melanoma.
• Breast mass or other evidence of primary cancer.
• Weight loss, malaise: metastases.
DIFFERENTIAL DIAGNOSIS
Acute onset
• Intervertebral disc prolapse.
• Vertebral body collapse (spinal angulation: tuberculosis,
tumor).
• Trauma.
• Epidural hemorrhage.
• Intramedullary hemorrhage: arteriovenous malformation.
• Spinal cord infarction.
Subacute onset
• Epidural abscess (e.g. pyogenic, tuberculous and fungal
granulomatous lesions).
• Paraneoplastic necrotizing myelopathy.
Slow onset
• Spondylosis.
• Syringomyelia.
• Tethered cord syndrome (see Spinal dysraphism, p.139).
• Radiation myelopathy.
• Meningeal carcinomatosis.
INVESTIGATIONS
• Full blood count and ESR.
• Liver function tests: secondary deposits.
• Syphilis serology.
• Urine: hematuria with renal cell carcinoma.
Chest x-ray
• Infection with tuberculosis.
• Tumor: primary or secondary.
• Paravertebral shadow (neurofibromatosis, Pott’s disease).
Spine x-ray
• Vertebral body collapse (osteoporosis, infection, tumor).
• Erosion of vertebral bodies or pedicles by tumor.
• Scalloping of posterior margin of vertebral body (chronic
tumor).
• Vertebral body alignment: subluxation, spondylolisthesis.
• Intervertebral disc space narrowing (spondylosis) or
destruction.
• Intervertebral exit foramina (oblique views of neck)
enlarged in neurofibroma, reduced in spondylosis.
• Spinal canal width, osteophytes.
Imaging
If the patient has established primary malignant disease,
unequivocal clinical features of progressive spinal cord
and/or root compression, and plain x-ray changes of a
metastatic deposit in the appropriate site to cause the
neurologic lesion, there may be nothing to gain from
further investigation (with MRI or myelography),
particularly in the presence of multiple metastases and a
poor prognosis. The aim of management is usually palliative.
If there is no known primary malignancy, then the spine
must be imaged with MRI or myelography and, if a
compressive mass is found that has the features of a tumor
(i.e. not those of a disc or spondylotic bar), then a tissue
diagnosis may be possible by CT-guided percutaneous
biopsy or surgery.
CT scan
CT scan of the vertebral canal with contrast enhancement
may demonstrate tumors and delineate the extraspinal
extent of tumors.
Myelography followed by CT scan (709–711)
Useful if MRI (see below) is not available. Widening of the
spinal cord in the antero-posterior (AP) view may be due to
anterior or posterior cord compression but widening in the AP
and lateral view suggests cord tumor, myelitis, or a syrinx.
 Spinal Cord Tumors 569

CSF MRI spine

Lumbar puncture may precipitate acute deterioration if
there is cord compression and may damage the spinal cord
if it is tethered to the low lumbar or sacral vertebral bodies.
CSF cytology may reveal malignant cells. Froin syndrome:
xanthochromia with clotting of CSF, due to isolation or
loculation of the CSF below the site of the tumor which has
blocked the circulation of CSF from above.
The imaging method of choice as it displays bones and soft
tissues impinging on spinal cord and roots better than
myelography and CT, and it images inside the spinal cord
and can detect intramedullary tumors (712, 713) and
exclude a syrinx, which myelography cannot do. However,
it may need to be backed up by plain x-rays or CT to
examine bone detail and if a percutaneous imaging-guided
biopsy is to be planned.

709, 710 Lateral 709

(709) and antero-
posterior (710)
views from a
myelogram in a
patient with
symptoms of cord
compression. Note 710
the dura is
compressed inwards
towards the cord in a
pattern typical of
extradural lesions.
This was a secondary
deposit. Note the
absent pedicle of the
vertebral body
(arrow) indicating
bony involvement.

711 712 713

711 Myelogram of the lumbar region from a patient with breast carcinoma and symptoms of multiple nerve root compression, showing cut-off of
the lumbar nerve roots, and an irregular outline of the dura due to multiple meningeal secondary breast cancer nodules.

712, 713 MRI cervical spine, sagittal (712) and axial (713) sections showing a hyperdense mass (arrows) in the left hemicord (causing a
Brown–Séquard syndrome) due to metastatic malignant melanoma.
570 Spinal Cord Diseases

Extradural lesions If a secondary deposit is found without a known primary

Lesions arise outside the dura and compress the cord from the source, then further investigation is indicated because it
outside, either circumferentially or mainly anteriorly or helps general and specific management strategies:
posteriorly depending on the site (714). They are most • Breast and pelvic examination.
commonly secondary deposits from bronchus, breast, prostate, • Serum liver function tests.
renal, and testicular carcinomas, other adenocarcinomas or • Acid phosphatase and protein electrophoresis.
lymphomas. Bone involvement varies as the tumor can simply • Mammography.
sit as a cuff in the spinal canal with minimal bone involvement, • Bone scan (skeletal survey is more sensitive in myeloma).
though more commonly bone involvement is substantial. On • Fecal occult bloods and, if positive, colonoscopy or
imaging, the cord appears normal width or narrowed, with the barium enema.
CSF obliterated around it at the level of the lesion, but visible • Urine occult blood and, if positive, ultrasound imaging
above and below, and a mass around the outside plus or minus of the renal tract.
bone destruction. MRI is best as it demonstrates not only the • Ultrasound of the liver.
extent of the symptomatic lesion, but also the presence of
other asymptomatic deposits at other levels. Myelography (± DIAGNOSIS
CT) may only show up to the lower level of the lesion, as if MRI spine and tissue biopsy in a patient with appropriate
the block is complete, the contrast will not pass it to outline clinical features.
the cord above.
TREATMENT
Intradural extramedullary lesions (meningiomas, • Rapidly progressive spinal cord compression by
schwannomas, neurofibromas, lipomas, arachnoid cysts) extradural tumor calls for emergency MRI, immediate
Also best seen on MRI (715, 716). They appear as a mass high dose corticosteroids, and a tissue diagnosis either
within the CSF space displacing (and compressing) the cord by CT-guided percutaneous biopsy or open surgical
to one side. Meningiomas are isointense on T1WI, enhance biopsy.
and are commonest in the thoracic region in females. Nerve • If the tumor is benign it should be removed surgically if
sheath tumors may contain mixed signal elements and lie technically possible.
within the nerve root exit canal as well as the spinal canal. • If the tumor is malignant, the spinal cord and roots
There are often other stigmata of neurofibromatosis. They should be decompressed by surgery, radiotherapy,
usually enhance. Lipomas have characteristic signal and chemotherapy or hormonal therapy, depending on
usually lie in the lumbar region. Arachnoid cysts can be very tumor type and the clinical circumstances; surgical
difficult to demonstrate and may be better seen on decompression is probably no more effective and should
myelography including delayed films (with CT if possible) be avoided except perhaps in acute cases of malignant
to watch for delayed filling of the cyst. The precise site of tumor compression.
the cyst may be difficult to demonstrate on imaging in terms
of its relationship to the dural sac.
714 714 T1W midline sagittal
Intramedullary tumors MRI showing metastatic
Tumors cause expansion of the spinal cord which may fill extradural lesions in the
and obliterate the CSF space if pronounced. Primary upper thoracic and upper
(astrocytoma, ependymoma, hemangioblastoma) or lumbar regions (arrows).
secondary tumors (metastases from breast carcinoma) are Note the involvement of the
the main neoplastic causes of cord expansion (717, 718, vertebral bodies in the
719). Non-neoplastic causes include MS, ADEM, AIDS, malignant process as shown
sarcoid, SLE, syrinx, hemorrhage, infarct, AVM. MRI is the by the altered marrow signal.
imaging modality of choice as it demonstrates the full extent
of the lesion, and the signal characteristics give some clues
as to the composition and likely type of lesion. Astrocytomas
mainly affect the thoracic and cervical cord, usually are large,
diffuse and involve the whole thickness of the cord, are
often cystic and often enhance. Ependymomas are usually
more focal, well circumscribed, enhancing, with evidence of
cyst formation and hemorrhage. They tend to occur around
the conus and filum terminale. Hemangioblastomas have
cystic and solid components (the latter enhancing
markedly), may appear eccentric, have hemorrhagic
components, and sometimes flow voids can be seen due to
the intense capillary network and sinus channels.
Angiography shows a capillary blush and draining vein.
Metastases appear as lumps which enhance within the cord.

Isotope bone scanning

Also widely used to look for bone involvement by malignant
secondary (and some primary tumors) but is rather limited
and will not be discussed further here.
 Spinal Cord Tumors 571

• If a secondary deposit is found without a known primary PROGNOSIS

source, then further investigation is indicated (see above).
• Operative fixation of the vertebral column may be
worthwhile in patients with unremitting pain due to
spinal instability.
• Prognosis depends on the underlying cause and duration
and degree of spinal cord and nerve root compres-
sion/infiltration.
• In contrast to brain tumors, many spinal tumors are
benign and produce their effects mainly by compression
of the spinal cord rather than by invasion.

715 716

715, 716 T1W sagittal (715) and T2W axial (716) MRI of the
cervical spine showing a meningioma at C2 level (arrows). Note how
the lesion is surrounded by CSF and pushes the dura away from the
cord in a pattern typical of an intradural extramedullary lesion.

717 718 719

717 T2W sagittal MRI of the lumbar spine showing a lobulated mass (arrow) in the lower lumbar canal within the dura.This was an ependymoma.

718, 719 T2W (718) and T1W (719) sagittal MRI of a cord astrocytoma. Note how the whole cord appears expanded and the signal within it is
diffusely abnormal.There appear to be cystic and solid elements.
572 Spinal Cord Diseases

Treatment ACUTE TRANSVERSE MYELITIS

FURTHER READING
HEREDITARY SPASTIC PARAPARESIS
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Spastic Paraplegia Working Group (1996)
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Furukawa Y, Graf WD, Wong H, et al. (2001)
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paraplegia due to tyrosine hydroxylase (TH)
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McDermott CJ, White K, Bushby K, et al. (2000)
Hereditary spastic paraparesis: a review of new
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McDermott CJ, Dayaratne RK, Tomkins J, et al.
(2001) Paraplegin gene analysis in hereditary
spastic paraparesis (HSP) pedigrees in north-
east England. Neurology, 56: 467–471.
Reid E, Dearlove AM, Whiteford ML, Rhodes M,
Rubinsztein DC (1999) Autosomal dominant
spastic paraplegia. Refined SPG8 locus and ad-
ditional genetic heterogeneity. Neurology, 53:
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Tallaksen CME, Dürr A, Brice A (2001) Recent
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White KD, Ince PG, Lusher M, et al. (2000)
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MOTOR NEURON DISEASE
General
Rowland LP, Schneider NA (2001) Amyotrophic
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Miller RG, Rosenberg JA, Gelinas DF, et al.
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CERVICAL SPONDYLOTIC MYELOPATHY
AND RADICULOPATHY
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Rowland LP (1992) Surgical treatment of cervical
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HUMAN IMMUNODEFICIENCY VIRUS
MYELOPATHY
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SPINAL CORD TUMORS
Byrne TE (1992) Spinal cord compression from
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Epidemiology ACUTE SLIPPED DISC

Piemonte and Valle D’Aosta Register for Amy-
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Incidence of ALS in Italy. Evidence for a uni-
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 Chapter Twenty 573

Autonomic Nervous
System Disorders
AUTONOMIC NEUROPATHY thoracic root (T1) and course through the ventral roots and
white rami to synapse in the superior cervical ganglion.
Postganglionic fibers travel from the superior cervical
DEFINITION ganglion along the common carotid artery to its bifurcation.
Autonomic neuropathy is a disorder of the autonomic The pupillodilator fibers and fibers responsible for sweating
nervous system. on the medial aspect of the forehead then follow the course
of the internal carotid artery to the carotid siphon. At the
ANATOMY petrous temporal bone and cavernous sinus, they join the
The autonomic nervous system consists of two major ophthalmic (first) division of the trigeminal nerve and travel
divisions: sympathetic (thoracolumbar division) and to the pupil. Interruption of these fibers causes ipsilateral
parasympathetic (craniosacral outflow). ptosis and miosis.
Preganglionic fibers responsible for sweating and
Sympathetic nervous system (720) vasomotor control in the face accompany the second and
Efferent third thoracic nerve roots (T2,T3) and synapse in the
Sympathetic nerve fibers descend from the hypothalamus superior cervical ganglion. Postganglionic fibers travel along
and other regions of the brain, through the lateral the external carotid artery in the periarterial plexus before
tegmentum of the midbrain, pons and medulla, to the passing along the peripheral branches of the trigeminal
intermediolateral cell columns of the spinal cord between nerve to the skin.
T1 and L2, where they synapse with neurons of the Preganglionic sympathetic fibers to the bladder travel
preganglionic sympathetic efferents. The nerve fibers exit from the intermediolateral columns in the T11-L2 segments
from the spinal cord through the anterior roots, join the of the spinal cord to the ventral roots, white rami and
proximal part of the nerve root, and then leave the root via hypogastric plexus. Postganglionic fibers join the subserosal
the white rami communicantes to join the sympathetic chain plexus on the bladder wall and innervate mainly the trigone
which consists of a series of ganglia and nerve fibers and neck of the bladder.
extending from the base of the skull to
the coccyx. 720 Intermediolateral column of spinal cord
Preganglionic sympathetic fibers,
which are myelinated and cholinergic,
Posterior root
enter the sympathetic chain through
the white rami, may synapse in the
nearest ganglion, pass up or down the
sympathetic chain before making their
synapse, or pass through the chain to
White ramus
synapse at more peripheral ganglia
such as the celiac or other mesenteric Anterior root Gray ramus
ganglia.
Blood vessels
Postganglionic sympathetic fibers, Sympathetic
which are unmyelinated and arise from chain
Adrenal medulla
the ganglia of the sympathetic chain,
join the main nerve trunks by way of Sweat gland
the gray rami communicantes and are Some muscle vessels
distributed to the sweat glands
(cholinergic) and blood vessels of the Gut
Celiac
skin (adrenergic vasoconstrictor) and ganglion
muscles (cholinergic vasodilator). The
peptides released may play a role in the 720 Schematic diagram of the sympathetic nervous system showing the thoracic spinal cord
control of vasomotor tone and the and nerve roots at one level in cross-section, preganglionic myelinated cholinergic fibers (solid
regulation of regional blood flow. blue line), postganglionic unmyelinated noradrenergic fibers (dashed blue line) and postganglionic
Preganglionic sympathetic fibers to unmyelinated cholinergic fibers (dashed red line). (Modified from McLeod JG, Lance JW, Davies L
the eye leave the spinal cord at the first (1995). Introductory Neurology, 3rd edn, Blackwell Science, Carlton, Austrialia.)
574 Autonomic Nervous System Disorders

Afferent
Mainly conveys painful sensation.
Parasympathetic nervous system (721)
Efferent
• Parasympathetic preganglionic nerve fibers descend from
the hypothalamus and other regions of the brain (e.g.
Edinger–Westphal nucleus) to the brainstem and the
intermediolateral columns of the sacral spinal cord.
• The nerve fibers exit from the brain stem in cranial
nerves III, VII, XI, X, and from the sacral spinal cord in
the S2, S3, S4 nerve roots.
• The fibers in the S2–4 nerve roots travel in pelvic nerves
to form a diffuse subserosal network in the bladder wall.
• Preganglionic fibers are long and post ganglionic fibers
are short because the ganglia lie close to the innervated
structures.
PHYSIOLOGY
Blood pressure and heart rate
• These are controlled by baroreflex pathways.
• Baroreceptors in the carotid sinus, aortic arch and other
thoracic regions respond to alterations in blood pressure,
and send information, from the carotid sinus (via afferent
fibers in the glossopharyngeal nerve) and from the aortic
arch and thoracic low pressure receptors (via fibers in the
vagus nerve), to the nucleus of the tractus solitarius in
the brainstem.
• Efferent fibers are carried in the vagus nerve to the heart
and in the sympathetic nerves to the heart, mesenteric
vascular bed and blood vessels in the skin and muscles.
• A fall in blood pressure results in a compensatory
increase in heart rate and peripheral vasoconstriction
(particularly in the splanchnic vascular bed) to maintain
blood pressure.

Parasympathetic fibers innervate the following: Sweating

• Pupillary and ciliary muscles (via cranial nerve III, the
ciliary ganglion, and ciliary nerve).
• Lacrimal, submandibular and sublingual glands (cranial
nerve VII, and branches of the greater superficial petrosal
and chorda tympani nerves).
• Parotid gland (cranial nerve IX).
• Thoracic and abdominal viscera (cranial nerve X).
• Bladder smooth muscle fibers, large bowel, and genital
system (sacral outflow).
Pre- and postganglionic fibers in the parasympathetic
nervous system are cholinergic.
721
Iris
Ciliary body
The sweat glands are innervated mainly by cholinergic
postganglionic sympathetic fibers and are under
hypothalamic control.
Bladder and bowel
Bladder
Afferent:
• Parasympathetic afferent fibers convey sensations of
bladder fullness and pain of overdistension and
overcontraction. They also mediate the reflex for bladder
contraction through S2–4 segments.
• Sympathetic afferent fibers transmit painful sensation
from the trigone area, and a vague sensation of bladder
fullness. They play no part in the micturition reflex.
• Somatic fibers in the pudendal nerve convey sensations
from the urethra and sphincter of urethral pain and
temperature, urine passing and bladder emptying.
III

Efferent:
Lacriminal gland VII
• Parasympathetic efferent impulses cause the detrusor
Submandibular
and sublingual IX muscles of the bladder to contract and the bladder neck
glands to shorten, thus allowing the passage of urine.
Parotid gland X • Sympathetic efferents may inhibit the detrusor but
appear to play little part in the act of micturition. During
ejaculation, sympathetic activity causes the bladder neck
Heart to contract, preventing retrograde ejaculation.
Lungs • Somatic fibers in the pudendal nerve (S2–4) innervate the
GI tract external sphincter of the bladder and the anal sphincter,
causing relaxation of the sphincter during micturition (as
the detrusor is contracting). It can also be voluntarily
contracted to terminate the act of micturition.

Rectum
Bladder
Genitalia
721 Schematic diagram of the parasympathetic nervous system.
(Modified from McLeod JG, Lance JW, Davies L (1995). Introductory
Neurology, 3rd edn, Blackwell Science, Carlton, Austrialia.)
Pupillary reflexes
Light reflex
• The normal pupil contracts briskly in the eye to which
S2
the light is directed (direct response) and also in the
S3 opposite eye (consensual response).
S4 • The afferent pathway is from the retina, along the optic
nerve, to the optic tract, where fibers separate from those
destined for the lateral geniculate body and go to the
pretectal region and then to part of the cranial nerve III
nucleus (Edinger–Westphal nucleus) of both sides.
• The efferent pathway is from both Edinger–Westphal
nuclei via the IIIrd cranial nerves to the pupils, account-
ing for both the direct and consensual light reflexes.
 Autonomic Neuropathy 575

Accommodation reflex Disorders associated with peripheral neuropathy

• Normal pupils constrict as the eyes converge (‘near Autonomic dysfunction which is clinically important:
response’). • Diabetes.
• Pathways descend from the parieto-occipital cortex to • Acute inflammatory radiculoneuropathy (Guillain–Barré
the Edinger–Westphal nucleus in the midbrain, and then syndrome).
as pupilloconstrictor fibers in both IIIrd nerves to the • Acute intermittent porphyria.
pupil. • Primary and familial amyloidosis.
• Familial dysautonomia (Riley–Day syndrome; dopamine
Relative afferent pupillary defect β-hydroxylase deficiency, hereditary sensory and
Also known as the Marcus Gunn pupil or swinging torch autonomic neuropathy-3 [HSAN3]).
sign. If the IIIrd cranial nerve is intact bilaterally, then the • Chronic sensory and autonomic neuropathy.
contribution of the optic nerve to the light reflex can be
assessed by swinging a torch from one eye to the other Autonomic dysfunction which is not usually clinically
every 2 seconds or so. If there is impaired conduction in one important:
optic nerve relative to the other, the direct response of light • Alcoholism and nutritional diseases.
in the affected eye and consensual response in the • Toxic neuropathies (vincristine sulfate, acrylamide, heavy
unaffected eye will be suboptimal. Swinging the torch from metals).
the affected eye to shine light in the unaffected eye evokes • Metabolic disorders (vitamin B12 deficiency, chronic renal
a brisker and more profound direct and consensual response failure, chronic liver disease).
so that the pupils in both eyes will constrict further (and • Charcot–Marie–Tooth disease.
realize the paradox that shining a light in the unaffected eye • Malignancy.
actually leads to further constriction of the pupil). Swinging • Rheumatoid arthritis.
the torch back to shine in the affected eye leads to dilatation • Systemic lupus erythematosus.
of both pupils. The effect may not be obvious initially, but • Chronic inflammatory neuropathy.
after one or two swings of the torch, the pupillary response • HIV infections.
of the affected eye rapidly fatigues (see p.484). • Prion disorders: fatal familial insomnia.
• Chagas’ disease (South American trypanosomiasis): may
ETIOLOGY AND PATHOPHYSIOLOGY target the autonomic plexus intrinsic to the heart and
Autonomic disorders may be localized (e.g. Holmes–Adie gut.
pupil) or generalized (e.g. primary chronic autonomic
failure). Drugs
• Antidepressants.
Disorders affecting CNS • Anti-hypertensive drugs.
Primary autonomic failure • Barbiturates.
• Pure autonomic failure (PAF) or idiopathic orthostatic • Phenothiazines.
hypotension (IOH). • Atropine.
• Autonomic failure with Parkinson’s disease (AF-PD). • Epidural anesthesia.
• Autonomic failure with multiple system atrophy (AF-
MSA). CLINICAL FEATURES
Autonomic dysfunction
Spinal cord lesions above T6 The most common clinical manifestations of autonomic
• Trauma. dysfunction are:
• Transverse myelitis. • Postural (orthostatic) hypotension; impotence.
• Syringomyelia. • Disorders of bladder function.
• Tabes dorsalis. • Abnormalities of sweating.
• Vasomotor disturbances.
Wernicke’s encephalopathy
Sympathetic adrenergic failure
Miscellaneous disorders • Postural hypotension.
• Cerebrovascular disease. • Ejaculatory failure.
• Brainstem tumors.
• Multiple sclerosis. Sympathetic cholinergic failure
• Adie’s syndrome. Anhidrosis.
• Tabes dorsalis.
Parasympathetic failure
Disorders affecting the peripheral nervous system • Fixed heart rate.
Disorders with no associated peripheral neuropathy • Sluggish urinary bladder and bowel.
• Acute and subacute autonomic neuropathy. • Erectile failure.
• Pandysautonomia.
• Cholinergic dysautonomia.
• Botulism.
• Bilateral lumbar sympathectomy.
576 Autonomic Nervous System Disorders

Pupillary reflexes Respiratory system

Light reflex • Stridor.
• Lesions of cranial nerve III cause ipsilateral pupil • Inspiratory gasps.
dilatation. Shining a light into either eye fails to evoke a • Apneic episodes.
direct or consensual response in the affected eye because
of the defect in the efferent arc of the reflex. However, Gastrointestinal system
shining a light in the eye ipsilateral to the lesion (the • Constipation.
affected eye) evokes a consensual reaction in the eye • Diarrhea (occasionally).
contralateral to the lesion (the unaffected eye). • Dysphagia.
• Bilateral occipital lobe lesions (beyond the optic nerves
and tracts) which cause bilateral blindness are associated Renal and urinary bladder
with preserved direct and consensual reflexes. • Nocturia.
• Frequency.
Accommodation reflex • Urgency.
Any lesion involving the pupilloconstrictor fibers will impair • Incontinence.
the reaction of accommodation. Selective impairment of • Retention of urine.
accommodation may occur in some midbrain lesions.
Reproductive system
Relative afferent pupillary defect Erectile and ejaculatory failure.
Also known as the Marcus Gunn pupil or swinging torch
sign (see p.575). ASSOCIATED FEATURES
Involvement of other neurologic systems (see
Adie’s pupil (tonic pupil of Adie; Holmes–Adie syndrome) Multiple systems atrophy, p.435)
(see p.497) • Extrapyramidal dysfunction (Parkinsonism).
• Cerebellar dysfunction.
Horner’s syndrome (see p.494) • Pyramidal dysfunction.
• Peripheral neuropathy: peripheral autonomic fibers may
Argyll Robertson (AR) pupil be damaged in peripheral neuropathies, particularly those
• Described by Douglas Argyll Robertson, an Edinburgh affecting small myelinated and unmyelinated fibers (e.g.
physician. diabetes, primary amyloidosis), or those which cause acute
• Small, irregular pupils that are non-reactive to light, but demyelination of the preganglionic sympathetic fibers and
reactive to accommodation (AR pupils are ‘accommo- the vagal afferent and efferent fibers (e.g. Guillain–Barré
dation retaining’.) They dilate poorly with mydriatics. syndrome). The usual clinical manifestations are postural
• The site of the lesion is uncertain but is probably in the hypotension, impairment of heart rate control, loss of
pretectal region. sweating, and impotence.
• Causes include syphilis and diabetes.
SPECIAL CONDITIONS
Clinical features of autonomic failure PAF or IOH
Neurologic system (see Multiple systems atrophy, p.435). • Degeneration of postganglionic (i.e. peripheral)
• Extrapyramidal dysfunction (Parkinsonism). sympathetic fibers.
• Cerebellar dysfunction. • Age of onset: 40–60 years.
• Pyramidal dysfunction. • Gender: M=F.
• Postural hypotension (dizziness and weakness on
Eye standing or walking).
• Anisocoria. • Impotence.
• Horner’s syndrome (see p.494). • Bladder disturbances.
• Dry eyes, rarely excessive lacrimation. • Loss of sweating.
• Normal neurologic examination.
Sudomotor system • Slowly progressive course.
• Sweating abnormalities (anhidrosis usually, but
occasionally gustatory facial sweating in a diabetic). Autonomic failure associated with multiple system
• Heat intolerance. atrophy (see p.435)

Cardiovascular system DIFFERENTIAL DIAGNOSIS

Postural (orthostatic hypotension): symptoms include Postural (orthostatic) hypotension
lightheadedness, dizziness, faintness, visual disturbances or • Dehydration.
loss of consciousness (syncope) on standing upright. It is • Blood loss.
usually defined as a fall in systolic blood pressure of at least • Drugs.
4 kPa (30 mmHg) or to <10.7 kPa (80 mmHg) within a
minute or two of standing, but such falls are neither Argyll Robertson pupils
sensitive nor specific (e.g. they can occur in the normal Pseudo-Argyll Robertson pupils: pupils that do not react to
asymptomatic elderly, cardiac failure, Addison’s disease). light but are not small or irregular. May occur in midbrain
lesions.
 Autonomic Neuropathy
DIAGNOSIS
The clinical approach to the patient with clinical features of
dysautonomia aims to determine:
• Whether autonomic function is affected.
• Which organ systems are affected.
• The site of the lesion (central, preganglionic and
postganglionic).
• The cause of the lesion.
INVESTIGATIONS
Is autonomic function normal or abnormal?
Change of blood pressure with posture (postural hypotension)
• Normally, changing from the supine to the standing
position alters the blood pressure very little.
• A fall exceeding 4/2 kPa (30/15 mmHg) is abnormal,
indicating significant postural hypotension.
Change of heart rate with posture (reflex tachycardia; the
30:15 ratio)
• Normally, changing from the supine to the standing
position increases the heart rate by about 11–29 beats
per minute, reaching a maximum after 15 beats, after
which a reflex bradycardia ensues, reaching a maximum
at about the 30th beat.
• The ratio of the R–R interval (heart period) on an EKG
corresponding to the 30th and 15th beats, is the 30:15
ratio. The ratio is normally considerably greater than one,
but varies with age.
• Autonomic neuropathies affecting the afferent or efferent
fibers of the reflex arc reduce the rise in heart rate associated
with a change of posture, and reduce the 30:15 ratio.
Change of heart rate with deep breathing (sinus arrhythmia)
• Normally, inspiration is associated with an increase in
heat rate and expiration with a decrease in heart rate
(sinus arrhythmia). This difference is less pronounced in
older individuals.
• Autonomic neuropathies involving the vagus nerve are
associated with impaired variation of the heart rate with
respiration (loss of sinus arrhythmia).
Valsalva maneuver
Normally, forced expiration against a closed glottis or
mouthpiece (Valsalva maneuver) alters the heart rate (HR)
and blood pressure (BP):
• Phase I: BP rises due to the raised intrathoracic pressure
associated with the Valsalva causing mechanical
compression of the aorta and increased peripheral
resistance. A compensatory fall in HR, mediated by the
parasympathetics in the vagus nerve, follows.
• Phase II: BP falls due to the fall in venous return (associated
with continuously high intrathoracic pressure) and thus fall
in stroke volume. A compensatory rise in HR (due to
parasympathetic vagal withdrawal) and total peripheral
resistance (due to peripheral vasoconstriction) follows.
• Phase III: forced expiration ceases and venous return
increases rapidly, increasing the stroke volume and blood
pressure and decreasing the heart rate.
• Phase IV: BP rises further and overshoots because the
peripheral circulation is still vasoconstricted for up to 30
seconds because of the increase in peripheral sympathetic
vasoconstrictor tone induced by stages II–III. Therefore,
stage IV is a measure of sympathetic vascular tone.
577
The patient assumes the semi-recumbent posture and is
asked to expire forcefully, maintaining a column of mercury
at 5.3 kPa (40 mmHg) pressure for 10–15 seconds, while
the EKG and BP are continuously recorded (intra-arterial
catheter for BP).The ratio of the longest pulse interval to
the shortest pulse interval recorded on the EKG during the
maneuver (the Valsalva ratio) normally exceeds 1.45 in
young adults. Increased age and parasympathetic and sym-
pathetic neuropathies are associated with a reduced ratio.
Isometric contraction
• Normally, sustained isometric contraction (e.g. a firm
handgrip) for up to 5 minutes increases the heart rate
(and thus cardiac output) and total peripheral resistance
(by peripheral vasoconstriction), leading to an increase
in systolic and diastolic BP. Diastolic BP rises by 2 kPa
(15 mmHg) or more.
• Autonomic neuropathies affecting sympathetic efferent
fibers are associated with an impaired response.
Response to emotional and other stimuli
• Normally, mental arithmetic, a loud noise, or cold or
painful stimuli usually evoke peripheral vasoconstriction,
increase the total peripheral resistance and arterial blood
pressure. In some normal people, this response may not
be present.
• Autonomic neuropathies affecting sympathetic efferent
fibers are associated with an impaired response.
Sweating
• Autonomic neuropathies affecting sympathetic efferent
fibers are associated with impaired sweating.
• The thermoregulatory sweat test (TST) determines the
distribution of sweat loss (anhidrosis). The skin is
covered with a powder such as alazarine red or
quinazarine that changes color when sweating occurs.
The patient is warmed by radiant heat sufficient to raise
the body temperature by 1°C (1.8°F).
• Local sweating may also be tested by injection or ion-
tophoresis of acetylcholine which stimulates an axon reflex,
or pilocarpine which stimulates the sweat glands directly.
Pupillary responses
• Metacholine (methacholine) 2.5%, installed into the
conjunctival sac, does not affect the size of the normal
pupil but it causes pupillary constriction if para-
sympathetic innervation is impaired. This is because of
the denervation supersensitivity of the constrictor muscle
of the pupil.
• Epinephrine 0.1% has no effect on the normal pupil but
causes pupillary dilatation if postganglionic sympathetic
innervation is impaired, also because of denervation
supersensitivity.
• Cocaine 4% eye drops cause dilatation of the normal
pupil because cocaine blocks the re-uptake of noradrena-
line (norepinephrine), but if peripheral sympathetic in-
nervation is impaired, pupillary dilatation does not occur.
• Tyramine 2% eye drops produce dilatation of the normal
pupil because tyramine releases noradrenaline (norepine-
phrine) from peripheral nerve terminals, but if sympathetic
innervation is impaired, noradrenaline (norepinephrine) is
depleted and pupillary dilatation does not occur.
578 Autonomic Nervous System Disorders

Where is the lesion (i.e. site) and what is the
functional deficit?
In addition to the above tests, a number of other tests of
baroreflex sensitivity, vasomotor control, and bladder
control exist but are more difficult to perform.
Sudomotor function
Quantitative sudomotor axon reflex test (Q-SART): a test
of postganglionic sympathetic sudomotor function. If the
TST is abnormal (i.e. anhidrosis) and the Q-SART is
normal, then the site of the sympathetic lesion is
preganglionic.
Vasomotor function
• Skin vasomotor reflexes: measured by laser doppler flow
meters (e.g. on the pulp of index finger) in response to
stimuli such as standing, Valsalva, cold water. Limited if
the patient is nervous and resting skin blood flow is
minimal.
• Axonal flare response: measure at same time as Q-SART.
• Veno-arteriolar reflex: a test of post ganglionic adrenergic
function.
Heart period (R–R interval) recordings (see above)
Responses to deep breathing, Valsalva maneuver, and
standing.
What is the cause?
Underlying and associated disorders, such as diabetes
mellitus and amyloidosis (see above), need to be excluded.
Seropositivity for antibodies that bind to or block ganglionic
acetylcholine receptors identifies patients with various forms
of autoimmune autonomic neuropathy and distinguishes
these disorders from other types of dysautonomia.
TREATMENT
Aims to remove the underlying cause if possible and relieve
symptoms.
Postural hypotension
• General advice:
– Maintain hydration and salt intake (150 mmol/l
[150 mEq] salt).
– Avoid dehydration, diuretics and other hypotensive drugs
and deconditioning.
– Rise slowly from the lying and sitting positions, particularly
in the morning, after hot baths and heavy meals.
– Avoid straining and extremes of temperatures.
– Wear light clothes.
• Elevate the head of the bed by 10–15 cm (4–6 in)
(reduces renal arterial pressure and thus increases the
secretion of renin, resulting in retention of sodium and
water, and increased blood volume).
• Elastic stockings with lower abdominal constriction
(reduce the volume of the venous capacitance bed).
• Drugs:
– 9-α-fluorohydrocortisone (fludrocortisone), a mineralo-
corticoid which increases circulating effective blood
volume and probably sensitizes peripheral blood vessels
to catecholamines, is the most useful drug. The dose is
0.1 mg/day and can be increased. The main adverse
effects are supine hypertension, fluid retention (and heart
failure), worsening of diabetes mellitus, and potassium
depletion.
– Indomethacin 25–50 mg three times per day, but may
cause headache.
– Alpha antagonists: ephedrine 15–50 mg three times
daily; methylphenidate hydrochloride (Ritalin) 5–10 mg
three times daily, and midodrine, a recently introduced
α-adrenergic agonist which acts by improving arterial and
venous constriction in response to standing. May be
limited by supine hypertension which itself may respond
to beta blockade.
– Ambulatory norepinephrine infusion via intravenous
indwelling catheter and an infusion pump.
• Atrial tachypacing may help in patients who do not have
a tachycardia on standing up.
Bladder dysfunction
Frequency of micturition
Anticholinergic drugs:
• Propantheline bromide 15 mg two to four times daily.
• Penthienate bromide 5 mg three to four times daily.
• Tricyclic antidepressant drugs (e.g. amitriptyline
25–100 mg/day).
Botulinum toxin injections into the detrusor muscle
(2.5 MU of Botox injected per single site, up to 30
injections).
Distended bladder with incomplete emptying
Cholinergic drugs: bethanechol chloride 10 mg three to
four times daily.
Gastroparesis
• Metoclopramide 10 mg before meals and at night.
• Cisapride 15–40 mg daily in two to four divided doses.

FURTHER READING
Donofrio PD, Caress JB (2001) Autonomic dis-
orders. The Neurologist, 7: 220–233.
Kauffmann H (2000) Primary autonomic failure:
three clinical presentations of one disease?
Ann. Intern. Med., 133: 382–384.
Mathias CJ (1997) Autonomic disorders and their
recognition. N. Engl. J. Med. 336: 721–724.
Naumann M, Jost WH, Toyka KV (1999) Vernino S, Low PA, Fealey RD, et al. (2000)
Botulinum toxin in the treatment of Autoantibodies to ganglionic acetylcholine
neurological disorders of the autonomic receptors in autoimmune autonomic
nervous system. Arch. Neurol., 56: 914–916. neuropathies. N. Engl. J. Med., 343: 847–855.
Oldenburg O, Mitchell A, Nurnberger J, et al..
(2001) Ambulatory norepinephrine treatment
of severe autonomic orthostatic hypotension.
J. Am. Coll. Cardiol., 37: 219–223.
Schatz IJ (2001) Treatment of severe autonomic
orthostatic hypotension. Lancet, 357:
1060–1061.
 Chapter Twenty-one 579

Diseases of the
Peripheral Nerve
PERIPHERAL NEUROPATHY Epineurium Fascicles Perineurium 722

DEFINITION
A disorder of any or all of the peripheral nerves or nerve
roots.
Regional
EPIDEMIOLOGY artery
• Incidence: 69 per 100 000 per year.
• Lifetime prevalence: 3 per 1000.
Nutrient
• Age: any age, but usually the middle-aged and elderly. artery
• Gender: M=F.

ANATOMY (722–725)
A peripheral nerve consists of a cell body and about six
fascicles, each of which contains many myelinated and
unmyelinated axons. Each fascicle has small nutrient blood
vessels which are integral to its function.
722 Diagrammatic representation of peripheral nerve trunk and its
blood supply. Regional arteries arranged longitudinally outside the
nerve trunk give rise to nutrient arteries that penetrate the epineurium
and form an anastomosis. Small arterioles penetrate the perineurium
of the fascicles and form an endocapillary network.

723 Diagrammatic 723

representation of Dorsal root
components of the
peripheral nerve trunks.
Peripheral nerve Afferent fibers
Efferent fibers
Post-ganglionic
sympathetic
efferents
Preganglionic Ventral
sympathetic efferents root

724 725

724 Transverse section of a peripheral nerve stained with toluidine 725 Electron micrograph of a transverse section through a normal
blue.The circular shaped myelin is dark blue. myelinated nerve fiber, showing the axon in the center surrounded by
several layers of myelin.The major dense lines of the myelin arise by
the fusion of the inner surfaces of the Schwann cell surface membrane.
580 Diseases of the Peripheral Nerve

Anatomic classification selectively affect small unmyelinated nerve (e.g. alcohol and
• Focal neuropathy or mononeuropathy. amyloid) leading to the characteristic autonomic disturbance
• Multifocal neuropathy. seen in these neuropathies. Inflammatory and vasculitis
• Generalized polyneuropathy. disorders often lead to multiple, random pathologic lesions
within the nerve.
PATHOLOGY (726–728)
Peripheral neuropathy results from a disturbance of Pathologic classification
structure and function of the peripheral sensory, motor and • Demyelinating.
autonomic neurons. The disturbance of structure and • Axonal.
function may affect the:
• Cell body: neuronopathy. ETIOLOGY
• Axon: axonopathy. Worldwide, the most common cause of peripheral nerve
• Myelin sheath: myelinopathy. disease is leprosy (see Differential diagnosis below).

Neuronopathy CLINICAL HISTORY

• Anatomy: anterior horn cells (AHC) or dorsal root
ganglia (DRG).
• Pathology: degeneration of central and peripheral
processes.
• Examples: spinal muscular atrophy (AHC), toxic
neuronopathy, paraneoplastic neuropathy (DRG).
Axonopathy
• Anatomy and pathology: metabolic derangement within
axon (e.g. uremia); begins distally and progresses
proximally: ‘dying-back’ neuropathy; secondary
breakdown of myelin sheath.
• Clinical features: distal (legs>arms), symmetric, mixed
sensorimotor neuropathy.
• Recovery: slow, often incomplete.
• Causes: alcohol, diabetes, uremia, Fabry’s disease.
As the peripheral nerves supply motor power, sensation, and
autonomic function, patients with peripheral nerve disease
may experience symptoms of any of these functions.
Symptoms
Sensory
• Numbness and tingling, usually beginning in the feet
(supplied by the longest nerves) are common symptoms
of patients with sensory axonal neuropathies, particularly
those involving damage to the cell body (e.g. vitamin B12
deficiency).
• Pain beneath the sole, and a feeling as if the socks are
ruffled are other common symptoms.
• Upper limb symptoms, if present, generally include
difficulty picking up small objects such as pins, numbness
or a sandpaper feeling on the fingers.

Myelinopathy Motor
• Anatomy and pathology: damage to myelin sheath or • Limb weakness.
Schwann cell (with sparing of axon); segmental • Falls.
demyelination ± conduction block. • Double vision.
• Clinical features: profound weakness, mild sensory loss • Difficulty swallowing.
(relative sparing of small myelinated and unmyelinated • Slurred speech.
fibers). • Shortness of breath.
• Recovery: rapid, within weeks; repeated demyelination
and remyelination; Schwann cell proliferation (‘onion Autonomic disturbances
bulb’ layering) around the axon. • Postural hypotension.
• Causes: Guillain–Barré syndrome. • Impotence.
• Bladder dysfunction.
Wallerian degeneration • Diarrhea.
• Anatomy: interruption of a healthy axon. • Constipation.
• Pathology: distal degeneration of axon and myelin • Loss of sweating.
sheath.
• Clinical features: immediate weakness and sensory loss. Sometimes these symptoms are preceded by severe pain,
• Recovery: slow and incomplete. and are usually due to pathologies that affect small fibers
• Causes: trauma, ischemia. within nerves, such as amyloid, alcohol, Guillain–Barré
syndrome) and diabetes (20–40% of patients).
Disorders of the peripheral nerve can primarily damage
myelin (e.g. Guillain–Barré syndrome) or the axon (e.g. Bulbar dysfunction
vincristine and many other drugs), or can interfere with the Due to cranial neuropathies which may occur in some
blood supply of the peripheral nerve leading to areas of peripheral neuropathies:
necrosis in the distribution of the small nutrient vessels (e.g. • Double vision.
polyarteritis nodosa). Many toxic processes that produce • Slurred speech.
slowly progressive damage to nerve cell bodies lead to a • Difficulty swallowing.
‘dying-back’ type of neuropathy, in which the longest axons • Respiratory problems.
show damage initially and the neuropathic symptoms ascend
from the feet. Alternatively, pressure on one portion of a History targeted to the underlying etiology
nerve at a site of entrapment can lead to myelin loss and, if A careful history is essential, and should be targeted to
severe, axonal damage. Some pathologic processes include the following details:
 Peripheral Neuropathy 581

• Family history: at least 25% of neuropathies without an Multifocal neuropathy

obvious cause are genetic in origin. A thoroughly • Inflammation:
researched family tree often reveals details of forgotten – Leprosy.
relatives with foot deformity or death at an early age with – Lyme disease.
an unusual inherited disorder. – Sarcoidosis.
• Drug exposure. • Infiltration:
• Alcohol intake. – Amyloidosis.
• Systemic disease (e.g. diabetes). – Malignancy.
• Environmental toxins. • Immune reaction:
• HIV. – Immunization.
• Travel (infections). – Foreign serum and proteins.
• Malignancy. • Trauma: multiple nerve injuries.
• Vascular disease:
PHYSICAL EXAMINATION – Diabetes.
Lower motor neuron lesion – Polyarteritis nodosa.
Any or all of the following in any combination: – Rheumatoid arthritis.
• Muscle wasting and fasciculations, commonly in distal – Sjögren’s syndrome.
muscles of hands and feet. – Systemic lupus erythematosus.
• Muscle weakness (e.g. limbs, face, eyelids, diaphragm). – Wegener’s granulomatosis.
• Depressed or absent reflexes. – Vasculitis (non-systemic).
• Sensory loss: pain and heat sensation (small fiber); fine
touch, proprioception, two-point discrimination (large
fiber). 726
Myelin
• Autonomic disturbance (postural hypotension, loss of
sinus arrhythmia) may be present. Axon

Chronic denervation
Trophic changes:
• Skin: thin, red, shiny, transparent, indolent ulcers
(repeated trauma).
• Nails: transversely striped, thickened, brittle.
• Hair: disappears from denervated areas.
• Joints, bones: immobility: disuse atrophy.

Underlying cause
• Pes cavus (inherited). Skin or
• Diabetic retinopathy. muscle
• Hepatomegaly (alcohol). A B C D

DIFFERENTIAL DIAGNOSIS
Anatomic 727 728
Focal neuropathy or mononeuropathy
• Local entrapment.
• Mononeuritis.
• Trauma.

726 Diagrammatic representation of pathologic changes in peripheral

nerve fibers. A: normal myelinated nerve fiber; B:Wallerian
degeneration of the axon and myelin following section or crush of
nerve fiber; C: axonal degeneration (with secondary myelin
degeneration) of the distal portion of nerve fiber in ‘dying-back’
neuropathy; D: segmental demyelination, with degeneration of the
myelin in one internode but preservation of the axon.

727 Teased nerve fiber (osmium tetroxide) showing segmental

demyelination (yellow axons [myelin normally appears black]) and
active Wallerian degeneration due to focal interruption of axons
(numerous myelin ovoids which appear as black blobs).

728 Teased nerve fiber showing segmental demyelination (of the

bottom half of the strip).
582 Diseases of the Peripheral Nerve

Generalized polyneuropathy • Hereditary sensory and autonomic neuropathy (HSAN type

• Alcohol. 1) – autosomal dominant, small fibre loss, acromutilation).
• Diabetes. • Hypothyroidism.
• Uremia. • Lyme disease.
• Vitamin B12 deficiency. • Paraneoplastic sensory neuropathy.
• Guillain–Barré syndrome. • Vasculitic neuropathies.
• Chronic inflammatory demyelinating polyneuropathy
(CIDP). Autonomic neuropathies
• Hereditary. • Amyloidosis (primary or familial).
• Diabetes.
Clinical • Guillain–Barré syndrome.
Acute onset • HSAN 3 (autosomal recessive; Riley–Day syndrome).
• Critical illness polyneuropathy. • Porphyria (acute intermittent porphyria).
• Diabetes, uremia (rarely).
• Diphtheria. Pathologic
• Guillain–Barré syndrome. Demyelinating neuropathies
• Malignancy. Acute onset:
• Porphyria. • Diphtheria.
• Serum sickness (post immunization). • Guillain–Barré syndrome (AIDP).
• Toxic (e.g. arsenic, nitrofurantoin).
Subacute/chronic onset:
Predominantly motor • Hereditary neuropathies:
• Botulism. – Hereditary motor and sensory neuropathy (HMSN)
• Charcot–Marie–Tooth disease. types 1 and 3.
• Diabetes (diabetic amyotrophy). – Refsum’s syndrome.
• Diphtheria. – Metachromatic leukodystrophy.
• Guillain–Barré syndrome. – Krabbe’s disease.
• Lead. • Inflammatory neuropathies:
• Porphyria. – Chronic inflammatory demyelinating polyneuropathy
(CIDP).
Predominantly sensory – Motor neuropathy with multifocal conduction block.
• Amyloidosis (primary or familial). – Chronic inflammatory polyneuropathy associated with
• Diabetes (distal sensory polyneuropathy). paraproteinemia.
• Fabry’s disease. – Inflammatory neuropathy associated with HIV infection.
• Guillain–Barré syndrome. • Malignancy: some acute and subacute neuropathies
• Hereditary sensory and autonomic neuropathies. associated with carcinoma and lymphoma.
• Hypothyroidism. • Metabolic neuropathies:
• Infections: – Diabetes (sometimes).
– HIV infection. – Uremia (sometimes).
– Leprosy. • Toxic neuropathies:
– Lyme disease. – Amiodarone.
– Syphilis (tabes dorsalis). – Hexacarbons.
• Mitochondrial cytopathy. – Perhexilene (perhexiline) maleate.
• Neoplastic (carcinomatous) and paraneoplastic
neuropathy. Axonal degeneration
• Sarcoidosis. Acute:
• Sjögren’s syndrome. • Guillain–Barré syndrome (AMAN).
• Toxicity: • Toxins.
– Arsenic. • Porphyria.
– Thallium. • Vasculitis (polyarteritis nodosa, systemic lupus erythe-
• Uremia. matosus).
• Vasculitis.
• Vitamin B12 or thiamine deficiency. Chronic:
• Hereditary:
Radicular – HMSN type 2.
• Diabetic truncal neuropathy. – Giant axonal neuropathy.
• Lyme disease. – Hereditary ataxias.
• Sjögren’s syndrome. • Inflammatory: systemic lupus erythematosus, sarcoid.
• Infectious: leprosy.
Painful neuropathies • Paraneoplastic:
• Alcohol, nutritional deficiencies. – Lymphoma.
• Arsenic. – Carcinoma of the lung.
• Cryoglobulinemia. • Metabolic:
• Diabetes (acute painful neuropathy). – Diabetes.
 Peripheral Neuropathy 583

– Uremia. • Hexacarbon neuropathy.

• Toxic: • IgM kappa paraproteinemia neuropathy.
– Alcohol. • Metachromatic leukodystrophy.
– Drugs (dapsone, gold, isoniazid, metronidazole, • Krabbe’s disease.
platinum, vincristine, vitamin B6). • Fabry’s disease.
• Deficiencies:
– Vitamin B12. Diagnosis of a chronic axonal neuropathy, the most
– Thiamine. common neuropathy, is not usually helped by nerve biopsy.
– Vitamin E. About one-third of patients experience persistent increased
– Nicotinamide. pain at the biopsy site.
• Miscellaneous:
– Primary amyloid. Other investigations
Core screen
INVESTIGATIONS • Full blood count with differential.
Nerve conduction studies and electromyography (EMG) • ESR.
• The most useful investigations in peripheral nerve • Fasting blood glucose and hemoglobin A1C.
disease. • Serum vitamin B12 level.
• Determines whether a neuropathy is present, its • Serum protein electrophoresis.
distribution (e.g. focal or generalized) and in some cases • Chest x-ray.
the precise location (e.g. carpal tunnel), whether the
process is axonal or demyelinating, and also whether Targeted
there is any evidence of conduction block. • Thyroid function tests.
• Conduction block implies a focal area of demyelination • Antinuclear antibodies, rheumatoid factor, antineutrophil
which is characteristic of diseases such as CIDP or cytoplasmic antibody, cryoglobulins.
multifocal motor neuropathy. • HIV, Lyme disease, hepatitis B and C, syphilis serology.
• Serum vitamin E.
Nerve conduction velocity (NCV) • Peripheral autonomic skin response: to determine if a
Depends on the: small fiber neuropathy.
• Diameter of the fiber. • Anti-Hu-antibody (encephalomyelitis with sensory
• Distance between the nodes of Ranvier. neuropathy).
• Integrity of the myelin sheath. • CSF: cells, protein, glucose, cytology, serology.

Segmental demyelination: DIAGNOSIS

• NCV reduced by >40% of mean normal values.
• Conduction block.
• Slowing of F-wave responses.
Axonal neuropathies:
• NCV normal or slightly reduced.
• NCVs are those of the fastest conducting fibers (large
myelinated axons).
Action potential amplitude
The amplitude is an indication of the number of motor units
present.
• Segmental demyelination: CMAP amplitude: normal or
slightly reduced (dispersed).
• Axonal neuropathies: CMAP amplitude: declines
progressively with fallout of axons.
• Does the patient have a peripheral neuropathy?
• What type of neuropathy is it (anatomy, pathology)?
• What is the course of the neuropathy (acute [1–4 weeks],
subacute [1–3 months], chronic [>3 months], or
relapsing)?
• What is the cause of the neuropathy?
TREATMENT
• Specific treatment of the underlying cause if possible (e.g.
vitamin B12 replacement).
• Ameliorate the decline in function and optimize
adaptation to any disability:
– Physiotherapy: to maintain muscle strength.
– Occupational therapy: orthotic aids, wheelchair.
– Podiatry (cf. foot deformity [pes cavus] and sensory loss).

Nerve biopsy
Sural nerve biopsy may reveal characteristic histopatho-
logical appearances, and be helpful in patients suspected to
have the following conditions:
• Chronic demyelinating neuropathy where immunologi-
cally-mediated disorders (e.g. CIDP) requiring treatment
with steroids or other immunosuppressants are better
managed with supportive histology.
• Charcot–Marie–Tooth disease type 1.
• Vasculitic neuropathies (e.g. multiple mononeuropathies).
• Sarcoidosis.
• Leprosy.
• Amyloid.
• Giant axonal neuropathy.
584 Diseases of the Peripheral Nerve
HEREDITARY NEUROPATHIES
DEFINITION
• A genetically heterogeneous group of several familial and
slowly progressive disorders of peripheral nerves and
anterior horn cells of the spinal cord which are inherited
as an autosomal dominant, autosomal recessive, or X-
linked trait, and which have overlapping clinical and
electrophysiologic characteristics.
• They were formerly known as Charcot–Marie–Tooth
(CMT) disease, or peroneal muscular atrophy but,
following recent major advances in the understanding of
the genetics of hereditary motor and sensory neuropathy
(HMSN), they are now classified according to their
genetic and etiologic basis.
EPIDEMIOLOGY
• Prevalence: 8–41 per 100 000 population.
• Age: onset in second or third decade of life.
• Gender: M=F.
CLASSIFICATION
HMSN CMT] with known genetic basis
HMSN (CMT) type 1 (see p.585)
• HMSN (CMT) 1A.
• HMSN (CMT) 1B.
• HMSN (CMT) X.
HMSN (CMT) type 3 (see p.585)
HMSN with unknown genetic basis
Demyelinating neuropathies
• Autosomal dominant.
• Autosomal recessive.
Axonal neuropathies
• HMSN (Charcot–Marie–Tooth) type 2 (see p.585)
• Complex HMSN.
Hereditary neuropathy with liability to pressure
palsies (see p.587)
Etiology: autosomal dominant; deletion, or sometimes a
point mutation, at 17p 11.2.
Syndromic hereditary peripheral neuropathies
Refsum’s disease (heredopathia atactica polyneuritiformis)
• Inheritance: autosomal recessive.
• Age: onset in first or second decade.
• Pathology and etiology: demyelination due to abnormal
storage of phytanic acid as a result of a defect in alpha-
oxidation of beta-methylated fatty acids.
• Clinical features: night blindness (retinitis pigmentosa);
dry, scaling, ichthyosis-like skin; polyneuropathy.
Cerebellar ataxia and cardiac abnormalities are late
features. Cochlear hearing loss occurs in 80% of cases
• Treatment: a low phytanate diet is rarely very successful.
Fabry’s disease
• Prevalence: 1 per 40 000 (rare).
• Age and gender: 10–30 year old males.
• Inheritance: X-linked (Xq22).
• Pathology and etiology: a disorder of glycolipid
catabolism associated with defective lysosomal alpha-
galactosidase, and resulting in accumulation of tri-
hexosylceramide in various tissues.
• Clinical features: painful neuropathy affecting hands and
feet, with pain crises in the palms and soles. Other
manifestations affect the eye (angiokeratomata with lipid
inclusions on microscopy), eye (corneal opacities in 80%),
heart (arrhythmias) and kidney (renal failure and
birefringent lipid on microscopy).
• Treatment: symptomatic; the pain usually responds to
carbamazepine.
Porphyrias
• Inheritance: autosomal dominant.
• Etiology: impaired porphyrin metabolism.
• Clinical features: predominantly motor peripheral neuro-
pathy which may mimic Guillain–Barré syndrome or multi-
ple mononeuropathy. The course is relapsing and exacer-
bations are usually triggered by medications, such as female
sex hormones, benzodiazepines, and anti-epileptic drugs.
Neuropsychiatric manifestations are seen in acute intermit-
tent and variegate porphyria. The relapsing course and
psychiatric symptoms may lead to a misdiagnosis of hysteria.
• Investigations: the urine turns red-brown on standing,
due to urinary porphyrins.
• Treatment: supportive and symptomatic with avoidance
of precipitating medications. Other family members
should be considered for testing.
Familial amyloid polyneuropathies
• Inheritance: autosomal dominant.
• Pathology and etiology: small fiber neuropathy due to
deposition of amyloid in the extracellular space. The most
common fibrillar proteins deposited as amyloid are
transthyretin apolipoprotein A-1 (transthyretin is
produced in the liver) and gelsolin. For transthyretin
alone there are 40 amyloidogenic point mutations
(chromosome 18q). The commonest mutation causes the
substitution of methionine for valine at position 30 which
results in a late onset, progressive, painful, predominantly
sensory neuropathy, formerly called the Portuguese type
or familial amyloid neuropathy type 1.
• Clinical features: pain, loss of pain and temperature sen-
sation, autonomic dysfunction, cardiomyopathy, and occa-
sional vitreous, renal and other organ involvement (729).
• Diagnosis: by nerve biopsy.
• Treatment: symptomatic, but liver transplantation in
young adults can halt the progression of this subtype.
729 729 Macroglossia
due to amyloid
infiltration of the
tongue in a patient
with primary
amyloidosis.
 Hereditary Motor and Sensory Neuropathy (Charcot–Marie–Tooth Disease)
HEREDITARY MOTOR AND
SENSORY NEUROPATHY
(CHARCOT–MARIE–TOOTH DISEASE)
DEFINITION
A general name for a group of genetic disorders affecting
peripheral nerves. First described by Jean Martin Charcot
and Pierre Marie in France in 1886.
EPIDEMIOLOGY
• The most common inherited peripheral neuropathy.
• Prevalence: 5/100 000.
• Age: onset in second or third decade of life.
• Gender: M=F.
HMSN (Charcot–Marie–Tooth disease [CMT])
• HMSN type 1: up to 80% of cases:
– HMSN (CMT) 1A: 70% of patients with HMSN 1.
– HMSN (CMT) X: 25% of families with HMSN 1.
• HMSN type 2: up to 20% of cases.
ETIOLOGY
Genetically heterogeneous: autosomal dominant, autosomal
recessive, X-linked and spontaneous cases occur.
HMSN (CMT) with known genetic basis
HMSN (CMT) type 1
• Autosomal dominant inheritance.
• Caused by mutations in one of several genes expressed
in Schwann cells, the myelin producing cells of the
peripheral nervous system.
– HMSN (CMT) 1A: duplication of the gene coding for a
22 kDa peripheral nerve myelin protein 22 (PMP 22), a
Schwann cell adhesion molecule, on the short arm of
chromosome 17, at position 17p 11.2.
– HMSN (CMT) 1B: point mutations in the protein zero
(P0) gene, which encodes the major PNS myelin
structural protein.
– HMSN (CMT) X: point mutations in the connexin-32
gene on the X chromosome, which encodes the gap
junction channel protein connexin-32 which is expressed
in myelinating Schwann cells but not incorporated in the
myelin sheath.
– Point mutations in the early growth response gene 2
(EGR-2), or Krox 20, encoding a zinc finger
transcription factor expressed in myelinating Schwann
cells.
HMSN (CMT) type 3:
• Déjérine–Sottas syndrome (a severe and early-onset
form).
• Caused by some point mutations in the PMP22 gene.
HMSN with unknown genetic basis
Demyelinating neuropathies
• Autosomal dominant: HMSN 1 non-A non-B is the
term applied to the disease in families where linkage to
chromosomes 17 and 1 have been excluded; their
genotypes await identification.
• Autosomal recessive: a rare, severe, early-onset disorder
mapping to chromosome 8q. Some forms have focally
folded myelin sheaths on nerve biopsy.
585
Axonal neuropathies
• HMSN (CMT) type 2: caused by mutations to a number
of as yet unknown genes. Distinguished from HMSN 1 by:
– Autosomal recessive inheritance; the responsible genes
have not been identified.
– Axonopathy rather than demyelination (i.e. sparse
demyelination and no onion bulbs).
• Complex HMSN: other categories of HMSN with
associated features have yet to be fully characterized.
Some have pyramidal features (retained reflexes and
extensor plantar responses), optic atrophy, deafness, or
pigmentary retinal degeneration.
PATHOLOGY
HMSN (Charcot–Marie–Tooth) type 1
• Nerve fiber loss with segmental demyelination and
remyelination in surviving fibers.
• ‘Onion bulbs’, comprising concentrically proliferated
Schwann cells surrounding surviving myelinated fibers,
are characteristic beyond adolescence.
HMSN (Charcot–Marie–Tooth) type 2
A predominantly axonal neuropathy (neuronal form).
PATHOPHYSIOLOGY
HMSN (Charcot–Marie–Tooth) type 1
The mutations disrupt myelin and Schwann cell function in
a number of complex ways, leading to segmental
demyelination and secondary axonal damage of the
peripheral nervous system. It is the secondary axonal damage
which is the major cause of weakness in HMSN (CMT) 1.
CLINICAL FEATURES
HMSN (CMT) type 1
• Widely variable, even within families.
• Symptoms develop in childhood (particularly HMSN
1A) and include: ‘weak ankles and legs’, ‘tripping’, ‘can’t
run’, ‘can’t walk on heels’, ‘poor balance’.
• Progressive, predominantly distal muscle wasting and
weakness involves mainly the legs. Advances cases show
‘inverted champagne bottle’-shaped legs due to atrophy
of the peroneal and calf muscles and relative sparing of
the quadriceps muscles.
• Reduced or absent deep tendon reflexes.
• Thickened greater auricular nerves may be visible in the
neck, and enlarged ulnar and peroneal nerves may be
palpable in some patients.
• Severe childhood cases with marked nerve thickening are
a feature of Déjérine–Sottas disease (or HMSN 3).
• Upper limb tremor may be present, and when prominent
is known as Roussy–Levy syndrome.
• Pes cavus is common as the weakness progresses.
• Scoliosis is sometimes present.
• High stepping gait due to foot drop tends to develop late.
• Weakness in the hands is present in some patients, and
may cause difficulty writing and manipulating small
objects, but is seldom severe.
• Claw hands in some patients, late in the disease.
• Sensory involvement is slight, and positive sensory
symptoms such as tingling or pain are not expected.
• Autonomic function is preserved.
• Positive family history is common: many people have
mild symptoms and may not seek medical help until
another family member has more severe problems.
586 Diseases of the Peripheral Nerve

HMSN type 2 TREATMENT

• Dominant or recessive inheritance.
• Similar clinical presentation to type I but may not
develop symptoms until the fourth or fifth decade and
may produce more extensive wasting.
Recessive disorders are usually of earlier onset, more
clinically severe, and less variable in their clinical expression
because there are two mutant genes. Dominant disorders
are less severe, of later onset, and more clinically variable
because there is one mutant gene and one normal gene.
DIFFERENTIAL DIAGNOSIS
Other hereditary motor and sensory neuropathies
(see p.584)
• Hereditary neuropathy with liability to pressure palsies
(see p.587).
• Refsum’s disease.
• Fabry’s disease.
• Porphyria.
• Familial amyloid polyneuropathy.
Distal myopathy
Miyoshi myopathy (dysferline positive staining):
• Autosomal recessive inheritance.
• Onset: 15–30 years.
• Wasting and weakness of muscles of posterior
compartment of leg (e.g. calves), which may be
asymmetric.
• Ankle reflexes may be absent.
• Marked elevation of serum creatine kinase.
• Normal nerve conduction studies.
• Myopathic EMG findings.
• Hypertrophic muscle fibers with patchy necrosis,
occasional regenerating fibers, and positive dysferlin
staining.
• Variable progression.
• Treatment is a team approach incorporating neurologists,
GPs, genetic counsellors, physiotherapists, podiatrists, and
if necessary orthotists and orthopedic surgeons.
• There is still no specific pharmacologic treatment.
• The emphasis is on symptomatic management, aimed
primarily at maintaining lower limb function and
preventing forefoot drop creating pes cavus and other
deformities by regular physiotherapy (e.g. stretching,
exercises) and providing appropriate splints, ankle-foot
and in-shoe orthotics and footwear. In children the aim
is to prevent bone deformity caused by muscle imbalance.
• As with any genetic disorder, genetic advice to the patient
and family is of paramount importance. Coming to terms
with having a genetic disorder can be a difficult process
for the patient and other existing family members.
Furthermore, the risk of passing on the condition to their
children needs to be evaluated and recognized.
PROGNOSIS
• Depending on the type, HMSN has the potential to
cause significant disability if ignored and prevention
measures are not initiated early and maintained.
• The level of disability therefore depends on how early the
patient is diagnosed and whether there has been
consistent use of splints and compliance with exercise.
• If patients are well monitored and aware of their
limitations, many can lead active lives with little need of
reliance on medical care. Nevertheless, many do have to
modify their activities, for example, by avoiding jobs that
involve fine hand movements or constant standing.

INVESTIGATIONS
Electrophysiologic studies
HMSN type 1
Uniform and severe slowing of peripheral motor conduction
velocity (usually <38 m/sec in the median nerve) due to
peripheral demyelination.

HMSN type 2
A predominantly axonal neuropathy (neuronal form), in
which nerve conduction velocities are normal or near 730
normal but the compound muscle action potentials are of
reduced amplitude.

Molecular DNA analysis

Sural nerve biopsy (730)

DIAGNOSIS
Establish from clinical and neurophysiologic assessment of
the type of HMSN (CMT), and the pattern of inheritance
in the family:
• HMSN (CMT) type 1: DNA analysis for the three types
of HMSN (CMT) 1.
• HMSN (CMT) type 2: clinical and neurophysiologic; 730 Teased fibers from a sural nerve showing segmental
there is no direct DNA test. demyelination in several strips in a patient with HMSN (CMT) type 1.
 Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)
HEREDITARY NEUROPATHY
WITH LIABILITY TO PRESSURE
PALSIES (HNPP)
DEFINITION
An autosomal dominant inherited disease characterized by
recurrent episodes of acute weakness or sensory disturbance,
due to single or multiple peripheral nerve palsies, often
precipitated by minor compression or traction.
EPIDEMIOLOGY
• Incidence: unknown, but most neurologists see at least
one family with this condition.
• Age: onset is usually by the second decade of life.
• Gender: in some families the disorder predominates in
males, but this may reflect a difference in everyday
activities.
PATHOLOGY
• Nerve fiber loss with demyelination and remyelination
(731).
• Focal, large, sausage-shaped enlargement/thickening
(‘tomacula’) of the myelin sheath after teasing and
staining of individual nerve fibers in biopsy specimens of
the sural or another cutaneous nerve. These
abnormalities are also found in carriers in whom pressure
palsies have yet to occur.
• Electron microscopy reveals the tomacula which
correspond to regions of uncompacted myelin lamellae,
folded back longitudinally or circumferentially.
ETIOLOGY AND PATHOPHYSIOLOGY
Autosomal dominant inheritance. The gene defect is a large
1.5 Mb interstitional deletion of DNA at chromosome 17p
11.2-12. The deleted region appears uniform in unrelated
pedigrees. It includes the gene for peripheral myelin protein
22 (PMP-22), and involves the same chromosomal region
that is duplicated in Charcot–Marie–Tooth type 1A disease
(also known as hereditary motor and sensory neuropathy type
1a). This region is now called the ‘CMT1A/HNPP
monomer unit’. This finding suggests that the two disorders
may be reciprocal products of unequal crossover during
meiosis: HNPP with a single allele (monosomy, through
deletion) and HMSN 1A with three alleles (trisomy, through
reduplication). The genetic relationship between the two
diseases may explain why some patients show the phenotype
of a symmetric demyelinating sensorimotor polyneuropathy
after a series of pressure palsies, or sometimes as the
presenting feature.
CLINICAL FEATURES
History
• Recurrent episodes of painless compressive neuropathy
(e.g. peroneal neuropathy) or plexopathy at common
pressure points, often induced by relatively minor
trauma, such as repeated occupational squatting and
kneeling or carrying heavy objects on the shoulders.
• Onset is usually acute, but progressive weakness may
occur.
EXAMINATION
• Generally yields little information besides a focal
compressive neuropathy or plexopathy.
587
• Patients may have mild talipes cavus or other features sug-
gestive of a generalized inherited disorder of peripheral nerve.
• Tendon reflexes are often depressed or abolished.
• Pes cavus or skeletal deformities are rare.
• There is no nerve hypertrophy or CNS involvement.
DIFFERENTIAL DIAGNOSIS
Clinically, HNPP can be difficult to distinguish from other
inherited neuropathies, notably hereditary neuralgic
amyotrophy (HNA) and CMT. Patients with HNPP may
manifest only recurrent brachial plexus palsy or a familial
tendency to brachial plexus palsy. However, these episodes,
associated with diffuse nerve conduction abnormalities, are
usually painless, without amyotrophy, and usually associated
with other mononeuropathies.
The confusion with CMT may relate to the possible
presence of pes cavus and abolished ankle jerks or peroneal
amyotrophy in HNPP or to tomaculous changes in CMT.
Hereditary neuralgic amyotrophy
• Recurrent episodes of acute painful arm weakness.
• Amyotrophy.
• A focal axonal disorder with focal electrophysiologic
abnormalities.
Charcot–Marie–Tooth disease
• Recurrent acute nerve palsies are absent.
• The median MNCV is markedly reduced in CMT1A,
mostly below 30 m/sec.
• Conduction blocks are absent.
Other causes of multiple mononeuropathy
• Vasculitis.
• Diabetes.
INVESTIGATIONS
Nerve conduction studies
Electrophysiologic evidence of a mild generalized
neuropathy with slowing of motor and sensory nerve
conduction velocities or conduction block at common nerve
entrapment sites (pressure points), such as the ulnar groove
or fibula head, in clinically affected and unaffected nerves.
It is the coexistence of mild-to-moderate slowing of nerve
conduction in clinically unaffected nerves that is the crucial
731
731 Nerve biopsy, transverse section, showing demyelinating
neuropathy. A few enlarged myelin rings remain but most axons are
devoid of myelin and there is early ‘onion bulb’ formation.
588 Diseases of the Peripheral Nerve
finding. HNPP is the only hereditary neuropathy in which
conduction blocks occur.
Bilaterally delayed median distal motor latency and
reduced sensory velocity in the palm-wrist segment and a
delayed distal motor latency or reduced motor nerve
conduction velocity in the peroneal nerve are highly
suggestive of HNPP when there is a family history of
HNPP. Bilaterally normal median nerve DML and sensory
velocity at the wrist would exclude this possibility.
Electromyography
Secondary signs of denervation are found in severe cases.
Molecular analysis
This is a rapid and reliable diagnostic tool. The 17p 11.2
deletion is found in most families (22/24 to date). Since
the possibility of genetic heterogeneity exists, combined
molecular and electrophysiologic examinations can be
performed, obviating the need for nerve biopsies to
diagnose HNPP.
Nerve biopsy
Specimens show myelin redundancy or duplication in
discrete areas of the myelin internode. These sausage-shaped
thickenings of myelin sheaths, most easily detected on
teased fiber preparations, were designated by Madrid and
Bradley as ‘tomacula’, which led to coining of the term
‘tomaculous neuropathy’. The tomaculous changes are not
specific to HNPP and occur, although with a lesser
frequency and intensity, in other inherited neuropathies such
as HNA, CMT, and Déjérine–Sottas disease.
DIAGNOSIS
• Painless.
• No amyotrophy.
• Diffuse nerve conduction abnormalities.
• Median MNCV is often reduced but rarely below
40 m/sec.
• Slowing of MNCV in other nerves is heterogeneous and
frequently marked in entrapment sites.
• Conduction blocks in one or more nerves are suggestive
of HNPP.
• Molecular DNA analysis – 17p11.2 deletion.
• Nerve biopsy – tomaculae.
TREATMENT
• Inform patients and their siblings about the practical
implications of the diagnosis.
• Practices to avoid include:
– Sitting with legs crossed.
– Wearing rucksacks.
– Choosing a profession where frequent kneeling is necessary.
– Careless positioning of limbs during general anesthesia.
• Genetic counselling can help identify children who may
be affected.
• There is no effective medical or surgical treatment.
PROGNOSIS
The individual palsies are often slow to recover (conduction
blocks may last for weeks, months or even several years) but
they do tend to recover completely. However, repeated
episodes do occur and may result in some degree of residual
deficit (e.g. foot drop) and absent tendon reflexes.
GUILLAIN–BARRÉ SYNDROME (GBS)
(ACUTE INFLAMMATORY
DEMYELINATING POLYRADICULO-
NEUROPATHY [AIDP])
DEFINITION
An acute, reactive, self-limited, autoimmune disease,
triggered by a preceding viral or bacterial infection, and
characterized by progressive muscle weakness and
respiratory paralysis associated with absent deep tendon
reflexes, which develops over a period of 3–4 weeks. The
name honors the French neurologists who described an
acute idiopathic polyneuritis in two soldiers in 1916.
EPIDEMIOLOGY
• Incidence: about 2 per 100 000 per year.
• Age: any age, but rare in infancy. The incidence increases
with age after 40 years of age, and is maximal at 50–74 years.
• Gender: M>F.
PATHOLOGY
• Early lymphocyte infiltration in spinal roots and peri-
pheral nerves, and deposition of activated complement
components along the outer Schwann-cell surface mem-
brane of myelinated nerve fibers. Vesicular disruption of
myelin sheaths progresses from outward to inward.
• Subsequent recruitment of macrophages and invasion of
nerve fibers, followed by macrophage-mediated seg-
mental (multifocal) demyelination of peripheral nerves.
• Variable disruption and loss of nerve axons accompanies
inflammatory demyelination in severe cases, and is
thought to be a secondary ‘bystander’ effect, possibly
caused by intense inflammation, edema, and swelling of
nerves. The degree of axonal loss is an important
determinant of recovery and prognosis.
• Repair and remyelination begin when the immune
reactions cease.
• Denervation atrophy of groups of muscle fibers if there
is axonal degeneration (732).
732
732 Muscle biopsy showing denervation atrophy of groups of muscle
fibers due to axonal degeneration.There is a reduction in size of
muscle fibers within the denervated motor units (and enlargement of
intact motor units due to collateral innervation).
 Guillain–Barré Syndrome (GBS)
ETIOLOGY AND PATHOPHYSIOLOGY
An autoimmune disorder triggered by exposure to an
antigen that is usually infectious.
Antecedent exposure to an antigen
Infection
50–60% of cases give a history of a recent viral or other
infection.
Bacteria:
• Campylobacter jejuni: the most frequent antecedent
pathogen (26–41% of cases). A gastrointestinal pathogen
which causes gastroenteritis and diarrhea. Associated with
the Miller Fisher variant and an acute motor-axonal
neuropathy variant of GBS (see below).
• Mycoplasma pneumoniae.
Viruses:
• Cytomegalovirus (CMV): 10–22% of cases of GBS,
particularly young women presenting with prominent
involvement of the sensory and cranial nerves. Many
have high serum titers of antibodies reacting with GMs
gangliosides and with sulfated glycolipids.
• Epstein–Barr virus (EBV).
• Varicella-zoster virus.
• HIV: a GBS-like syndrome most commonly occurs
around the time of seroconversion, but the CSF has a
lymphocytic pleocytosis.
Vaccination:
• Rabies.
• Swine influenza.
Autoimmune response
The infecting organism induces humoral immune responses
(e.g. production of antibodies to GM1, GM2 and GQ1b)
and cellular immune responses that, because of the sharing
of homologous epitopes (molecular mimicry) between the
lipopolysaccharides of the infecting organism and the surface
components of peripheral nerves (e.g. ganglioside), cross-
react with surface components of peripheral nerves.
Subsequent pathogenic mechanisms are heterogeneous.
The humoral immune response results in complement
activation on the outer Schwann cell plasmalemma, which
leads to entry of calcium into the cell with subsequent
activation of PLA and protease, resulting in demyelination.
The cellular immune response involves macrophages and T
cells which attack healthy myelin in peripheral and cranial
nerves, resulting in block in conduction of nerve impulses.
However, the immune responses are more complex, and
host factors contribute substantially to disease susceptibility
and to the clinical pattern of GBS.
Immune reactions against target epitopes in Schwann cell
surface membrane or myelin result in acute inflammatory
demyelinating polyradiculoneuropathy (85% of cases), and
reactions against epitopes contained in the axonal
membrane cause acute axonal forms of GBS (15% of cases).
589
CLINICAL FEATURES
Acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) (85–90% of cases)
• Progressive symmetric weakness of the limbs which
develops acutely (within days) or subacutely (up to
4 weeks), and progresses over a period of 1–8 weeks in
an ascending fashion (caudal to rostral), reaching a
plateau, and then spontaneously resolving.
• Paresthesiae in the hands and feet: not as prominent as
motor signs.
• Back pain (30% of cases).
• Depressed or absent deep tendon reflexes.
• Cranial neuropathies, particularly facial neuropathies:
(50% of cases).
• Progression of disability for up to 4 weeks.
The common initial symptoms are numbness and tingling
in the lower limbs, which are soon followed by weakness in
the legs and arms, which may be proximal as well as distal
and sometimes more pronounced in the proximal muscles.
About a half of patients develop cranial neuropathies, usually
bilateral facial paresis (of lower motor neuron type). Ptosis
and double vision occur in about 10% of cases. Back pain is
a major symptom in about one-third of patients. Sensation
is usually impaired in a glove and stocking distribution but
profound sensory loss is uncommon. Sphincter disturbances
are present in only a small proportion of cases and suggest
another diagnosis such as spinal cord compression.
DIFFERENTIAL DIAGNOSIS
Anxiety or hysteria
In the early stages of the illness there may be few objective
neurologic signs and patients may be misdiagnosed as being
anxious or hysterical, and sent home, only to soon become
very weak with respiratory paralysis.
Spinal cord lesions
Transverse myelitis.
Anterior horn cell lesions (part of spinal cord)
Poliomyelitis: caused by an enterovirus (like GBS is
predominantly caused by an enteral agent).
Peripheral nerve disorders
• Vasculitis.
• HIV infection: may cause a syndrome like GBS but the
CSF white cell count is usually elevated (>30 × 106/l).
• Diphtheria: more likely to have a bulbar onset, lead to
respiratory failure, evolve more slowly, take a biphasic
course and cause death or long term disability.
• Lyme disease.
• Lymphoma.
• Carcinoma of the lung.
• Diabetes.
• Acute intermittent porphyria.
• Heavy metals and other toxins.
• Alcohol-related acute axonal neuropathy (in combination
with malnutrition).
• Vitamin B12 deficiency.
590 Diseases of the Peripheral Nerve
Neuromuscular junction disorders
• Myasthenia gravis.
• Botulism.
Muscle disorders
• Hypokalemia.
• Periodic paralysis.
• Polymyositis.
INVESTIGATIONS
• Vital capacity: should be measured every 2–4 hours in
the initial stages.
• Nerve conduction studies and EMG:
– Demyelination: slowing of nerve conduction velocities,
prolongation of distal and F-wave latencies, and
conduction block.
– Axonal degeneration: reduction in amplitude of sensory
nerve action potentials (SNAP) and compound muscle
action potentials (CMAP), EMG evidence of
denervation.
• Lumbar puncture: CSF white cell count is normal and
protein elevated.
• Full blood count.
• ESR.
• Serum electrolytes, urea and creatinine.
• Blood glucose.
• Serology for Campylobacter jejuni (serotypes HS-2, 4
and 19), Mycoplasma pneumoniae, CMV, EBV, varicella-
zoster, HIV, Lyme disease.
• Stool culture (Campylobacter jejuni): may be positive for
several weeks after the end of the diarrheal illness.
VARIANTS
AIDP is the most common, and traditional, condition
causing GBS. But recently there have been described other
conditions which also cause, or fall within, GBS (e.g.
AMSAN, AMAN, MFS).
Acute motor-sensory axonal neuropathy (AMSAN)
• Abrupt onset of severe generalized paralysis and muscle
atrophy.
• Association with antecedent diarrheal or flu-like illness.
• Acute axonal degeneration of motor and sensory nerve
fibers, extending to proximal nerve roots, due to a
primary attack on axons, rather than Schwann cells; scant
lymphocytes and little evidence of demyelination.
• Low amplitude or absent SNAP and CMAP on distal
supramaximal stimulation.
• Antiganglioside antibodies (i.e. anti-GM1) are common.
• Rapid progression.
• Delayed and very poor recovery.
Acute motor axonal neuropathy (AMAN)
(10–20% of cases of GBS)
• Originally described during summer epidemics in
children of farm families in northern China.
• Antecedent enteric Campylobacter jejuni infection
(heterostrain 019) in 80% of cases.
• IgG and activated complement components bind to the
axolemma at nodes of Ranvier in large motor fibers.
Macrophages are attracted to these nodes and track
underneath the detached myelin lamellae along the
periaxonal space, dissecting the axon from the overlying
Schwann cell and compact myelin. The axolemma, in
contact with invading macrophages, is focally destroyed,
resulting in selective loss of motor axons distally or along
the entire length due to axonal degeneration. Distal
sensory fibers are intact.
• Little or no demyelination.
• Little or no lymphocyte infiltration.
• Normal SNAP and CMAP.
• Normal conduction velocities and latencies.
• Early denervation.
• High titers of antibodies to GM1, GD1a and GD1b which
parallel the clinical course.
• The variable severity of the axonal destruction is reflected
by the variable time span of recovery, and overall good
prognosis in many children.
• Reasonable prognosis, similar to AIDP, in contrast to
AMSAN: mortality 4%.
Miller Fisher syndrome (MFS)
• Ophthalmoparesis.
• Ataxia.
• Areflexia.
• No significant weakness or sensory disturbance.
• Antibodies to GQ1b ganglioside in 96% of cases of MFS
(the only form of GBS where a serum test has sensitivity
and specificity) which parallel the disease course.
• The antibodies recognize epitopes that are expressed
specifically in the nodal regions of oculomotor nerves,
but also in dorsal-root ganglion cells and cerebellar
neurons.
• Antecedent infection sometimes: e.g. Campylobacter spp.
Acute sensory loss with absent reflexes
• A predominantly sensory AIDP.
Acute autonomic neuropathy (acute
pandysautonomia)
• Postural hypotension.
• Impaired sweating, lacrimation, bladder and bowel
function.
Chronic inflammatory demyelinating
polyneuropathy (see p.593)
• Similar pathogenesis to AIDP.
• Slower onset, over weeks or months.
• Course may be relapsing and remitting, or progressive.
• Abnormal nerve conduction studies.
• Responds to treatment with corticosteroids, immuno-
suppressive agents, plasmapheresis and intravenous
immunoglobulin.
 Guillain–Barré Syndrome (GBS)
DIAGNOSIS
Diagnostic criteria for typical GBS
Features required for diagnosis
• Progressive weakness in both arms and both legs.
• Areflexia.
Features strongly supporting diagnosis
• Progression of symptoms over days to 4 weeks.
• Relative symmetry of symptoms.
• Mild sensory symptoms or signs.
• Cranial nerve involvement, especially bilateral weakness
of facial muscles.
• Recovery beginning 2–4 weeks after progression ceases.
• Autonomic dysfunction.
• Absence of fever at onset.
• High concentration of protein in CSF, with fewer than
10 leucocytes/mm3.
• Typical electrodiagnostic features.
Features excluding diagnosis
• Diagnosis of botulism, myasthenia, poliomyelitis, or toxic
neuropathy.
• Abnormal porphyrin metabolism.
• Recent diphtheria.
• Purely sensory syndrome, without weakness.
TREATMENT
The key to management is to anticipate complications
before they occur, and implement appropriate prevention
strategies.
General
• Careful nursing, particularly attention to the patient’s
vital signs, fluid and nutritional status, comfort (e.g.
pain), emotional status, and care of the trachea, pharynx,
mouth, eyes, skin, bladder and bowels.
• Tracheostomy or intubation and artificial ventilation may
be necessary.
• Feeding by nasogastric tube, percutaneous gastrostomy
tube, or intravenous routes may be required.
• Bladder and bowel infections require prompt treatment.
• Deep vein thrombosis prophylaxis: subcutaneous heparin
5000 U bd.
• Physiotherapy should begin immediately.
• Splints to prevent foot- and wrist-drop may be required.
• Occupational therapy.
• Speech and swallowing therapy.
• Psychologic support and counselling may be necessary,
particularly for patients on ventilatory support.
• Social worker.
• GBS support groups.
Specific
Plasma exchange (PE) and high-dose IV immunoglobulin
(IVIG) improve the rate of motor recovery in at least 60%
of patients. They are of equivalent efficacy, and there is no
additional benefit from combining the treatments consecu-
tively. CSF filtration is proposed as a new treatment for
GBS, which may also be effective when combined with PE
or IVIG; future studies are needed.
Plasmapheresis (plasma exchange):
• Start as soon as possible, certainly within the first
2 weeks.
591
• Exchange 200–250 ml plasma/kg total in 4–5 exchanges
over a 7–14-day period.
• Restore intravascular volume with albumin or artificial
plasma solution.
• Wait for a response, which may take 3–4 weeks.
Intravenous human immunoglobulin:
• 0.4 g/kg daily for 5 days is equally effective as plasma-
pheresis, and is safer and more readily administered, but
is more expensive and difficult to access. Again, wait for
a response.
Corticosteroids and immunosuppressive drugs:
• No evidence of benefit.
If intravenous immunoglobulin (IVIG) or plasma exchange
are not successful, consider:
• Repeating the IVIG (but not often: ‘don’t throw good
money after bad’).
• Steroids after IVIG (but not steroids alone).
• ?Tryptophan staphylococcal exchange column.
• Do not use sequential plasma exchange and IVIG; the
combination is as effective as either alone but is not
superior to either alone.
About 10% of responders have a limited relapse after
either treatment with IVIG or plasma exchange. At the time
it is not known which of these patients will go on to develop
CIDP (see p.593) or not. Firstly, re-treat them with the
previously effective IVIG or plasma exchange. If this is not
effective, consider steroids (?CIDP).
Intensive care
Problems
• Respiratory failure: 25% (reduced from 30% by IVIG and
plasma exchange).
• Cardiovascular dysautonomias
• Medical complications:
– Pneumonia: 25% in ICU patients.
– Urinary tract infection: 18%.
– Hyponatremia: 14%.
– Pulmonary embolism.
– Gastrointestinal bleeding: 5%.
– Gut perforation: 3%.
– Hypercalcemia (after third week): 3%.
– Sepsis/shock: 1%.
• Iatrogenic: tube and line insertion: pneumothorax: 3%.
• Patient comfort and communication.
Respiratory failure
• The best measure of diaphragmatic power is mid-
inspiratory flow rate.
• Vital capacity is a poor measure of diaphragmatic power;
it is a volumetric measure and thus an epiphenomenon.
• Vital capacity (VC):
– 30 ml/kg: poor cough, poor airway clearance.
– 20 ml/kg (about 1.5 l): compromise of the sigh
mechanism (yawn) and reduced tidal volume; alveoli at
peripheral and base of lungs collapse, resulting in pul-
monary arteriovenous shunting, ventilation/perfusion
mismatch, mild hypoxia, and stimulus to increase the
respiratory rate.
– 12–15 ml/kg: loss of sigh; intubate and ventilate.
– 10 ml/kg: hypoventilation and carbon dioxide retention.
592 Diseases of the Peripheral Nerve

Dysautonomia CLINICAL COURSE AND PROGNOSIS

• Urinary retention in 15–20% of cases (do not confuse
with a spinal cord lesion).
• Cardiovascular:
– Pulse: no beat-to-beat variation; vagotomized.
– Arrhythmias:
Tachycardia (5–30%; differential diagnosis of a fixed
tachycardia is a pericardial effusion; the onset of tachy-
cardia in third week: suspect pulmonary embolism).
Bradycardia (2–10%; often with suctioning and eye ball
pressure).
Asystole (1%).
Ventricular arrhythmias.
– Blood pressure may swing wildly (e.g. from 8 to
26.7 kPa [60 to 200 mmHg] systolic), and leads to
cardiac arrest. This is due to a centrally mediated vaso-
depressor response leading to sympathetic vasodilatation
and hypotension.
Course
• The interval from onset to peak disability may vary from
hours to weeks.
• About 30% reach their maximum deficit within 7 days;
others progress for up to 4 weeks.
• About 60% of cases are unable to walk at the height of
their illness.
• Respiratory function is impaired in about half of patients,
and about 20–30% require assisted ventilation.
Recovery
• One-third of patients begin to show signs of recovery
within 2 weeks.
• One-third begin to recover in the second to fourth
weeks.
• One-third may have to wait up to 3 months before
definite improvement is evident.

Hyponatremia Outcome
Due to a natriuresis as a result of pulse secretion of atrial • Good recovery (includes paresthesiae, mild weakness):
natriuretic factor. The patient loses water as well as salt, so 80%.
do not restrict fluids. • Unsteady gait with or without orthosis: 5%.
• Walk with callipers: 5%.
Pulmonary embolism • Wheelchair-bound: 3%.
• Tends to occur after 2–3 weeks. • Chronic or relapsing course: 3%.
• Completely avoidable. • Mortality: 5%.
• Intermittent pneumatic compression air boots are most
effective. Mortality
• Subcutaneous heparin may lose its effectiveness after Most common causes of death: complications of respiratory
about 8–10 days unless the dose is increased (e.g. failure, pulmonary embolism, cardiac arrhythmias,
doubled). Check the APTT about 40 minutes after the autonomic failure, infection.
heparin dose, and if not twice normal, then increase the
dose of heparin. Prognostic factors
• DVTs most commonly arise in pelvic veins. • Advanced age.
• Can be diagnosed with plethysmography. • Axonal injury (electrophysiologic evidence).
• Mechanical ventilation for 3 months: the patient will be
Ileus wheelchair bound.
• Suspect if abdominal pain.
• May lead to perforation and peritonitis.
• Ranitidine and cissapride (cisapride) promote gut
motility.

Iatrogenic
Beware sensory deafferentation and motor weakness when
inserting a nasogastric tube: patients may not cough if the
tube goes into bronchi, alveoli, or even through the lung
into pleural cavity and mediastinum. Always perform an x-
ray after inserting a nasogastric tube and before feeding;
deaths have occurred by feeding into the mediastinum!

General treatment
• Early intubation: don’t wait until the patient is breathless;
intubate when VC is about 12 ml/kg.
• Treat severe pain with epidural analgesics (or try
narcotics or high dose i.v. steroids).
• ICU techniques for infection surveillance and DVT
prophylaxis.
• Nutrition, skin and eye care.
• Communication and psychologic support: to
communicate with mute patients, use a transparent
plexiglass with grid and letters, and phrases such as
‘please turn me’, ‘suction me’, ‘I’m in pain’; and watch
the patient’s eyes as they look at these phrases.
 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
CHRONIC INFLAMMATORY
DEMYELINATING POLYNEUROPATHY
(CIDP)
DEFINITION
A subacute or chronic demyelinating polyneuropathy with
a chronic relapsing-remitting, monophasic or progressive
course, lasting months to years.
EPIDEMIOLOGY
• Incidence: 0.15 per 100 000 per year (crude).
• Prevalence: 2 per 100 000.
• Age: any age, mean and median age of onset: about 50
years.
• Gender: M≥F.
PATHOLOGY
Endoneurial inflammation and primary demyelination of spinal
roots and peripheral nerves without infection or vasculitis.
ETIOLOGY AND PATHOPHYSIOLOGY
• Probably an autoimmune response caused by both
cellular and humoral immune processes:
– Associated with an increased frequency of HLA DR3.
– Target antigens remain elusive.
• Macrophages penetrate the Schwann cell basement
membrane, ingest the myelin sheath and denude the
axon. If the inflammation is severe, the axons may
undergo ‘bystander’ degeneration.
CLINICAL FEATURES
• Typically subacute onset and progressive (over >8 weeks)
asymmetric weakness and/or numbness of the distal and
proximal limbs, with pain, sensory ataxia, and areflexia.
• Occasionally patients present with nerve root pain, a pure
motor syndrome, and ataxic sensory variant, with
mononeuritis multiplex, involvement of lower limbs only
or one-limb only, or with repeated episodes of acute
Guillain–Barré syndrome.
• Limb or back pain is not uncommon at presentation or
relapse.
• A postural tremor occasionally occurs.
• It is rarely severe enough to require ventilatory support.
CLINICAL VARIANTS
Multifocal motor neuropathy with conduction block
• An uncommon demyelinating motor neuropathy.
• Originally described as a subgroup of CIDP and some
authorities still regard it as such, whereas others argue
that it is a distinct entity.
• Predilection for young adults.
• Immune-mediated.
• Clinically it is characterized by slowly progressive, patchy,
asymmetric limb weakness, usually beginning and
becoming most prominent in the forearms but the lower
limbs may be affected (usually later).
• Weakness may be associated with cramps, muscle
wasting, fasciculations, decreased tendon reflexes and
sometimes minor sensory symptoms.
• The clinical features are often confined to the territory
of individual nerves.
• Clinical misdiagnosis as motor neuron disease is possible
because of the predominant motor phenotype and
593
occurrence of fasciculations (see pp.534, 538).
• Serum IgM anti-GM1 ganglioside antibodies are present
in about 40% of patients. The role of anti-GM1
antibodies remains obscure because they are neither
sensitive nor specific to the disease. Alone they do not
mediate conduction block or block sodium channels.
• The diagnostic hallmark is the electrophysiologic
demonstration of multiple, persistent localized sites of
motor conduction block (reduction in amplitude and
area of compound muscle action potential by >50%,
across the block), but sensory conduction remains
normal in the same nerve segments.
• There have been no controlled trials of therapy but many
open studies have reported benefit from intravenous
immunoglobulin (IVIG) and from oral or intravenous
cyclophosphamide therapy.
• IVIG, 2 g/kg (1.0 g/kg on 2 consecutive days, or
2.0 g/kg in 24 hours), is the preferred initial treatment.
It appears to induce short term improvement in up to
80% of patients, but treatment usually needs to be
repeated monthly (which is expensive). Long term IVIG
is effective in maintaining improvement in about 60% of
cases, but it does not eradicate the disease. Prognostic
factors for a response to immunoglobulin treatment
include lower age at onset, lower number of affected
limb regions, creative kinase level <180 U/l, elevated
anti-GM1 antibodies, and definite conduction block.
• Oral cyclophosphamide (1–3 mg/kg/day) may help to
induce a sustained remission but evidence of efficacy is
lacking and its adverse effects are significant. It should,
therefore, be reserved for patients who require frequent
IVIG infusions to maintain improvement. However,
because of the very high cost of IVIG, in practice, several
patients are treated with cyclophosphamide.
• The course is slowly progressive.
Sensory ataxic CIDP
Pure motor CIDP
DIFFERENTIAL DIAGNOSIS
Chronic autoimmune inflammatory neuropathies
• Chronic inflammatory demyelinating polyneuropathy.
• Multifocal motor neuropathy with conduction block.
• Paraproteinemic demyelinating neuropathy.
• Chronic relapsing axonal neuropathy.
Chronic inflammatory neuropathies are distinguished
from other chronic neuropathies by reduced or absent
reflexes, raised CSF protein, usually demyelinating
neurophysiology and lack of a family history.
Other chronic inflammatory neuropathies
• Vasculitis/connective tissue disease (axonal) (see p.597).
• Infection (axonal, demyelinating): leprosy, herpes zoster,
HIV.
Toxins
• Alcohol (axonal).
• Chemicals (axonal): acrylamide, carbon disulfide, heavy
metals.
• Drugs: amiodarone (demyelinating); dapsone, disulfiram,
isoniazid, metronidazole, nitrofurantoin, phenytoin,
platinum, vincristine (axonal).
594 Diseases of the Peripheral Nerve
Metabolic (axonal)
• Diabetes mellitus.
• Acromegaly.
• Myxedema.
• Uremia.
Nutritional deficiencies (axonal)
• Vitamin B12.
• Pyridoxine.
• Thiamine.
• Niacin.
• Folic acid.
Paraneoplastic (axonal, demyelinating)
• Carcinoma.
• Polycythemia rubra vera.
Miscellaneous (axonal)
• Primary amyloidosis.
• Celiac disease.
• Primary biliary cirrhosis.
Hereditary neuropathy (HMSN type 1)
• HMSN type 1 positive genetic test.
CIDP is distinguished from HMSN type 1 by:
• Ability to date the onset of symptoms.
• Positive sensory symptoms (e.g. tingling).
• No pes cavus.
• Palpable nerve thickening (e.g. greater auricular nerve).
• Proximal and distal weakness.
• Raised CSF protein.
• Asymmetric clinical and electrophysiologic findings.
INVESTIGATIONS
CSF
• White cell count: normal.
• Protein: elevated in 50%.
Nerve conduction studies
Slowed conduction, particularly in motor nerves, and there may
be variable degrees of multifocal conduction block. In chronic
and severe cases, the superimposition of axonal degeneration
may make the distinction from axonal neuropathy difficult.
Sural nerve biopsy (733)
• Indicated only if the diagnosis is uncertain, because
unpleasant dysesthesiae may result as an adverse effect.
• Changes are non-specific: chronic demyelination with
relatively little inflammatory infiltrate, or sometimes
axonal change from Wallerian degeneration.
• Increased numbers of macrophages express the inflam-
mation-associated antigens MRP14, 25F9 and MRP8.
MRI of cervical and lumbosacral regions
• May show nerve hypertrophy, sometimes of a massive
degree.
• Increased signal intensity on T2W images and nerve
enlargement correlate with demyelinative foci, and gado-
linium enhancement with disease activity (progression or
relapse), emphasizing the influence of the blood–nerve
barrier. Where the barrier is deficient, significant nerve
hypertrophy is not uncommon suggesting a continuing
process of demyelination and remyelination.
DIAGNOSIS
Diagnostic criteria
• Symptomatic motor or sensory demyelinating polyradicu-
loneuropathy of presumed autoimmune origin, causing
progressive or relapsing weakness of more than one limb.
• Onset extending over 2 months or more (progression
over 2 months distinguishes CIDP from the acute
demyelinating neuropathy of Guillain–Barré syndrome).
• Electrophysiologic (slowing or block of nerve
conduction) or morphologic features of demyelinating
or demyelinated nerve fibers on sural nerve biopsy.
• No detectable alternative cause of neuropathy (e.g.
exclusion of monoclonal gammopathy; HIV infection;
hereditary, metabolic and paraneoplastic disorders; and
ischemic neuropathy).
TREATMENT
First line
• Prednisolone or IVIG is the recommended initial
treatment. A recently published trial comparing oral
prednisolone (tapering from 60 mg to 10 mg daily over
6 weeks) with IVIG (2.0 g/kg given over 1–2 days)
showed slightly, but not significantly, more improvement
after IVIG than prednisolone; the mean difference
between the groups in change in disability grade, being
0.16 (95% CI: –0.35–0.66) (Hughes et al., 2001). For
patients who respond to their first course of treatment
and do not require prolonged medication, IVIG is
associated with slightly more short term efficacy, but
slightly more short term adverse effects than oral steroids
(i.e. the choice of treatment is evenly balanced). For
patients who require long term treatment, IVIG may be
preferable because of the known serious adverse effects
of prolonged steroid treatment.
• Steroids (e.g. prednisolone 120 mg alternate days,
reducing after 2 weeks and over 3 months; or
prednisolone 60 mg each morning [mane] for 2 weeks,
40 mg mane for 1 week, 30 mg mane for 1 week, 20 mg
mane for 1 week, and then 10 mg mane for 1 week) are
usually effective. Osteoporosis prophylaxis should be
considered.
• IVIG 0.4 g/kg/day for 5 days was effective in about
two-thirds of patients in a randomized, double-blind,
placebo-controlled study, but is expensive, invasive and
there are theoretical concerns with its long term safety
(i.e. transmission of infectious agents, as it is a human
blood product). Other regimes (e.g. IVIG on days 1, 2
and 21 in a dose of 1g/kg) have also been shown in trials
to be more effective than placebo. Some patients with
chronic progressive disease have a long lasting remission
after a single course of treatment and patients with
relapsing disease can be maintained and stabilized by a
single treatment before the expected relapse. Other
patients need to be treated every 2–12 weeks. The
precise mechanisms of IVIG action in CIDP are not
known. Anti-idiotypic neutralization of antibodies,
binding of complement, and blockade of macrophages
may prevent the ongoing inflammatory demyelination.
• Plasma exchange (10 exchanges over 4 weeks), is
effective in about 80% of newly diagnosed patients, but
most require long term immunosuppression (usually
azathioprine with or without steroids) for stabilization.
• Plasma exchange and IVIG probably confer equal benefit
in the short term.
 Neuralgic Amyotrophy
Second line
• Azathioprine, cyclophosphamide, cyclosporine A, and
interferon alpha-2a have not been tested in randomized
controlled trials, but have been reported to be effective
in some patients.
• Azathioprine or cyclosporine may sometimes be effective
in resistant cases. Cyclosporine A may be effective in
small maintenance doses of <5 mg/kg, which may avoid
the most serious complication of cyclosporine A, that of
dose-dependent reversible nephrotoxicity. Some patients
have entered long lasting remissions following its use for
a limited period.
• Interferon alpha-2a and interferon-β1a may provide an
alternative therapy for patients who do not respond to
first line therapies but remains to be evaluated in
controlled trials.
• Combinations of steroids and immunoglobulin or
another immunosuppressive agent are commonly used
empirically.
N.B. If treatment fails, the diagnosis should be re-
evaluated and a paraprotein re-sought.
PROGNOSIS
• About 80% of patients respond to treatment, which may
need to be continued for many years.
• About 13% of patients deteriorate sufficiently to become
permanently dependent, bed-bound or chair-bound.
About 87% of prevalent patients are able to walk without
walking aids or other assistance, and 54% are still being
treated.
• About half of patients have a relapsing remitting course.
• The mean duration of the disease amongst prevalent
cases is about 7 years (median 5 years).
733
733 Sural nerve biopsy showing multiple regions of segmental
demyelination.
595
NEURALGIC AMYOTROPHY
DEFINITION
A vague and incompletely understood condition which
affects the brachial plexus on one side, and usually on only
one occasion in life. Many variants exist, such as
involvement of separate nerves, cranial nerves, and even the
lumbosacral plexus; and hereditary and recurrent forms. It
is sometimes called the ‘Parsonage Turner syndrome’,
following its original description in 1948 by Parsonage and
Turner, and ‘brachial plexus neuropathy’.
EPIDEMIOLOGY
• Incidence: 1.64 per 100 000 per year.
• Age: any age.
• Gender: M=F.
PATHOLOGY
Uncertain. Abundant, multifocal mononuclear inflam-
matory cell infiltrates were seen in biopsies of the brachial
plexus in four patients with typical clinical features, but in
whom there was also focal enlargement or enhancement of
lesions on CT or MRI scans of the plexus, or a severe or
progressive course suggesting an alternative possible
malignant disorder.
ETIOLOGY AND PATHOPHYSIOLOGY
• Unknown; possibly an autoimmune reaction to
preceding immunization or infection (high levels of
complement-fixing antibodies against peripheral nerve
myelin have been detected in the acute phase of the
illness in three patients, which fell during subsequent
recovery, compared with 25 controls).
• Most often arises in healthy individuals with no
antecedent events.
• Rarely, inherited as an autosomal dominant disorder
which is heterogeneous genetically (i.e. not all map to
chromosome 17q25).
• Several potential causal factors have been implicated but
remain unproven.
Injection with foreign material
• Preceding vaccination, particularly against tetanus.
• Botulinum toxin A injections.
Infection
• Parvovirus B19 ± CMV.
• Salmonella.
• Leptospirosis.
• Yersiniosis.
Other
• Surgery.
• Parturition.
• Strenuous exercise.
PATHOGENESIS
Focal conduction block plays a significant part in the
pathogenesis of neuralgic amyotrophy, which is generally
regarded as an axon loss process.
596 Diseases of the Peripheral Nerve

CLINICAL FEATURES • Episodes may be precipitated by pregnancy and non-

History
• Usually healthy prior to onset.
• Pain in the shoulder and neck:
– Onset quite sudden, and often in the evening or night.
– Typically severe, deep and sometimes excruciating.
Rarely mild.
– May radiate to the medial part of the scapula or down
the arm to involve the whole arm or part of the upper
arm or forearm.
– Lasts from a few hours to a few weeks; usually several days.
The pain may linger as a dull ache for some time, however.
• Mild numbness may be present over the deltoid muscle
in the rough distribution of the axillary nerve;
paresthesiae occur rarely.
• Severe, and often unilateral, weakness of the muscles of
the shoulder, arm or both develops over a few hours,
frequently overnight, during the pain or more commonly
just after it has mainly subsided. The weakness is maximal
soon after onset, but occasionally it progresses.
Examination
• Early wasting and flaccid weakness of one or any
combination of muscles of the shoulder and arm: serratus
anterior, rhomboids, supra- and infraspinatus, deltoid,
latissimus dorsi, or one or more arm muscles innervated
by major nerves or their branches (734, 735).
• Normal, depressed or absent deep tendon reflexes of the arm.
• Sensory loss is less apparent and, if present, is usually in
the area of innervation of the axillary nerve.
CLINICAL VARIANTS
Involvement of single nerves or their branches
rather than a large part of the brachial plexus
These nerves usually have their origin in the brachial plexus,
e.g.:
• Long thoracic nerve to serratus anterior.
• Suprascapular nerve.
• Axillary nerve.
• Anterior interosseous nerve.
• Lateral antebrachial cutaneous nerve.
• Median nerve trunk.
• Median palmar cutaneous branch.
specific illness, and tend to recur.
• Congenital anomalies, such as syndactyly and hypotelor-
ism, are common in affected members of these families.
Recurrent episodes of neuralgic amyotrophy
Rare.
DIFFERENTIAL DIAGNOSIS
• Guillain–Barré syndrome: usually involves the legs first,
and pain is not commonly severe and prominent.
• Poliomyelitis: the CSF is usually abnormal (unlike
neuralgic amyotrophy).
• Rucksack paralysis: direct mechanical injury to the
brachial plexus from wearing a heavy back pack.
• Compression of the brachial plexus during sleep: unlikely
to cause severe pain.
• Isolated lesions of the long thoracic nerve to serratus
anterior: need to exclude a local cause.
• Radiation therapy: may cause painful lesions of the
brachial plexus but usually a relevant history and scarring,
and slower onset.
• Multifocal motor neuropathy: bilateral, but asymmetric,
painless, and slower in onset.
• Lead poisoning: may cause bilateral brachial neuropathy
but usually painless.
INVESTIGATIONS
Nerve conduction studies
• Motor conduction velocity to proximal muscles may be slow.
• Sensory nerve action potentials may be reduced.
734

In these cases, it has been proposed that the pathology

is probably within the corresponding fascicle of the brachial
plexus rather than a separate trunk of the respective nerve.
However, this would not explain occasional cases with 735
involvement of nerves remote from the brachial plexus such
as the lower cranial nerves (facial nerve, vagus nerve,
recurrent laryngeal nerve, accessory nerve, and cranial
nerves IX, X, XI and XII combined) and the phrenic nerve.

Bilateral involvement
Occurs in about 5–10%, but up to one-third, of cases.

Lumbosacral plexus involvement

Rare.

Familial neuralgic amyotrophy

• Inherited as an autosomal dominant trait. 734, 735 Winging of the right scapula due to neuralgic amyotrophy of
• Associated with a mutation in distal chromosome 17q. the brachial plexus causing weakness of the serratus anterior (supplied
• Genetically distinct from hereditary neuropathy with by the long thoracic nerve). (Courtesy of Dr AM Chancellor,
liability to pressure palsies. Neurologist,Tauranga, New Zealand.)
 Vasculitic Neuropathy
Needle EMG
Usually reveals normal paraspinal muscles and multifocal
axonal lesions within the brachial plexus or its branches, but
can be consistent with an isolated lesion of a peripheral nerve.
MRI brachial plexus
If a local compressive or infiltrative cause is suspected (e.g.
neuroma).
DIAGNOSIS
Typical clinical picture of rather sudden onset of neuropathic
shoulder pain and weakness, supported by EMG studies, and
followed by spontaneous resolution of pain and gradual, but
often incomplete, resolution of weakness.
TREATMENT
• Physiotherapy, particularly passive (and later active) exercises
of the shoulder joint for patients with impaired shoulder
elevation, to prevent a ‘frozen shoulder’ syndrome.
• No effective medical treatment; no convincing evidence
for corticosteroids.
• Therapeutic interventions should perhaps be directed to
patients with persistent conduction block with the aim
of eradicating the block and possibly minimizing
subsequent axon loss. Intravenous immunoglobulin is
worthy of future study.
PROGNOSIS
Pain usually resolves within 1–2 weeks but weakness may not
recover for months or even years. In one series of 99 patients,
one-third had made a functional recovery after one year,
three-quarters after 2 years, and 89% at 3 years. Weakness of
the shoulder muscles had recovered by the end of 1 year in
60% of cases whereas no patient with predominantly lower
plexus involvement recovered normal function.
VASCULITIC NEUROPATHY
DEFINITION
Ischemia and infarction of one or more peripheral nerves
due to vasculitis of the vasa nervorum.
EPIDEMIOLOGY
• Rare.
• Age: any age.
• Gender: M=F.
PATHOLOGY
• Vasculitis of the vasa nervorum (50–300 μm diameter).
• Ischemia and infarction of one or more peripheral nerves.
ETIOLOGY
Primary vasculitis
• Allergic granulomatosis and angiitis (Churg–Strauss
syndrome): a granulomatous necrotizing vasculitis which
predominantly affects the lungs. A prodromal phase of
asthma and eosinophilia commonly precedes the onset
of systemic vasculitis, which may involve one or more
peripheral nerves. Other features include vasculitic rash,
glomerulonephritis and positive anti-neutrophil cyto-
plasmic antibody in 60–70%.
597
• Polyarteritis nodosa: affects medium-sized arteries (e.g.
cerebral, gastrointestinal, renal), and causes peripheral
neuropathy in about half of patients, usually as a
mononeuritis multiplex or symmetric polyneuropathy.
Presents at any age and is twice as common in men than
women. It is characterized commonly by malaise, fever,
weight loss, and tachycardia; and may be associated with
an acute abdomen, vascular event of the brain or heart,
or severe or treated hypertension. Anti-neutrophic
cytoplasmic antibodies are rare, and when present, may
indicate coincident vasculitis of small vessels, and may be
associated with a lupus anticoagulant and alpha1-
antitrypsin deficiency.
• Wegener’s granulomatosis: a systemic necrotizing granu-
lomatous vasculitis of the upper and lower respiratory
tract, with or without glomerulonephritis or arthralgia.
Multiple mononeuropathy or polyneuropathy may occur,
as may cranial neuropathies. Anti-neutrophil cytoplasmic
antibody is positive in 90% of cases.
• Giant cell arteritis (see p.234): may be complicated by
multiple mononeuropathy, as well as mononeuropathy
and polyneuropathy.
Vasculitis associated with systemic
autoimmune disease
• Rheumatoid arthritis: vasculitis may affect small arteries,
arterioles, capillaries, and venules, and often causes few
symptoms. When present, it is associated with long-standing
disease, seropositivity, and florid subcutaneous nodule
formation. Polyneuropathy, and particularly multiple
mononeuropathy, are rare. More common causes are joint
deformities and synovial swellings causing entrapment
neuropathies, and medication-induced neuropathy.
• Sjögren’s syndrome.
• Systemic lupus erythematosus: occasionally presents with
a multiple mononeuropathy or chronic inflammatory
demyelinating polyneuropathy.
Vasculitis associated with other conditions
• Cryoglobulinemia, particularly mixed (often hepatitis C
positive).
• Behçet’s disease: a small vessel vasculitis with mono-
nuclear cell infiltrate in the skin, gastrointestinal ulcers
and the CNS (occasionally), characterized by relapsing
ocular lesions and recurrent oral and genital ulcers,
meningo-encephalitis, and rarely peripheral neuropathy,
usually in the form of multiple mononeuropathy.
• Human immunodeficiency virus (HIV) infection.
• CREST syndrome (calcinosis, Raynaud’s phenomenon,
esophageal dysmotility, sclerodactyly and telangiectasis).
• Non-systemic vasculitis of peripheral nerves.
• Angiitis associated with amphetamine use.
• Paraneoplastic vasculitis: lymphoma, small cell lung
carcinoma.
598 Diseases of the Peripheral Nerve
CLINICAL FEATURES
• Depend on the size and extent of the nerves involved:
– Large nerve infarction: multiple mononeuropathy.
– Smaller nerve infarction: asymmetric sensorimotor
neuropathy.
– Nerve ischemia: distal symmetric sensorimotor neuropathy.
• Onset is typically rapid over several weeks.
• Pain is prominent: deep, aching and neuropathic.
• Symptoms and signs of the underlying disease may or
may not accompany the neurologic deficits.
• Multiple mononeuropathy:
– Several peripheral or cranial nerves become involved, one
after another, within days or weeks.
– Pain, paresthesia, loss of sensation, and muscle weakness
in the dermatomes and myotomes supplied by the
diseased nerve(s).
– As more nerves become involved, the clinical picture
resembles a polyneuropathy.
• Symmetric polyneuropathy: in polyarteritis nodosa and
Wegener’s granulomatosis this pattern is as common as
multiple mononeuropathy.
DIFFERENTIAL DIAGNOSIS
Multiple mononeuropathy
Hematologic disorders
• Acute myeloid leukemia.
• Myelodysplastic syndrome.
• Plasmacytoma.
• Paraproteinemia.
• Waldenström’s macroglobulinemia.
• Lymphoma.
Inflammation/infection
• Meningococcal septicemia.
• Infective endocarditis.
• Cutaneous polyarthritis, in children.
• Non-vasculitis, steroid-responsive form.
• Sarcoidosis (see p.350): a chronic multisystem disease of
unknown cause. There is infiltration of affected tissues
(most commonly lung) by T lymphocytes and mono-
nuclear phagocytes, with formation of non-caseating
epithelioid granuloma. The central and peripheral nervous
system is involved in about 5% of cases, and the peripheral
nervous system alone in about 3%. The most common
neurologic presentation is cranial neuropathy, frequently
involving the facial nerve. The course may be fluctuating,
as with Wegener’s granulomatosis. Peripheral nervous
system involvement is usually as a mononeuropathy
multiplex, which may be accompanied by lesions of the
CNS and cranial nerves, but can also be as a symmetric
polyneuropathy, compressive median neuropathy due to
synovitis, or multifocal sensory neuropathy with large
areas of sensory loss over the trunk.
Other conditions
• Diabetes mellitus.
• Neurofibromatosis.
• Jellyfish stings.
Symmetric sensorimotor neuropathy (see p.579)
Guillain–Barré syndrome (see p.588)
Fulminant forms of vasculitic neuropathy (e.g.
Churg–Strauss syndrome) may present like this.
Mass lesions
Suspect if the affected nerves lies close together.
INVESTIGATIONS
Nerve conduction studies
Normal or mildly decreased nerve conduction velocities,
compound muscle action potentials, and sensory nerve
action potentials in the involved nerves. Conduction block
in a few cases.
EMG
Typical changes of an axonal neuropathy (e.g. denervation
and reinnervation) in most cases.
Blood tests
• ESR
• Antinuclear antibodies.
• Antineutrophic cytoplasmic antibodies.
• Rheumatoid factor.
Tissue biopsy (muscle or sural nerve)
A nerve biopsy (736–738) is essential as a basis for long
term immunosuppression. It is positive in 90% of cases of
vasculitis if the nerve is abnormal neurophysiologically. An
additional muscle biopsy increases the diagnostic yield:
• Eosinophilic infiltrates: suggestive of Churg–Strauss
syndrome.
• Epineurial and endoneurial granulomas, with secondary
demyelination, are diagnostic of sarcoidosis.
DIAGNOSIS
A histologic diagnosis requiring confirmation by tissue biopsy.
TREATMENT
Corticosteroids are the mainstay of treatment despite the
lack of evidence from controlled clinical trials. Steroids
combined with cyclophosphamide are generally required for
severe forms, or those with systemic features of vasculitis.
The drawbacks of cyclophosphamide include opportunistic
infection, gonadal failure and bladder carcinoma (15%). For
patients with giant cell arteritis, steroids should be
continued for many months, or even years; the clinical
features and ESR are useful measures for titration of dosage.
PROGNOSIS
Depends on the cause:
• Polyarteritis nodosa: poor in untreated patients.
Corticosteroid therapy is associated with partial or
complete recovery of neurologic function in about half
of patients over a few months to years.
• Rheumatoid arthritis: outcome varies, and may not be
that bad.
• Systemic lupus erythematosus: tends to recover
spontaneously.
• Wegener’s granulomatosis: peripheral (and cranial) neuro-
pathies may resolve spontaneously over several hours.
• Sarcoidosis: corticosteroids are the treatment of choice
but the response is extremely variable.
• Non-systemic form confined to nerve or nerve and
muscle: much better prognosis and an excellent response
to therapy.
 Herpes Zoster Infection 599

736 HERPES ZOSTER INFECTION

DEFINITION
A predominantly dermatologic condition caused by
reactivation of the varicella-zoster virus which is latent in
nerve cells.

EPIDEMIOLOGY
Varicella-zoster virus is a ubiquitous infectious agent. More
than 90% of the adult population in the western world, and
50% in tropical countries, are infected with the virus.
• Incidence of shingles: 100–225 per 100 000 general
population per year.
• Cumulative incidence: at least 20% of all adults suffer
from zoster at some time.
• Age: any age, but the chances rise with age. 5% of cases
737 occur in children younger than 15 years of age.
• Gender: M=F.

PATHOLOGY
• Dorsal root ganglia: inflammation (mononuclear cell
infiltration) with intranuclear varicella-zoster virus
inclusions in neurons and satellite cells; neuronal loss and
necrosis. Destruction of ganglion cells is prominent in
areas of hemorrhage. Sclerosis occurs months to years
after the acute attack.
• Posterior nerve roots: inflammation, destruction of
myelin and axonal swelling within 1–2 weeks after the
onset of rash, followed by macrophage and fibroblastic
proliferation.
• Posterior columns: myelin breakdown in severe
infections.

738 ETIOLOGY AND PATHOPHYSIOLOGY

• Transmission is largely through inhalation of infectious
aerosols. Direct contact with active varicella or zoster
lesions less often leads to infection.
• Incubation period: 10–21 days.
• Primary infection in the non-immune host is chickenpox.
• Following the acute, often trivial, primary infection, the
virus becomes latent in nerve cells.
• In the immune host, reactivation of the virus results in
zoster, which is predominantly an infection of the skin
(shingles).

Risk factors
• Increasing age.
• Immunosuppression.
• HIV infection.
736–738 Sural nerve biopsy from a patient with ischemic neuropathy
due to polyarteritis nodosa. H&E stain, x100 magnification (736), and
H&E, x400 (737), show infiltration of the arteriolar wall by neutrophils,
and fibrinoid necrosis of the vessel wall as a homogenous pink. Martius
scarlet blue stain for fibrin, x400 (738), shows the fibrin (of the
fibrinoid necrosis) as red.
600 Diseases of the Peripheral Nerve
CLINICAL FEATURES
• Site of involvement of nerve root dermatomes:
– Trigeminal nerve: 12% of patients.
– Cervical: 17%.
– Thoracic: 50%.
– Lumbar: 10%.
– Sacral: 5%.
• Pain, and sometimes paresthesia, in the region of the
involved dermatome may precede the skin eruption by up
to 3 weeks. This may lead to misdiagnosis (e.g. of chole-
cystitis) and inappropriate treatment (e.g. cholecystectomy).
• Skin lesions (vesicular eruption) and sensory loss in the
affected dermatomes (739–742). The vesicles are initially
clear, become turbid, begin to crust within 5–10 days,
and occasionally leave residual scars.
• Low grade fever, general malaise, headache, neck stiffness, and
regional lymphadenopathy may accompanying symptoms.
• In 3–5% of patients with cutaneous zoster, concomitant
infection of the ventral roots at the same level of the
spinal cord lead to weakness of the affected myotome
(‘segmental zoster paresis’).
• Pain usually abates after the skin has healed, but at least
10–20% of patients develop post-herpetic neuralgia.
739
741
739–741 Vesicular skin rash in the distribution of the T5 dermatome,
around the trunk in the mid thoracic level, due to herpes zoster
infection of the right T5 dorsal root ganglia.
COMPLICATIONS
• Aseptic meningitis: some degree is often, although not
always present, particularly in the early stages.
• Encephalitis (see p.292).
• Cerebral infarction via infiltration and arteritis of major
intracranial arteries.
• Brachial plexus neuropathy.
• Myelitis.
• Acute ascending polyradiculopathy.
• Mononeuropathy (median, ulnar, long thoracic,
recurrent laryngeal, or phrenic nerves).
• Post-herpetic neuralgia: point-prevalence in community
studies is about 19% at 1 month, 7% at 3 months, 3% at
1 year, and 1% at 3 years. Usually mild to moderate
severity. Risk factors include increased age (>60 years),
prodrome of dermatomal pain before appearance of rash,
and severity of pain and rash.
INVESTIGATIONS
• Swab and culture infected vesicles.
• Viral serology.
• Electromyography: may show evidence of motor
denervation in paraspinal muscles adjacent to involved
sensory roots, indicating concomitant involvement of
ventral roots (clinically or subclinically).
740
742
742 Vesicular skin rash over the left side of the sacrum in a patient
with a left L5 radiculopathy due to herpes zoster infection.
 Human Immunodeficiency Virus (HIV) Neuropathy 601

TREATMENT HUMAN IMMUNODEFICIENCY VIRUS

Herpes zoster (HIV) NEUROPATHY
Acyclovir
• 800 mg five times a day, orally for 7 days (intravenously if
immunocompromised). DEFINITION
• Speeds healing and reduces the period of pain and skin Peripheral neuropathy (‘neuritis’ in its true sense) caused by
lesions. infection with the human immunodeficiency virus.
• Reduces the incidence of post-herpetic neuralgia.
• Combining acyclovir with oral prednisolone does not EPIDEMIOLOGY
prevent the occurrence of post-herpetic neuralgia. • Prevalence: uncommon; about 1–2% of HIV positive
• A related drug to acyclovir, such as valacyclovir or fam- individuals. Much more common in the late stages of the
ciclovir, is an alternative. As they have better bioavail- disease.
ability, they can be given three times daily. Famciclovir • Age: young adults.
oral 500 mg or 750 mg three times daily, given within • Gender: M≥F.
72 hours of the onset of rash for 7 days, but once- or
twice-daily dosing interval in patients with renal PATHOLOGY
impairment, decreases the duration and symptoms of Acute and chronic inflammatory demyelinating
acute herpes zoster and post-herpetic neuralgia. Adverse polyneuropathy
effects are few. Segmental demyelination.

Post-herpetic neuralgia Distal, symmetric, painful, predominantly sensory

Analgesia axonal neuropathy
• Topical: • The most common peripheral nerve syndrome associated
– Lignocaine gel 5%. with HIV infection, occurring clinically in about one-
– Capsaicin. third of patients late in the disease course, and demon-
– Acetylsalicylic acid (aspirin). strable pathologically in up to 100% of small series (743).
• Oral: tricyclic antidepressants. • A progressive axonal degeneration with endoneurial and
• Parenteral: epineurial inflammation may be found on nerve biopsy.
– Ketamine.
– Narcotics. Sensory ataxic neuropathy
– Intravenous lidocaine. Ganglioneuronitis.
• Nerve blockade/solvents:
– Selective sympathetic or somatic nerve blockade.
– Alcohol.
– Chloroform.
– Low-energy laser.
• Systemic and intralesional corticosteroids: ineffective.

Antiviral therapy
• Famciclovir (500 mg or 750 mg three times a day for
7 days) halves the duration of post-herpetic neuralgia (by
about 2 months on average from 163 days [4 months]
to 63 days [2 months]) in immunocompetent patients,
particularly those over 50 years of age.
• Valaciclovir (valacyclovir).
743
PROGNOSIS
• Herpes zoster infection usually resolves spontaneously
over a week or so, particularly with supplementation in
the form of antiviral agent.
• Recovery from post-herpetic neuralgia occurs in most
cases, but may take up to 2 years.

743 Sural nerve biopsy, teased osmicated preparation, three nerve

fibers. In the upper and middle fibers paranodal demyelination is seen
and in the lowermost fiber there are myelin ovoids indicating Wallerian
degeneration.
602 Diseases of the Peripheral Nerve
Mononeuritis multiplex and progressive
polyradiculopathy
Necrotizing arteritis of the vasa nervorum (744, 745).
Isolated mononeuropathy without apparent local
compression (e.g. facial nerve, median nerve, lateral
cutaneous nerve of thigh, common peroneal nerve)
Iatrogenic dose-related toxic neuropathy
ETIOLOGY AND PATHOPHYSIOLOGY
Acute inflammatory demyelinating polyneuropathy
• A rare event which occurs early in the course of HIV
infection and may represent a reaction to seroconversion.
• Presumed to result from an immune reaction that
transiently causes peripheral demyelination.
• Secondary to perivascular replication of HIV in
infiltrating mononuclear cells.
• Usually recovers completely.
Chronic inflammatory demyelinating
polyneuropathy
May occur at any disease stage, presumably as a result of
immune mediated demyelination.
Distal, symmetric, painful, predominantly sensory
axonal neuropathy
• Etiology unknown.
• Rare in the early stages of infection.
• Clear temporal relation between onset of symptoms or
abrupt change in severity of symptoms and
cytomegalovirus (CMV) infection.
Mononeuritis multiplex and progressive
polyradiculopathy
Usually arise in AIDS patients with CD4 counts <50 and
CMV infection.
Iatrogenic dose-related toxic neuropathy
Due to treatment for HIV with dideoxynucleotides,
particularly ddC.
CLINICAL FEATURES
• Onset especially in the late stages of the disease, when
the CNS is also commonly involved.
744
744, 745 Nerve biopsy showing mild inflammatory cell infiltrate around the veins of the vasa nervorum (744) and marked neutrophil infiltration
(dark, nucleated cells) and fibrinoid necrosis (homogeneous pink substance) of the arteriolar wall of the vasa nervorum (745).
• Several subtypes of peripheral neuropathy: the most
common patterns involve several rather than single nerves.
Acute inflammatory demyelinating polyneuropathy
• Subacute onset over days.
• Progressive motor weakness, beginning in the lower
extremities and ascending.
• Areflexia.
• Variable sensory and autonomic symptoms.
• Some patients progress to respiratory insufficiency
requiring mechanical ventilatory support.
Chronic inflammatory demyelinating
polyneuropathy
• Progressive motor weakness, beginning in the lower
extremities and ascending.
• Areflexia.
• More prominent sensory symptoms than AIDP.
• May follow a progressive or relapsing course over months
Distal, symmetric, painful, predominantly
sensory axonal neuropathy
• Distal symmetric sensory involvement beginning in the
feet and gradually ascending in the legs.
• Severe neuralgic pain; burning or shooting in character.
• Feet are numb, and paresthesiae in upper and lower
limbs are usually present.
• Examination reveals impairment of vibration and pinprick
sensation distally, loss of or diminished angle reflexes with
variable depression of other reflexes and sensory ataxia.
• Motor weakness in distal muscles may be present but this
is overshadowed by the sensory symptoms.
Sensory ataxic neuropathy
Progressive polyradiculopathy
Cauda equina syndrome.
Mononeuritis multiplex
Bilateral radial nerve palsy.
Isolated mononeuropathy without apparent
local compression
• Facial neuropathy.
• Median neuropathy.
745
 Human Immunodeficiency Virus (HIV) Neuropathy
• Lateral cutaneous nerve of thigh neuropathy.
• Common peroneal neuropathy.
DIFFERENTIAL DIAGNOSIS
Acute and chronic inflammatory demyelinating
polyneuropathy (see pp. 589, 593)
Distal, symmetric, painful, predominantly sensory
axonal neuropathy
• Toxic effects of dideoxynucleoside antiretroviral agents,
which may mimic or exacerbate this neuropathy.
• Other potentially neurotoxic agents commonly used in
HIV patients such as dapsone, isoniazid, and vincristine.
• Vitamin B12 deficiency is common in these patients.
• Lymphoma may produce neuralgia by direct invasion or
by paraneoplastic effects.
• Diabetes mellitus.
• Alcoholic neuropathy.
Sensory ataxic neuropathy due to ganglioneuronitis
• Paraneoplastic syndrome.
• Sjögren’s syndrome.
Mononeuritis multiplex
• Vasculitis.
• Herpes zoster infection.
INVESTIGATIONS
CD4 lymphocyte count
Most opportunistic complications appear after significant
immunosuppression has occurred, as reflected by CD4
lymphocyte counts of 200/mm3 or less.
Plasma HIV viral RNA load
Serology
• HIV.
• CMV.
CSF
• Acute and chronic inflammatory demyelinating
polyneuropathy.
• Prominent elevation of CSF protein.
• Moderate lymphocytic pleocytosis, in contrast with the
non-HIV-infected population with acute IDP.
• A polymorphonuclear pleocytosis suggests CMV infection.
Electrophysiologic studies
Acute and chronic inflammatory demyelinating
polyneuropathy:
• Prominent slowing and motor nerve conduction blocks.
• Prolonged or absent F-wave responses.
• Variable degrees of axonal damage and denervation.
Distal, symmetric, painful, predominantly
sensory axonal neuropathy
• Diminished amplitudes and conduction in sural nerves
and variable amplitude decrements in other nerves with
relatively preserved conduction.
• EMG may detect symmetric denervation and
reinnervation.
603
Sural nerve biopsy
Performed if the differential diagnosis includes other
treatable conditions that can be diagnosed by sural nerve
biopsy (see Peripheral neuropathy, pp.579, 583).
TREATMENT
General principles
• Correct any metabolic deficiency and discontinue
potential neurotoxic agents, particularly dideoxynucleo-
sides, if possible.
• Physiotherapy to prevent contracture formation and
improve strength and function.
• Occupational therapy.
• Subcutaneous heparin 5000 U bd and compression
stockings to prevent deep vein thrombophlebitis in non-
ambulatory patients.
• Disabling sensory symptoms (neuralgic pain) may
respond to any of the following:
– Amitriptyline.
– Carbamazepine (starting with 100 mg bd and increasing
by 200 mg weekly to 800–1200 mg/day if tolerated and
needed).
– Diphenylhydantoin (phenytoin) (100 mg tds).
– Gabapentin (300–600 mg tds).
– Mexiletene (mexiletine) (150 mg bd, increasing to 300
mg bd as required), if the above measures fail.
• Narcotic analgesia, if the above measures fail.
Acute inflammatory demyelinating polyneuropathy
• May recover spontaneously.
• If significant motor impairment:
– Plasma exchange totalling 200–250 ml/kg divided in five
exchanges over a 2-week period with 5% albumin
replacement. Or:
– Pooled human immunoglobulin 0.4 g/kg daily for
5 days given as an i.v. infusion at 0.05–4.0 ml/kg/hour
as tolerated.
• Electively intubate patients with impending respiratory
failure (vital capacity <1000 cm3) until adequate
ventilatory function returns.
Chronic inflammatory demyelinating
polyneuropathy
• Maintenance therapy with one treatment every
2–4 weeks of pooled human immunoglobulin (or plasma
exchange). Intervals can be gradually extended as
response occurs.
• Corticosteroid therapy probably should not be used
because of the potential for facilitating opportunistic
infections.
Distal, symmetric, painful, predominantly sensory
axonal neuropathy
• Direct HIV therapy has variable benefit.
• Treat disabling sensory symptoms (neuralgic pain) as
above.
Iatrogenic dose-related toxic neuropathy
Discontinue potential neurotoxic agents, particularly
dideoxynucleosides, if possible.
604 Diseases of the Peripheral Nerve
PROGNOSIS
Mononeuritis multiplex and progressive
polyradiculopathy
Usually progressive unless antiviral treatment with
ganciclovir is given.
Acute inflammatory demyelinating polyneuropathy
Natural history is similar to that of Guillain–Barré syndrome
in the non-HIV-infected population and usually recovers
completely.
Chronic inflammatory demyelinating
polyneuropathy
• Neurologic symptoms may be relapsing or progressive.
• Residual neurologic impairment is common.
Iatrogenic dose-related toxic neuropathy
Toxic symptoms may persist for 6–8 weeks after
discontinuation.
LEPROSY
DEFINITION
An ancient disease caused by the obligate intracellular
parasite Mycobacterium leprae.
EPIDEMIOLOGY
Leprosy occurs mostly in tropical areas of the world, but
also in cooler regions of China, Japan and Korea.
• Incidence: unchanged: 685 000 new patients registered
throughout the world in 1997, many at an early stage of
the disease, and 42% were multibacillary.
• Prevalence: varies among countries, but most cases arise
in developing countries, led by India and Brazil, where
the prevalence is as high as 1% or more. Less than one
million cases registered worldwide in 1998, compared
with 5.4 million in 1985 (probably due to the
introduction of multi-drug therapy [rifampicin
(rifampin), dapsone, and clofazimine] by the World
Health Organization).
• Age: any age.
• Gender: M>F (1.5:1).
CLASSIFICATION
Ridley–Jopling immunologic classification (based on
sensorimotor, skin smear and skin biopsy findings):
• Indeterminate (I).
• Tuberculoid (TT).
• Borderline tuberculoid (BT).
• Mid-borderline (BB).
• Borderline lepromatous (BL).
• Lepromatous (LL).
WHO classification
Paucibacillary leprosy
• ≤5 skin lesions with no bacilli on skin smears.
• Equivalent to I, TT, and BT diseases of Ridley–Jopling
classification.
Multibacillary leprosy
• ≥6 skin lesions and may be skin-smear positive.
• Equivalent to BB, BL, and LL diseases of Ridley–Jopling
classification.
There is a continuous spectrum from paucibacillary or
tuberculoid leprosy (TT) with high cell-mediated immunity
and low acid-fast bacilli counts, to multibacillary or
lepromatous leprosy (LL) with low cell-mediated immunity
and high acid-fast bacilli counts.
ETIOLOGY AND PATHOPHYSIOLOGY
Mycobacterium leprae is the causative bacterium of leprosy.
It is an obligate intracellular parasite which grows best at
27–30°C (81–86°F), hence its predilection for cooler areas
of the body. It is most probably spread by the respiratory
route. Most people are not susceptible to leprosy and after
typical exposure will not develop it. Those who do, after an
incubation period of several years, may have only a single
lesion (indeterminate leprosy), which often self-heals. When
self-healing does not occur and when the single lesion is not
treated, the disease may progress to the paucibacillary or
multibacillary stages.
Those who develop the disease, particularly the
multibacillary type, demonstrate an impaired cell-mediated
immune response to M. leprae. The source of the impaired
immune response is uncertain but probably genetic. M.
leprae selectively enters the small sensory intracutaneous
nerve endings, and leads to granulomatous inflammation
with thickening of the affected nerve or nerves.
Tuberculoid (localized) leprosy
M. leprae often involves only a single nerve, most commonly
the posterior tibial nerve (sensory), the ulnar and median
nerves or the common peroneal nerve. The superficial
branch of the radial nerve is affected only later in the
disease. The bacteria slowly proliferate, spreading from the
intracutaneous nerve endings in a centripetal direction to
thicker parts of the nerve. Eventually motor branches are
also involved. If nerves are infected at well-recognized
entrapment sites (e.g. the carpal tunnel, ulnar groove, and
tarsal tunnel) the nerve may swell leading to secondary
compression and dysfunction.
Lepromatous leprosy
Many bacilli with high infectivity lead to an extensive and
diffuse form of the disease.
CLINICAL FEATURES
Incubation period is at least 3 years and often longer.
History
• The first and major symptoms are altered sensation: pain,
paresthesia and pruritus.
• Patchy hypopigmentation of the skin with analgesia is
commonly, but not always present at an early stage.
 Leprosy 605

Examination Lepromin skin test

• Fusiform and tender thickening/enlargement of one or
more peripheral nerves over part of their course in
superficial locations (e.g. the ulnar nerve at the elbow,
the median and superficial radial cutaneous nerve at the
wrist, the common peroneal nerve at the head of the
fibular, and the greater auricular nerve in the neck).
Detected by brushing the skin carefully with a fingertip.
• Hypopigmented areas of skin may be present, but can be
difficult to detect in whites (746, 747).
• Loss of pain sensation (and often anhidrosis) in the
affected skin areas despite ability to distinguish blunt
from sharp sensations, and preserved position sense and
vibration sense.
• Painless ulcerations of the fingers and toes may be
present if affected.
DIFFERENTIAL DIAGNOSIS
Thickening of nerves
• Hypertrophic forms of hereditary neuropathies: often
other family members are affected because of an
autosomal dominant inheritance.
• Von Recklinghausen’s disease (neurofibromatosis): often
other family members are affected because of an
autosomal dominant inheritance.
• Refsum’s disease (phytanic acid deficiency): autosomal
recessive.
• Amyloidosis.
Utilizes a suspension of killed M. leprae, and is used as a
measure of the cell-mediated immune response, but its
usefulness is limited. It is generally positive in paucibacillary
cases and negative in multibacillary leprosy. A positive
response in normal individuals is associated with a reduced
likelihood of developing the disease.
DIAGNOSIS
• Suspect in any patient with skin lesions, sensory loss
and/or enlarged nerve(s), particularly if an immigrant or
a local returning home after having lived in an endemic
area.
• The diagnosis rests mainly on the skin and peripheral
nerve, but other areas can be affected such as the eyes,
nose and testicles.
• Acid-fast bacilli must be demonstrated for a definitive
diagnosis.
TREATMENT
Multi-drug therapy (rifampicin [rifampin], dapsone, and
clofazimine), administered for a minimum period of 2 years
or until after a skin smear is negative for acid-fast bacilli,
whichever is later, is recommended by the World Health
Organization.

INVESTIGATIONS
Nerve conduction studies 746
May reveal electrophysiologic involvement of other nerves
in cases where only a single nerve is affected clinically.

DNA amplification
Detection of M. leprae in tissue by the polymerase chain
reaction.

Phenolic glycolipid-1 (PGL-1) antibodies

Stained smears of nasal swabs

May detect bacilli (often transmitted by nasal secretions) if
there is diffuse involvement.

Skin smears
• Take from skin lesions and the ears, elbows and/or
knees. 747
• Small slits are made in pinched skin (to avoid bleeding),
the edges of the cut skin are scraped, and the tissue fluid
obtained is smeared on a slide and stained for acid-fast
bacilli. The bacterial index can range from 0 (none found
in 100 oil-immersion fields) to 6+ (over 1000 bacilli per
field).

Skin biopsy
Taken from entirely within a skin lesion, focusing on the
extent and type of infiltrate and involvement of dermal
nerves.

Sensory nerve biopsy

Performed if skin biopsy is uninformative and leprosy is still
suspected. 746, 747 Patchy hypopigmentation of the skin in an Australian
Aboriginal patient with normally pigmented skin and hypopigmented
areas on the skin of the hands (746) and knee (747) due to leprosy.
606 Diseases of the Peripheral Nerve
Single-lesion paucibacillary leprosy
Single dose of rifampicin (rifampin) 600 mg, ofloxacin 400
mg, and minocycline 100 mg (ROM).
Paucibacillary leprosy
Rifampicin (rifampin) 600 mg monthly, supervised, and
dapsone 100 mg daily, unsupervised, for 6 months.
Multibacillary leprosy
Rifampicin (rifampin) 600 mg and clofazimine 300 mg
monthly, supervised; and dapsone 100 mg and clofazimine
50 mg daily, unsupervised, for at least 12 months, if not 24
months.
Adverse effects
Uncommon
• Dapsone: mild hemolytic anemia (can be severe with
glucose-6-phosphate dehydrogenase deficiency), agranu-
locytosis and skin eruptions. Safely taken in pregnancy.
• Clofazimine: gastrointestinal upset and skin pigmentation
(which clears when the drug is discontinued). Safely
taken in pregnancy.
• Rifampicin (rifampin): rarely causes side effects given as
a once monthly dose of 600 mg, but experience in
pregnancy is limited.
PROGNOSIS
If appropriately treated, the average relapse rate is slightly
>1% for paucibacillary cases and <1% for multibacillary cases.
If relapse does occur, the patient should be re-treated with
the same regimen since drug resistance is very unlikely if the
patient’s M. leprae was originally fully sensitive to the drugs
used.
PARAPROTEINEMIC NEUROPATHIES
DEFINITION
A group of neuropathies associated with the presence of
excessive amounts of abnormal immunoglobulins, which are
usually monoclonal serum proteins (termed M protein or
M spike) and are the product of a single clone of plasma
cells.
EPIDEMIOLOGY
• Prevalence: account for 10% of demyelinating
neuropathies and 10% of neuropathies of otherwise
unknown etiology.
• Age: more common in the elderly (i.e. >50 years of age).
• Gender: M>F.
ETIOLOGY
Monoclonal gammopathy of uncertain significance (MGUS)
(most common):
• Comprises two-thirds of patients with paraproteinemic
neuropathy.
• Among patients with MGUS and neuropathy, the
paraprotein is of any immunoglobulin (Ig) class, but is
usually IgM (60%) and sometimes with κ light chains,
and less commonly IgG (30%) and IgA (10%).
• Some paraproteins (mostly polyclonal) react with GM1
gangliosides or disialosyl groups on gangliosides GD1b,
GT1b, and GQ1b.
Systemic disorders
• Multiple myeloma.
• Osteosclerotic myeloma (solitary or multiple plasma-
cytomas), or the POEMS (polyneuropathy, organo-
megaly, endocrinopathy, monoclonal paraproteinemia,
and skin hyperpigmentation) syndrome.
• Waldenström’s macroglobulinemia.
• Amyloidosis.
• Cryoglobulinemia.
• Other lymphoproliferative disorders:
– Non-Hodgkin’s lymphoma.
– Leukemia.
– Castleman’s disease.
– Hypersensitivity lymphadenopathy.
PATHOLOGY (748)
MGUS
• The IgM polyneuropathy is usually of demyelinating type
and predominantly causes large fiber sensory dysfunction.
• Immunocytochemistry may show binding of IgM to
myelin with widening of the interperiod line within
myelin.
• Electron microscopy may show characteristic widening
of external myelin lamellae.
• The IgG polyneuropathy may be an axonal neuropathy,
and there may be antibodies directed against sulfatide or
chondroitin sulfate C, both of which are epitopes on the
axon.
Systemic disorders
Multiple myeloma
• Usually a dying-back peripheral neuropathy with
destruction of both axons and myelin; presumably
primary axonal degeneration with secondary
demyelination.
• Amyloid deposition is present in about one-third of
cases.
• Neoplastic root infiltration occurs rarely.
748
748 Transverse section though a nerve fascicle showing loss of
myelinated fibers and axonal degeneration.
 Paraproteinemic Neuropathies
Osteosclerotic myeloma
• A rare plasma-cell dyscrasia characterized by single or
multiple plasmacytomas that manifest as sclerotic bone
lesions.
• Accounts for 3–5% of myelomas.
• 85% of patients present with a demyelinating
polyneuropathy, with secondary axonal degeneration,
and with or without inflammation.
• The M protein, which is usually IgG or IgA in low
concentration, is present in 90% of cases, and virtually
always with a λ subtype of light chain.
• Essentially the same disease as the POEMS syndrome.
Waldenström’s macroglobulinemia
• Demyelination, but distal axonopathy and sensory
neuropathy occur rarely.
• The IgM paraprotein is derived from lymphocytoid cells
that proliferate in the marrow and lymph nodes, much
the same as in IgM MGUS, from which Waldenström’s
macroglobulinemia may arise.
Amyloidosis
Amyloid polyneuropathies are of two types:
• Inherited amyloidosis-associated neuropathy.
• Primary (non-familial) systemic amyloidosis-associated
neuropathy:
– More common than inherited amyloidosis-associated
neuropathy.
– An M spike is present in serum or urine in 90% of
patients, usually consisting of IgG with a λ light chain or
the light chain alone.
– A symmetric sensorimotor small-diameter sensory fiber
axonal polyneuropathy with amyloid deposition.
Cryoglobulinemia
• Cryoglobulins are proteins (usually IgG or IgM) which
precipitate when cooled, re-dissolve when warmed, and
are deposited as immune complexes in blood vessels.
• The immunoglobulin may be monoclonal, both
monoclonal and polyclonal (mixed essential
cryoglobulinemia), or polyclonal.
• Neuropathy is quite common in patients who have mixed
essential cryoglobulinemia, the type unassociated with
lymphoproliferative diseases, chronic infections, or
autoimmune disorders.
• The neuropathy is a confluence of complete and
incomplete multiple axonal mononeuropathies caused by
vasculitis in numerous nerve fascicles.
PATHOPHYSIOLOGY
• Some of the abnormal immunoglobulins have properties
of antibodies which are directed against components of
the myelin sheath or axolemma.
• Others have an uncertain pathophysiologic role
intermediate between that of proteins associated with
neuropathies and proteins associated with
lymphoproliferative disorders.
• The nerves may also be damaged by deposition of the
amyloid byproduct of the circulating paraprotein.
• Immunoglobulin M antibodies are more likely to be
pathogenic than IgG or IgA.
607
• Myelin associated glycoprotein (MAG) is the most
common target epitope. The carbohydrate epitope on
myelin-associated glycoprotein also reacts with the HNK-
1 epitope and there is shared reactivity with two other
myelin proteins, P0 and PMP-22, and a sulfated
glycosphingolipid sulfate-3-glucuronyl paragloboside.
• A few patients with a sensory form of axonal neuropathy
have autoantibodies (usually IgG) directed against
sulfatide or chondroitin sulfate C, both of which are
epitopes on the axon.
• In the CANOMAD syndrome (chronic ataxic neuropathy,
ophthalmoplegia, M protein, agglutination, anti-disialosyl
antibodies), the antibody binds to human dorsal roots and
dorsal root ganglia and to femoral and oculomotor nerves.
• In osteosclerotic myeloma, the deposition of light chains
in the endoneurium suggests that the paraprotein has a
proximate role in nerve damage. Greatly elevated levels
of proinflammatory cytokines, such as tumor necrosis
factor, have also been implicated.
• In amyloidosis, the pathogenesis of the generalized
sensory neuropathy is uncertain; both a direct toxic effect
of amyloid and vascular insufficiency have been
proposed. Amyloid concentration in the flexor
retinaculum causes carpal tunnel syndrome (see p.630).
CLINICAL FEATURES
Heterogeneous clinical picture.
Peripheral neuropathy associated with MGUS
IgM (usually κ) paraproteinemic neuropathy syndrome with
antibodies to myelin-associated glycoprotein
• A relatively homogeneous subgroup clinically.
• Men, over 50 years of age are principally, but not
exclusively, affected.
• Slowly progressive, predominantly sensory, sensorimotor
demyelinating neuropathy characterized by foot
numbness, paresthesiae, imbalance and gait ataxia
progressing over a few months. Touch, joint position and
vibration sensation in the legs (referable to conduction
in large fibers) are most affected.
• Aching, discomfort, dysesthesiae or lancinating pains
occur in half the patients.
• An upper limb postural tremor is often present.
• Weakness of the distal leg muscles with variable wasting
occurs as the illness advances.
• A few patients have a pure motor disorder.
IgG and IgA paraproteinemic neuropathy syndromes
• More heterogeneous clinical picture.
• Clinical features and response to treatment commonly
resemble CIDP, although a few have a sensory form of
axonal neuropathy.
Neuropathic syndrome due to paraproteins (mostly polyclonal)
which react with GM1 gangliosides
Purely motor syndrome.
Neuropathic syndrome due to paraproteins specific for disialosyl
groups on gangliosides GD1b, GT1b and GQ1b
• Progressive sensory ataxic neuropathy due to altered
position sense.
• CANOMAD syndrome develops in a subgroup of these
patients.
608 Diseases of the Peripheral Nerve
Systemic malignant disorders
(precede or accompany neuropathy)
Multiple myeloma
• Neuropathy is present neurophysiologically in about one-
third of patients, and clinically in about 5–10% of
patients.
• Usually mixed sensorimotor peripheral neuropathy but
purely sensory or relapsing and remitting forms occur.
• Autonomic dysfunction may be present in some patients,
and suggests the presence of systemic amyloidosis.
• Weakness and numbness of the distal limbs appear
subacutely over several weeks, beginning occasionally in
the upper limbs.
Osteosclerotic myeloma, or the POEMS syndrome
Commonly presents with a slowly progressive neuropathy
which is mainly motor and demyelinating, and may be part
of the POEMS syndrome (polyneuropathy associated with
organomegaly, endocrinopathy, M protein, skin thickening
and hyperpigmentation, and clubbing).
Waldenström’s macroglobulinemia
• Sensorimotor neuropathy occurs frequently, very similar
to that which occurs in IgM paraprotein associated
neuropathies of benign type.
• Fatigue, weight loss, and bleeding dominate the clinical
picture.
• Paresthesiae and numbness in the feet are followed by
weakness and wasting of the lower legs, causing foot
drop and a steppage gait, and months later, by arm
weakness.
Amyloid neuropathy
• A symmetric sensorimotor small fiber polyneuropathy is
the presenting feature in 15% of patients.
• Numbness in the feet is the most common presenting symp-
tom, but the signature symptoms are burning and aching
pains with lancinating electric sensations and loss of pain and
temperature sensation in the distal parts of the limbs.
• Autonomic symptoms can be extreme, particularly
postural hypotension, diarrhea (also from infiltration of
the gut wall), impotence and bladder dysfunction.
• Carpal tunnel syndrome is common.
• Systemic symptoms include weight loss, and those
referable to amyloid deposition in other organs, such as
the heart and kidneys.
Cryoglobulinemia
• The most common clinical picture is that of a
progressive, symmetric, distal sensorimotor neuropathy
(due to a confluence of incomplete mononeuropathies)
combined with one or two clearly recognizable
mononeuropathies (e.g. wrist or foot drop).
• The other typical presentation is that of a multiple
mononeuropathy.
• Onset is acute in about one-third of patients who have
multiple mononeuritis.
• Pain is almost always present at onset.
• Paresthesiae and Raynaud’s phenomenon are precipitated
by cold in some patients.
• Weakness may be multifocal or generalized.
DIFFERENTIAL DIAGNOSIS
Chronic inflammatory demyelinating
polyneuropathy (see p.593)
• About one-quarter of patients with CIDP also have a
paraproteinemia (which is of uncertain relevance).
• The cardinal EMG feature of CIDP (a focal block of
electric conduction in motor nerves) sometimes also
occurs in MGUS.
• The CSF protein level is usually elevated in both CIDP
and MGUS.
• Both CIDP and MGUS respond to immunomodulating
treatment.
Multifocal motor neuropathy (see CIDP, p.594):
• A purely motor disorder of middle-aged men,
characterized by slowly progressive, painless weakness
that is asymmetric and confined to one limb.
• Linked to high titers of IgM antibodies directed at GM1
ganglioside on myelin membranes. The circulating
paraprotein is often polyclonal, but monoclonal in 20%
of cases.
• Electric conduction block in the proximal or middle
segments of motor nerves, with normal sensory
conduction in the same nerves.
• 90% of patients respond to immune globulin, but require
repeated infusions.
Motor neuron disease (see p.534)
Multiple myeloma
• Absence of systemic features of myeloma (bone pain,
fatigue, anemia, hypercalcemia, renal insufficiency).
• Smaller amount of paraprotein (<3 g/dl serum, and
usually 0.75–1.5 g/dl).
• Amyloidosis (cf. sensory form of axonal neuropathy that
may occur with IgG MGUS).
INVESTIGATIONS
Nerve conduction studies
IgM paraproteinemic demyelinating neuropathy with anti-
myelin-associated glycoprotein antibodies
• Slowing of motor nerve conduction velocity which is
more distal than proximal.
• Distal motor latencies prolonged representing a marked
distal accentuation of conduction slowing.
• Absence of conduction block.
Multiple myeloma
Neurophysiologic evidence of axonal damage, which may
be severe.
Waldenström’s macroglobulinemia
Neurophysiologic evidence of demyelination, but
occasionally a distal axonopathy or sensory neuropathy.
Amyloid neuropathy
Features of a symmetric sensorimotor small fiber axonal
neuropathy.
Cryoglobulinemia
Neurophysiologic evidence of axonal damage in multiple
nerves.
 Paraproteinemic Neuropathies
Immunoglobulins and serum protein electrophoresis
• Immunoglobulins can be detected by immunoelectro-
phoresis or the more sensitive immunofixation tests.
• The detection of cryoglobulins requires that the blood
specimen is transported to the laboratory in a warm-
water bath.
CSF
CSF protein is often raised, and in osteosclerotic myeloma
the CSF protein is almost invariably elevated to >1 g/l
(>100 mg/dl).
Bone marrow examination or radiologic
skeletal survey
Performed if suspected plasmacytoma or myeloma (e.g.
patients with IgG and IgA paraproteins, particularly if
resistant to treatment).
Nerve biopsy
MGUS: most common
• Immunocytochemistry may show binding of IgM to
myelin with widening of the interperiod line within
myelin.
• To rule out amyloid deposition in patients with sensory
axonal neuropathy due to suspected IgG MGUS.
Amyloid neuropathy
Confirms the diagnosis in 90% of cases.
Biopsy of other tissues
Amyloid neuropathy
Amyloid is detected in biopsies of bone marrow and rectal
mucosa in 70% and 80% of cases, respectively.
TREATMENT
Treatment of the underlying cause may improve the
neuropathy.
MGUS
IgG or IgA MGUS
• Plasma exchange (a total of 220 ml/kg, given in four or
five treatments) has been shown in a controlled trial to
sometimes afford at least short-term benefit within days
or weeks of administration in about one-third of patients.
• Intravenous immunoglobulin in high dose (0.4 g/kg
body weight daily for 5 days) appears to benefit some
patients.
• Corticosteroids, sometimes in combination with
immunosuppressants, may be effective but is more often
ineffective.
• Cyclophosphamide, melphalan, azathioprine, chlorambucil,
fludarabine and interferon-alpha have been used.
• Immunoadsorption (in which IgG and immune
complexes are removed by passing the patient’s blood
through a plastic column containing covalently bound
staphylococcal protein) generally produces only transient
amelioration, and needs to be repeated every few
months.
609
IgM MGUS
• Generally more refractory to treatment than IgG or IgA
MGUS.
• May respond to same regimens as IgG or IgA MGUS,
particularly if chlorambucil or cyclophosphamide is added
in a dose sufficient to reduce the amount of M protein.
• Patients with anti-MAG antibodies generally require
prolonged therapy with monthly plasma exchange and
continuous oral or pulsed intravenous cyclophosphamide.
• Interferon-alpha was beneficial in one trial.
Systemic disorders
Multiple myeloma
Removing the paraprotein by plasma exchange has no
consistent effect on the neuropathy.
Osteosclerotic myeloma
• Treatment of solitary bone lesions (e.g. resection,
focused radiotherapy, or chemotherapy) may stabilize or
improve the neuropathy in about half of patients but the
response may not be forthcoming for several months.
• Plasma exchange is generally ineffective, as in neuropathy
associated with myeloma.
Waldenström’s macroglobulinemia
• Plasma exchange may slow the progression of the
neuropathy.
• Prednisone, melphalan, and chlorambucil may be helpful.
Amyloid neuropathy
• Prednisone and melphalan prolongs survival in a small
proportion of patients for several years but has little effect
on the neuropathy.
• Autologous stem-cell transplantation may stabilize or
improve the condition in a few patients in the short term
at least.
Cryoglobulinemia
• Corticosteroids, cyclophosphamide, and plasma exchange
are variably successful in stabilizing the neuropathy.
• Interferon alpha is promising in cases associated with
hepatitis C.
PROGNOSIS
MGUS
• Usually benign, mild and stable, but about 20% of
patients will in time acquire a malignant plasma-cell
disorder, usually myeloma.
• The syndrome of predominantly sensory neuropathy due
to IgM κ paraprotein with antibodies to myelin-
associated glycoprotein is associated with a benign clinical
course.
• Neuropathies associated with benign paraproteins of the
IgG and IgA class respond better to treatment than those
associated with an IgM paraprotein. However, patients
with IgM paraprotein neuropathies may improve after
plasma exchange or intravenous immunoglobulin,
particularly when used in association with
cyclophosphamide or chlorambucil.
• In patients with polyneuropathy associated with IgM
monoclonal gammopathy, antibody tests to MAG (myelin-
associated glycoprotein) SGPG (sulfoglucuronyl para-
globoside), and sulfatide do not have prognostic value.
610 Diseases of the Peripheral Nerve
DIABETIC NEUROPATHY
DEFINITION
Neuropathic complications of diabetes mellitus.
EPIDEMIOLOGY
• Incidence: 54 (95% CI: 33–83) per 100 000 per year.
• Lifetime prevalence: 2 (95% CI: 1–3) per 1000
population. One of the most common causes of
peripheral neuropathy:
– At the time of diagnosis, 8% of non-insulin dependent
diabetics have definite or probable neuropathy, compared
with 2% of an age-and sex matched control population.
– After 10 years of follow-up, the prevalence of neuropathy
increases to 42% among diabetic patients and to 6% in
controls.
– At any one time, about 34% of insulin dependent
diabetics and 26% of non-insulin dependent diabetics
have distal symmetric polyneuropathy; and 58% of insulin
dependent diabetic patients aged 30 years or more have
distal symmetric polyneuropathy
– At any one time, about 17% of diabetics have at least one
abnormal test of autonomic function but, besides erectile
dysfunction, only 2.4% report symptoms attributable to
autonomic dysfunction.
• Age: adults, increases with duration of diabetes.
• Gender: M=F.
PATHOLOGY
Axonal degeneration of nerve fibers of all sizes, both
myelinated and unmyelinated.
ETIOLOGY AND PATHOPHYSIOLOGY
• Diabetes renders nerves vulnerable to injury and may also
involve the vasa nervorum.
• Hyperglycemia play a central role in the pathogenesis of
diabetic peripheral neuropathy.
Risk factors for neuropathy
• Poor glycemic control.
• Duration of diabetes.
• Age.
• Height.
• Male gender.
• Alcohol consumption.
Risk factors for neuropathy in insulin-
(but not non-insulin) dependent diabetics
• Systemic hypertension.
• Cigarette smoking.
• Hyperlipidemia.
CLINICAL SYNDROMES
Onset
May be acute, but more commonly insidious.
Rapidly reversible phenomena
Hyperglycemic neuropathy
• Presumably related directly to hyperglycemia or to a
metabolic abnormality correlated with it (e.g. hypoxia, a
switch to anerobic glycolysis in the diabetic nerve).
• Patients with severe uncontrolled hyperglycemia.
• Uncomfortable sensory symptoms, mainly in the legs.
• Nerve conduction velocity is reduced.
• Rapidly corrected by establishing diabetic control.
Generalized polyneuropathies
Distal symmetric predominantly sensory
(and motor) axonal polyneuropathy
• The most common type of diabetic neuropathy.
• Very common in diabetes, particularly with poorly
controlled disease of long duration.
Pathology: a distal axonal degeneration of dying back type
with relative preservation of dorsal root ganglion cells (749).
This may well be a central-peripheral distal axonopathy in
which there is also a rostral degeneration of nerve fibers in
the dorsal columns of the spinal cord. An important aspect
is a failure of axonal regeneration, which probably
contributes to the lack of reversibility of the neuropathy once
it is established, even with good glycemic control.
Pathophysiology: it remains to be established whether the
mechanism is a direct metabolic effect or whether it is
secondary to hypoxia from microvascular disease. A major
metabolic abnormality in nerve is the accumulation of
sorbitol because of increased flux in the polyol pathway
secondary to hyperglycemia. The sorbitol in diabetic nerve
is not sufficient in quantity to produce osmotic damage but
it is possible that it may have deleterious effects on neural
metabolism. However, trials with aldose reductase inhibitors
that reduce the production of sorbitol have failed so far to
show any substantial effects on diabetic polyneuropathy.
Other possible metabolic disturbances of relevance include
alterations in the metabolism of essential fatty acid and non-
enzymatic glycation of proteins.
Clinical: distal symmetric predominantly sensory (and
motor) loss characterized by sensory impairment in a glove
and stocking distribution and distal motor weakness. The
sequelae of longstanding severe distal sensory loss, such as
neuropathic joints, may be present (750).
Treatment: strict control of blood glucose concentrations
by an insulin pump or multiple daily insulin injections can
prevent or greatly diminish the risk of developing
neuropathy. This treatment however, is only applicable to
patients with type I insulin-dependent diabetes and only a
small proportion of them. Good glycemic control can only
be achieved in practice in about 25% of patients. Once
DSSP is established, it fails to improve significantly even
with satisfactory glycemic control. Treatment is therefore
required that will prevent the occurrence of neuropathy or
halt its deterioration if present.
Prognosis: after 25 years of diabetes, about half will have
developed neuropathy. Further research is required to help
identify, perhaps by genetic markers, those patients who are
more susceptible to developing neuropathy.
Autonomic neuropathy
• Symptoms include nocturnal diarrhea, postural
hypotension and syncope.
• Mild degrees are common in both type I and type II
diabetes, but severe forms are virtually only encountered
in type I diabetic patients.
 Diabetic Neuropathy
Acute painful sensory neuropathy
• Uncommon.
• Mechanism: uncertain.
• Severe burning or aching pain, mainly in the legs but
sometimes more widespread.
• Precipitants include treatment with insulin.
• Examination reveals intense cutaneous contact
hyperesthesia but only mild sensory loss.
• May be associated with uncontrolled hyperglycemia and
precipitous weight loss.
• Nerve biopsy shows acute axonal degeneration.
• Prognosis: resolves over several months with adequate
glycemic control.
Focal and multifocal neuropathies
More common in diabetics than in the general population.
Pathogenesis
The abrupt onset of a diabetic IIIrd cranial nerve palsy is
consistent with an ischemic basis and this has been
supported by sound pathologic studies. The pathology is a
focal demyelination, accounting for the usually satisfactory
recovery that occurs, presumably by remyelination.
Although nerve ischemia usually gives risk to axonal loss
rather than segmental demyelination, it is possible that
demyelination in focal diabetic lesions is the result of
reperfusion injury (which is known to produce
demyelination).
749
749 Teased nerve fiber (osmium tetroxide) showing segmental
demyelination(yellow axons [myelin normally appears black]) and active
Wallerian degeneration due to focal interruption of axons (numerous
myelin ovoids which appear as black blobs).
611
Other focal peripheral nerve lesions are likely to result
from an abnormal susceptibility of diabetic nerve to
compression. The reasons for this is uncertain, but in non-
diabetic individuals entrapment neuropathies are related to
longitudinal axoplasmic displacement away from the site of
compression and the consequent distortion and breakdown
of the myelin sheath of larger myelinated fibers. The basal
lamina surrounding nerve fibers is known to be abnormally
rigid in patients with diabetic neuropathy, possibly due to
increased cross linking of collagen because of abnormal
glycation related to advanced glycation end product (AGE)
formation.
In some patients with proximal lower limb diabetic
neuropathy, inflammatory lesions, including vasculitis,
affecting small epineurial vessels, are present in peripheral
nerves, raising the possibility of a superimposed auto-
immune process.
Cranial neuropathies
The IIIrd and VIIth cranial nerves are affected particularly.
Thoracoabdominal radiculoneuropathy
750
750 Deformed (Charcot) ankle joints in a patient with distal
symmetric sensory neuropathy due to diabetes.
612 Diseases of the Peripheral Nerve

Focal limb mononeuropathies (including entrapment
and compression neuropathies)
• Located at the well-known sites of entrapment or
external compression, and commonly involve the median
nerve at the wrist (751) and ulnar nerve at the elbow.
Other common sites are the radial and peroneal nerves
(as in patients without diabetes), as well as the superficial
branch of the radial nerve (cheiralgia paresthetica).
• Symptomatic carpal tunnel syndrome is found in about
11% of patients with diabetes mellitus (751).
• Not uncommonly superimposed on a polyneuropathy,
which may be symptomatic or asymptomatic and only
evidenced from nerve conduction studies. A coexistent
polyneuropathy is found in about 80% of diabetics with
an ulnar nerve palsy, and about 20% of diabetics with
carpal tunnel syndrome.
• Frequently it is difficult to determine whether the cause
is external pressure or intrinsic focal nerve ischemia or
infarction secondary to occlusion of small blood vessels
supplying the nerve.
• Femoral neuropathy is not caused by entrapment.
• Acute painless peroneal neuropathy: usually caused by
compression to at least some degree in diabetics.
• Brachial plexus neuropathy:
– Unilateral or bilateral.
– May be associated with a typical radiculo-plexopathy of
the legs (symmetric or asymmetric) and a background
generalized sensorimotor polyneuropathy.
– Onset: subacute or gradual.
Proximal diabetic neuropathy (diabetic amyotrophy,
‘diabetic radiculo-plexopathy’, ‘lower limb asymmetric
motor neuropathy’)
• Acute, painful, unilateral or asymmetric proximal leg
weakness with particular involvement of the sensorimotor
territory of the L2–L4 nerve roots (weakness of hip
flexion and knee extension, absent knee jerk, and
numbness of the anterior thigh and leg).
• Onset in middle-aged or elderly diabetics.
• May be the first manifestation of diabetes.
• May arise in patients with diabetes that is mild and well
controlled.
751
• May occur against a background of a chronic, symmetric
polyneuropathy.
• Severe pain in the anterior thigh may be present at onset.
• Weakness of the quadriceps and iliopsoas is most marked,
but the adductor muscles (obturator nerve) may also be
weak.
• Absent knee jerk.
• Sensory deficits are rare.
• Weight loss is usual.
• Differential diagnosis includes autoimmune vasculitis:
MRI scan showing enhancement of the lumbar nerve
roots suggests autoimmune vasculitis rather than diabetes
as the cause.
• Nerve conduction studies and EMG usually show
features consistent with axonal degeneration of the
lumbar spinal nerve roots.
• Pathologic studies show inflammatory change or small
infarcts in the lumbosacral plexus and trunks of the
femoral and other (e.g. obturator) nerves.
• Treatment is symptomatic although steroids have been
used in severe cases despite the diabetes.
• At least some degree of recovery begins within weeks of
onset and continues over 12–18 months; if no
improvement at all has occurred after several months the
diagnosis is in doubt.
• Recovery is incomplete in nearly half of patients.
Superimposed chronic inflammatory demyelinating
polyneuropathy
• CIDP is more frequent in diabetics.
• A secondary autoimmune process may be responsible.
DIFFERENTIAL DIAGNOSIS
Predominantly sensory neuropathies
• Diabetes.
• Thiamine deficiency.
• Malignancy.
• Leprosy.
• Hereditary sensory neuropathies.
• Amyloid.
• Uremia.
Predominantly motor neuropathies
• Guillain–Barré syndrome.
• Porphyria.
• Diphtheria.
• Botulism.
• Lead.
• Charcot–Marie–Tooth disease.
• Disorders of the neuromuscular junction or muscle.

INVESTIGATIONS
• Nerve conduction studies: a more pronounced decrease
in sensory and motor compound action potential
amplitudes than in nerve conduction velocities,
consistent with axonal degeneration.
• Blood glucose: fasting.
• Hemoglobin A1C.
• Nerve biopsy if the diagnosis remains uncertain.

DIAGNOSIS
A typical clinical and neurophysiologic profile in a diabetic
751 Wasting of the left abductor pollicis brevis muscle (arrow) in a patient, after excluding differential diagnoses.
patient with a median neuropathy at the wrist due to diabetes.
 Further Reading 613

TREATMENT PROGNOSIS
• Good diabetic control probably prevents the develop- • Depends on the intensity of glycemic control.
ment of neuropathy. • Poor glycemic control and low plasma concentrations of
• Pancreatic transplantation may relieve the progression. insulin independent of concentrations of glucose are
• Aldose reductase inhibitors do not appear to be effective. associated with increased risk of development and
• Recombinant human nerve growth factor 0.1µg/kg was progression of neuropathy.
not effective in a recently published randomized • Autonomic neuropathy in diabetes probably carries a
controlled trial involving 1019 patients with diabetic poor prognosis (i.e. increased risk of death).
polyneuropathy.
• Intravenous immunoglobulin may be helpful for diabetic
amyotrophy, but controlled trials are needed.
• Painful neuropathy may respond to tricyclic
antidepressants; gabapentin 900 mg/day is probably
ineffective or only minimally effective.

HEREDITARY NEUROPATHIES CHRONIC INFLAMMATORY

FURTHER READING
PERIPHERAL NEUROPATHY
Epidemiology
MacDonald BK, Cockerell OC, Sander JWAS,
Shorvon SD (2000) The incidence and life-
time prevalence of neurological disorders in a
prospective community-based study in the
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Martyn CN, Hughes RAC (1997) Epidemiology
of peripheral neuropathy. J. Neurol. Neurosurg.
Psychiatry, 62: 310–318.
Etiology
Bird SJ, Rich MM (2000) Neuromuscular com-
plications of critical illness. The Neurologist, 6:
2–11.
Subtypes
Bryer MA, Chad DA (1999) Sensory neu-
ronopathies. The Neurologist, 5: 90–100.
Holland NR, Crawford TO, Hauer P, et al.
(1998) Small-fibre sensory neuropathies: clin-
ical course and neuropathology of idiopathic
cases. Ann. Neurol., 44: 47–59.
Windebank AJ, Blexrud MD, Dyck PJ, Daube JR,
Karnes JL (1990) The syndrome of acute sen-
sory neuropathy: clinical features and electro-
physiologic and pathologic changes. Neur-
ology, 40: 584–591.
Investigation
Gabriel CM, Howard R, Kinsella N, et al. (2000)
Prospective study of the usefulness of sural
nerve biopsy. J. Neurol. Neurosurg. Psychia-
try, 69: 442–446.
McLeod JG (1995) Investigation of peripheral
neuropathy. J. Neurol. Neurosurg. Psychiatry,
58: 274–283.
Said G (2001) Value of nerve biopsy? Lancet, 357:
1220–1221.
Wolfe GI, Nations SP (2001) Guide to autoanti-
body testing in peripheral neuropathies. The
Neurologist, 7: 195–207.
Management
Hughes RAC (2000) Management of chronic pe-
ripheral neuropathy. Proc. R. Coll. Physicians
Edin., 30: 321–327.
De Jonghe P, Timmerman V, Nelis E, et al.
(1999) A novel type of hereditary motor and
sensory neuropathy characterised by a mild
phenotype. Arch. Neurol., 56: 1283–1288.
Lupski JR (2000) Recessive Charcot-Marie-Tooth
disease. Ann. Neurol., 47: 6–8.
HEREDITARY MOTOR AND SENSORY
NEUROPATHY
Kamholz J, Menichella D, Jani A, et al. (2000)
Charcot-Marie-Tooth disease type 1. Molecu-
lar pathogenesis to gene therapy. Brain, 123:
222–233.
HEREDITARY NEUROPATHY WITH
LIABILITY TO PRESSURE PALSIES
Duborg O, Mouton P, Brice A, et al. (2000)
Guidelines for diagnosis of hereditary neu-
ropathy with liability to pressure palsies. Neu-
romuscular Disorders, 10: 206–208.
GUILLAIN–BARRÉ SYNDROME
Feasby TE, Hartung H-P (2001) Drain the roots.
A new treatment for Guillain–Barré syndrome.
Neurology, 57: 753–754.
Hahn AF (1998) Guillain-Barré syndrome.
Lancet, 352: 635–641.
Hartung H-P (1999) Infections and the Guillain-
Barré syndrome. J. Neurol. Neurosurg. Psychi-
atry, 66: 277.
Hughes RAC, Gregson NA, Hadden RDM,
Smith KJ (1999) Pathogenesis of
Guillain–Barré syndrome. J. Neuroimmunol.,
100: 74–97.
Hughes RAC (2001) Sensory form of Guil-
lain–Barré syndrome. Lancet, 357: 1465.
Logina I, Donaghy M (1999) Diphtheritic
polyneuropathy: a clinical study and compari-
son with Guillain-Barré syndrome. J. Neurol.
Neurosurg. Psychiatry, 67: 433–438.
Oh SJ, La Ganke C, Claussen GC (2001) Sen-
sory Guillain–Barré syndrome. Neurology, 56:
82–86.
Seneviratne U (2000) Guillain-Barré syndrome.
Postgrad. Med. J., 76: 774–782.
Wollinsky KH, Hülser P-J, Brinkmeier H, et al.
(2001) CSF filtration is an effective treatment
of Guillain–Barré syndrome. A randomized
clinical trial. Neurology, 57: 774–780.
DEMYELINATING POLYNEUROPATHY
Duarte J, Martinez AC, Rodriguez F, et al. (1999)
Hypertrophy of multiple cranial nerves and
spinal roots in chronic inflammatory demyeli-
nating neuropathy. J. Neurol. Neurosurg. Psy-
chiatry, 67: 685–687.
Dyck PJ, Dyck PJB (2000) Atypical varieties of
chronic inflammatory demyelinating neu-
ropathies. Lancet, 355: 1293–1294.
Haq RU, Fries TJ, Pendlebury WW (2000)
Chronic inflammatory demyelinating
polyradiculoneuropathy. A study of proposed
electrodiagnostic and histologic criteria. Arch.
Neurol., 57: 1745–1750.
Hughes R, Bensa S, Willison H, et al. (2001) Ran-
domized controlled trial of intravenous im-
munoglobulin versus oral prednisolone in
chronic inflammatory demyelinating
polyradiculoneuropathy. Ann. Neurol., 50:
195–201.
McLeod JG, Pollard JD, Macaskill P, et al. (1999)
Prevalence of chronic inflammatory demyeli-
nating polyneuropathy in New South Wales,
Australia. Ann. Neurol., 46: 910–913.
Mendell JR, Barohn RJ, Freimer ML, et al. (2001)
Randomised controlled trial of IVIg in un-
treated chronic inflammatory demyelinating
polyradiculoneuropathy. Neurology, 56:
445–449.
Pestronk A (1998) Multifocal motor neuropathy:
Diagnosis and treatment. Neurology, 51
(Suppl 5): S22–S24.
Van den Berg-Vos RM, Franssen H, Wokke JHJ,
et al. (2000) Multifocal motor neuropathy:
Diagnostic criteria that predict the response to
immunoglobulin treatment. Ann. Neurol., 48:
919–926.
VASCULITIC NEUROPATHY
Moore PM (2000) Vasculitic neuropathies. J.
Neurol. Neurosurg. Psychiatry, 68: 271–276.
HERPES ZOSTER INFECTION
Choo PW, Galil K, Donahue JG, et al. (1997)
Risk factors for post herpetic neuralgia. Arch.
Intern. Med., 157: 1217–1224.
Cunningham AL, Dworkin RH (2000) The man-
agement of post-herpetic neuralgia. BMJ, 321:
778–779.
614
Helgason S, Petursson G, Gudmundsson S, Sig-
urdsson JA (2000) Prevalence of postherpetic
neuralgia after a first episode of herpes zoster:
prospective study with long term follow up.
BMJ, 321: 794–796.
Tyring S, Barbarash RA, Nahlik JE, et al., and the
Collaborative Famciclovir Herpes Zoster Study
Group (1995) Famciclovir for the treatment
of acute herpes zoster: effects on acute disease
and postherpetic neuralgia. A randomized,
double-blind, placebo-controlled trial. Ann.
Intern. Med., 123: 89–96.
Wood MJ, Johnson RW, McKendrick MW (1994)
A randomized trial of acyclovir for 7 days or
21 days with or without prednisolone for
treatment of acute herpes zoster. N. Engl. J.
Med., 330: 896–900.
Wood MJ, Kay R, Dworkin RH, Soong SJ, Whit-
ley RJ (1996) Oral acyclovir therapy acceler-
ates pain resolution in patients with herpes
zoster: a meta-analysis of placebo-controlled
trials. Clin. Infect. Dis., 22: 341–347.
LEPROSY
Croft RP, Nicholls PG, Steyerberg EW, et al.
(2000) A clinical prediction rule for nerve-
function impairment in leprosy patients.
Lancet, 355: 1603–1606.
Hietaharju A, Croft R, Alam R, et al. (2000)
Chronic neuropathic pain in treated leprosy.
Lancet, 356: 1080–1081.
Diseases of the Peripheral Nerve
Jacobsen RR, Krahenbuhl JL (1999) Leprosy.
Lancet, 353: 655–660.
Young D (2001) Leprosy and the genome – not
yet a burnt-out case. Lancet, 357: 1639–1640.
NEURALGIC AMYOTROPHY
Lo Y-L, Mills KR (1999) Motor root conduction
in neuralgic amyotrophy: evidence of proximal
conduction block. J. Neurol. Neurosurg. Psy-
chiatry, 66: 586–590.
Watts GDJ, O’Briant KC, Borreson TE, et al.
(2001) Evidence for genetic heterogeneity in
hereditary neuralgic amyotrophy. Neurology,
56: 675–678.
PARAPROTEINEMIC NEUROPATHIES
Eurelings M, Moons KGM, Notermans NC
(2001) Neuropathy and IgM M-proteins.
Prognostic value of antibodies to MAG,
SGPG, and sulfatide. Neurology, 56: 228–233.
Natov N (1995) Pathogenesis and therapy of neu-
ropathies associated with monoclonal gam-
mopathies. Ann. Neurol., 37 (Suppl 1):
S32–S42.
Pollard JD, Young GAR (1997) Neurology and
the bone marrow. J. Neurol. Neurosurg. Psy-
chiatry, 63: 706–718.
Ropper AH, Gorson KC (1998) Neuropathies as-
sociated with paraproteinaemia. N. Engl. J.
Med., 338: 1601–1606.
DIABETIC NEUROPATHY
Apfel SC, Schwartz S, Adornato BT (2000) Effi-
cacy and safety of recombinant human nerve
growth factor in patients with diabetic
polyneuropathy. A randomized controlled
trial. JAMA, 284: 2215–2221.
Courtney AE, McDonnell GV, Patterson VH
(2001) Human immunoglobulin for diabetic
amyotrophy – a promising prospect? Postgrad.
Med. J., 77: 326–328.
Gorson KC, Schott C, Herman R, et al. (1999)
Gabapentin in the treatment of painful dia-
betic neuropathy: a placebo controlled, dou-
ble blind, cross over trial. J. Neurol. Neurosurg.
Psychiatry, 66: 251–252.
MacDonald BK, Cockerell OC, Sander JWAS,
Shorvon SD (2000) The incidence and life-
time prevalence of neurological disorders in a
prospective community-based study in the
UK. Brain, 123: 665–676.
Thomas PK (1999) Diabetic neuropathy: mecha-
nisms and future treatment options. J. Neurol.
Neurosurg. Psychiatry, 67: 277–281.
 Chapter Twenty-two 615

Mononeuropathies
DORSAL SCAPULAR NERVE (TO ANATOMY
RHOMBOIDS) NEUROPATHY Course of the dorsal scapular nerve (to rhomboids):
• Arises from the upper trunk of the brachial plexus (752),
carrying fibers from the C4 and C5 nerve roots.
DEFINITION • Pierces the medial scalenus muscle.
Dysfunction of the dorsal scapular nerve to rhomboids. • Innervates the levator scapulae, which elevates the
scapula.
EPIDEMIOLOGY • Courses along the medial border of the scapula to
Uncommon. innervate the rhomboids, which adduct the medial
border of the shoulder blade.

752

Dorsal scapular nerve to rhomboids

Nerve to subclavius
C4
Long thoracic nerve to serratus anterior
Suprascapular nerve to supraspinatus and infraspinatus C5
Lateral cord C6

C7
Pectoralis minor
Posterior cord T1
Musculocutaneous nerve
Axillary nerve T2
Short head of biceps
Coracobrachialis Scalenus anterior
Medial pectoral nerve
Lateral pectoral nerve
Radial nerve
Median nerve Medial cord
Ulnar nerve
Subscapular nerves
Medial cutaneous nerve of forearm to subscapularis and
Medial cutaneous nerve of arm teres major

Thoracodorsal nerve
to latissimus dorsi

752 Diagram of the brachial plexus. (Adapted from Aids to examination of the peripheral nervous system (1986). Baillière Tindall, London.)
616 Mononeuropathies

ETIOLOGY LONG THORACIC NEUROPATHY

• Neuroma (753, 754).
• Neuralgic amyotrophy may involve the dorsal scapular
nerve. DEFINITION
• No descriptions of isolated entrapment or other Dysfunction of the long thoracic nerve to serratus anterior.
compressive lesions.
EPIDEMIOLOGY
EXAMINATION Uncommon.
Stand behind the patient and ask the patient to put their
hand behind their back, face the palm of the hand ANATOMY
backwards, and to push backwards against the resistance of Course of the long thoracic nerve to
your hand. The muscle bellies of the rhomboids can be felt serratus anterior
medial to the medial border of the scapula and sometimes • Arises from the motor roots of C5, C6 and commonly
seen (755). also from C7.
• Courses downward through and in front of the medial
DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS, scalenus muscle, and descends further dorsal to the
TREATMENT AND PROGNOSIS brachial plexus, along the medial wall of the axilla and
As for neuralgic amyotrophy (see p.595). innervates the serratus anterior muscle.

ETIOLOGY
• Inherited brachial plexus neuropathy: rare.
• Trauma:
– Carrying heavy loads on the back (‘rucksack paralysis’).
– Pushing loads above the head.
– Fall on outstretched arms.
– Trauma to shoulder or lateral part of the chest.
• Athletic activities:
753 – Archery.
– Ballet.
– Volleyball.
• Surgery to the chest wall:
– Transaxillary breast augmentation.
– Axillary node dissection (malignant melanoma, breast
carcinoma).
– Thoracostomy for pneumothorax.
– Scalenotomy and cervical/first rib resection for thoracic
outlet syndrome.
• Chiropractic manipulation.
• Neuralgic amyotrophy (see p.595): often involves
additional nerves.
• Borrelia infection (Lyme disease): rare.
• Radiation therapy: for breast cancer.

HISTORY
754 • Difficult elevating the upper arm (e.g. shaving or
combing hair).
• Dull shoulder ache, mainly because of strain on the
shoulder muscles and ligaments in the absence of the
serratus anterior muscle tightening the scapula against
the rib cage.

EXAMINATION
• Stand behind the patient and inspect for winging of the
scapula, which may be present in the resting position.
Then, ask the patient to push against a wall with both
arms slightly flexed at the elbow, or elevate the arms to
a forward position.
• Weakness is indicated by winging of the scapula on the
affected side(s) (and sometimes also abduction of the
arm) (735, 756).
753, 754 T1W coronal pre- (753) and T1W coronal post contrast
(754) MRI of the brachial plexus showing a neuroma. Note the
discrete mass closely related to the nerves in the left supraclavicular
fossa which enhances following contrast (arrows).
 Long Thoracic Neuropathy
• If weakness is so severe that the patient cannot flex the
extended arm at the shoulder, do this for the patient and
then ask the patient to push the fist forward against your
other hand. Look for winging of the scapula during this
maneuver.
• Elevation of the arm may become possible if you press
the patient’s scapula against the chest wall, and thereby
take over the function of the paralysed serratus anterior.
DIFFERENTIAL DIAGNOSIS
• C6 or C7 radiculopathy: but usually additional weakness
of extensors of the arms, wrist or fingers.
• Myopathy: weakness is usually bilateral and involving
additional muscles of the shoulder and upper arm.
• Disruption of the serratus anterior muscle:
– Rheumatoid arthritis.
– Fracture of the scapula.
• Trapezius muscle weakness: may also cause winging of
the scapula (upper part), particularly on abduction of the
arm.
INVESTIGATIONS
Nerve conduction studies
Motor latencies from stimulation at Erb’s point to the
serratus anterior may be prolonged.
EMG
• Place your (the examiner’s) index finger and ring finger
in the intercostal spaces on either side of the fifth (or
sixth) rib between the anterior and middle axillary lines
(to avoid puncture of the intercostal muscles and pleura)
and introduce the needle electrode between these fingers
at an acute angle until it touches the rib, and then
withdraw it slightly.
755
Patient
Examiner
755 The patient is pressing the palm of the hand backwards against
the examiner’s hand.The muscle bellies of the rhomboids (arrow) can
be felt and sometimes seen.
617
• If there has been axonal damage more than 2–3 weeks
previously, spontaneous muscle fiber potentials in the
form of fibrillation potentials, positive sharp waves, or
both may be seen and heard (‘denervation activity’).
During voluntary contraction, there will be poor
recruitment of motor units, and a reduction in the EMG
pattern. If partial denervation is followed by collateral re-
innervation, enlarged and polyphasic motor unit
potentials (MUPs) will be seen. Recent re-innervation is
characterized by polyphasic MUPs with unstable
configuration.
• The EMG features of degeneration are only present in
the muscles innervated by the nerve.
TREATMENT
• Conservative.
• Surgical stabilization of the scapula:
– Wait until at least 2 years have elapsed before even
considering surgery (i.e. await spontaneous recovery).
– Shoulder function usually remains impaired despite the
operation.
– The fixation may give way after several years.
PROGNOSIS
• Depends on the cause and severity of the neuropathy.
• Usually recovers spontaneously in most patients with
neuralgic amyotrophy or partial traumatic injury, even
following complete loss of function.
756
756 The patient is pushing against a wall and there is winging of the
right scapula due to weakness of the right serratus anterior muscle.
618 Mononeuropathies

SUPRASCAPULAR NEUROPATHY • Idiopathic:

– Acute onset: presumably autoimmune, inflammatory
neuropathy.
DEFINITION – Subacute onset: possible entrapment by transverse
Dysfunction of the suprascapular nerve. superior or inferior scapular ligament.
• Local mass:
EPIDEMIOLOGY – Ganglion cyst.
Uncommon. – Hematoma associated with fracture.
– Sarcoma.
ANATOMY – Chondrosarcoma.
Course of the suprascapular nerve (757) – Metastases.
• Arises from upper trunk of brachial plexus, carrying fibers
from the C5 and C6 nerve roots. HISTORY
• Passes under the trapezius muscle and courses from the • Precipitating factors may include vigorous exercise, such
upper border of the scapula beneath the transverse as baseball, tennis, or volleyball; and prolonged cradling
superior scapular ligament. of a mobile telephone between an ear and a shoulder.
• Innervates supraspinatus and infraspinatus muscles. • Pain at the superior margin of the scapula, radiating
• Fibers to infraspinatus pass separately through the towards the shoulder, is common but not invariable; it
spinoglenoid notch, which is covered by the transverse may be painless.
inferior scapular ligament. • Difficulty with movements of the shoulder may be
present.
Entrapment sites (757)
• Suprascapular notch. EXAMINATION
• Spinoglenoid notch. • Stand behind the patient and inspect the supra- and
infraspinatus muscles from behind and above, for
ETIOLOGY wasting/atrophy.
• Trauma: • Test the supraspinatus muscle by asking the patient to
– Heavy lifting. abduct the upper arm, from the adducted position,
– Blow on shoulder. against resistance (758). This is because the first 30° of
• Athletic activities: forceful and extreme movement of the abduction of the upper arm are effected by the
shoulder (ballet [professional], baseball, boxing, fencing, supraspinatus muscle (not the deltoid muscle). The
pitching, tennis, volleyball). muscle belly can be felt and sometimes seen.

757
Suprascapular nerve

Compression
C5 sites
C6

Supraspinatus
muscle

Infraspinatus
muscle

757 Course of the suprascapular nerve and sites of compression.

 Suprascapular Neuropathy 619

• Test the infraspinatus muscle by asking the patient to EMG

externally rotate the upper arm at the shoulder (from the
adducted position, with the elbow flexed) against
resistance (759). The examiner supports the patient’s
elbow and prevents abduction of the arm by holding the
elbow with one hand and resisting the movement of
external rotation of the shoulder with the other hand
placed around the patient’s wrist.
• There should be no restriction of passive shoulder
movements and the deltoid muscle is of normal size and
strength (cf. soft tissue injury of the shoulder), except for
a small minority of cases in which the suprascapular nerve
lesion may cause a frozen shoulder.
• Increasing pain upon moving the arm across the chest is
non-specific and also occurs with other painful disorders
of the shoulder.
• Needle examination of the supra- and infraspinati may
help identify the presence and severity of denervation
activity in these muscles.
• Needle examination of other muscles may distinguish
lesions of the suprascapular nerve from lesions of the
cervical nerve roots or brachial plexus.
MRI scan
If no improvement with rest, scan to exclude local
compression by a mass lesion.
DIAGNOSIS
Requires the presence of focal neurologic deficits, and not
just regional pain (as with entrapment syndromes of other
peripheral nerves).

DIFFERENTIAL DIAGNOSIS TREATMENT

Non-neurogenic disorders of the shoulder Depends on the cause:
• Soft tissue injuries of the shoulder (‘frozen shoulder’) • Conservative:
which lead to pain, inhibited mobility of the shoulder – Await natural history.
joint, wasting and weakness of muscles around the – Avoid provoking activities if possible.
shoulder (especially the supraspinatus but also the – Hydrocortisone injections may be effective but
deltoid). unproven.
• Rotator cuff syndrome. • Surgical decompression: resection of the transverse
• Tendinitis of the supraspinatus muscle. suprascapular ligament ± widening of the spinoglenoid
notch.
Neurogenic
• C5 or C6 radiculopathy: but usually pain radiates into PROGNOSIS
the arm, and the biceps reflex is diminished. • Depends on the cause and severity of the neuropathy.
• Neuralgic amyotrophy: may be confined to one or both • Following surgery, about half of patients experience
of the spinatus muscles and, if so, is probably auto- immediate pain relief, and most of the remainder recover in
immune rather than due to entrapment. the next few months.

INVESTIGATIONS
Nerve conduction studies
Motor latencies from stimulation of the brachial plexus at
Erb’s point to the supraspinatus may be prolonged.

758 759

Patient Patient

Examiner
Examiner

758 Testing the supraspinatus muscle.The arm is abducted against 759 Testing the infraspinatus muscle.The upper arm is externally
resistance. rotated against resistance.
620 Mononeuropathies
AXILLARY NEUROPATHY
DEFINITION
Dysfunction of the axillary nerve.
EPIDEMIOLOGY
Uncommon.
ANATOMY
Course of the axillary nerve
• Arises from the posterior cord of brachial plexus, carrying
fibers from the C5 and C6 nerve roots.
• Passes just below the shoulder joint, encircles the
humerus from behind until it is under the deltoid muscle
at the posterior aspect of the shoulder and then passes
through the quadrilateral space, defined by teres minor
above, teres major below, the long head of the triceps
medially, and the neck of the humerus laterally.
• Innervates the deltoid and teres minor muscles.
• The sensory branch, the upper lateral cutaneous nerve of
the upper arm, follows a short and separate route, and
innervates a small area of skin overlying the deltoid
muscle.
ETIOLOGY
• Trauma:
– Subcapital fracture of the humerus.
– Anterior-inferior dislocation of the shoulder joint (e.g.
blow at the tip of the shoulder) or attempted
repositioning of this type of dislocation.
– Blunt trauma of the shoulder.
• Iatrogenic:
– Intramuscular injections into deltoid.
– Faulty positioning on operating table with upper arm
elevated to 90° for 4.5 hours.
– Birth injury.
• Athletic activities:
– Volleyball.
760
760 Area of skin innervated by the axillary nerve (upper lateral
cutaneous nerve of the upper arm).
HISTORY
• Weakness of abduction of the shoulder >30° above the
horizontal.
• Precipitating injury (see above).
EXAMINATION
• Wasting (atrophy) of the deltoid muscle, evident
particularly when the patient is seated and inspected from
above and behind.
• Prominence of the acromion and head of the humerus
(due to deltoid wasting).
• Weakness of the anterior and middle parts of the deltoid
muscle, elicited by asking the patient to keep the arm
abducted in the horizontal plane against resistance. (N.B.
The first 30° of abduction of the upper arm are effected
by the supraspinatus muscle.)
• Weakness of the posterior part of the deltoid, elicited by
retracting the abducted arm against resistance.
• The teres minor muscle cannot be examined in isolation
because it acts together with the infraspinatus muscle
(suprascapular nerve) in external rotation of the upper
arm.
• Loss of sensation to light touch and pin prick in a small
area of skin overlying the deltoid muscle (760).
DIFFERENTIAL DIAGNOSIS
Non-neurogenic disorders of the shoulder
• Soft tissue injuries of the shoulder (‘frozen shoulder’)
which lead to pain, inhibited mobility of the shoulder
joint, wasting and weakness of muscles around the
shoulder (especially the supraspinatus but also the
deltoid).
• Rotator cuff syndrome.
Neurogenic
• C5 radiculopathy: but usually pain radiating into the
arm, and the biceps reflex is diminished.
• Neuralgic amyotrophy: may be confined to one or both
of the spinatus muscles and, if so, is probably auto-
immune rather than due to entrapment.
INVESTIGATIONS
Nerve conduction studies
Motor latencies from stimulation of the brachial plexus at
Erb’s point to the deltoid muscle may be prolonged.
EMG
• Needle examination of the deltoid muscle, and perhaps
also the teres minor muscle (which is difficult to localize)
may help identify the presence and severity of
denervation activity in these muscles.
• Needle examination of other muscles may distinguish
lesions of the axillary nerve from lesions of the cervical
nerve roots or brachial plexus.
X-ray of shoulder and upper humerus
Performed if an history of trauma, or joint deformity.
 Musculocutaneous Neuropathy 621

DIAGNOSIS
Requires the presence of isolated weakness of the deltoid
(and teres minor muscles) and sensory loss over the deltoid.
Can be confirmed by EMG.
TREATMENT
Depends on the cause:
• Conservative: mobilize the shoulder joint by active and,
if necessary, passive exercises if the deltoid is weak, to
avoid a frozen shoulder syndrome (particularly in older
patients).
• Surgical: nerve grafting should be considered in patients
with axillary neuropathy due to trauma if there are no
signs of recovery of paralysis of the deltoid muscle after
>4 months.
PROGNOSIS
Depends on the cause and severity of the neuropathy:
• Partial lesions tend to recover spontaneously.
• Neuralgic amyotrophy (an autoimmune inflammatory
response) may recover very slowly over many months.
MUSCULOCUTANEOUS
NEUROPATHY
DEFINITION
Dysfunction of the musculocutaneous nerve.
EPIDEMIOLOGY
Very rare in isolation.
ANATOMY
Course of the musculocutaneous nerve (761)
• Arises from the lateral cord of brachial plexus, carrying
fibers from the C5, C6 and C7 nerve roots.
• Passes through the axilla, pierces the coracobrachialis
muscle (giving off branches to it), descends between the
biceps and brachialis muscles (giving off branches to both
parts of the biceps muscle and the brachial muscle) and
continues as the lateral cutaneous nerve of the forearm,
which pierces the fascia lateral to the tendon of the biceps
muscle and just above the elbow, and innervates the skin
of the radial part of the volar side of the forearm as far as
the wrist.
• Innervates the coracobrachialis, biceps and brachialis
muscles.
• The sensory branch, the lateral cutaneous nerve of the
forearm, innervates the skin of the radial part of the volar
side of the forearm as far as the wrist.

ETIOLOGY
• Trauma:
– Dislocation of the shoulder joint.
761 – Fracture (closed) of the clavicle.
– Shoulder operations for habitual luxation (dislocation)
or instability of the clavicle.
– Axillary node dissection for malignant melanoma or
breast carcinoma.
Coracobrachialis – Penetrating injury of the upper arm (gunshot or knife).
• Athletic activities: strenuous exercise of the arms (e.g.
weight-lifting, repetitive push-ups [e.g. 500 times]).
Musculocutaneous • Neuralgic amyotrophy.
nerve • Opportunistic infection by Capnocytophaga canimorsus,
probably of the vasa nervorum.
Biceps • Compression:
– Sleep.
– Excessive exercise with elbow extension and forearm
pronation.
Brachialis
HISTORY
• Numbness or paresthesia of the lateral/radial part of the
forearm.
• Pain in the elbow and forearm may be present.
• Weakness of flexion of the elbow (with the forearm
supinated).
• Precipitating injury (see above).

761 Diagram of the musculocutaneous nerve and the muscles which

it supplies.
622 Mononeuropathies

EXAMINATION DIAGNOSIS
• Weakness of the biceps and brachialis muscles, elicited by Requires the presence of isolated weakness of the biceps,
flexion of the elbow, with the forearm in full supination, brachialis, and coracobrachialis and sensory loss over the
against resistance. Also there is some weakness of lateral (radial) border of the forearm. Can be confirmed by
supination of the forearm with the elbow in flexion EMG.
(biceps muscle).
• Weakness of the coracobrachial muscle may be present TREATMENT
exceptionally, evident by some weakness on elevation of Depends on the cause:
the arm. • Conservative.
• Loss of superficial sensation on the skin of the radial part • Surgical: only if direct penetrating trauma with severe
of the volar side of the forearm as far as the wrist (762). axonal injury or complete interruption of nerve
continuity.
DIFFERENTIAL DIAGNOSIS
Non-neurogenic PROGNOSIS
Ruptured biceps tendon: no sensory loss, and on Depends on the cause and severity of the neuropathy; partial
contraction of the biceps muscle a hardening mass evolves lesions tend to recover spontaneously.
under the insertion of the pectoralis major muscle.

Neurogenic
C6 radiculopathy: but this is usually accompanied by
sensory loss in the hand; weakness of supination with the
forearm extended (supinator muscle [radial nerve]), and
wrist extension (at least toward the radial side [extensor
carpi radialis muscle]), and absence of an obviously visible
muscle belly of the brachioradialis muscle on flexion of the
elbow (radial nerve).

INVESTIGATIONS
Nerve conduction studies
• Decreased or absent sensory nerve action potential
(SNAP) and delayed sensory conduction in the lateral
cutaneous nerve of the forearm as measured by means of
an antidromic technique. A decreased or absent SNAP
reflects axonal degeneration distal to the spinal ganglion;
sensory root lesions proximal to the spinal ganglion cause
no degeneration of the peripheral sensory axon, and 762
thereby do not influence the SNAP.
• Motor latencies from stimulation of the brachial plexus
at Erb’s point to the biceps muscle may be prolonged.

EMG
• Needle examination of the biceps, brachialis, and
coracobrachialis muscles may help identify the presence
and severity of denervation activity in these muscles.
• Needle examination of other muscles may distinguish
lesions of the musculocutaneous nerve from lesions of
the C6 cervical nerve root or brachial plexus.

X-ray of clavicle, shoulder and upper arm

Performed if an history of trauma, or joint deformity.

762 Area of skin innervated by the musculocutaneous nerve (lateral

cutaneous nerve of the forearm).
 Radial Neuropathy 623

RADIAL NEUROPATHY Wrist

The superficial terminal branch of the radial nerve passes
superficially on the lateral/radial side of the forearm, over
DEFINITION the styloid process just proximal to the wrist (where it lies
Dysfunction of the radial nerve. exposed and is easily compressed), and towards the dorsum
of the thumb. It supplies the lateral/radial part of the
EPIDEMIOLOGY dorsum of the hand and ends in five dorsal digital nerves,
Reasonably common. of which two supply the dorsum of the thumb (except the
nail area), two supply the dorsum of the index finger
ANATOMY (proximal to the middle phalanx), and one supplies the first
Course of the radial nerve (763) phalanx of the middle finger.
Arises (together with the axillary nerve) from the posterior
cord of the brachial plexus, carrying fibers from the C5, C6, ETIOLOGY
C7, C8 and T1 nerve roots. Axillary lesions
• Rare.
Axilla • Compression: long crutches, but usually also involves the
Courses through the axilla, giving off branches to the triceps median and ulnar nerves.
muscles, then down between the medial and lateral heads • Local trauma.
of the triceps muscle, before winding around the back of the
mid-humerus, in the spiral groove (where it is most often
damaged by compression, particularly the motor fibers).

Upper arm
In the spiral groove, two sensory nerves, the posterior
cutaneous nerve of the upper arm and the posterior
cutaneous nerve of the forearm, leave the radial nerve to
supply a small area of skin on the dorsal aspect of the upper
Axillary nerve
763
arm and a larger area of the skin on the dorsal aspect of the
forearm respectively.
At the distal third of the upper arm, the nerve gives off
Deltoid
the lower lateral cutaneous nerve of the upper arm which
innervates the skin of the lateral and posterior surface of the
distal third of the upper arm and a small portion of the back Teres minor
of the proximal forearm. The radial nerve then pierces the
intermuscular septum between the brachialis muscle and Triceps, long head
lateral head of triceps, and gives off branches to the
brachioradialis muscle and extensor carpi radialis longus and Triceps, lateral head
brevis. Triceps,
medial head
Within 3 cm (1.2 in) of the humero-radial joint (above
or below it) the nerve divides into a deep motor branch
(which continues as the posterior interosseous nerve) and a
superficial sensory branch (the superficial branch of the Radial nerve
radial nerve).
Brachioradialis
Forearm
The posterior interosseous nerve passes through and
Extensor carpi radialis longus
supplies the supinator muscle and then runs dorsal to the
interosseous membrane of the forearm to innervate the Extensor carpi radialis brevis
extensor carpi ulnaris, all extensor muscles of the fingers and Spinator Posterior
thumb, and abductor pollicis longus muscle. Extensor carpi ulnaris interosseous
Extensor digitorum nerve
Extensor digiti minimi
Abductor pollicis longus
Extensor pollicis longus
Extensor pollicis brevis
Extensor indicis

763 Diagram of the axillary and radial nerves and the muscles which
they supply.
624 Mononeuropathies

Upper arm lesions Finger lesions (dorsal digital nerves)

• Trauma: supracondylar fracture of the humerus.
• External compression against the spiral groove:
– Intoxicated sleep (e.g. with the arm folded over the back
of a chair or resting on a hard ridge [‘Saturday night
palsy’, ‘Parkbanklähmung’, paralysie des ivrognes’]).
– Improper positioning during general anesthesia.
– Prolonged (e.g. 3 hours) shooting practice in a kneeling
position with the upper arm resting on the ipsilateral knee.
– Akinetic rigid syndromes (e.g. Parkinson’s disease)
causing severe immobility.
– Hereditary liability to pressure palsies (see p.587): palsy
after normal sleep.
– Lipoma adjacent to the nerve.
– Traumatic aneurysm of the radial artery.
– Callus bone formation following fracture of the shaft of
the humerus.
– Myositis ossificans of the shaft of the humerus.
– Prolonged labor or forceps extraction in the neonate, or
repeated blood pressure measurement in the premature
infant.
• Athletic activities (compression by lateral head of triceps
or a fibrous arch at the lower part of the humeral
groove):
– Involving extension at the elbow against strong
resistance.
– ‘Windmill’ pitching motion of competitive softball.
• Medical mononeuropathy:
– Diabetes mellitus.
– Arteritis.
• Nerve tumor.
Forearm (posterior interosseous nerve) lesions
• Congenital hemihypertrophy of the supinator muscle.
• Entrapment of the motor branch of the radial nerve, the
deep radial nerve or the posterior interosseous nerve,
between ‘normal’ anatomic structures, at the level of the
supinator muscle.
• Accessory brachioradialis muscle.
• Dislocation of the elbow, fracture of the ulna with
dislocation of the radial head, or Monteggias’s fracture.
• Arthroscopy of the elbow joint.
• Rheumatoid arthritis of the elbow joint.
• Traumatic aneurysm of the posterior interosseous artery.
• Arteriovenous fistula for hemodialysis.
• Lipoma.
• Intramuscular myxoma.
• Cysts.
• Ganglia.
• Professional and daily use of scissors (thumb).
• Palmar ganglion.
HISTORY
Axillary lesions
• Short history of weakness stretching the elbow, wrist, all
fingers and thumb.
• Pain is not prominent.
Upper arm lesions
• Often sudden onset of inability to extend wrist, fingers
and thumb.
• Numbness or paresthesia of the lateral/radial part of the
forearm.
• Pain in the elbow and forearm may be present.
• Precipitating injury or predisposing factors (e.g. alcohol
or drug intoxication; see above).
Forearm (posterior interosseous nerve) lesions
(supinator syndrome)
• Slowly progressive onset of symptoms.
• Initially, difficulty stretching the little finger (it gets
curled up during tasks such as retrieving something from
a trouser pocket).
• Later, inability to extend metacarpophalangeal joint of
the little finger and then similar weakness begins in other
fingers, one after the other.
• Consequently, difficulty playing the piano but writing
remains normal and grip powerful if the fingers are
passively placed around an object.
• Pain is uncommon.
• Bilateral symptoms may occur.
Wrist lesions
• Shooting pain in the radial side of the wrist.
• Painful paresthesia in the thumb and index finger evoked
by touching or knocking the radial side of the wrist.
• Reduced sensation on the radial side of the hand (764).
764

Wrist lesions (superficial terminal branch

of radial nerve)
• Handcuffs and other tight wrist bands (e.g. watch band).
• Direct injury:
– Accidental.
– Post-surgery:
Stenosing tenosynovitis (de Quervain’s disease).
Open reduction of fractures of radius and ulna.
Shunt operations for hemodialysis.
• Transposition of a flexor tendon towards the thumb.
• Repeated movements of pronation and supination of
forearm, or abduction and adduction of the wrist with
the forearm in pronation and the wrist in flexion. 764 Areas of skin innervated by the radial nerve (superficial terminal
• Stenosing tenosynovitis (de Quervain’s disease). branch of radial nerve).
 Radial Neuropathy 625

EXAMINATION Wrist lesions

Axillary lesions
• Weakness of the triceps and all muscles extending wrist,
fingers and thumb.
• Mild decreased sensation on the back of the upper arm
and forearm, in the web between index finger and
thumb, and the radial side of dorsum of the hand.
Reduced sensation over the lateral/radial part of the dorsum
of the hand, and the dorsum of the thumb (except the nail
area), index finger (proximal to the middle phalanx) and
first phalanx of the middle finger.

Upper arm lesions

• Dropped hand and fingers due to weakness of extensors
of wrist and metacarpophalangeal joints (765, 766).
• Spares triceps muscle and sensation in the upper arm, and
often posterior cutaneous nerve of forearm leading to
preserved sensation in the web between the index finger
and thumb.
• Weakness of brachioradialis (elbow flexion with forearm
pronated [not supinated cf. biceps]), supinator
(supination of forearm with elbow extended [not flexed,
cf. biceps]).
765
Forearm (posterior interosseous nerve) lesions
(supinator syndrome)
• Dropped fingers without dropped hand: inability to
extend the fingers and thumb at the metacarpophalangeal
joints. Despite severe weakness of extensor carpi ulnaris,
wrist extension remains possible because extensor carpi
radialis muscles function normally (because the branch to
extensor carpi radialis leaves the main stem of the radial
nerve above the elbow and proximal to entry of the
supinator muscle). If extensor carpi ulnaris is weak, a
distinct radial deviation of the extended hand occurs when
the patient is asked to make a fist.
• There may be some extension of the index finger at the
interphalangeal joints (by contraction of the lumbrical
muscles innervated by the median nerve) and some
weakness of the supinator muscle, but brachioradialis
remains powerful (unless the lesion is above the elbow).
• The interossei may appear to be weak (although they are
not weak) with any radial nerve lesion above the wrist
because of weakness of finger extension; in order for the
fingers to be abducted they need to be extended first. If
the fingers are supported on a flat surface, the action of
the interossei can be assessed and, in the event of a radial
nerve lesion, the fingers can spread apart (to some extent
at least), whereas in an upper motor neuron lesion, a T1
root lesion, or a combined lesion of the radial and ulnar
nerves, there is weakness of finger abduction.

766

765, 766 Upper arm scar indicating the

site of injury to the radial nerve (765), and
dropped hand and fingers due to weakness
of extensors of wrist and
metacarpophalangeal joints following upper
arm radial nerve injury (766).
626 Mononeuropathies
DIFFERENTIAL DIAGNOSIS
Neurogenic
• Central weakness (upper motor neuron lesions): dropped
hand and fingers but also weakness of the radial wrist
extensors and interossei, an involuntary extension of the
wrist when making a fist or gripping an object, and other
upper motor neuron signs such as increased limb tone
and deep tendon reflexes and an extensor plantar
response.
• Spinal muscular atrophy: not infrequently begins with
partial deficits, such as weakness of extensors of the wrist,
but weakness is often present in muscles of the hand and
forearm beyond the innervation of the radial nerve.
• C7 radiculopathy: weakness in the triceps and extensors
of the fingers but the wrist extensors (mainly C6 root)
are mostly spared, the triceps reflex is depressed, and the
history almost invariably begins with pain (mainly in the
neck and extensor aspect of upper arm) and pins and
needles in the middle (and index) finger.
• Neuralgic amyotrophy (see p.595).
Non-neurogenic
• Diseases of extensor tendons.
• Compartment syndrome of the deep extensor muscles of
the forearm.
INVESTIGATIONS
Nerve conduction studies
• Decreased or absent sensory nerve action potential
(SNAP) and delayed sensory conduction in the lateral
cutaneous nerve of the forearm occurs as measured by
means of an antidromic technique. A decreased or absent
SNAP reflects axonal degeneration distal to the spinal
ganglion; sensory root lesions proximal to the spinal
ganglion cause no degeneration of the peripheral sensory
axon, and thereby do not influence the SNAP.
• Motor latencies from stimulation of the brachial plexus
at Erb’s point to the biceps muscle may be prolonged.
The main trunk of the radial nerve and its final motor
(and sensory) branches can be stimulated at several sites,
so that conduction can be studied in all segments of
interest.
767
767 Forearm splint to facilitate hand function.
EMG
• Needle examination of muscles innervated by the radial
nerve may help identify the presence and severity of
denervation activity in these muscles, and help localize
the site and severity of a radial nerve lesion; fibrillation
potentials and other signs of axonal degeneration may be
found in all or some of the muscles supplied by the radial
nerve that are distal to the nerve lesion. For example,
EMG evidence of denervation in the extensor capri
ulnaris (and more distal muscles innervated by the radial
nerve) but not in the extensor carpi radialis longus and
brevis is consistent with the supinator syndrome.
• Needle examination of other muscles may distinguish
lesions of the radial nerve from lesions of the C7 cervical
nerve root, brachial plexus or upper motor neuron.
X-ray of shoulder, humerus, elbow joint
Performed if a history of trauma, or joint deformity.
DIAGNOSIS
Requires the presence of isolated weakness of muscles and
loss of sensation of skin innervated by the radial nerve.
TREATMENT
Upper arm lesions
Depends on the cause, but generally conservative with
functional aids (767).
Surgical exploration
• If slowly progressive radial nerve palsy (e.g. if nerve
compression by a structural local mass lesion such as
callus bone formation, myositis ossificans, aneurysm of
the radial artery, or lipoma).
• If direct penetrating trauma with severe axonal injury or
complete interruption of nerve continuity (e.g.
immediate and complete radial nerve palsy after a
complex fracture of the humerus).
• Possibly for immediate and complete radial nerve palsy
after a closed fracture of the humerus, but remembering
that MRI and even CT provide a lot of information and
that recovery is the rule even in radial nerve palsies
immediately after a fracture of the humerus, particularly
if nerve conduction studies show that the deficit is mainly
caused by conduction block.
Conservative
Partial radial nerve lesion (e.g. following humeral fracture).
Forearm (posterior interosseous nerve) lesions
Surgical exploration
If the nature of the nerve lesion has been shown to be
consistent with compression, and the site established,
decompression surgery is likely to be effective.
PROGNOSIS
Depends on the cause and severity of the neuropathy: partial
lesions tend to recover spontaneously and over about 6–8
weeks. Neurophysiologic studies can help determine
prognosis.
 Median Neuropathy 627

MEDIAN NEUROPATHY Anomalies

DEFINITION
Dysfunction of the median nerve.
EPIDEMIOLOGY
Common.
ANATOMY
Course of the median nerve (768)
Arises from the lateral and medial cords of the brachial
plexus, carrying fibers from the C5–C8 and T1 nerve roots.
Axilla
Emerges from the axilla with the radial and ulnar nerves and
the axillary artery and vein, through the inelastic axillary
sheath.
Upper arm
Descends through the upper arm and bicipital sulcus, giving
off no branches, to the elbow, where it lies medial to the
brachial artery.
Elbow
Courses through the antecubital fossa, medial to the biceps
tendon and beneath the bicipital aponeurosis, where it gives
off branches to the pronator teres, flexor carpi radialis,
palmaris longus and flexor digitorum superficialis muscles.
Forearm
Proximally, the nerve lies deep, between the two heads of
the pronator teres muscle. Distal to the pronator teres the
anterior interosseous nerve arises. It is a motor nerve which
descends anterior to the interosseous membrane (joining
the radius and ulna) and between the flexor digitorum
profundus (I and II) and flexor pollicis longus, which it
innervates, together with the pronator quadratus muscle.
• Fibers from the median nerve in the forearm may cross
to the ulnar nerve (the Martin–Gruber anastomosis) in
15–30% of normal individuals and almost all, if not all,
with Down’s syndrome. The most common variety, in
60% of cases with this variant, is that fibers of the anterior
interosseous nerve travel with the ulnar nerve to
innervate muscles normally innervated by the median
nerve. In 35% of cases, the anastomosing fibers from the
median nerve supply muscles normally innervated by the
ulnar nerve (e.g. adductor pollicis and the first dorsal
interosseous).
• The median nerve may innervate the hypothenar muscles
via an anomalous branch, arising from its course in the
carpal tunnel.
• An ‘all median hand’ may occur rarely.
• The deep motor branch of the ulnar nerve may
communicate with the median nerve in the hand
(Riche–Cannieu anastomosis).
• The flexor pollicis brevis may be innervated entirely by
the ulnar nerve or have double innervation by the
median and ulnar nerves.
• An anastomotic branch of the radial nerve may innervate
the abductor pollicis brevis muscle very rarely.
• The musculocutaneous nerve may innervate muscles
normally innervated by the median nerve.
768
Median nerve

Wrist and hand

• A few centimeters proximal to the wrist, the palmar
cutaneous branch leaves the main trunk of the median
nerve and travels over the transverse carpal ligament to
the thenar eminence. It innervates the skin on the
proximal half of the radial side of the palm.
• Immediately proximal to the wrist the median nerve Pronator teres
Anterior
becomes more superficial and enters the carpal tunnel. Flexor carpi radialis interosseous
Palmaris longus nerve
• Within, or distal to, the carpal tunnel the recurrent
Flexor digitorum
motor branch to the thenar eminence arises and supeficialis
Flexor digitorum
innervates the abductor pollicis brevis, opponens pollicis, profundus I, II
and flexor pollicis brevis muscles. More distal branches Flexor pollicis
supply the superficial head of the flexor pollicis brevis and longus
the first and second lumbrical muscles.
• The digital nerves innervate the skin on the volar aspect Pronator
of the thumb, index finger, middle finger, radial half of quadratus
the ring finger, and the adjoining portion of the palm; Abductor pollicis brevis
and the dorsal aspect of the entire middle finger, and Flexor pollicis brevis
middle and terminal phalanges of the index and ring Opponens pollicis
finger (radial half). First lumbrical Second lumbrical

768 Diagram of the median nerves and the muscles which it supplies.
Note: the white rectangle signifies that the muscle indicated receives a
part of its nerve supply from another peripheral nerve.
628 Mononeuropathies
ETIOLOGY
Axillary lesions
• Trauma.
• Iatrogenic:
– Repositioning of shoulder luxation.
– Axillary angiography causing a false aneurysm or
inflammatory fibrosis.
• Lipoma.
Upper arm lesions
• Tourniquet paralysis.
• Nerve tumor.
• Soft tissue tumor: non-Hodgkin lymphoma.
• Closed reduction after supracondylar fracture of the
humerus.
• Sleep paralysis from pressure of a partner’s head on the
upper arm (‘honeymoon palsy’ or ‘paralysie des
amoureux’).
Elbow lesions
Entrapment
• Between the two heads of the pronator teres muscle
(pronator teres syndrome).
• By a fibrous band between the deep head of the pronator
muscle and the flexor digitorum superficialis (anterior
interosseous syndrome): rare, <1% of median neuropathies.
Compression
• Externally, by heavy objects being carried.
• Externally during general anesthesia.
• Tight band for the treatment of lateral epicondylitis
(‘tennis elbow’).
• Anterior interosseous artery.
• Persistent median artery in the forearm.
• Hematoma or false aneurysm after a puncture of the
brachial artery.
• Venepuncture or intravenous catheterization or injection
in the forearm.
• Vascular shunts for hemodialysis.
• Fibrous brand from the supracondylar process to the
medial epicondyle of the humerus, or Struthers’ ligament.
• Fibrous band at the humeral head of the pronator
muscle.
• Synovial bursa from partial rupture of distal biceps
brachii tendon.
• Closed reduction of a dislocated elbow.
• Intra-articular fracture of the humerus.
‘Overuse’ of pronator muscle, probably in combination
with one of the anatomic factors listed above.
Carpal tunnel lesions (see p.630)
Palmar cutaneous branch of the median nerve
• Ganglion of the flexor carpi radialis tendon, immediately
proximal to the wrist flexion crease.
• Entrapment within the antebrachial fascia.
• An atypical palmaris longus muscle.
• Iatrogenic injury following carpal tunnel release.
Digital branches of the median nerve
• Frequent use of scissors (e.g. by orthopedic surgeons).
• The rim of the hole in bowling balls (‘bowler’s thumb’).
• Intrinsic lesions of the skin, tendons or bony structures
of the fingers.
HISTORY
Pronator teres syndrome
• Pain along the ventral surface of the proximal forearm.
• Paresthesia in the median nerve distribution in the hand
(thumb, index, middle and ring fingers), but not as
intense as that experienced in carpal tunnel syndrome
(see p.630).
Anterior interosseous syndrome
• Subacute onset of weakness of the index finger and
thumb.
• Pain may be present.
Carpal tunnel syndrome (see p.630)
Palmar cutaneous branch of median nerve
Pain, paresthesia and numbness in the palm, particularly the
thenar region.
Digital branches of the median nerve
Reduced sensation in adjoining halves of two fingers and in
the web space between them (common digital nerve lesion),
or in one-half of a single finger (proper digital nerve lesion).
EXAMINATION
Pronator teres syndrome
• Weakness in one or more muscles in the hand innervated
by the median nerve (e.g. abductor pollicis brevis, flexor
pollicis longus, opponens pollicis, flexor digitorum
profundus I and II).
• Sensory loss in the entire median nerve distribution in
the hand (thumb, index, middle and ring fingers) or,
more commonly, restricted to the radial aspect of the
index finger and ulnar side of the thumb (769).
• Pressure on the pronator teres muscle may produce pain
along the ventral surface of the proximal forearm or,
more convincingly, paresthesia in the median nerve
distribution in the hand.
Anterior interosseous syndrome
• Weakness of flexion of the interphalangeal joint of the
thumb (flexor pollicis longus) and terminal phalanx of
the index finger (flexor digitorum profundus of the index
finger), and sometimes less severe weakness of pronator
quadratus (which should be tested with the elbow
flexed).
• The patient is unable to form a small circle by pinching
the terminal phalanx of the thumb and index finger
together: the so-called ‘pinch sign’ (770).
• The ‘straight thumb sign’ is elicited by asking the patient
to attempt to grasp something.
• No sensory loss.
Carpal tunnel syndrome (see p.630)
Palmar cutaneous branch of the median nerve
• Loss of sensation in the skin of the proximal half of the
radial side of the palm, particularly the thenar region.
• The Hoffmann–Tinel sign (distal tingling on percussion
of the nerve) may be present.
 Median Neuropathy
Digital branches of the median nerve
• Sensory impairment in the adjoining halves of two
fingers and in the web space between them if injury to a
common digital nerve in the palm.
• Sensory impairment in one-half of a single finger if injury
to a proper digital nerve distal to the division of a
common digital nerve to the two fingers.
• Sensation at the tip of the finger may be spared,
depending on the overlap with the proper digital nerve
of the other half-finger.
DIFFERENTIAL DIAGNOSIS
Neuralgic amyotrophy: weakness is preceded or
accompanied by acute or severe pain in the shoulder or
upper arm.
INVESTIGATIONS
Nerve conduction studies and EMG
Pronator teres syndrome
• Fibrillation potentials and other signs of axonal
degeneration may be found in the forearm and hand
muscles innervated by the median nerve, including the
pronator teres muscle itself. Therefore, EMG does not
allow differentiation from more proximal lesions of the
median nerve.
• Nerve conduction studies are usually normal.
769
769 Areas of skin innervated by the median nerve.
629
Anterior interrosseous syndrome
• EMG abnormalities exclusively in the flexor digitorum
profundus (I and II), flexor pollicis longus, and pronator
quadratus muscles, without involvement of muscles of
the arm and shoulder (cf. neuralgic amyotrophy).
• Usually no slowing in conduction of the anterior
interosseous nerve.
• Normal motor and sensory conduction in the main trunk
of the median nerve.
X-ray of elbow joint, forearm, wrist
Performed if an history of trauma, or joint deformity.
DIAGNOSIS
Requires the presence of isolated weakness of muscles and
loss of sensation of skin innervated by the median nerve,
confirmed by EMG.
TREATMENT
Depends on the cause.
PROGNOSIS
Depends on the cause and severity of the neuropathy: partial
lesions tend to recover spontaneously and over about 6–8
weeks. Neurophysiologic studies can help determine the
prognosis.
770
770 Weakness of flexion of the interphalangeal joint of the thumb
(flexor pollicis longus) due to an anterior interosseous nerve palsy
resulting in an inability to form a small circle by pinching the terminal
phalanx of the thumb and index finger together: the so-called ‘pinch
sign’ (i.e. the thumb is straight, not bent, and so this is only a semi-circle).
630 Mononeuropathies
CARPAL TUNNEL SYNDROME (CTS)
DEFINITION
A compression neuropathy of the median nerve at the wrist.
EPIDEMIOLOGY
• Incidence: 0.1% per year.
• Prevalence: at least 2.1% of the population:
– Symptoms (hand pain/numbness/tingling): 14.4% (95%
CI: 13–16%) of the general population.
– Clinically certain CTS: 3.8% (95% CI: 3.1–4.6%).
– Neurophysiologic CTS: 4.9% (95% CI: 4.1–5.8%).
– Clinical and neurophysiologic CTS: 2.7% (95% CI:
2.1–3.4%).
• Age: most common in middle age.
• Gender: M<F (1:1.4).
PATHOLOGY
Focal demyelination (and, if severe enough, axonal
degeneration) of the median nerve in the carpal tunnel
beneath the flexor retinaculum at the wrist with deformation
of the myelin lamellae by the mechanical stress.
PATHOPHYSIOLOGY
Chronic increased tissue pressure within the carpal tunnel,
causing chronic focal compression of the median nerve, with
deformation of the myelin lamellae, and probably also nerve
ischemia (which could account for the intermittent
paresthesia that occurs at night or with wrist flexion).
ETIOLOGY
• Idiopathic: 45% of cases of CTS.
• Obesity (body mass index ≥25 kg/m2): present in
45–70% of cases of CTS.
• Pregnancy, hormonal agents (e.g. oral contraceptive pill),
and oophorectomy: present in 10% of cases of CTS.
• Active blue collar workers (3.5%; vs. active white collar
workers: 1.7%; p=0.03); hard work with hands and
repetitive wrist movements and vibrations.
• Diabetes: present in 3–6% of cases of CTS.
• Rheumatoid arthritis and other inflammatory joint
diseases of the wrist: 2–5%.
• Thyroid disorders: 3%.
• Wrist (Colles’) fracture or sprain: 10%.
• Carpal tunnel/hand surgery: 1%.
• Miscellaneous others:
– Carpal bone hypertrophic osteoarthropathy.
– Acromegaly.
– Flexor tenosynovitis.
– Anomalous flexor tendons.
– Proximal origin of lumbrical muscles.
– Aberrant muscles.
– Bifid median nerve.
– Persistence of median artery and other vascular variants.
– Cysts and tumors in the carpal tunnel.
– Amyloidosis.
– Hemodialysis.
CLINICAL FEATURES
Symptoms
• Paresthesia (e.g. tingling), with or without numbness and
pain, involving the palmar surface of the hand
(particularly the thumb, index, middle and ring fingers
innervated by the median nerve) and often extending
proximally into the forearm, arm and even neck.
• The symptoms are frequently worse at night (waking the
patient ‘brachialgia paresthetica nocturna’) and after use
of the hand, and characteristically are relieved by rapid
flexion and extension movements of the wrist (unlike the
discomfort associated with soft tissue injury and
arthritis).
• Often bilateral, but symptoms are usually markedly worse
on one (mostly the dominant) side.
Signs
Median nerve provocative tests
• Tinel’s sign (paresthesia in the median nerve territory
elicited by gentle tapping/percussion over the flexor
retinaculum of the carpal tunnel).
• Phalen’s sign (paresthesia in the median nerve territory
elicited by asking the patient to flex the wrists and keep
the wrists in forced flexion for 60 seconds).
• In most cases, these maneuvers are negative.
Severe nerve compression
• Sensory loss over some or all of the digits innervated by
the median nerve (thumb, index, middle and
radial/lateral half of ring fingers).
• Wasting and weakness of abductor pollicis brevis (thumb
abduction), flexor pollicis brevis (thumb flexion at the
interphalangeal joint), and opponens pollicis (opposition
of thumb to little finger) (771, 772).
DIFFERENTIAL DIAGNOSIS
• Cervical (C6, C7, C8) radiculopathy.
• Brachial plexopathy.
• Proximal median neuropathy.
• Diffuse peripheral neuropathy.
• Motor neuron disease.
• Spondylotic myelopathy.
• Syringomyelia.
• Multiple sclerosis.
INVESTIGATIONS
Nerve conduction studies
Ensure the temperature of the hands is at least 30°C (86°F).
• Median nerve distal sensory latency (index or middle
finger-wrist).
• Wrist-palm sensory conduction velocity.
• Ulnar nerve distal sensory latency (fifth finger-wrist).
• Sensitivity only about 70% in diagnosing CTS based on
history and examination, and yet also a high rate of false-
positives (about 76%).
MRI of the median nerve in the carpal tunnel
• May image the compressed median nerve.
 Carpal Tunnel Syndrome (CTS) 631

DIAGNOSIS
The key to diagnosis is a careful history and examination,
including a search for the underlying cause. There is no
consensus as to whether CTS is a clinical or electrophysio-
logical diagnosis, and no standard diagnostic criteria have
been established. However, normal electrophysiologic
studies do not rule out CTS. Indeed, carpal tunnel
syndrome should be suspected on the history because it is
not until the condition is moderate to severe that relevant
sensory and motor deficits are detectable on physical
examination (and nerve conduction studies).
Clinically certain CTS
• Recurring nocturnal and/or activity-related pain,
numbness or tingling involving palmar aspects of at least
two of the first four fingers at least twice weekly during
the preceding 4 weeks.
• Positive nerve percussion and/or wrist flexion tests.
• Median nerve sensory and/or motor deficit is supportive
but not necessary for the diagnosis.
Electrophysiologic CTS
Median-ulnar peak sensory latency difference ≥0.8 ms.
Ultrasound
20 sessions of ultrasound (1 MHz, 1.0 W/cm2, pulsed
mode 1:4, 15 minutes per session) applied to the area over
the carpal tunnel, on a once daily basis (5 sessions per week)
for the first 2 weeks, and then twice weekly for the next 5
weeks, may result in satisfying short and medium term (6
months) benefits for patients with mild to moderate
idiopathic CTS. If effective, the mechanism may be an anti-
inflammatory effect of such treatment, or stimulation of
nerve regeneration or nerve conduction.
Yoga-based intervention
A yoga-based intervention consisting of 11 yoga-postures
designed for strengthening, stretching, and balancing each
joint in the upper body, along with relaxation, given twice
weekly for 8 weeks may be associated with pain reduction
and improvement in grip strength and the Phalen sign.
771

TREATMENT
Avoid or treat any precipitating/causal factors
• Limit repetitive wrist and hand movements.
• Achieve ideal body weight.
• Treat underlying disease (e.g. arthritis) appropriately (e.g.
with splinting and non-steroidal anti-inflammatory
drugs).
• Diuretics may be helpful, particularly for patients who
develop CTS late in pregnancy.

Immobilization with splints

Palmar wrist splints, maintaining the wrist in a neutral or 772
slightly extended position, and worn at night may be
appropriate and helpful, particularly when symptoms are
mainly nocturnal.

Local injection of corticosteroid and

anesthetic into the carpal tunnel
A single injection of 1 ml of fluid containing a long-acting
corticosteroid (methylprednisolone 40 mg) and local
anesthetic (lignocaine 10 mg) by a 3 cm long 0.7 mm
needle, inserted 4 cm proximal to the carpal tunnel (wrist
crease), between the tendons of the radial flexor muscle and
the long palmar muscle, and angled acutely (about 10–20°
depending on the thickness of the wrist) toward the carpal
tunnel improves the symptoms of CTS in about three-
quarters of patients at 1 month after treatment (compared
with 20% of patients who are not treated), and is still
effective at 1 year in half of patients. It is also safe; there are
no adverse effects. The purpose of the lignocaine is to afford
a painless injection and to ensure that the injection was
carried out properly by demonstrating diminished sensation
in the median nerve territory after the injection.
N.B. Corticosteroid injections into the carpal tunnel may
damage the median nerve and tendons, and any treatment
benefits may be of short duration. Success is less likely in
patients with structural abnormalities or with denervation 771, 772 Wasting of the thenar eminence of the left hand due to
on electromyography. weakness and wasting of the left abductor pollicis brevis as a result
of a median neuropathy at the left wrist due to compression in the
carpal tunnel.
632 Mononeuropathies
Surgical decompression (endoscopic, open)
Rationale
Aims to create the appropriate circumstances under which
the nerve can recover, and thus the symptoms resolve. It
does not aim to improve nerve function itself. The capacity
of the nerve to recover also depends on the age of the
patient, coexisting disease, and the severity and duration of
the deficit.
Possible indications
• No improvement with conservative (non-surgical)
management.
• Deterioration clinically or on serial electrodiagnostic
studies.
• Nerve conduction block localized on nerve conduction
studies.
Possible outcomes
• Immediate benefit should be realized if ‘positive’
symptoms (i.e. pain and paresthesiae) dominate in a
patient with neurophysiologically confirmed CTS.
• Improvement will be slow, or not at all, if the main
clinical features are ‘negative’ (i.e. loss of sensory and/or
motor function); axons regrow at only 1–2 mm
(0.04–0.08 in)/day. The main goal of surgery in these
patients is prevention of further loss of function.
Adverse effects
Some patients complain of a vague lack of strength in the
wrist following section of the flexor retinaculum.
PROGNOSIS
• Depends on the cause and outcome of treatment.
• An increasingly recognized cause of work disability.
ULNAR NEUROPATHY
DEFINITION
Dysfunction of the ulnar nerve.
EPIDEMIOLOGY
Reasonably common.
ANATOMY
Course of the ulnar nerve (773)
Arises from the lower trunk and medial cord of the brachial
plexus, carrying fibers from the C8 and T1 (and sometimes
also from C7) nerve roots.
Axilla
Travels through the axilla in close proximity to the median
nerve and axillary artery.
Upper arm
Halfway down the upper arm, the nerve pierces the
intermuscular septum and descends on the dorsomedial side
of the upper arm between the intermuscular septum and the
medial head of the triceps muscle. It gives off no branches
in the upper arm.
Elbow
Enters the ulnar groove behind the medial epicondyle of the
humerus, where the nerve is exposed and most easily injured.
Forearm
• Enters through the so-called ‘cubital tunnel’ which is
confined by ligaments and the medial epicondyle, and
reduces in size when the elbow is flexed.
• The ulnar nerve courses between the two heads of the
flexor carpi ulnaris muscles, giving off branches to this
muscle and to the flexor digitorum profundus III and IV
(ring and little finger).
• The palmar cutaneous branch originates in the middle of
the forearm and supplies the skin of the proximal part of
the hypothenar eminence.
• The dorsal cutaneous branch arises about 5 cm (2 in)
proximal to the wrist crease and innervates the skin on
the dorsal side of the hand on the ulnar side, extending
from the wrist to the little finger, proximal phalanx of the
ring finger, and part of the base of the middle finger.
Wrist and palm
The ulnar nerve, together with the ulnar artery and vein,
enters Guyon’s canal, passing over the transverse carpal
ligament (the median nerve passes under it), and beneath the
palmar fascia bridging the pisiform bone and the hamulus of
the hamate bone. Within Guyon’s canal, at the inner side of
the pisiform bone, it divides into its two terminal branches:
the superficial terminal branch, which is almost purely sensory,
and the deep terminal branch, which is purely motor.
The superficial terminal branch innervates the skin on
the distal part of the hypothenar eminence and then
terminates as digital nerves which supply the skin on the
palmar side of the little finger and ring finger, and the dorsal
side of the tips of these two fingers, distal to the parts
supplied by the dorsal cutaneous branch. The superficial
terminal branch also innervates the palmaris brevis muscle.
In the palm, the deep terminal motor branch innervates
consecutively the abductor, opponens and flexor of the little
finger, the third and fourth lumbricals, the interossei and,
finally, the adductor pollicis. Consequently, ulnar nerve
entrapment proximal to the wrist generally causes sensory
and motor signs, whereas entrapment distal to the wrist
causes motor deficits only.
ETIOLOGY
Axillary and upper arm lesions
• Rare.
• Compression:
– Long crutches or inappropriately tied tourniquets: but
usually also involves the median and radial nerves.
– Chondroepitrochlaris muscle, arising from pectoralis
major and crossing over the neurovascular bundle in the
axilla, before inserting into the brachial fascia and medial
epicondyle of the humerus.
– Aneurysm of the axillary or brachial artery.
• Median sternotomy (?traction on brachial plexus).
Elbow lesions
Common: 87% of all ulnar neuropathies, and often bilateral.
There are two potential sites of compression.
 Ulnar Neuropathy 633

The shallow condylar groove (where the nerve lies directly – Rheumatoid synovial cyst.
beneath the skin) – Ruptured medial head of triceps muscle.
• External pressure: – Trauma.
– ‘Drivers’ elbow’: resting the elbow against the lower • Hypertrophic ulnar neuropathy.
edge of the car window. • Leprosy.
– Prolonged bed rest. • Nerve tumors.
– Prolonged leaning with the elbow on a desk (e.g. shoe
workers, telephone operators). The cubital tunnel (the aponeurosis of the flexor carpi
– Malpositioning during general anesthesia. ulnaris forms the roof and the medial ligament of the
– Hemodialysis shunt, with proliferating granulation tissue. elbow joint forms the floor)
– Steroid injection for medial epicondylitis, with Flexion of the elbow increases pressure in the cubital tunnel
undetected dislocation of the nerve. Repeated flexion/extension of the elbow (e.g. diamond
• Deformities or abnormalities at the elbow joint: sorters, or operating the handle of a mounted drill or a
– Aneurysm of the ulnar collateral artery. chain-saw).
– Arthrosis.
– Arthritis, chondromatosis. Forearm lesions
– Diffuse idiopathic skeletal hyperostosis (Forestier’s • Uncommon; 1% of all ulnar neuropathies.
disease). • Fibrous or fibrovascular bands at the distal part of flexor
– Epineural cyst. carpi ulnaris.
– Heterotopic calcifications. • Greenstick fracture of the ulna.
– Hypertrophic ulnar neuropathy. • Compartment syndrome of the forearm (e.g. forearm
– Ganglia. hemorrhage associated with bleeding diathesis).
– Gout. • Local hypertrophic neuropathy.

Wrist and palm lesions

773 Uncommon: 12% of all ulnar neuropathies.

External pressure
The most common cause:
• Cyclist’s palsy: pressure from handlebars.
• Occupational: handling screwdrivers, pliers, knives,
shears, pneumatic drills.
• Crutches and cane use.
• Handcuffs.

Ulnar nerve
Acute injury
• Penetrating wounds.
• Fractures of the radio-ulnar joint, hamulus of the hamate
bone, or fifth metacarpal bone.
• Carpo-metacarpal luxation.

Acquired lesions
• Benign giant cell tumor.
Flexor carpi • Benign chondroblastoma of the hamate.
ulnaris • Ganglion.
• Lipoma, with hemorrhage.
• Nodular synovitis.
Flexor digitorum • Pathologic calcifications, idiopathic or associated with
profundus III, IV scleroderma.
• Pyrophosphate arthropathy.
• Thrombo-angiitis of the ulnar artery.
Digiti minimi:
Adductor pollicis Abductor Congenital anomalies
Flexor pollicis brevis Opponens • Accessory muscles: palmaris brevis, palmaris longus, or
1st dorsal interosseous Flexor abductor digiti minimi.
1st palmar interosseous • Anomalous origin of flexor digiti minimi.
Fourth lumbrical • Anomalous course of ulnar nerve, beneath flexor retinaculum.
Third lumbrical • Duplication of the tendon of the flexor carpi ulnaris
muscles, with splitting of the ulnar nerve.
• Fusion between pisiform and hamate bones.
• Reversed palmarus longus muscle.
773 Diagram of the ulnar nerve and the muscles which it supplies. • Thickened piso-hamate ligament.
N.B.The white rectangle signifies that the muscle indicated receives a • Tortuosity of the ulnar artery.
part of its nerve supply from another peripheral nerve.
634 Mononeuropathies
Infections
• Leprosy.
• Tuberculosis.
• Phlegmon of the palm.
Hereditary liability to pressure palsies (see p.587)
HISTORY
Axillary and upper arm lesions
Same as elbow lesions unless evidence of concomitant median
or radial neuropathy.
Elbow and forearm lesions
Sensory symptoms
• Numbness, pins and needles, and occasionally burning pain
in the ring and little finger, and sometimes the hypothenar
region (but not outside the sensory area of the ulnar nerve,
nor causing the patient to wake at night, in contrast to the
carpal tunnel syndrome).
• Leaning on the elbow (e.g. against the lower edge of a car
window) or flexing the elbow (e.g. reading in bed) may
precipitate or exacerbate the symptoms.
• The elbow or the nerve in the ulnar groove may be painful
or tender to touch.
Motor symptoms
Weakness and clumsiness of fine finger movements (e.g.
zipping trousers, releasing a belt, buttoning and unbuttoning
clothing, sewing, guitar playing) may be the presenting
symptoms, depending on the fascicles involved, but usually
follow the sensory symptoms.
EXAMINATION
Axillary and upper arm lesions
Same as elbow lesions unless evidence of concomitant median
or radial neuropathy.
Elbow and forearm lesions
Sensory signs
Altered sensation on the little finger (palmar and dorsal sides),
ring finger (ulnar half), and often adjoining parts of the hand,
but may be restricted to the tips of the little and ring fingers,
or even absent (774).
Autonomic signs
• Uncommon.
• Furrowed or atrophic nails of the little and ring fingers.
• Trophic skin lesions may also be present in the cutaneous
distribution of the ulnar nerve.
Motor signs
• Weakness (and wasting) of first dorsal interosseous and
hypothenar eminence (adduction of the thumb and little
finger respectively) may be the only initial signs (775–778);
the flexor carpi ulnaris and flexor digitorum profundus
muscles are rarely wasted (medial border of forearm) or
weak in the early stages.
• A useful test of thumb adduction is to ask the patient to
squeeze a sheet of paper between the base of the thumb
and the index finger; weakness of the adductor pollicis is
present if the interphalangeal joint of the thumb flexes, due
to use of the median-innervated flexor pollicis longus
(Froment’s sign).
• If the patient has a radial neuropathy (in isolation or
combination), it is not possible to test precisely finger
abduction because the fingers need to be extended first. In
this situation, finger abduction should be tested with the
palm faced downwards on a hard surface, and the fingers
resting in an extended position but, even then, the
movements will not be quite normal even if the ulnar nerve
is preserved.
• The flexor digitorum profundus III and IV are tested by
testing flexion of the distal interphalangeal joint of the little
and ring finger against resistance, while the middle proximal
interphalangeal joint is fixed in extension.
• The flexor carpi ulnaris often escapes compression at the
elbow but if not, there may only be a slight radial deviation
of the hand on wrist flexion; wrist flexion remains generally
unaffected because of the action of the (median-innervated)
flexor carpi radialis.
• Severe ulnar neuropathy gives rise to the so-called ‘ulnar
claw hand’ with guttering of the dorsum from atrophy of
the interosseous muscles and third and fourth lumbricals,
hyperextension of the fourth and fifth metacarpophalangeal
joints, mild flexion of the interphalangeal joints and
abduction of the little finger (779, 780).
Wrist and palm lesions
Deep and superficial branch: just proximal to or within
Guyon’s canal
• Pure weakness, and possibly wasting, of all hand muscles
innervated by the ulnar nerve (adductor pollicis,
interosseous muscles, hypothenar muscles [abduction of
little finger], and palmaris brevis [no skin dimple on
extreme abduction of the little finger]).
• Sparing of flexor carpi ulnaris and flexor digitorum
profundus (as for more proximal lesions at the elbow).
• Loss of sensation on palmar aspect of the little finger and
ulnar half of the ring finger, corresponding to the
cutaneous innervation of the superficial terminal branch.
• Normal sensation over the proximal part of the hypo-
thenar and the dorsal part of the ring and little fingers.
• Little pain.
Deep branch, proximal part: at the pisiform bone
• Pure weakness, and possibly wasting, of all hand muscles
innervated by the ulnar nerve, excluding palmaris brevis
(which contracts during strong abduction of the little
finger and causes indentation of the skin overlying the
hypothenar).
• Normal sensation (the lesion is beyond the branching of
the superficial terminal branch within Guyon’s canal).
Deep branch, distal part: at (or distal to) the hamate bone
• Weakness and wasting of the radial hand muscles
innervated by the ulnar nerve (adductor pollicis,
interossei), with sparing of function of the hypothenar
muscles, and palmaris brevis muscle.
• Normal sensation.
Superficial branch: at or distal to Guyon’s canal
• Weakness of palmaris brevis muscle (no skin dimple on
extreme abduction of the little finger).
• Loss of sensation of the little and ring finger (ulnar half)
on the palmar side.
 Ulnar Neuropathy 635

774 Approximate area in which light touch and pain sensation are 774
reduced in an ulnar nerve lesion. N.B. Nerve root, plexus and cord
lesions do not ‘split’ the ring finger.

775 776

775, 776 Severe ulnar neuropathy causing wasting of the dorsal interossei (775) and wasting of the adductor pollicis and an ‘ulnar claw hand’ (776).

777 778

777, 778 Compressive mononeuropathy of the deep palmar branch of the ulnar nerve in a cyclist, causing wasting (and weakness) of the interossei.

779 780

779, 780 Severe ulnar neuropathy due to forearm injury causing the so-called ‘ulnar claw hand’ with flexion of the interphalangeal joints and
abduction of the little finger (777) and hyperextension of the fourth and fifth metacarpophalangeal joints (780).
636 Mononeuropathies
DIFFERENTIAL DIAGNOSIS
• Central weakness (upper motor neuron lesions):
diminished adduction of the little finger as an isolated
sign in the upper limb may also occur in patients with
supranuclear lesions.
• Motor neuron disease (amyotrophic lateral sclerosis):
brisk deep tendon reflexes and extensor plantar
responses.
• Spinal muscular atrophy: no sensory signs, but differs
from a pure motor ulnar neuropathy in that weakness is
beyond the distribution of the ulnar nerve.
• Syringomyelia: may mimic an ulnar neuropathy with
muscle wasting and weakness and sensory loss in the
hands, but the sensory loss is dissociated (impaired pain
and temperature with intact position and vibration sense)
and often outside the ulnar nerve territory (on the
forearms, shoulders and trunk), the upper limb reflexes
depressed or absent and sometimes there are long tract
signs.
• Spondylotic myelopathy: may cause weakness and
wasting of intrinsic hand muscles, but is usually
associated with urinary incontinence and long tract signs
(e.g. corticospinal tracts and posterior columns).
• T1 radiculopathy (e.g. cervical rib and band, Pancoast
tumor): weakness and wasting of the small muscles of the
hand, but also involves the thenar muscles and a
Horner’s syndrome may be present.
• Cervical radiculopathy (e.g. C8 nerve root compression
by a rare lateral disc prolapse between the vertebrae of
C7 and T1): the finger flexors rather than the intrinsic
hand muscles are weak.
• Lower brachial plexus lesion: weakness and sensory loss
outside the distribution of the ulnar nerve.
INVESTIGATIONS
Nerve conduction studies
Motor nerve conduction studies
• Stimulation of the ulnar nerve at the wrist, and above
and below the elbow (with the elbow flexed at 90° or
135°), while recording the compound muscle action
potential (CMAP) from an ulnar-innervated muscle in
the hand (e.g. abductor digiti minimi, first dorsal
interosseous), may reveal slowing of conduction across
the elbow segment (of >10 or 11 m/s compared with
the conduction velocity in the elbow) and/or a reduction
in amplitude of the CMAP with proximal stimulation, if
there is a lesion of the ulnar nerve at the elbow.
• Conduction velocity in the deep motor branch can be
compared with ulnar and median distal motor latencies
to the second interosseous space.
Sensory conduction studies
• An ulnar neuropathy at the elbow may cause a reduced
or absent SNAP at the little finger, while the SNAP of
the dorsal cutaneous branch is spared. This combination
alone therefore cannot reliably localize the site of an
ulnar nerve lesion at the wrist.
• For a suspected lesion of the superficial branch, sensory
conduction in the segment between the wrist and ring
finger (superficial branch) can be compared with that in
the median nerve fibers from the same finger.
EMG
• May identify ulnar nerve lesions that have led to axonal
degeneration even when nerve conduction velocity is
normal.
• May distinguish lesions of the T1 cervical nerve root,
brachial plexus or upper motor neuron.
MRI scan of site of compression
May identify compressive soft tissue masses (ganglia, cysts,
tumors).
Cervical spine x-ray
Not required if clinical and neurophysiologic findings point
to a lesion at the elbow. Otherwise, very common findings
in the middle aged and elderly population, such as
‘foraminal narrowing’, tend to be over-interpreted.
MRI scan of cervical spine
May exclude suspected syringomyelia or intramedullary
cervical spine tumor, but cavitation of the spinal cord may
also be present without causing symptoms.
DIAGNOSIS
Requires the presence of isolated weakness of muscles
exclusively in the distribution of the ulnar nerve (i.e. with
largely intact muscle contour of the thenar eminence)
and/or loss of sensation of skin innervated by the ulnar
nerve.
TREATMENT
Prevention
Adequate support of the arms in bedridden patients,
particularly paralysed arms.
Conservative treatment
• Avoid elbow flexion of >30°:
– Keep elbow extended as much as possible.
– Avoid leaning on the elbows or crossing the arms while
sitting.
– Hold the telephone receiver with the other hand.
– Wear a towel or thermoplastic splint at night.
• Avoid direct nerve compression:
– Place a pillow under the arm when sitting at a desk.
– Use a book-stand if reading for a prolonged period.
Surgical treatment
• If chronic compression excluded and if no improvement
in symptoms or if persistent disabling paresthesiae, pain,
or motor deficits.
• If habitual subluxation or luxation of the ulnar nerve
from the ulnar groove.
• If nerve compression by an arthrotic elbow joint.
PROGNOSIS
Depends on the cause and severity of the neuropathy; partial
lesions tend to recover spontaneously and over about 6–8
weeks. Severe ulnar neuropathy caused by compression at
the elbow may take 6–12 months after operation to recover,
and may not recover at all. Neurophysiologic studies can
help determine the prognosis.
 Lateral Cutaneous Nerve of the Thigh Neuropathy 637

LATERAL CUTANEOUS NERVE OF THE Trauma

THIGH NEUROPATHY • Avulsion fracture of the anterior superior iliac spine.
• Anterolateral thigh injury.

DEFINITION Iatrogenic
Dysfunction of the lateral cutaneous nerve of the thigh. • Misguided intramuscular injections.
• Abdominoplasty.
EPIDEMIOLOGY • Transfemoral angiography.
Not uncommon. • Gastroplasty for morbid obesity.
• Groin flap (plastic surgery).
ANATOMY • Laparoscopic repair of inguinal hernia.
Course of the lateral cutaneous nerve of the thigh • Laparoscopic cholecystectomy.
• Arises from the L2 and L3 nerve roots (781). • Lithotomy position for gynecologic procedures.
• Descends from the lateral border of the psoas muscle, • Removal of bone graft from ileum.
across the iliacus muscle, and just medial to the anterior • Renal transplantation.
superior iliac spine it is enclosed between two folds of the • Rotational osteotomy of acetabulum for congenital
lateral attachment of the inguinal ligament. dysplasia of the hip.
• Leaves the pelvis in various ways:
– Through a notch between the anterior superior iliac Tumors
spine and the inferior area of the iliac spine. • Psoas muscle tumor.
– Through the inguinal ligament, sometimes with two or • Osteoid osteoma of the hip.
three separate branches.
– Medial to the inguinal ligament, near the femoral nerve. The most common causes, after idiopathic syndrome, are
• Enters the upper anterior thigh in a fibrous canal within pregnancy, tight clothing or belts, scars, iliac bone grafts and
the fascia lata, and abruptly changes course from roughly intrapelvic masses.
horizontal to vertical; the degree of angulation is
influenced by flexion and extension of the hip.
• A few centimeters distal to the inguinal ligament,
the nerve divides into several branches which 781
innervate the skin on the lateral part of the thigh, Iliohypogastric nerve
as far down as the knee, but not beyond the upper
Ilioinguinal nerve
ridge of the patella.

ETIOLOGY Psoas muscle

Idiopathic entrapment
Nerve to
iliacus
Familial
Autosomal dominant meralgia paresthetica. Genitofemoral nerve

External compression Femoral nerve

• Pocket watch.
• Pregnancy.
Pudendal nerve
• Seat-belt trauma. Nerve to levator
• Tight trousers. ani and external
sphincter
Superior and
inferior gluteal nerves
Exercise or postural factors Perineal nerve

• Pregnancy. Sciatic nerve Dorsal nerve of

penis or clitoris
• Body building.
Nerve to Inguinal canal
• Gymnastics. sartorius muscle Ilioinguinal nerve
• Falling asleep in the siddha yoga position. Genitofemoral nerve:
Genital branch
Femoral branch
Cutaneous
nerves of thigh: Obturator nerve
Lateral Branches to:
Intermediate Obturator externus
Medial Adductor longus
Adductor brevis
Nerves to quadriceps: Adductor magnus
Rectus femoris Gracilis
Vastus lateralis Cutaneous
Vastus intermedius
Vastus medialis Posterior cutaneous
nerve of thigh
Saphenous nerve Sciatic nerve
781 Diagram of the lumbosacral plexus. (Reproduced with Common peroneal
permission from Aids to examination of the peripheral nervous Tibial
system 1986. Baillière Tindall, London.)
638 Mononeuropathies

HISTORY
• Variable pain, tingling, burning, and numbness in the
skin of the lateral thigh, commonly underlying where
one’s hands would rest in one’s trouser pockets, and
rarely as far down as the knee (‘meralgia paresthetica’)
(782).
• Pressure on the presumed point of entrapment, medial
to the anterior superior iliac spine, and hyperextension
of the hip; standing or walking may aggravate the
unpleasant sensations, and hip flexion may alleviate them.
• Occasionally, the syndrome is bilateral.
TREATMENT
Depends on the cause.
Conservative
• Remove constrictive items around the waist.
• Cool with ice packs three times daily.
• Non-steroidal anti-inflammatory drugs.
• Injection of steroid and an analgesic agent (e.g.
lignocaine) at the suspected trigger point at the inguinal
ligament.
• Transcutaneous nerve stimulation.

EXAMINATION Surgical
• Altered sensation of the skin in the center of the territory • Often a last resort.
innervated by the nerve; sensation to touch may be • Usually involves removal of a 4 cm (1.6 in) segment of
reduced, unpleasant, or even painful. the nerve (hopefully containing a neurinoma), at its
• Local hypertrichosis or alopecia may result from frequent passage through the inguinal ligament. The resulting
rubbing of the skin or dysfunction of autonomic sensory deficit does not usually lead to anesthesia
innervation. dolorosa.
• Neurolysis is an alternative to nerve transection. Re-
DIFFERENTIAL DIAGNOSIS exploration after an initially unsuccessful neurolysis is
L2 radiculopathy: usually unsuccessful.
• L2 vertebral body metastases.
• Retroperitoneal tumor. PROGNOSIS
• Thoracic vertebral body collapse. About one-quarter of patients show spontaneous recovery
within months or years.
INVESTIGATIONS
Nerve conduction studies
• Limited because it is not possible to stimulate or record
at a short distance proximal to the suspected site of
compression.
• The site for stimulation or recording is not standardized
because of the variable course of the nerve. It is therefore
determined by eliciting maximal sensations in the lateral
aspect of the thigh.
• The more distal nerve segment is therefore studied.
Results should always be compared with those of the
unaffected side (e.g. bilateral absence of SNAPs may
occur in normal subjects). Any asymmetric slowing of
conduction implies loss of the thickest fibers, which is 782
often accompanied by reduced amplitude of the SNAPs.
• Somatosensory evoked potentials (SSEPs) may also be
used to diagnose lesions of the lateral cutaneous nerve of
the thigh. To distinguish a lesion of the nerve from a
radiculopathy or plexopathy, the dermatomal SSEP of
the ilioinguinal nerve can be used for comparison.

EMG
Needle examination should be normal and, if abnormal,
may distinguish lesions of the lumbar nerve roots, lumbar
plexus and femoral nerve.

Lumbar spine x-ray

If there are associated symptoms (e.g. back pain, weight
loss) or if the area of sensory disturbance extends beyond
that innervated by the lateral cutaneous nerve of the thigh.

Other
• MRI upper lumbar spine.
• Abdominal and pelvic ultrasound.

DIAGNOSIS
Requires the presence of isolated sensory loss confined to
the distribution of the lateral cutaneous nerve of the thigh. 782 Area of skin innervated by the lateral cutaneous nerve of the thigh.
 Posterior Cutaneous Nerve of the Thigh Neuropathy 639

POSTERIOR CUTANEOUS NERVE Trauma

OF THE THIGH NEUROPATHY Wounds at the dorsal aspect of the thigh.

Iatrogenic
DEFINITION • Misguided intramuscular injections in the buttock.
Dysfunction of the posterior cutaneous nerve of the thigh. • Gluteal thigh flaps for reconstruction of the vagina
following resection of infiltrating carcinoma.
EPIDEMIOLOGY
Uncommon. Tumors
• Colorectal tumor.
ANATOMY • Hemangiopericytoma.
Course of the posterior cutaneous nerve of the thigh: • Venous malformation.
• Arises from the lower part of the lumbosacral plexus,
carrying fibers from the S1, S2, and S3 nerve roots. HISTORY
• Descends together with the inferior gluteal nerve Paresthesia and numbness in the skin over the lower part of
through the greater sciatic notch, below the piriform the buttock and the posterior aspect of the thigh.
muscle.
• Enters the thigh at the lower border of the gluteus EXAMINATION
maximus and close to the sciatic nerve, giving off Altered sensation of the skin over the lower part of the
branches to the skin of the perineum and scrotum (or buttock and the posterior aspect of the thigh may or may
labia majora). not be present (783).
• Descends superficially over the hamstring muscles to the
popliteal fossa, supplying fibers to the skin over the lower DIFFERENTIAL DIAGNOSIS
part of the buttock, the dorsal aspect of the thigh, and S2 radiculopathy.
the proximal third of the calf.
INVESTIGATIONS
ETIOLOGY EMG
External compression Needle examination may identify lesions of the S2 nerve
Prolonged sitting on the buttocks: roots, or sacral plexus.
• Sedentary occupation.
• Extensive cycling. DIAGNOSIS
• Prolonged gymnastic exercises performed on the Requires the presence of isolated sensory loss confined to
buttocks. the distribution of the posterior cutaneous nerve of the
thigh.

TREATMENT
Depends on the cause.
• Conservative: avoid pressure to the lower buttock and
dorsal thigh.
783 Area of skin 783 • Surgical: removal of the responsible mass lesion.
innervated by the
posterior cutaneous
nerve of the thigh.
640 Mononeuropathies
FEMORAL NEUROPATHY
DEFINITION
Dysfunction of the femoral nerve.
EPIDEMIOLOGY
Uncommon.
ANATOMY
Course of the femoral nerve
• Arises from the L2, L3 and L4 nerve roots within the
psoas muscle.
• Descends along the lateral border of the psoas muscle,
within the fascia between the psoas and the iliacus muscles.
• Proximal to the inguinal ligament it gives off branches
to the iliopsoas muscle.
• Descends further, beneath the inguinal ligament, lateral
to the femoral artery, and gives off branches to the
sartorius and the four parts of the quadriceps muscle.
• Distal to the inguinal ligament, sensory branches arise:
the intermediate cutaneous nerve of the thigh, and the
medial cutaneous nerve of the thigh, which innervate the
skin on the anterior and medial aspects of the thigh.
• The terminal branch of the femoral nerve, the purely
sensory saphenous nerve, passes within the quadriceps
muscle through Hunter’s canal, and about 10 cm (4 in)
above the knee it leaves this canal and gives of the infra-
patellar branch, which innervates the skin on the medial
aspect of the knee down to the tuberosity of the tibia.
• More distally, the saphenous nerve descends along the
medial side of the tibia and the anterior surface of the
medial malleolus, to supply the skin at the anterior and
medial surface of the knee, and the medial aspect of the
lower leg, including the ankle and arch of the foot.
ETIOLOGY
Femoral nerve
Compression (in the iliac fossa most commonly, and in the
inguinal region)
• Spontaneous hematoma in the psoas or iliacus muscle:
– Bleeding diathesis: anticoagulation, hemophilia (may be
bilateral).
– Ruptured aortic aneurysm.
– Trauma.
• Abdominal or pelvic surgery:
– Hematoma after nerve block.
– Catheterization via the femoral artery causing retro-
peritoneal hematoma or pseudoaneurysm in the groin.
– Laparoscopy.
– Stapling in laparoscopic hernia repair.
– Inadvertent suturing.
– Retractor blades (self-retaining) used in abdominal surgery.
– Vaginal delivery.
– Vaginal hysterectomy in lithotomy position (extreme
abduction and exorotation of the thighs may stretch the
femoral nerve).
– Abdominal hysterectomy.
– Hip abscess after parturition.
– Hip arthroplasty.
– Renal transplantation, associated with pressure from
retractor blades, hematoma or ischemia from ‘stealing’.
• Synovial cyst of the hip.
• Prolonged pressure on the abdomen after intoxication.
Penetrating injuries
Inflammation
• Inguinal lymphadenitis.
• Rheumatoid bursitis of the iliopsoas muscle.
• Heterotopic calcification.
Irradiation
Vincristine toxicity
Saphenous nerve
Iatrogenic
• Arthroscopy or menisectomy.
• Saphenous vein graft.
• Stripping of varicose veins, endoscopic dissection of
perforating veins, cryosurgery.
• Arterial reconstruction in the thigh.
Compression
• Entrapment:
– At the medial side of the knee.
– In the subsartorial canal.
– By a branch of the femoral artery.
• Neurilemmoma
• Bursitis of the pes anserinus, distal to the adductor canal.
Irradiation
HISTORY
Femoral nerve
• Sudden falls caused by buckling of the knee, particularly
if walking on an uneven road surface, climbing up an
incline, or descending a staircase (i.e. when the body
weight has to be supported with some knee flexion).
• Deep, severe, nerve trunk pain, with or without numb-
ness and paresthesia on the anterior aspect of the thigh
or inner aspect of the lower leg, may be present,
depending on the cause. Pain is common in diabetic
amyotrophy and psoas hematoma, which may mimic
femoral neuropathy, and is minimized by full flexion of
the hip. Acute pain in the flank of the abdomen is
reported particularly by patients with hematomas in the
iliacus muscle that compress the femoral nerve.
Saphenous nerve
Pain, numbness and paresthesia on the inner aspect of the
knee (if the infrapatellar branch is involved) and lower leg.
EXAMINATION
Femoral nerve
• Weakness of iliopsoas and the quadriceps, with iliopsoas
tested in the supine position, and quadriceps tested at a
mechanical disadvantage (because it is such a massive and
strong muscle) with the knee in flexion and the patient
sitting and trying to bring the lower leg forward against
resistance. This method also avoids testing the knee in
extension where a locked joint would have to be wrenched
open (which is painful and mild weakness easily missed).
• The most reliable proof of normal strength of the
quadriceps is the ability to rise from the floor, whilst
squatting on one knee, transferring the weight to the
other leg, flexed at the knee, and extending the other leg.
Of course, with advanced age this is determined more
and more by non-neurologic factors such as joint
stability, and the test becomes less reliable.
 Femoral Neuropathy 641

• A decreased or absent knee jerk is consistent, but not specific. EMG

• Wasting of the anterior aspect of the thigh invariably
occurs after some time.
• Loss of sensation over the anterior and medial aspect of
the thigh and the medial aspect of the lower leg is
present (784, 785).
• With progressive weakness, the knee is locked in a hyper-
extended position (genu recurvatum) during walking.
Saphenous nerve
Reduced sensation on the inner aspect of the knee (if the
infrapatellar branch is involved) and lower leg.
DIFFERENTIAL DIAGNOSIS
• Lumbosacral plexopathy or lumbar radiculopathy (L2,
L3, L4): it is crucial to carefully assess the strength of the
adductor muscles of the hip because weakness of the hip
adductors is not consistent with a femoral neuropathy
and more suggestive of a lesion in the lumbosacral
plexus, lumbar nerve roots L2, L3, L4; or obturator
nerve.
• Diabetic lumbar radiculopathy/plexopathy: an axonal
plexopathy (rather than demyelination) with EMG
features of denervation in the quadriceps as well as the
hip adductors and paravertebral muscles, indicating a
proximal root lesion.
INVESTIGATIONS
Nerve conduction studies
The saphenous nerve can be examined using peripheral
nerve conduction studies and with SSEPs.
Needle examination helps to distinguish femoral neuropathy
from diabetic amyotrophy which is an axonal neuropathy
(rather than demyelination) with features of denervation in
the quadriceps as well as the hip adductors and paravertebral
muscles.
CT scan of the pelvis
Reliably detects mass lesions in the pelvis that may cause
femoral neuropathy.
DIAGNOSIS
Requires the presence of isolated weakness of the iliacus,
iliopsoas, sartorius and/or quadriceps femoris and sensory
loss over the anterior thigh and medial lower leg. Can be
confirmed by EMG.
TREATMENT
Depends on the cause.
Conservative
Painful paresthesia may be alleviated with carbamazepine or
phenytoin.
Surgical
• Only if direct penetrating trauma with severe axonal
injury or complete interruption of nerve continuity.
• Retroperitoneal hematomas are usually decompressed
surgically or aspirated but this is to relieve pain; there is
no evidence that it improves recovery.
PROGNOSIS
Depends on the cause and severity of the neuropathy.
Femoral neuropathy after operation, from stretch or
compression tends to be followed by spontaneous recovery,
although this may take weeks or even months.

784 785

Area supplied by the

lateral cutaneous
nerve of the thigh
Area supplied by the
lateral cutaneous Area supplied by the
nerve of the thigh obturator nerve
Area supplied by the
obturator nerve
Area supplied by the
Posterior cutaneous femoral nerve
nerve of the thigh

Cutaneous branch of Cutaneous branch of

the peroneal nerve the peroneal nerve

Area supplied by the cutaneous

branches of the tibial nerve

784, 785 Area of skin innervated by the femoral nerve.

642 Mononeuropathies

OBTURATOR NEUROPATHY DIFFERENTIAL DIAGNOSIS

• Lumbosacral plexopathy or lumbar radiculopathy (L2–
L4).
DEFINITION • Femoral neuropathy: weakness of quadriceps muscle and
Dysfunction of the obturator nerve. depressed knee jerk.
• Osteitis or other disorders of the symphysis: pain in the
EPIDEMIOLOGY groin and medial part of the thigh similar to the
Rare, in isolation. neuralgic pain of an obturator neuropathy, but usually
local tenderness.
ANATOMY
Course of the obturator nerve (786)
• Arises from the union of the ventral branches of the L2,
L3 and L4 nerve roots within the belly of the psoas
muscle.
• Emerges on the medial border of the psoas muscle.
• Descends over the sacroiliac joint, along the wall of the
pelvis.
• Enters the obturator canal and gives off anterior branches
and posterior branches, before entering the thigh.
• The posterior branches innervate the adductor muscles
of the thigh (adductor brevis, adductor longus, and
adductor magnus) which stabilize the hip.
• The anterior branch ends as a sensory nerve innervating 786
an area of skin on the inner side of the thigh.
Iliacus
ETIOLOGY Femoral nerve
Psoas
• Obturator hernia. Obturator nerve
• Normal labor.
• Scar formation in the thigh.
• Pelvic masses (frequently also cause a femoral
neuropathy): Adductor brevis
– Psoas muscle hematoma.
– Retroperitoneal schwannoma. Quadriceps femoris:
Adductor longus
– Endometriosis Rectus femoris
• Iatrogenic: Vastus lateralis Gracilis
– Hip surgery, damaging the nerve by overstretching, Vastus intermedius
retractor blades, fixation screws, and cement.
Vastus medialis Adductor magnus
– Fixation of acetabular fracture.
– Urologic surgery with prolonged hip flexion.
– Intrapelvic surgery.
– Laparoscopic dissection of pelvic nodes.
– Gracilis flap operations. Common peroneal
nerve
HISTORY Superficial peroneal Deep peroneal nerve
• Weakness in the leg. nerve
Peroneus longus Tibialis anterior
• Pain, numbness and paresthesia on the inner aspect of
the knee (if the infrapatellar branch is involved) and Extensor digitorum
Peroneus brevis longus
lower leg. Extensor hallucis
longus
EXAMINATION
• Weakness of hip adduction.
• Depressed adductor muscle tendon reflex. Peroneus tertius
• Normal power of quadriceps muscle and normal knee
jerk.
• Reduced sensation on the inner aspect of the thigh Extensor digitorum
(787). brevis
• Broad based gait may be present.

786 Diagram of the obturator, femoral and common peroneal nerves

and the muscles that they supply.
 Gluteal Neuropathy 643

INVESTIGATIONS GLUTEAL NEUROPATHY

Nerve conduction studies
No nerve conduction technique is described.
DEFINITION
EMG Dysfunction of the superior and/or inferior gluteal nerves.
Needle examination may indirectly confirm the diagnosis by
demonstrating denervation activity confined to the hip EPIDEMIOLOGY
adductors. Uncommon.

CT scan of the pelvis ANATOMY

May detect a mass lesion in the pelvis causing obturator
neuropathy.
DIAGNOSIS
Requires the presence of isolated weakness of the hip
adductors, with or without sensory loss over the inner thigh.
Can be confirmed by EMG.
Course of the superior gluteal nerve (788)
• Arises from the L4, L5 and S1 nerve roots.
• Descends over the piriformis muscle, through the
suprapiriform foramen, and then between the gluteus
medius and minimus muscles.
• Innervates the gluteus medius and minimus and the
tensor fasciae latae muscles.

TREATMENT Course of the inferior gluteal nerve (788)

Depends on the cause.
• Conservative: painful paresthesia may be alleviated with
carbamazepine or phenytoin.
• Surgical: retroperitoneal hematomas are usually
decompressed surgically or aspirated but this is to relieve
pain; there is no evidence that it improves recovery.
PROGNOSIS
Depends on the cause and severity of the neuropathy.
787
• Arises from the L5, S1 and S2 nerve roots.
• Descends through the infrapiriform foramen, dorsolateral
to the sciatic nerve.
• Innervates the gluteus maximus muscle.
ETIOLOGY
Superior gluteal nerve
Trauma
• Fall on the buttocks (acute transient entrapment of the
superior gluteal nerve between the piriformis muscle and
the major sciatic incisure, or more permanent damage
due to secondary muscle fibrosis).
• Intramuscular injections in the buttocks:
– Incorrectly placed injections may damage the sciatic
nerve and superior gluteal nerve.
– Correctly placed injections, in the upper outer quadrant
of the buttock, may cause a partial lesion, with weakness
of only the tensor fasciae latae muscle.
• Hip surgery via a posterior approach (the so-called
‘Hardinge approach’).

788

L4
L5
Gluteus medius
S1 Gluteus minimis
S2
Superior Tensor fasciae latae
gluteal nerve
Inferior gluteal Gluteus maximus
nerve

787 Area of skin innervated by the obturator nerve. 788 Diagram of the gluteal nerves and the muscles that they supply.
644 Mononeuropathies

Compression SCIATIC NEUROPATHY

Coma or anesthesia injections: may damage the superior
gluteal nerve and the sciatic nerve.
DEFINITION
Inferior gluteal nerve Dysfunction of the sciatic nerve.
Compression
Colorectal tumor (often there is concurrent involvement of EPIDEMIOLOGY
the posterior cutaneous nerve of the thigh, with altered Not uncommon.
sensation of the inferior lateral buttock).
ANATOMY
Bilateral gluteal neuropathy Course of the sciatic nerve (789)
• Prolonged labor. • Arises from the L4, L5, S1, S2 and S3 nerve roots.
• Spondylolisthesis of L4 on L5 (perhaps by entrapment • In the pelvis (or gluteal region below) the fibers that will
within the piriform muscle). eventually form the tibial and common peroneal nerves
are arranged in two separate divisions: the medial and
CLINICAL FEATURES lateral trunk respectively. The peroneal nerve fibers
Superior gluteal nerve within the lateral division of the sciatic nerve are more
• Pain in the buttock. prone to compression than the tibial nerve fibers in the
• Difficulty walking (weakness of gluteus medius and medial division, so that a partial lesion of the sciatic nerve
minimus leads to weakness of hip abduction, which at this level may be indistinguishable from that of a
causes defective tilting of the pelvis and difficulty peroneal nerve palsy in the leg, including preservation of
swinging the contralateral leg forward). the ankle jerk.
• Leaves the pelvis through the sciatic foramen.
Inferior gluteal nerve • Courses below the piriformis muscle, although the
• Pain in the buttock. division that is destined to become the peroneal nerve
• Difficulty walking, and particularly descending stairs and (and sometimes the entire nerve) may pierce the
arising from a chair, due to weakness of hip extension piriformis muscle, or pass over it.
(gluteus maximus). • In the gluteal region, the nerves passes laterally and then
vertically downwards. Beneath the gluteus maximus it
DIFFERENTIAL DIAGNOSIS lies between the greater trochanter and the ischial
Proximal myopathy (all symmetric and slowly tuberosity, just posterior to the hip joint.
progressive) • At the inferior part of the buttock, the nerve is situated
• Dystrophinopathy. superficially in the subgluteal space amongst collagen and
• Limb girdle dystrophy. fat tissue. This is a site where the nerve may be damaged
• Polymyositis. by an inflammatory process or wrongly applied injection
• Acid maltase deficiency. fluids that can easily spread.
• The nerve descends dorsal to the femur, between the
Hip joint disorder knee flexor muscles.
• The medial division consecutively supplies the semi-
INVESTIGATIONS tendinosus, biceps femoris (long head) and semimem-
EMG branosus muscles, and contributes to the innervation of
Needle examination of the gluteii identifies denervation the adductor magnus muscle.
activity. • The lateral division innervates the short head of the
biceps femoris.
MRI scan pelvis • The sciatic nerve terminates at the proximal part of the
popliteal fossa, where it divides into the tibial and
DIAGNOSIS common peroneal nerve.
Requires the presence of isolated weakness of the gluteal • The main sciatic trunk does not have sensory branches
muscles. Can be confirmed by EMG. but the nerve is accompanied by the posterior cutaneous
nerve of the thigh (S1–S3) which innervates the skin of
TREATMENT the dorsal aspect of the thigh and the proximal part of
Depends on the cause. the calf.
• Conservative.
• Surgical: if more or less total nerve damage and no ETIOLOGY
evidence of recovery. Pelvis
Tumors
PROGNOSIS • Metastatic carcinoma.
Depends on the cause and severity of the neuropathy. • Neurofibroma, schwannoma.
• Lipoma.
 Sciatic Neuropathy 645

Vascular abnormalities Gluteal region

• Arteriovenous malformation. Compression
• False aneurysm of the abdominal aorta. • Prolonged sitting:
• Unruptured aneurysm of the common iliac artery or – Alcoholic- or drug-induced stupor on a toilet, or hard
internal iliac artery. rail.
• Ruptured aneurysm of the hypogastric artery. – Anesthesia in a sitting position.
– Meditation/sleeping in a cross legged position.
Endometriosis • Coma (usually drug induced with rhabdomyolysis).
• ‘Backpocket sciatica’ from credit cards or coins.
Childbirth
Cesarian section with epidural anesthesia. Vascular lesions
• Hematoma (bleeding diathesis).
Infection • Persistent sciatic artery.
Clostridium septicum, with immuno-incompetence. • False aneurysm, loop or abnormal collateral of the
inferior gluteal artery or superior gluteal artery.

Tumors
• Neurofibroma, schwannoma.
• Lipoma.
• Lymphoma.
• Hemangiopericytoma.
789
Gluteus medius Gluteus miniums Iatrogenic
Superior gluteal nerve • Hip surgery (total hip arthroplasty):
Piriformis Tensor fasciae latae – Ipsilateral: trochanteric wiring or extruding cement.
– Contralateral: rhabdomyolysis.
Inferior gluteal nerve
• Intramuscular injections that are not placed in the upper
and outer quadrant of the buttock or, even if
Gluteus maximus appropriately placed, cause muscle necrosis or fibrosis.
Sciatic nerve • Scoliosis surgery: Harrington’s operation.
• Femoral fracture surgery: closed nailing.
Semitendinosus • Heart surgery: mechanical compression or femoral artery
Biceps, long head occlusion.
• Femoral artery catheterization.
Semimembranosus Biceps, short head
Trauma
Adductor magnus • Hip fracture–dislocation.
• Femur fracture.
Tibial nerve Common peroneal
nerve
‘Pyriformis syndrome’
An anatomic variation in which the piriformis muscle
Gastrocnemius, compresses the sciatic nerve as it emerges from the pelvis
medial head through the greater sciatic notch. There must be objective
Gastrocnemius,
lateral head neurologic and neurophysiologic signs of sciatic nerve
Soleus
dysfunction (not just pain in the buttock); reproduction of
pain with deep palpation via the gluteal or rectal route;
Tibialis posterior negative EMG findings in the paraspinal muscles;
Flexor digitorum
Flexor hallucis longus
appropriate radiologic studies excluding lumbosacral nerve
longus root compression, and masses in the paravertebral area,
lower pelvis and sciatic notch; negative CSF examination
Tibial nerve (i.e. no signs of inflammation that could reflect nerve root
inflammation or infection); and ultimately confirmation by
operation and subsequent relief with nerve decompression.
Medial plantar nerve Lateral plantar nerve
to: to: Thigh
Abductor hallucis Abductor digiti minimi Tumors
Flexor digitorum brevis Flexor digiti minimi
Flexor hallucis brevis • Neurofibroma, schwannoma.
Adductor hallucis • Lipoma.
Interossei
Vascular lesions
Aneurysm of persistent sciatic artery or popliteal artery.

789 Diagram of the gluteal, sciatic, tibial and common peroneal nerves
and the muscles that they supply.
646 Mononeuropathies
CLINICAL FEATURES
• Wasting and weakness of the muscles innervated by the
sciatic nerve (see above): knee flexion (‘hamstring
muscles’– semitendinosus, semimembranosus, and biceps
femoris), and all movements of the foot and toes.
• Decreased or absent biceps femoris jerk.
• Decreased or absent ankle jerk. N.B. The peroneal nerve
fibers within the lateral division of the sciatic nerve are
more prone to compression than the tibial nerve fibers
in the medial division, so that a partial lesion of the sciatic
nerve may be indistinguishable from those of a peroneal
nerve palsy, including preservation of the ankle jerk.
However, if weakness of muscles innervated by the
peroneal nerve is accompanied by a depressed ankle
reflex, a lesion of the sciatic nerve or spinal roots is likely.
Isolated lesions of the medial division of the sciatic nerve
are far less common, usually non-compressive (e.g.
neurilemmoma), and manifest clinical features similar to
a tarsal tunnel syndrome (see tibial nerve, p.647).
• Diminished sensation of the posterior thigh and calf if
there is associated damage to the posterior cutaneous
nerve of the thigh, otherwise there may be sensory loss
in the territory of supply of the common peroneal and
tibial nerve branches of the sciatic nerve (790).
DIFFERENTIAL DIAGNOSIS
• L5 or S1 radiculopathy (deficits of motor, reflex and
sensory function in the typical distribution of the
myotome (tibialis anterior and posterior [L5] and
gastrocnemius/soleus and ankle jerk [S1]) and
dermatome (the dorsum of the foot and big toes [L5]
and the lateral border of the foot [S1]):
– Disc herniation.
– Radiculitis due to infection (e.g. borrelia).
• Lumbosacral plexopathy.
790
790 Area of skin innervated by the sciatic nerve (i.e. common
peroneal nerve and tibial nerve).
INVESTIGATIONS
Nerve conduction studies
• Motor nerve conduction studies are difficult to
undertake, unless needle electrodes are used for
stimulation, because the nerve lies so deeply.
• Abnormal late responses (soleus H-reflex, foot muscle F-
waves) are non-specific and may reflect a lesion of the
lumbosacral nerve roots or plexus or sciatic nerve, but
diminished sensory nerve action potentials of the sural
and/or superficial peroneal nerve are unlikely with
radiculopathy.
EMG
• Needle EMG can be extremely helpful in distinguishing
sciatic nerve lesions from other lesions.
• Denervation activity outside the territory of supply of the
sciatic nerve indicates a lumbosacral radiculopathy or
plexopathy.
• Denervation in the paraspinal muscles at the lumbosacral
level is typical of a lumbosacral radiculopathy, but even
in the absence of paraspinal muscle denervation EMG
can still identify denervation in the distribution typical of
a root lesion.
• Sciatic nerve lesions are more commonly characterized
by EMG signs of axonal loss than demyelination.
• Denervation in the short head of biceps femoris
distinguishes a lesion of the lateral division of the sciatic
nerve from the common peroneal nerve.
• EMG abnormalities may be very limited in particular
cases, such as sciatic nerve tumors which may damage
only a single, or very few fascicles. This can make it
difficult to localize the lesion accurately.
MRI of the lumbosacral spine, pelvis
or gluteal region
Reliably detects compressive lesions such as an intervertebral
disc or paraspinal mass.
DIAGNOSIS
Requires the presence of isolated weakness of the hip flexors
and muscles below the knee, and sensory loss over the
lateral lower leg and foot. Can be confirmed by EMG.
TREATMENT
Depends on the cause.
• Conservative: painful paresthesia may be alleviated with
carbamazepine or phenytoin. A systematic review of 19
randomized controlled trials of conservative treatments
for sciatica indicates that neither traction, non-steroidal
antinflammatory drug therapy (piroxicam, indomethacin,
phenylbutazone) nor exercise therapy was unequivocally
effective. Epidural steroids may be effective for sub-
groups of nerve root compression. More trials are
needed.
• Surgical: fasciotomy may be indicated if local pressure has
caused rhabdomyolysis of the gluteal compartment.
PROGNOSIS
Depends on the cause and severity of the neuropathy.
 Tibial Neuropathy 647

TIBIAL NEUROPATHY Synovial cyst

• Knee joint.
• Superior tibio-fibular joint.
DEFINITION
Dysfunction of the tibial nerve. Ankle strain (stretch injury)

EPIDEMIOLOGY Tumors of the nerve sheath

Not uncommon.
Tibial neuropathy at the ankle (in the tarsal tunnel)
ANATOMY Entrapment
Course of the tibial nerve • Idiopathic.
Proximal to the ankle • Poorly fitting footwear.
• Arises from a separate trunk within the ventral part of
sciatic nerve at a variable level above the knee. Trauma to the foot
• Carries fibers from the L4, L5, S1, S2 and S3 nerve roots. • Fractures or soft tissue injuries.
• In the popliteal fossa and calf, the nerve lies deep and • Strained flexor digitorum accessorius muscle.
well protected. • Post-traumatic fibrosis.
• In the popliteal fossa, the tibial nerve gives off the medial
cutaneous nerve (and the peroneal nerve gives off the Hypermobile ankle joint
lateral sural cutaneous nerve). In the calf, these two
branches unite to form the sural nerve. Hypertrophy of the abductor hallucis muscle
• In the calf, the tibial nerve innervates the two heads of
gastrocnemius, soleus, tibialis posterior, flexor digitorum Inflammation
longus and flexor hallucis longus muscles. • Rheumatoid arthritis.
• Leprosy (suspect residents of areas where leprosy in
At the ankle endemic, particularly when nerves are palpable).
• The tibial nerve descends behind and below the medial • Tenosynovitis.
malleolus through the tarsal tunnel which is superficial
and covered by the laciniate ligament, or flexor Metabolic disorders
retinaculum, that extends between the malleolus and the • Hypothyroidism.
medial aspect of calcaneus. The tarsal tunnel also contains • Hyperlipidemia (deposition of fat).
the posterior tibial artery and the tendons of tibialis
posterior, flexor digitorum longus and flexor hallucis Tumors
longus. • Ganglion arising from flexor hallucis longus tendon
• Within or immediately beyond the tarsal tunnel, the tibial sheath.
nerve branches into the medial and lateral plantar nerves • Intraneural ganglion.
and the calcaneal nerve. • Lipoma.
• The calcaneal nerve is purely sensory and carries • Nerve sheath cyst.
sensation from the medial side of the heel. • Neurilemmoma.
• The medial plantar nerve innervates the abductor hallucis
and short flexor digitorum muscles. Varicose veins
• The lateral plantar nerve supplies the flexor and abductor
digiti minimi, abductor hallucis and the interossei. Calcaneal neuropathy (sensory branch of the tibial
• The plantar nerves also carry sensory fibers from the sole nerve at the heel)
of the foot, and from their six terminal branches to the Compression below the deep fascia of the abductor hallucis
toes: the medial plantar proper digital nerve (from the muscle (often in athletes)
great toe), the lateral plantar proper digital nerve (from
the little toe) and four interdigital nerves (from the Medial plantar neuropathy
middle three toes). Entrapment
• The interdigital nerves course between the distal ends of the • Idiopathic:
metatarsal bones and each divide into two digital nerves. – Immediately distal to the tarsal tunnel.
– At the entrance of the fibromuscular tunnel behind the
ETIOLOGY navicular tuberosity.
Tibial neuropathy proximal to the ankle • Tight shoes.
Hematoma in the popliteal fossa • Prolonged standing on the rungs of a ladder with soft
• Blunt injury. shoes.
• Rupture of the popliteus muscle. • Immobilization in a bed with prolonged pressured
against the footboard (usually in hospital).
Entrapment • Local callus, fasciitis or arthritis.
• Idiopathic.
• Beneath a transverse fibrous band between the Physical exercise (‘jogger’s foot’)
gastrocnemius muscles.
• Beneath a tendinous arch at the origin of the soleus Inflammation
muscle. Leprosy.
648 Mononeuropathies

Tumors CLINICAL FEATURES

• Synovial cyst.
• Tibialis posterior tendon cyst.
• Malignant schwannoma.
• Plantar fibromatosis.
Lateral plantar neuropathy
Trauma to the foot
Fractures or soft tissue injuries.
Compression of its first branch between the intrinsic muscles
of the sole
Entrapment
• Tight shoes.
• Prolonged standing on the rungs of a ladder with soft
shoes.
• Immobilization in a bed with prolonged pressured
against the footboard (usually in hospital).
• Local callus, fasciitis or arthritis.
Medial plantar proper digital neuropathy
• Ill-fitting shoes.
• Scar tissue after bunion surgery.
• Arthritis of the first metatarsophalangeal joint.
Lateral plantar proper digital neuropathy
Traumatic neuroma secondary to bunion.
Plantar interdigital neuropathy (Morton’s
metatarsalgia)
Compression of one of the interdigital nerves of the foot,
which arise from the medial and lateral plantar nerves at the
point where they course between the metatarsal heads, just
before they divide into two digital nerves (791). The most
common site of compression is between the third and
fourth metatarsal bones, particularly in women. The heads
of the metatarsal bones and the deep transverse ligament
contribute to the compression. The swelling around the
nerve consists mainly of fibrous tissue; the term ‘neuroma’
is a pathologic misnomer.
791
Tibial nerve
Lateral plantar nerve
Medial plantar nerve
Inter digital nerves Compression site
Digital nerves
791 Compression site in Morton’s metatarsalgia.
Tibial neuropathy proximal to the ankle
• Wasting and weakness of plantar flexion (gastrocnemius,
soleus) and inversion (tibialis posterior), and toe flexion
(flexor digitorum longus):
– The calf muscles (gastrocnemius and soleus) are often
tested together (plantar flexion) but because they are so
strong, it is difficult to detect even marked weakness if
plantar flexion of the foot is tested against the examiner’s
hand with the patient supine. If the patient can walk, it is
preferable to examine the patient walking on their toes (i.e.
without the heel touching the floor) and then standing on
one leg, supporting the body weight on the toes, and then
hopping on the forefoot, without the heel touching the
floor. Of course, some people, such as the elderly, may not
be able to perform this maneuver due to other
impairments, despite normal power of the calf muscles.
– The soleus muscle can be tested reasonably selectively by
examining plantar flexion against resistance with hip and
knee flexed and the patient supine.
• Decreased or absent ankle jerk.
• Diminished sensation of the heel (calcaneal nerve), sole
of the foot (medial and lateral plantar nerves) and dorsal
aspect of the toes (digital nerves) (792).
Tibial neuropathy at the ankle (in the tarsal tunnel)
(Posterior) tarsal tunnel syndrome
• Unilateral usually, but may be bilateral.
• Pain (often burning) in the sole of the foot.
• Paresthesia in the toes.
• Symptoms may only be present at night or while
standing or exercising, such as walking, jogging, or
playing tennis.
• Wasting and weakness of the intrinsic muscles at the sole
of the foot (abductor hallucis and short flexor digitorum
muscles, and flexor and abductor digiti minimi, abductor
hallucis and the interossei) is usually asymptomatic and the
muscles are difficult to see or test separately. Indeed, many
normal individuals are unable to fan their toes. However,
there may be a difference compared with the normal,
particularly on palpating the muscle bulk of both feet.
• Sensory loss in the sole of the foot and toes in the
distribution of the medial (most commonly) or lateral
plantar nerve or both.
• Hoffmann–Tinel sign: local pain, paresthesia and an
electric sensation radiating across the sole of the foot
towards the toes, particularly the medial toes, elicited by
pressure or percussion over the tarsal tunnel, beneath the
medial malleolus, with the foot everted.
• An underlying cause may be apparent such as abnormal
postures of the foot, hypermobility of the ankle joint,
local masses and a perforating ulcer of the foot (cf.
leprosy).
Calcaneal neuropathy (sensory branch of the tibial
nerve at the heel)
Pain in one or both heels.
Plantar neuropathy
• Isolated paresthesia and sensory loss, usually in the
medial part of the sole (the medial plantar nerve is more
commonly affected).
• Weakness of the intrinsic foot muscles is usually
asymptomatic (see above).
 Tibial Neuropathy
Medial plantar proper digital neuropathy
• Pain, paresthesia and sensory loss on the medial side of
the great toe.
• Tenderness and thickening of the nerve.
Lateral plantar proper digital neuropathy
Pain, paresthesia and sensory loss on the lateral side of the
little toe.
Plantar interdigital neuropathy (Morton’s
metatarsalgia)
• Severe burning pain in the sole of the foot, between the
heads of the relevant metatarsal bones (usually the third
and fourth), and radiating to the relevant toes (usually
the third and fourth), with associated local paresthesia
and numbness. The pain may also radiate proximally.
• The symptoms are initially precipitated or exacerbated by
weight bearing on the feet (standing or walking),
external pressure between the heads of the metatarsal
bones, or passive dorsiflexion of the toes, but later
become continuous, unless footwear is removed.
• A sensory deficit may be present on the adjoining sides
of the toes.
DIFFERENTIAL DIAGNOSIS
Tibial neuropathy proximal to the ankle
• S1 radiculopathy (deficits of motor, reflex and sensory
function in the typical distribution of the myotome
(gastrocnemius/soleus and ankle jerk [S1]) and
dermatome (the lateral border of the foot [S1]):
– Disc herniation.
– Radiculitis due to infection (e.g. borrelia).
• Lumbosacral plexopathy.
792
792 Area of skin innervated by the tibial nerve.
649
Tibial neuropathy at the ankle (tarsal
tunnel syndrome)
• Musculoskeletal pain (no paresthesia, and normal
conduction in the tibial nerve):
– Plantar fasciitis.
– Stress fractures.
– Bursitis.
• Lumbar spinal stenosis (if pain and paresthesia in the foot
and toes during exercise).
• S1 radiculopathy: may cause paresthesia in the sole of the
foot, but usually other signs, such as absent ankle jerk
and weakness of the calf muscles.
• Morton’s neuralgia: shooting pain evoked by pressure
over one of the metatarsal bones (i.e. painful trigger
points over the sole of the foot).
• Medial plantar neuropathy: pain is precipitated by
pressure distal to the medial malleolus (as opposed to
immediately below it) and the clinical symptoms and
signs do not involve the lateral sole.
• Distal polyneuropathy, especially diabetic neuropathy,
causing burning feet may be quite similar to bilateral
tarsal tunnel syndrome, but there are usually additional
signs such as depressed ankle jerks and more extensive
sensory loss on both the ventral and dorsal aspects of the
feet.
• Sciatic nerve tumor may even initially mimic a tarsal
tunnel syndrome.
Plantar neuropathy
S1 radiculopathy: may cause paresthesia in the sole of the
foot, but usually other signs, such as absent ankle jerk and
weakness of the calf muscles.
Plantar interdigital neuropathy (Morton’s
metatarsalgia)
• Tarsal tunnel syndrome.
• Interdigital neuroma.
• Stress fracture or avascular necrosis of a metatarsal bone.
• Soft tissue injury to the foot.
INVESTIGATIONS
Nerve conduction studies
• A tibial neuropathy proximal to the ankle may be
detected by stimulating the tibial nerve in the popliteal
fossa and the ankle, and measuring the conduction
velocity between these points as well as the amplitude of
the motor evoked potential.
• Compression of the tibial nerve at the ankle (in the tarsal
tunnel) may be suspected if there is delayed motor
conduction (distal latency) in the medial and lateral
plantar nerves as assessed by stimulating at the ankle and
recording from the abductor hallucis and abductor digiti
minimi respectively. However, in order to distinguish
between a lesion in the tarsal tunnel and a more distal
lesion, both of which may affect one or more branches
of the tibial nerve, it is necessary to stimulate the tibial
nerve proximal to the tunnel and the plantar nerves distal
to the tunnel. Nevertheless, motor nerve conduction
velocity is not infrequently normal in tarsal tunnel
syndrome and the diagnosis may depend on sensory
conduction studies which are more sensitive.
650 Mononeuropathies
EMG
Needle EMG may be helpful if signs of denervation are
present in the intrinsic foot muscles, particularly abnormal
motor unit potentials, because fibrillation and fasciculation
potentials may occur in healthy people, particularly in the
abductor hallicus (and also the gastrocnemius).
Ultrasound, x-ray or MRI of the popliteal fossa,
lower leg, tarsal tunnel or foot
Frequently detects any mass lesion compressing the tibial
nerve (e.g. hematoma) or affecting the nerve (e.g. tumor).
DIAGNOSIS
Requires the presence of isolated weakness of plantar
flexion, ankle inversion and toe flexion, a depressed or
absent ankle jerk, and sensory loss over the sole of the foot.
Can be confirmed by EMG.
TREATMENT
Depends on the cause.
Tibial neuropathy proximal to the ankle
Treat the cause.
Tibial neuropathy at the ankle (tarsal tunnel
syndrome)
• Change footwear if it is poorly fitting.
• Antilepromatous drugs, if appropriate.
• Surgical decompression of the retinaculum: generally
successful, as in the carpal tunnel syndrome.
Calcaneal neuropathy (sensory branch of the tibial
nerve at the heel)
Surgical decompression.
Medial plantar proper digital neuropathy
• Change footwear or insert protective padding.
• Surgical excision of the nerve with concurrent
bunionectomy, if present, often provides dramatic relief
of persistent symptoms.
Plantar interdigital neuropathy (Morton’s
metatarsalgia)
• Review footwear and ensure appropriate fit without tight
pressure on the sole. Supplement with padding if
necessary.
• Injection of local anesthetic together with corticosteroid
affords recovery among one-third, and is associated with
later recovery after 2 years in another third.
• Carbamazepine taken orally may be helpful.
• Surgical excision of the abnormal tissue is radical but
frequently successful. A dorsal approach may facilitate
mobilization and prevent infection. A new ‘neuroma’
may form later.
• Neurolysis, by incision of the intermetacarpal ligament
above resection, is an alternative.
PROGNOSIS
Depends on the cause and severity of the neuropathy.
PERONEAL NEUROPATHY
DEFINITION
Dysfunction of the peroneal nerve.
EPIDEMIOLOGY
One of the most common mononeuropathies.
ANATOMY
Course of the peroneal nerve
Proximal to the ankle
• The common peroneal nerve arises from a separate
division within the sciatic nerve at a variable level above
the knee, sometimes as far proximal as the upper thigh.
• It carries fibers from the L4, L5, and S1 nerve roots.
• In the popliteal fossa, the lateral cutaneous nerve of the
calf arises from the common peroneal nerve to innervate
the skin of the upper third of the lateral lower leg (793).
• Below the knee the common peroneal nerve winds
around the head of the fibula, at which point it rests
directly on the periosteum and is particularly prone to
compression, stretch or other trauma.
• It then courses through the fibular tunnel (a fibro-
osseous canal between the insertion of the peroneus
longus muscle and the fibula) and enters the
compartment of the peroneal muscles, where it divides
into a deep and a superficial branch.
• The deep peroneal nerve innervates the tibialis anterior,
extensor digitorum longus and extensor hallucis longus
muscles.
• The deep peroneal nerve continues to descend as the
terminal branch of the deep peroneal nerve and lies
superficially at the dorsum of the ankle and foot where
it innervates the extensor digitorum brevis muscle and a
small area of skin in the web between the first and second
toes (794).
• The superficial peroneal nerve gives off motor branches
to the peroneus longus and brevis muscles about 10 cm
(4 in) proximal to the lateral malleolus and, in about
one-quarter of individuals, gives rise to a terminal motor
branch (the accessory deep peroneal nerve).
• The sensory branch of the superficial peroneal nerve
pierces the deep fascia of the lower leg and supplies the
skin of the lower half of lateral lower leg and dorsum of
the foot.
• A sural communicating branch joins the medial
cutaneous nerve of the calf, originating from the tibial
nerve, to form the sural nerve, which supplies the skin
on the lateral side of the heel, the sole and the little toe
(see pp.647, 654).
ETIOLOGY (CAUSES IN ISOLATION
OR COMBINATION)
Common peroneal neuropathy (or sometimes
only deep or superficial branch) at the level of
the fibular head
Postural change
• Prolonged squatting or kneeling (e.g. gardening,
strawberry picking, farming, delivering a baby).
• Sitting with legs crossed habitually.
• Bed rest, particularly with a bed rail.
 Peroneal Neuropathy 651

Running Compression of terminal branches of the

superficial peroneal nerve
Weight loss • Entrapment during sleep or sitting.
• Starvation (e.g. voluntary, prisoners of war). • Epidermoid cysts.
• Gastrointestinal or malignant disease. • Fascial bands.
• Anorexia nervosa. • Cannulation of foot veins.
• Arthroscopic knee surgery.
Iatrogenic • Intermittent pneumatic compression as prophylaxis for
• Plaster casts. deep vein thrombosis.
• Tight bandages.
• Arthroscopy of the knee. Lateral cutaneous nerve of calf lesions
• Arthrodesis (intramedullary) of the knee. Isolated compression.
• High tibial osteotomy.
• Malpositioning during anesthesia.

Congenital abnormalities
• Constriction band.
• Hereditary liability to pressure palsies.

Trauma
• Fracture of the femur or fibula. 793
• Inversion trauma of the foot.

Vascular
Hematoma in the popliteal fossa.

Tumors
• Exostosis of the fibular head or intraosseous cyst.
• Osteochondroma.
• Cysts of the lateral meniscus or tibio-fibular joint.
• Neurofibroma.
• Intraneural cysts.
• Hemangioma.
• Lipomatosis of the popliteal fossa due to steroids.

Pretibial myxoedema

Herniation of the gastrocnemius muscle

Peroneal neuropathy between the fibular

head and the ankle
Anterior compartment syndrome (deep peroneal nerve
compression) 793 Area of skin innervated by the common peroneal nerve.
• Swelling of necrotic muscle.
• Aneurysm of the tibial artery.
794
Lateral compartment syndrome (superficial
peroneal nerve compression)
• Compression as the superficial peroneal nerve as it
courses through the deep fascia of the lower leg after
giving off motor branches to the peroneal muscles.
Causes include athletic exercise (most commonly) and
callus formation after midshaft fracture of the fibula.
• Swelling of necrotic muscle.
• Idiopathic (may be bilateral).

Peroneal neuropathy at the ankle

Compression of the terminal branch of the deep peroneal
nerve at the anterior aspect of the ankle (‘anterior tarsal
tunnel syndrome’)
• Tight footwear (shoelaces, ski boots).
• Local contusion.
• Ganglion.
• Talotibial exostoses. 794 Area of skin innervated by the deep peroneal nerve.
652 Mononeuropathies
CLINICAL FEATURES
Common peroneal neuropathy at the level
of the fibular head
• The extent of the deficits depends on whether the lesion
involves the fascicles of the deep or the superficial
peroneal nerve or both, as well as the duration and
severity of the compression. Isolated deficits in the
distribution of the deep or superficial peroneal nerve are
most commonly due to a lesion of a separate fascicle at
the level of the head of the fibula than a more distal
lesion involving a single one of the two branches.
• Foot drop due to weakness of dorsiflexion of the ankle
(tibialis anterior; deep peroneal nerve), leading to a
typical stepping gait, in which there is compensatory
overaction of the hip and knee flexors to clear the
sagging foot during the swing phase. With mild
weakness, the gait may be normal but the foot swings
with less clearance from the floor than the normal side
and the patient may not be able to walk on the heel of
the affected side. With moderate weakness of tibialis
anterior, the foot may still land on the heel, but
immediately afterwards the ankle dorsiflexors give way
giving rise to a characteristic, flat-footed sound.
• Weakness of ankle eversion (peroneal muscles; superficial
peroneal nerve) and extension of the toes (extensor
digitorum longus and brevis and extensor hallucis
longus; deep peroneal nerve).
• Normal ankle jerk.
• Altered sensation (numbness or paresthesia) of the lateral
part of the lower leg and dorsum of the foot (superficial
peroneal nerve) and/or web between the first two toes
(deep peroneal nerve). The sensory deficit is often less
extensive, however, than might be expected from the
anatomic distribution of the innervation by the nerve(s).
Pain is uncommon, particularly when the neuropathy is
due to external compression.
N.B. Confusingly, dorsiflexors of the ankle and toes are
flexor muscles in the physiologic sense because they shorten
the leg, but have been called extensor muscles by
anatomists.
Peroneal neuropathy between the fibular
head and the ankle
Compartment syndromes (see below)
• Severe pain and red discoloration of the skin in the
affected part of the lower limb. The pain may arise
rapidly over hours and may also remit.
• Precipitated or exacerbated by strenuous physical exercise
(e.g. running).
• Dorsalis pedis arterial pulse may be absent.
Anterior compartment syndrome (deep
peroneal nerve compression)
• Weakness of dorsiflexion of the ankle (tibialis anterior)
and toes (extensor hallucis longus and extensor
digitorum longus), if it is possible to test in the presence
of severe pain.
• Sensory loss in the web between the first and second
toes.
Lateral compartment syndrome (superficial
peroneal nerve compression)
• Weakness of eversion of the ankle (short and long
peroneal muscles), if possible to test and if the cause
involves the superficial nerve before it gives off motor
branches to the peroneal muscles about 10 cm (4 in)
proximal to the lateral malleolus. Otherwise the only
neurologic deficits may be pain and sensory loss on the
dorsum of the foot.
• Sensory loss over the lower half of the lateral calf and
dorsum of the foot.
Peroneal neuropathy at the ankle
Compression of the terminal branch of the deep peroneal
nerve (‘anterior tarsal tunnel syndrome’)
• Painful paresthesia in the web space between the first and
second toes.
• Wasting of the extensor digitorum brevis on inspection.
Compression of terminal branches of the
superficial peroneal nerve
Pain and numbness in part of the dorsum of the foot.
Lateral cutaneous nerve of calf lesions
Pain and/or sensory loss in the popliteal fossa and lateral
part of the calf.
DIFFERENTIAL DIAGNOSIS
Common peroneal neuropathy at the level
of the fibular head
• Pyramidal tract lesions (e.g. stroke): cause weakness of
the flexor muscles of the leg, particularly dorsiflexion of
the ankle, and so may be confused with a peroneal
neuropathy, but because other flexor muscles of the leg
are affected, the gait pattern is different: there is
circumduction of the hip and the foot tends to be
dragged, rather than causing a stepping gait. Further-
more, the muscle tone and deep tendon reflexes are
increased and the plantar response extensor.
• Anterior horn cell lesions (e.g. motor neuron disease,
spinal muscular atrophy): may present with wasting and
weakness of the muscles innervated by the common
peroneal nerve, but usually there is clinical or
electrophysiologic evidence of denervation in at least
three of the four regions formed by the head, arms,
trunk and legs, and no sensory loss.
• L5 radiculopathy (e.g. L4/5 intervertebral disc herni-
ation or, less commonly, an extremely lateral prolapse of
the L5/S1 disc): also causes some weakness of the
extensors of the ankle and toes, nerve and sensory loss in
the lateral lower leg, but weakness of the extensor
hallucis longus is most pronounced and there is also
weakness of ankle inversion due to denervation of the
tibialis posterior muscle.
• Sciatic neuropathy: may present with a foot drop because
the lateral division of the sciatic nerve largely corresponds
with the peroneal nerve, and is more prone to compres-
sion than the portion corresponding to the tibial nerve.
• Compartment syndrome (anterior or lateral): often
involve the deep or superficial peroneal nerves.
• Distal myopathy: usually bilateral and involves muscles
outside those innervated by the peroneal nerves.
 Peroneal Neuropathy 653

INVESTIGATIONS Surgical decompression

Common peroneal neuropathy at the level
of the fibular head
Nerve conduction studies
• May be detected by stimulating the peroneal nerve at the
ankle, and below and above the fibular head while
recording from the extensor digitorum brevis muscle,
and identifying local slowing and/or conduction block.
Recording from tibialis anterior increases the chance of
detecting conduction block.
• Nerve conduction studies may also give a clue to the
prognosis. A reduced or absent SNAP of the superficial
peroneal nerve examined in a distal segment is consistent
with axonal loss in the peroneal nerve and indicates a
worse prognosis than conduction block.
EMG
Needle EMG may be particularly helpful if no conduction
abnormalities are found in the nerve segment across the
fibular head to differentiate a suspected common peroneal
neuropathy from an L4/5 radiculopathy, plexopathy or
sciatic neuropathy. Important muscles to study are the short
head of biceps femoris (innervated by the lateral division of
the sciatic nerve), and the tibialis posterior (supplied by L5
but not the peroneal nerve).
CT or MRI scan of the brain, spinal cord, lumbosacral
spine or leg
Frequently detects any lesion of the pyramidal tract or disc
protrusion.
• Clinical features compatible with entrapment of the distal
part of the superficial peroneal nerve where the nerve
pierces the fascia, 10 cm (4 in)above the lateral malleolus.
• Penetrating trauma, including immediate or delayed
peroneal palsy after surgery in the region of the knee,
which may have disrupted the continuity of the nerve
and which necessitates immediate exploration.
• Local mass lesion causing slowly progressive deficit such
as a nerve tumor, lipoma, cyst, or ganglion.
• Compartment syndrome, in which case immediate
fasciotomy is indicated.
PREVENTION
High risk patients
• Coma.
• Bedridden with leg paralysis: Guillain–Barré syndrome.
• Leg in plaster that reaches as high as the head of the
fibula.
Strategies of prevention
• Protect the common peroneal nerves at the head of the
fibular by soft padding around the head of the fibula.
• Make an appropriate window in plaster casts near the
head of the fibula.
• Instruct patients with a leg plaster to check the strength
of the toe extensors each day and if weak, to open the
plaster.
• Use care with removing a lower leg plaster by sawing or
cutting.

DIAGNOSIS
Requires the presence of foot drop due to weakness of
dorsiflexion of the ankle (tibialis anterior), eversion of the
ankle (peroneal muscles) and extension of the toes (extensor
digitorum longus and brevis and extensor hallucis longus);
a normal ankle jerk; and/or altered sensation of the lateral
part of the lower leg and dorsum of the foot (superficial
peroneal nerve) and/or web between the first two toes
(deep peroneal nerve). Can be confirmed by EMG.

TREATMENT
Depends on the cause.

Conservative
• Most cases are due to external compression or stretch
and recover spontaneously through remyelination within
weeks or months with a conservative approach of
observation and avoidance of further compression. A
lightweight plastic orthosis which does not further
compress the peroneal nerve at the head of the fibular
should be used to facilitate a safer and more comfortable
gait.
• Prolonged and severe compression during a long
anesthetic or deep coma may result in a persistent deficit
due to severe axonal damage (identified by EMG
examination). Surgical decompression is ineffective.
654 Mononeuropathies

SURAL NEUROPATHY • The sural nerve descends the calf more laterally, between
the Achilles tendon and the lateral malleolus.
• It curves around the lateral malleolus and ends at the
DEFINITION lateral border of the foot.
Dysfunction of the sural nerve. • It innervates the skin of the lateral side of the ankle, and
lateral border of the sole, up to the base of the fifth toe
EPIDEMIOLOGY (796).
Uncommon.
ETIOLOGY
ANATOMY Sural neuropathy in the popliteal fossa
Course of the sural nerve (795) • Baker’s cyst.
• Arises from the confluence of the medial cutaneous nerve • Arthroscopy, or other operations in the popliteal fossa
of the calf (from the tibial nerve) and the lateral (e.g. for varicose veins).
cutaneous nerve of the calf (from the common peroneal
nerve). Sural neuropathy in the calf
• The medial cutaneous nerve of the calf arises from the • Tight chains, lacing or elastic socks around the calf.
tibial nerve in the popliteal fossa and descends in the • High-topped footwear.
middle of the calf between the two heads of • Pressure against a hard ridge.
gastrocnemius. After it has pierced the fascia it is joined • Calf muscle biopsy.
beneath the skin by the branch from the lateral
cutaneous nerve of the calf, which originates from the Sural neuropathy at the ankle:
common peroneal nerve. • Sitting with, or on, crossed ankles.
• Adhesions after soft tissue injury.
• Avulsion fracture of the base of the fifth metatarsal bone.
795 • Fractured sesamoid bone in the peroneus longus tendon.
• Osteochondroma.
• Neuroma.
• Ganglion.
L4 • Sural nerve biopsy (complicated by persistent pain in
L5 about 5% of cases and infections or delayed wound
S1 healing at the site of biopsy in about 20% of patients).
S2
S3
S4 CLINICAL FEATURES
S5 • Pain, paresthesia or numbness of the lateral ankle or sole.
Sciatic nerve • Local pressure may aggravate the sensory symptoms
(Hoffmann–Tinel sign) and indicate the site of the
lesion.

DIFFERENTIAL DIAGNOSIS
S1 radiculopathy.

796
Common
peroneal nerve
Tibial nerve

Lateral cutaneous
Medial cutaneous nerve of the calf
nerve of the calf

Sural nerve

795 Origin and course of the sural nerve. 796 Area of skin innervated by the sural nerve.
 Pudendal Neuropathy 655

INVESTIGATIONS PUDENDAL NEUROPATHY

Nerve conduction studies
The amplitude of the SNAP is normally large and easy to
elicit with lesions proximal to the sensory ganglion (e.g. S1
radiculopathy) but are decreased or absent with lesions
causing axonal degeneration distal to the sensory ganglion
(e.g. of the sural nerve).
DIAGNOSIS
Requires the presence of isolated sensory loss the skin of the
lateral side of the ankle, and lateral border of the sole, up to
the base of the fifth toe. Can be confirmed by EMG.
TREATMENT
Depends on the cause:
• Advice how to avoid external compression, if causal (e.g.
special postures with crossed ankles, calves against hard
ridges, high-topped boots or tight chains).
• Surgery (neurolysis or nerve section) for compression by
post-traumatic fibrosis or tumors.
DEFINITION
Dysfunction of the pudendal nerve.
EPIDEMIOLOGY
Not uncommon.
ANATOMY
Course of the pudendal nerve (797)
• Arises from the S2, S3 and S4 nerve roots and innervates
most of the perineum.
• Descends from the pelvis below the piriformis muscle,
crosses the sacrospinous ligament, and enters the
perineum through the lesser sciatic notch.
• Courses anteriorly, with its associated blood vessels, along
the intrapelvic wall within a tunnel in the dense obturator
fascia (the obturator canal or Alcock’s canal) and
terminates by dividing into three branches:
– The inferior rectal (hemorrhoidal) nerve, which may also
arise from S3 and S4, supplies the external anal sphincter,
the perianal skin and the mucosa of the lower anal canal.
– The perineal nerve innervates the muscles of the
perineum (e.g. bulbocavernosus), the erectile tissue of
the penis, the external urethral sphincter, the distal part
of the mucous membrane of the urethra and the skin of
the perineum and labia/scrotum.
– The dorsal nerve of the clitoris/penis courses forward in
Alcock’s canal, pierces the urogenital diaphragm, and
sends a branch to the corpus cavernosum before running
forward on the dorsum of the clitoris/penis to innervate
the skin, prepuce and glans.

ETIOLOGY
External compression
• Prolonged bicycle ride.
• Colposcopy with suture through the sacrospinal ligament
and subsequent nerve entrapment.
• Operation on hip fracture using perineal post.

797 The pudendal nerve and its branches. 797

S2

S3

S4
Pubic bone

Pudendal nerve Striated urethral

sphincter
Inferior rectal nerve
Dorsal nerve of
External anal sphincter the penis
Perineal nerve
Bulbocavernosus muscle
656 Mononeuropathies

Stretch injury INVESTIGATIONS

• Childbirth: may cause anal sphincter muscle division, and
additional damage to the pudendal nerve. Vaginal
delivery also causes compression of the pudendal nerves.
• Straining during defecation.
• Pelvic fracture or surgery.
Polyneuropathy
• Diabetic.
• Alcoholic.
CLINICAL FEATURES
History
• Incontinence of urine or feces (pudendal neuropathy is
a common cause of fecal incontinence, mainly lesions in
the distal segment of the pudendal nerve or in the
inferior rectal nerve).
• Impotence.
• Altered sensation in one-half or all of the labia
majora/penis and perineum.
Examination
• Absent anal reflex (S3 and S4 nerve roots and pudendal
nerve): normally, pricking the perianal skin elicits a reflex
contraction of the external anal sphincter which can be
seen as a dimpling of the perianal skin.
• Absent bulbocavernosus reflex (S3 and S4 nerve roots
and pudendal nerve): normally, compression of the glans
penis evokes a contraction of the bulbocavernosus
muscle, which is best assessed clinically by palpation.
DIFFERENTIAL DIAGNOSIS
• Conus medullaris or cauda equina lesion.
• Polyneuropathy.
• Disturbance of vascular supply or autonomic innervation
(e.g. diabetes).
• Structural abnormalities of the pelvic floor and relevant
viscera.
Anorectal manometry
May assess the function of the pudendal nerve to some
degree.
Urodynamics
May assess the function of the pudendal nerve to some
degree.
Nerve conduction studies
Infrarectal stimulation of the terminal parts of the pudendal
nerves by mounting disposable surface electrodes on the
index finger of a disposable glove and recording the evoked
muscle potential from the external anal sphincter (inferior
rectal nerve) and urethral sphincter (perineal nerve), the
latter via electrodes mounted on a Foley catheter, is possible.
EMG
Needle EMG of the external anal sphincter, external urethral
sphincter (difficult and unpleasant for the patient),
bulbocavernosus and puborectalis muscles may be helpful.
Reflex responses
Stimulation of the clitoris/penis and recording from the
anal sphincter and bulbocavernosus.
Motor and somatosensory evoked potentials
Can be used to study central as well as peripheral nerve
conduction to and from the perineal region respectively.
CT or MRI scan of the sacral spine or pelvis
DIAGNOSIS
Requires the presence of incontinence of urine or feces,
impotence, and altered sensation in half or all of the labia
majora/penis and perineum.
TREATMENT
Depends on the cause.

FURTHER READING Etiology Treatments

SUPRASCAPULAR NEUROPATHY
Antoniadis G, Richter HP, Rath S, et al (1996).
Suprascapular nerve entrapment: experience
with 28 cases. J. Neurosurg., 85: 1020–1025.
Van Zandijcke M, Casselman J (1999) Supras-
capular nerve entrapment at the spinoglenoid
notch due to a ganglion cyst. J. Neurol. Neu-
rosurg. Psychiatry, 66: 245.
CARPAL TUNNEL SYNDROME
Epidemiology
Atroshi I, Gummesson C, Ornstein E, Ranstam J,
Rosen I (1999) Prevalence of carpal tunnel
syndrome in a general population. JAMA,
282: 153–158.
MacFarlane GJ (2001) Identification and preven-
tion of work-related carpal-tunnel syndrome.
Lancet, 357: 1146–1147.
Stevens JC, Beard CM, O’Fallon WM, Kurland
LT (1992) Conditions associated with carpal
tunnel syndrome. Mayo Clin. Proc., 67:
541–548.
Pathology
Jenkins PJ, Sohaib A, Akker A, et al. (2000) The
pathology of median neuropathy in
acromegaly. Ann. Intern. Med., 133:
197–201.
Diagnosis
D’Arcy CA, McGee S (2000) Does this patient
have carpal tunnel syndrome? JAMA, 283:
3110–3117.
Franzblau A, Werner RA (1999) What is carpal
tunnel syndrome? JAMA, 282: 186–187.
Witt JC, Stevens JC (2000) Neurological disor-
ders masquerading as carpal tunnel syndrome:
12 cases of failed carpal tunnel release. Mayo
Clin. Proc., 75: 409–413.
Dammers JWHH, Veering MM, Vermeulen M
(1999) Injection with methylprednisolone
proximal to the carpal tunnel: randomized
double blind trial. BMJ, 319: 884–886.
Ebenbichler GR, Resch KL, Wiesinger GF, Uhl F,
Ghanem A-H, Fialka V (1998) Ultrasound
treatment for treating the carpal tunnel syn-
drome: randomized ‘sham’ controlled trial.
BMJ, 316: 731–735.
Garfinkel MS, Singhal A, Katz WA, et al. (1998)
Yoga-based intervention for carpal tunnel syn-
drome. A randomized trial. JAMA, 280:
1601–1603.
SCIATIC NEUROPATHY
Vroomen PCAJ, de Krom MCTFM, Slofstra PD,
Knottnerus JA (2000) Conservative treatment
of sciatica: A systematic review. Journal of
Spinal Disorders, 13: 463–469.
 Chapter Twenty-three
Neuromuscular
Junction
Disorders
MYASTHENIA GRAVIS (MG)
DEFINITION
Myasthenia gravis is an acquired autoimmune
neuromuscular disorder in which serum IgG antibodies
(anti-AChRAb) to acetylcholine receptors (AChR) in the
post-synaptic membrane of the neuromuscular junction lead
to receptor loss, and skeletal muscle fatigue and weakness.
Myasthenic crisis is when weakness of the muscles of
respiration is severe enough for the patient to require
mechanical ventilation.
EPIDEMIOLOGY
• Prevalence: 5–18 cases per 100 000 population.
• Lifetime prevalence: 0.4 (95% CI: 0.2–0.7) per 1000.
• Incidence: 3(95% CI: 0.8–7) per 100 000 per year.
Incidence is age- and sex-related, with one peak in the
second and third decades affecting mostly women and a
peak in the sixth and seventh decades affecting mostly
men.
• Age: any age, from early childhood to old age.
– Thymoma-associated myasthenia gravis has a peak
incidence at 40–50 years of age.
– Non-thymoma-associated MG has a peak incidence at
10–30 and 60–70 years of age.
• Gender: M=F.
PATHOLOGY
End-plate abnormalities
A decrease in number (by about two-thirds) of nicotinic
acetylcholine receptors in the post-synaptic membrane at
neuromuscular junctions of skeletal muscle, with
simplification of postsynaptic folds and widening of the
synaptic cleft. The degree of reduction of AChRs generally
correlates with the severity of MG.
657
Thymus
• Thymoma occurs in 10% of patients, which may be
locally invasive.
• Medullary hyperplasia, characterized by lymphoid
follicles with germinal centers, occurs in about 60% of
patients, usually those presenting before 40 years of age.
ETIOLOGY
Autoimmune
• Anti-AChRAb reduce the number of AChRs by
accelerated endocytosis and degradation of the receptors,
functional blockade of acetylcholine (ACh) binding sites
and complement-mediated damage to the AChRs.
• B lymphocytes produce the anti-AChRAb but T
lymphocytes have a key role in the autoimmune response.
• The origin of the autoimmune response is unsolved. The
thymus has been implicated because about 75% of
patients have thymic abnormalities (85% thymic
hyperplasia [germinal-center formation] and 10–15%
thymoma) and thymectomy improves most patients.
• Genetic factors and abnormalities of immune regulation
may increase the likelihood of MG: there is a moderate
association with the HLA antigens B8 and DRw3; a
stronger association with HLADQw2 is still contro-
versial.
• A wide variety of other autoimmune diseases are
associated with MG (see below).
Disorders or factors that may exacerbate MG
• Thyroid disease: hyperthyroidism, hypothyroidism.
• Infection.
• Drugs: aminoglycoside antibiotics (streptomycin,
gentamicin, kanamycin, neomycin), polymyxin, colistin,
curare, quinidine, quinine and antiarrhythmic agents
such as procainamide.
658 Neuromuscular Junction Disorders
PATHOPHYSIOLOGY
• Muscle contraction depends on effective neuromuscular
transmission.
• Effective neuromuscular transmission depends on the
number of interactions between ACh molecules released
from the nerve terminal, and AChRs on the post-synaptic
membrane of the neuromuscular junction (798).
• The nicotinic ACh receptor is a glycoprotein that
projects through the muscle membrane and is composed
of five subunits (two a, one b, one d, and one g or e
subunit), arranged like barrel staves around a central
channel. Each of the two a subunits has an ACh-binding
site that is located extracellularly.
• In the resting state the ion channel of the AChR is closed.
• When ACh binds to the binding sites of both a subunits
of the AChR, the receptor’s cation channel opens
transiently, allowing the rapid passage of cations and
producing a localized electric end-plate potential.
• If the amplitude of this potential is sufficient, it generates
an action potential that spreads along the length of the
muscle fiber, triggering the release of calcium from
internal stores and leading to muscle contraction.
• At the normal neuromuscular junction, the end-plate
potentials are more than sufficient to generate muscle
action potentials consistently, without failures.
• At the myasthenic neuromuscular junction, the decreased
number of AChRs results in end-plate potentials of
diminished amplitude, which fail to trigger action
potentials in some fibers. When transmission fails at many
junctions, the power of the whole muscle is reduced,
causing muscle weakness. When contractions are
repeated, due to repeated nerve stimulation, the amount
of ACh released per nerve impulse normally declines
(runs down) after the first few impulses because the
nerve terminal is not able to sustain its initial rate of
release. If there is a reduced number of AChRs, as is the
case in MG, this ACh ‘rundown’ results in progressive
failure of transmission at more and more junctions and
muscle power progressively declines, causing fatiguability.
• AChRs normally undergo continuous turnover at the
neuromuscular junction, depending on regulating
influences of the motor nerves and neuromuscular
798
Axon
Vesicles
Mitochondria
Release site
Nerve terminal ↓ ACh
ACh receptors AChE
Muscle
Endplate
798 Diagrammatic representation of the neuromuscular junction,
showing the site of acetylcholine receptors of the post synaptic
membrane. (ACh = acetylcholine; AChE = acetylcholinesterase.)
transmission. Impairment of transmission induces
increased transcription of AChR genes. Consequently,
virtual complete recovery can occur in patients with MG
if the autoimmune attack can be controlled.
CLINICAL FEATURES
• The clinical hallmarks are muscular weakness and
fatiguability.
• The weakness tends to increase with repeated activity and
improves with rest.
• Weakness usually occurs in a characteristic distribution.
Ocular muscles
• The eyelid and extraocular muscles are the first muscles
to be involved in about 65% of patients, and are affected
at some stage of the disorder in >90% of patients, causing
ptosis (799) and diplopia, which are typically asymmetric.
• Weakness remains confined to the eyelid and extraocular
muscles in about 15% of patients (ocular myasthenia).
• At the bedside, fatiguable ptosis can be demonstrated by
asking the patient to maintain upward gaze without
blinking for 30–60 seconds.
Facial and bulbar muscle weakness
• Leads to loss of facial expression (a characteristic
‘flattened’ or ‘snarling’ smile), inability to whistle, and
difficulty with speech (‘mushy’ or nasal speech), chewing
and swallowing.
• Weakness of the neck extensors and muscles of
mastication may necessitate the patient to use one of
their hands to prop up their jaw.
Limb weakness
• Generalized weakness develops in about 85% of patients
and may affect the proximal and distal limb muscles, neck
extensors (and diaphragm).
• Initially, it may be episodic (e.g. sudden weakness of the
legs) and precipitated by emotional stress or infection.
• Characteristically, the weakness is increased by exercise,
tone is normal and deep tendon reflexes are generally
brisk.
• At the bedside, fatiguable limb weakness can be demon-
strated by asking the patient to elevate the outstretched
arm against resistance for 30–60 seconds, and comparing
the strength with the opposite rested limb.
799
799 Bilateral ptosis in a patient with myasthenia gravis.
 Myasthenia Gravis (MG) 659

Respiratory muscle weakness Botulism

May lead to shortness of breath and, in severe cases, • Generalized weakness.
ventilatory failure. • Dilated pupils.
• Ophthalmoplegia.
Associated other immune conditions • Nerve conduction studies: incremental response in
Susceptibility is determined through immune response repetitive nerve stimulation.
genes (e.g. HLA):
• Neuromyotonia (continuous muscle fiber activity caused Inflammatory demyelinating polyradiculoneuropathies
by peripheral nerve hyperexcitability). • Acute (Guillain–Barré) motor type.
• Thyroid disease: hyperthyroidism occurs in about 5% • Miller–Fisher syndrome.
(3–8%) of patients with MG, and hyper- and • Chronic.
hypothyroidism may aggravate myasthenic weakness.
• Polymyositis. Hyperthyroidism
• Rheumatoid arthritis. • Exacerbates MG.
• Systemic lupus erythematosus. • Generalized weakness.
• Thyroid function tests are abnormal.
SPECIAL FORMS
Neonatal myasthenia ‘Functional’ disorder
• A transient illness, lasting <1 month. MG is sometimes misdiagnosed as a ‘functional’ disorder,
• It occurs in 1/8 babies of myasthenic mothers. perhaps because of the fatiguing characteristics of the muscle
• It is due to placental transfer of maternal anti-AchRAb weakness, its worsening with stress, and the lack of other
to the baby. neurologic signs.
• Arthrogryposis (severe joint contractures occurring in
utero) is occasionally present. Ocular myasthenia
Progressive external ophthalmoplegia (mitochondrial
Juvenile myasthenia cytopathy)
Myasthenia in patients younger than 18 years of age is • Ptosis, diplopia.
termed juvenile myasthenia. The illness is similar to MG in • Generalized weakness in some cases.
young adults. • Mitochondrial DNA: abnormal.

Penicillamine-induced myasthenia Oculopharyngeal muscular dystrophy

• This is similar to adult MG, including the presence of
anti-AchRAb. Grave’s disease
• It usually resolves over several months after withdrawal • Diplopia.
of the drug. • Exophthalmos.
• Thyroid-stimulating immunoglobulin is present.
DIFFERENTIAL DIAGNOSIS
Generalized myasthenia Intracranial mass compressing cranial nerves
Congenital myasthenic syndromes • Ophthalmoplegia.
• Rare. • Cranial nerve weakness.
• Inherited, usually as recessive disorders. • CT or MRI brain abnormality.
• Early-onset.
• Not autoimmune disorders; anti-AchRAb is undetectable. Bulbar myasthenia
• Sophisticated electrophysiologic and immunocyto- Brainstem stroke
chemical tests required for diagnosis.
• Most forms are non-progressive. Motor neuron disease (pseudobulbar palsy)

Drug-induced myasthenia INVESTIGATIONS

• Penicillamine:
– Triggers autoimmune myasthenia.
– Recovery within weeks after drug withdrawal.
• Curare, procainamide, quinines, aminoglycosides:
– Weakness in normal people.
– Exacerbation of MG.
– Recovery after drug withdrawal.
Lambert–Eaton syndrome
• Weakness, fatigue, areflexia.
• 60% have associate small cell lung cancer.
• Nerve conduction studies: incremental response on
repetitive nerve stimulation.
• Antibodies to calcium channels are present.
Venoms (snakes, scorpions, spiders)
Anti-AChRAb assay
• 85–90% of patients with generalized MG and 60% of
patients with ocular disease have elevated titers of serum
antibodies to AChR that are detectable by an immuno-
precipitation assay.
• Anti-AchRAb is specific to MG and is therefore useful in
diagnosis.
• In an individual patient, the antibody titer generally
correlates with the severity of the disease, as shown by
the response to plasma exchange and, in the longer term,
to immunosuppressive drugs. Correlation of titer and
disease severity across patients, however, is poor (i.e. a
patient with mild disease can have a high titer and a
patient with severe disease can have a low titer) probably
because of antibody heterogeneity.
Continued overleaf
660 Neuromuscular Junction Disorders
Anti-AChRAb assay (continued)
• The antibody remains detectable in many patients in
clinical remission.
• Among the 10–20% of patients with MG who do not
have detectable anti-AChRAb, antibodies to another
neuromuscular junction protein muscle specific kinase
(MuSK) are present.
Antibodies to muscle specific kinase (MuSK)
• Inhibit the function of MuSK
• MuSK is a receptor tyrosine kinase that is an essential
component of the developing neuromuscular function.
Anti-striated muscle antibody assay
Detectable in >90% of patients with thymoma and in about
30% of other patients with MG.
Anticholinesterase (edrophonium chloride)
test (800, 801)
Edrophonium (Tensilon) is an anticholinesterase with a rapid
onset (30 seconds) and short duration (5 minutes) of action.
Indications
• The diagnosis has to be made immediately because of
disease severity.
• The patient is sero-negative for anti-AchRAb.
Procedure
• The test is undertaken in hospital where full resuscitative
equipment must be readily available.
• Pre-treat with atropine, 0.6 mg i.v. to counteract para-
sympathetic overstimulation and avoid occasional adverse
effects.
• Assess the strength of an objectively weak muscle or group
of muscles (e.g. degree of ptosis or diplopia; vital capacity).
• Inject a test dose of edrophonium (Tensilon) 1–2 mg i.v.
• If no adverse effects develop, inject a further 5–6 mg.
• A positive response is indicated by an obvious
improvement in strength within 1 minute (e.g. abolition
of ptosis, an increase in the length of time that the arm
can be kept outstretched, and increase in vital capacity)
which disappears within 5 minutes.
• This test can be combined with EMG measurements of
neuromuscular transmission.
An alternative, less commonly used, procedure
• Administer atropine intramuscularly into one leg and
wait for a placebo response.
• If negative, administer neostigmine 1.5 mg i.m. into the
other leg.
The atropine counteracts parasympathetic overstimu-
lation and also serves as a placebo control for motor effects.
Neostigmine i.m. provides more time for tests and is less
risky than i.v. edrophonium (i.e. from anaphylaxis).
EMG
Results can be misleading in patients who are already receiv-
ing anticholinesterase medication; in such patients the drug
should, if possible, be withdrawn for 1 week before the study.
Repetitive nerve stimulation
• A useful supplement to the clinical diagnosis when
antibody testing is negative.
• The nerve to a clinically weak or proximal muscle is stimu-
lated supramaximally at a rate of 3 per second and the
muscle action potentials are recorded from surface elec-
trodes over the muscle. A progressive decrement in the
amplitude of the evoked action potential of 15% or more is
considered abnormal (802). The test is generally unpleasant
for the patient, and false positives and negatives may occur.
Single fiber EMG
• This test detects delayed or failed neuromuscular
transmission in pairs of muscle fibers supplied by
branches of a single nerve fiber (803, 804).
• A sensitive but not highly specific test. Positive in about
90% (88–92%) of cases, its specificity is limited because
of positive findings in other disorders of nerves,
neuromuscular junction, and muscle.
Chest x-ray and CT or MRI of the mediastinum
(thymoma, thymic hyperplasia)
• CT and MRI reliably reveal enlargement of the thymus
gland.
• The thymus is normally detectable until mid-adulthood but
persistence of the thymus in a patient with MG who is over
40 years of age, or an increase in its size in any patient on
repeated scanning, raises the possibility of a thymoma.
• If negative initially, it should be repeated after 2–3 years
in those who are positive for anti-AchR and antistriated
muscle antibody.
Screen for other disorders
• Antinuclear antibody.
• Antithyroid antibodies.
• Rheumatoid factor.
• Fasting blood glucose.
• Thyroid function tests.
• Pulmonary function tests.
• Tuberculin test.
• Bone densitometry in older patients.
• Mitochondrial DNA analysis (if ocular myasthenia).
Screen for disorders that may interfere with
immunosuppressive therapy
• Hypertension.
• Unsuspected infections such as tuberculosis.
• Peptic ulcer.
• Occult gastrointestinal bleeding.
• Renal disease.
• Diabetes.
• Osteoporosis.
Tests
• Blood pressure, fundoscopsy, EKG, serum creatinine.
• Occult blood.
• Fasting blood glucose.
• Chest x-ray.
• Pulmonary function tests.
• Tuberculin test.
• Bone densitometry in older patients.
DIAGNOSIS
• As a diagnosis of MG almost commits the patient to long
term medical or surgical treatment that carries substantial
risks, every effort should be made to establish the
diagnosis before initiating treatment.
 Myasthenia Gravis (MG) 661

• Anti-AchRAb testing is reliable, and a positive result is Group I

virtually definitive in the majority of patients, although a • Onset: early (<40 years).
negative assay result does not exclude MG. The other • Gender: F>M.
tests listed above may be useful in patients with doubtful • Weakness: generalized usually.
anti-AchRAb results. • Thymus: hyperplasia.
• Other conditions that mimic MG should be excluded, • Anti-AChRAb titers: high.
and associated conditions that may influence the choice
of treatment should be searched for. Group II
• Gender: M=F.
CLASSIFICATION • Weakness: generalized weakness usually.
Four main groups of acquired myasthenia gravis can be • Thymus: thymoma (which may be benign or locally
distinguished which have implications for treatment: invasive).
• Anti-AChRAb titers: intermediate.

800, 801 Myasthenic ‘snarl’ 800 801

(800) as the patient tries to
open his eyes, due to facial
weakness, before an
edrophonium test. Restored
muscle power (801) within
minutes of injection of
edrophonium 5 mg i.v.
(Courtesy of Dr AM
Chancellor, Neurologist,
Tauranga, New Zealand.)

802 803

804
802 Supramaximal repetitive ulnar nerve stimulation at 5 Hz showing
ten successive muscle action potentials recorded over abductor digiti
minimi and a decrement in amplitude of more than 15% between the
first and fourth response.

803, 804 Single fiber EMG. 803 Normal ‘jitter’ of the second,
compared with the first muscle fiber, supplied by a single nerve fiber.
The responses of the second muscle fiber, relative to the first, are
virtually superimposed upon one another due to the absence of any
delay in neuromuscular transmission. 804 Myasthenia gravis patient in
whom ‘jitter’ is substantially increased due to variable delay in
neuromuscular transmission.
662 Neuromuscular Junction Disorders
Group III
• Onset: late (>40 years).
• Gender: M>F.
• Weakness: generalized or ocular.
• Thymus: atrophy/involution.
• Anti-AChRAb titers: low.
Group IV
• Weakness: ocular only or generalized.
• Thymus: atrophy/involution.
• Anti-AChRAb titers: absent, but autoantibodies to other
muscle cell targets are implicated.
MODES OF THERAPY
In general, four methods of treatment are used:
• Anticholinesterase agents.
• Thymectomy.
• Immunosuppression.
• Short term immunotherapies.
Anticholinesterase medication
• Most useful in mild cases.
• Pyridostigmine (Mestinon) 30–120 mg p.o., or
neostigmine bromide 15–30 mg p.o.; both given every
3–4 hours except at night.
• Neostigmine can also be given subcutaneously or
intramuscularly (15 mg p.o. is equivalent to 1 mg
subcutaneously or intramuscularly), preceded by atropine
0.5–1 mg.
• Pyridostigmine usually produces a smoother response.
• Adverse effects are caused by parasympathetic stimulation:
pupillary constriction; colic; diarrhea; increased salivation,
sweating, lacrimation, and bronchial secretions.
• Gastrointestinal adverse effects can be controlled with
propantheline bromide, atropine or loperamide.
Thymectomy
Thymectomy has two purposes: to prevent the spread of
thymoma and to induce remission, or at least improvement,
permitting a reduction in immunosuppressive medication.
Indications
Thymic tumors must be removed surgically since they may
spread locally and become invasive, though they rarely
metastasize. The tumor and remaining thymus gland should
be removed as completely as possible. If not, or if it is invasive,
marker clips should be placed at the tumor site during surgery
and focused radiation treatment carried out postoperatively.
After removal of a thymoma, some patients become weaker,
presumably as a loss of a suppressive effect of the thymoma,
and require further immunosuppressive treatment.
Thymectomy is indicated for generalized MG in patients
who are between adolescence and about 60 years of age.
The only reason for delaying thymectomy in pre-pubertal
children, if possible, is because of the role of the thymus in
development of the immune system. It is uncertain whether
thymic tissue persists in patients with MG who are older
than 60 years.
Thymectomy has also been undertaken in purely ocular
MG with good results. Thymectomy should never be
performed as an emergency procedure. The patient’s strength
and respiratory function in particular should be optimized
preoperatively, but not with immunosuppressive agents if they
can possibly be avoided because they increase the risk of
perioperative infection. If the vital capacity is below 2 l,
plasmapheresis should be carried out preoperatively.
Technique
Thymectomy should remove as much of the thymus as
possible. Although a cervical incision with mediastinoscopy
is associated with a smaller scar and less postoperative pain,
it has not been confirmed that this method consistently
enables the thymus to be removed completely. A sternal-
splitting approach with exploration extending into the neck
optimizes removal of all thymic tissue and related fat.
Epidural morphine minimizes postoperative pain and
thereby enhances respiratory effort. For a few days after
thymectomy, the requirement for anticholinesterase
medication may be decreased and so only about three-
quarters of the preoperative dose needs to be given
intravenously postoperatively.
Outcome
The benefits of thymectomy are usually delayed until
months to years after surgery. Clinical remission occurs in
about one-third of patients and remission in another half,
which is substantially better than if not treated surgically.
Mechanism of effect
The mechanism by which thymectomy produces benefit
in MG is still uncertain. Possible reasons include removal of
a source of continued antigenic stimulation, removal of a
reservoir of B cells secreting AChR antibodies, and
correcting a disturbance of immune regulation. Whatever,
generally, anti-AChRAb levels fall after thymectomy.
Immunosuppressive treatment
Indications
Immunosuppressive treatment should be considered when
weakness is not adequately controlled by anticholinesterase
drugs and is sufficiently distressing to outweigh the risks of
possible adverse effects of immunosuppressive drugs.
Duration
Treatment must be continued for a prolonged period, often
permanently.
Corticosteroids
The most consistently effective immunosuppressive drugs but
they have the largest array of adverse effects. When initiating
steroid therapy in patients with moderate to severe generalized
weakness, the patient should be hospitalized because of the
risk of transient steroid-induced exacerbation in the first few
weeks in up to one-half of patients. This risk is minimized by
beginning with a daily dose of 10–20 mg of prednisone and
increasing it gradually by about 5 mg every 2–3 days,
according to the patient’s clinical condition and response, until
a satisfactory response is achieved or the dose reaches
50–60 mg a day. However, the favorable effect of steroids may
take 2–4 weeks to become apparent and maximal benefit may
not be realized until after 6–12 months or more.
After about 3 months of daily high-dose treatment, a
switch to an alternate day regime may help to minimize
adverse effects but a small dose of prednisone may be
required on the ‘off ’ day if muscle strength fluctuates
significantly. Over the next few months to years, the total
dose should be tapered slowly (e.g. 5 mg/month) to the
minimum effective dose. Few patients are able to be weaned
off prednisone completely.
 Myasthenia Gravis (MG)
The mechanisms by which corticosteroids work in MG
may include a reduction in anti-AChRAb levels, diminished
anti-AChRAb reactivity of peripheral blood lymphocytes,
and increased synthesis of AChRs.
Azathioprine
Azathioprine is metabolized to the cytotoxic derivative 6-
mercaptopurine and acts predominantly on T cells. It is
most useful for patients in whom steroids are contraindi-
cated, in whom steroids evoked an insufficient response, or
as an adjunct to permit a reduction in steroid dose. The
drug is well tolerated but up to 10% of patients have an
idiosyncratic influenza-like reaction (fever, myalgia and
malaise) and it takes many months to 1 year to show its
therapeutic effect.
Treatment begins with a test dose of 50 mg daily for
1 week and, if tolerated, the dose is gradually increased to
the target dose of 2–3 mg/kg total body weight (not lean
body mass) per day. If patients are also taking allopurinol,
the dose of azathioprine must be reduced by as much as 75%
and the white blood cell count and mean corpuscular volume
monitored closely. Complete blood count and liver function
tests should be undertaken weekly for the first 8 weeks and
every 3 months thereafter. Treatment is usually lifelong.
Combined prednisolone and azathioprine
Among patients with moderate or severe symptoms, a
randomized controlled trial showed that the combination
results in lower doses of prednisolone, fewer relapses, longer
periods of remission, and fewer adverse effects than
prednisolone alone.
Methotrexate
Weekly methotrexate, 5–10 mg, is an alternative to the few
patients who are unable to tolerate, and need, azathioprine.
Mycophenolate mofetil
A novel and potent immunosuppressive agent, which blocks
purine synthesis in activated T and B lymphocytes. In an
open-label study, the addition of mycophenolate mofetil 1 g
twice daily for 6 months to corticosteroids improved
function within 2 weeks to 2 months in 8 out of 12 patients.
No major adverse effects were observed. Randomized
controlled trials are required.
Short term immunotherapies
Plasma exchange
Three to five daily exchanges of 50 ml/kg body weight may
produce striking short term clinical improvement. The
therapy is useful when combined with immunosuppressive
drug treatment, if patients have severe disease and can
enable patients who might normally require hospital
admission to remain at home.
Intravenous immunoglobulin (IVIG)
IVIG 0.4 g/kg body weight for 5 days may be as effective
as a 5-day course of plasma exchange.
663
TREATMENT
Treat or avoid disorders and drugs that interfere
with neuromuscular transmission
• Thyroid disease: hyperthyroidism, hypothyroidism.
• Infection.
• Drugs: aminoglycoside antibiotics (streptomycin,
gentamicin, kanamycin, neomycin), polymyxin, colistin,
curare, quinidine, quinine and antiarrhythmic agents
such as procainamide.
Anticholinesterase medication to enhance
neuromuscular transmission
• First line treatment for all patients.
• Pyridostigmine (Mestinon) 30–60 mg every 4 hours has
an effect within 30 minutes that peaks at 2 hours and
gradually declines thereafter. The timing of administra-
tion should be tailored to the patient’s needs, i.e. to
avoid peaks and valleys of strength, and before meals or
physical activity. The maximum daily dose rarely exceeds
120 mg every 3 hours. Higher doses may increase
weakness (receptor desensitization or rarely cholinergic
block). A sustained-release preparation of Mestinon
(Timespan) should only be used at bedtime, and only if
the patient experiences significant weakness during the
night or in the early morning.
• Provides symptomatic relief in most patients, particularly
when weakness is mild, but the improvement is often
incomplete and wanes after a few weeks or months.
• If weakness interfering with normal activities persists,
additional measures should be considered as described
below.
Ocular cases
• Anticholinesterase medication suffices for a few patients.
• Prednisolone, in relatively low dose (e.g. 30 mg on
alternate days), is commonly effective for these patients
who have persistent symptoms despite anticholinesterase
medication.
Thymoma patients
Group II patients
• Thymectomy is indicated because the tumor can infiltrate
local mediastinal structures.
• The myasthenic symptoms do not usually respond to
removal to the thymus and tumor in these patients.
• Immunosuppressive drug treatment (prednisolone and/or
azathioprine) is often effective in controlling myasthenic
symptoms before thymectomy and afterwards.
Patients without thymoma
Group I patients
• Thymectomy is indicated for patients in group I (see
above) with moderate or severe weakness; about 75% of
patients will show improvement or remission.
• Immunosuppressive drug treatment should be
considered in those who fail to respond to thymectomy
or who are too ill to undergo surgery.
Group III and IV patients
Immunosuppressive drug treatment should be considered
in these patients who have persistent symptoms despite
anticholinesterase medication; about 80% of patients treated
with prednisolone and/or azathioprine at optimal dose
regimens show marked improvement or remission.
664 Neuromuscular Junction Disorders
Pregnant patients with myasthenia
Weakness does not usually increase during pregnancy, but
may do so in the postpartum period for a few months:
• Maintain existing (pre-pregnancy) treatments, including
immunosuppressive drugs, during the pregnancy; there
is no evidence that prednisolone or azathioprine, as used
in MG, are teratogenic.
• Plasma exchange can also be used if needed.
Neonatal myasthenia
General care of the infant (intubation and assisted
ventilation, nasogastric feeding, and removal of pharyngeal
secretions) should be provided and anticholinesterase
medications given.
Myasthenic crisis
Crisis may be precipitated by infection, initiation of
corticosteroid treatment at high dosage, or inadequate
treatment:
• Maintain the airway and provide assisted ventilation and
anticholinesterase medication.
• Intravenous immunoglobulin (IVIG) therapy or plasma
exchange can be used if needed.
Cholinergic crisis
Crisis occurs due to excess anticholinesterase medication:
• Maintain the airway and provide assisted ventilation and
atropine, if not already being given.
• Withdraw anticholinesterase medication temporarily, and
reintroduce later at a reduced dose.
• Immunosuppressive drug therapy and/or plasma
exchange can be used if needed.
PROGNOSIS
The prognosis for patients with MG has improved
dramatically in recent years. Now, with optimal care, the
mortality rate is zero. Remission or substantial improvement
can be expected in 80% of patients and most patients lead
normal lives but take immunosuppressive medication indefi-
nitely. Without treatment, 20–30% will die within 10 years.
LAMBERT–EATON MYASTHENIC
SYNDROME (LEMS)
DEFINITION
Lambert–Eaton myasthenic syndrome is an antibody-
mediated autoimmune disorder of neuromuscular
transmission, characterized by muscle weakness, hyporeflexia
or areflexia and autonomic dysfunction.
HISTORY
In 1953 Anderson and colleagues reported a case of a
47 year old man with a bronchial neoplasm, progressive
muscle weakness and hyporeflexia who developed
progressive apnea following administration of succinyl-
choline. They concluded that there was ‘strong clinical
evidence for believing that the severe muscle weakness was
of the myasthenic type’.
In 1956, at a meeting of the American Physiological
Society, Lambert, Eaton and Rooke presented a report of
six patients with defective neuromuscular transmission
associated with malignant neoplasms. They identified that
some of the clinical and electrophysiologic features were
different from what was expected in myasthenia gravis.
Subsequently in 1957, Eaton and Lambert summarized the
clinical and electrophysiologic characteristics of the
myasthenic syndrome.
EPIDEMIOLOGY
• Incidence: rare.
• Age: onset >40 years in >80% of patients.
– Carcinoma-associated LEMS: mean age at presentation
58 years (rarely before 30 years of age).
– LEMS without carcinoma: mean age at presentation
48 years.
• Gender: M≥F (?dependent on smoking patterns).
ETIOLOGY AND PATHOPHYSIOLOGY
The release of neurotransmitters at presynaptic motor nerve
terminals of the neuromuscular junction and autonomic
neurons depends on the influx of calcium through the
presynaptic voltage-gated calcium channels (VGCC).
LEMS is caused by IgG autoantibodies directed against
the presynaptic VGCC, particularly the P/Q type of VGCC,
leading to inhibition of calcium flux, a reduction in release
of acetylcholine from the motor nerve terminal into the
synaptic cleft of the neuromuscular junction, and muscular
weakness.
There are two broad groups of patients with LEMS:
those with an underlying malignancy and those without, but
both share the same clinical and electrophysiologic
characteristics.
Malignancies associated with LEMS
• Small cell carcinoma of the lung (SCLC).
• Lymphoproliferative disorders.
• Carcinoma of the breast, colon, stomach, gall bladder,
kidney, ovary, and bladder.
• Adenocarcinoma of the lung, pancreas and prostate.
• Intrathoracic carcinoid.
Many patients with LEMS (60%) have an associated
SCLC. The SCLC tumor cells express VGCCs of L, N, and
P/Q subtypes, and appear to provide the antigenic stimulus
 Lambert–Eaton Myasthenic Syndrome (LEMS)
for antibody production which cross react with VGCCs in
the nervous system. The prevalence of LEMS in patients
with SCLC is 3%. In patients presenting with LEMS the
chance of having an underlying SCLC falls sharply after 2
years and becomes very small after 4–5 years. There is a
significant association of LEMS with HLA-B8, which is
stronger in the group without carcinoma.
Both LEMS groups (with and without malignancy) also
show an association with immunologic disorders, as
suggested by the presence of autoimmune diseases in about
25% of patients, organ-specific antibodies in about 40% of
patients, and also non-organ-specific antibodies. The
prevalence of autoantibodies is higher in the group with no
underlying carcinoma.
Immunologic disorders associated with LEMS
• Addison’s disease.
• Celiac disease.
• Diabetes mellitus of juvenile-onset.
• Pernicious anemia.
• Psoriasis.
• Rheumatoid arthritis.
• Scleroderma.
• Sjögren’s syndrome.
• SLE.
• Thyroiditis.
• Vitiligo.
805
805, 806 Bilateral ptosis, proximal limb wasting and weakness, and
gynecomastia in a patient with Lambert–Eaton myasthenic syndrome
associated with small cell carcinoma of the lung.
665
CLINICAL FEATURES
Onset of symptoms
Usually gradual and insidious, occasionally subacute.
Cardinal clinical features
Limbs and trunk
• Weakness and fatiguability of upper and lower limb
muscles (proximal>distal) occurs, with muscle pain and
stiffness. A temporary increase in strength can return
after voluntary exercise (unlike myasthenia gravis [MG]),
but the weakness can be exacerbated by prolonged
exercise, hot bath or hot weather.
• Respiratory muscle weakness (spontaneous or induced
by anesthesia).
• Depressed or absent deep tendon reflexes.
• Post-tetanic potentiation of tendon reflexes (i.e. after
sustained contraction of the appropriate muscle for
10–15 seconds).
• Peripheral paresthesiae may occur.
• Poor response of weakness to edrophonium and
neostigmine (unlike myasthenia gravis).
• Marked sensitivity to curare (as in MG).
Cranial nerves (70% of patients)
• Symptoms: often mild and transient, such as eyelid
drooping, diplopia, slurred speech, dysphagia, difficulty
chewing, weaker voice, head lolling.
• Signs: rare except for ptosis (54% of patients [805, 806])
and neck flexion weakness (34% of patients); other rare signs
include jaw weakness, facial weakness, and palatal weakness.
806
666 Neuromuscular Junction Disorders

Autonomic features (sympathetic and parasympathetic, Edrophonium test

80% of patients) May be positive, but the response is usually weaker than in
• Dry mouth. MG.
• Impotence.
• Constipation. Screen for an underlying malignancy and
• Poor bladder and bowel control. immunologic disorder
• Impaired sweating. • Full blood count.
• Tonic pupils. • ESR.
• Orthostatic hypotension/lightheadedness. • Urea and electrolytes.
• Impaired esophageal and intestinal motility. • Plasma glucose.
• Liver function tests.
N.B. Severe autonomic dysfunction may be found on • Thyroid function tests.
testing even when symptoms are minimal. • Autoantibody screen.
• Vitamin B12.
Features of underlying malignancy • Chest x-ray.
SCLC, lymphoma, and other cancers listed above. • Sputum cytology.
• Urinalysis.
DIFFERENTIAL DIAGNOSIS • Stool occult blood.
• MG.
• Myopathy. DIAGNOSIS
• Chronic fatigue syndrome. Diagnosis is based on the clinical findings and results of
investigations.
INVESTIGATIONS
Antibodies to VGCCs TREATMENT
• Antibodies to P/Q type VGCCs are present in >90% of The treatment strategy depends on the severity of the
patients, particularly those with carcinoma-associated symptoms, the degree of response to symptomatic treatment,
LEMS. and the presence or absence of an associated malignancy.
• Antibodies to N type VGCCs are present in <50% of
patients, but are more common in LEMS associated with Treatment of muscle weakness and
primary lung cancer. autonomic symptoms
3,4-diaminopyridine
Electrodiagnosis • Blocks voltage-gated potassium channels which leads to
Electrophysiologic tests are useful for diagnosis as well as prolongation of the action potential at motor nerve
for monitoring the course of the illness: terminals and the open time of the VGCCs, resulting in
• Amplitude of compound muscle action potential increased influx of calcium enhancing quantal
(CMAP) to a single supramaximal stimulus: decreased neurotransmitter release.
(normal or near normal in MG). • It improves muscle strength and autonomic disturbances
• Post activation potentiation: marked increase in CMAP without serious adverse effects.
amplitude by >100% immediately after maximal • The optimal dose varies from 5 mg tds to 25 mg qid.
voluntary contraction (an increase in CMAP may be seen • Onset of beneficial effect occurs within 20 minutes of
in MG, and when present is less marked than in LEMS). oral dose.
• Post activation exhaustion: a decrease in the CMAP • The beneficial effect lasts about 4 hours.
amplitude 2–4 min after maximal voluntary muscle • The maximum response occurs 3–4 days of treatment,
contraction (as also occurs in MG). due to cumulative effect of the drug.
• Repetitive nerve stimulation at slow rates (2–5 Hz): • Adverse effects include peri-oral paresthesia and seizures
decremental pattern (MG also has a decremental pattern (rarely).
in which >10% decrement is considered to be abnormal).
• Repetitive nerve stimulation at fast rates (30–50 Hz): 3,4-diaminopyridine plus anticholinesterase
incremental pattern of over 2–20 times (MG may show drugs (e.g. neostigmine)
an incremental pattern, but it is usually less marked than Anticholinesterases, such as neostigmine, produce mild or
in LEMS). no improvement alone, but seem to potentiate the effects
• Single fiber electromyography (SFEMG): increased jitter of 3,4-diaminopyridine.
and intermittent impulse blocking, which improve with
higher firing rates (MG shows increased jitter and Guanidine and pyridostigmine
impulse blocking which get worse with higher firing Guanidine effectively reduces symptoms but it may have
rates). serious adverse effects which include bone marrow toxicity,
• In vitro microelectrode studies: nephrotoxicity, hepatotoxicity, dermatitis and atrial fibrillation.
– Miniature end-plate potential (MEPP) amplitudes:
normal (small or undetectable in MG).
– End-plate potential (EPP) quantal content: low (normal
in MG).
– Distribution of end-plate potential amplitudes: Poisson’s
distribution (normal distribution in MG).
 Further Reading 667

Treatment of severe weakness Treatment of any underlying malignancy

Plasma exchange
Repeated plasma exchanges may improve symptoms in both
groups of LEMS, having a peak effect at 2 weeks and
subsiding by 6 weeks. Protein A immunoadsorption
removes IgG from plasma selectively.
Intravenous immunoglobulin (IVIG)
Given at 1 g/kg body weight/day for 2 days, IVIG
significantly increases muscle strength compared with
placebo, peaking at 2–4 weeks and lasting up to 8 weeks, in
patients with LEMS and no carcinoma. The clinical
response is associated with a significant fall in antibodies to
VGCCs. There are no data on IVIG therapy in LEMS
associated with carcinoma.
• The specific treatment of the underlying tumor usually
results in improvement or remission of symptoms, and
the only further treatment required may be continuation
of 3,4-diaminopyridine.
• If specific treatment for the tumor fails to resolve
symptoms, further treatment with prednisolone should
be considered, or, if severely weak, plasma exchange or
IVIG.
No response to treatment, and screening for
malignancy
Steroids or steroids and immunosuppressants
• Long term prednisolone may be beneficial, and if
remission is achieved, the dose can be tapered to the
minimum maintenance dose.
• Prednisolone combined with azathioprine may be more
effective than prednisolone alone in LEMS not associated
with carcinoma (but no randomized trial evidence has
been obtained).

FURTHER READING
GENERAL
Vincent A, Palace J, Hilton-Jones D (2001) Myas-
thenia gravis. Lancet, 357: 2122–2128.
MYASTHENIA GRAVIS
Epidemiology
Robertson NP, Deans J, Compston DAS (1998)
Myasthenia gravis: a population based epi-
demiological study in Cambridgeshire, Eng-
land. J. Neurol. Neurosurg. Psychiatry, 65:
492–496.
Clinical subtypes
Aarli JA (1999) Late-onset myasthenia gravis.
Arch. Neurol., 56: 25–27.
Investigations
Hoch W, McConville J, Melms A, et al. (2001)
Autoantibodies to the receptor tyrosine kinase
MuSK in patients with myasthenia gravis with-
out acetylcholine receptor antibodies. Nat.
Med., 7: 365–368.
Treatment
Ciafaloni E, Massey JM, Tucker-Lipscomb B
(2001) Mycophenolate mofetil for myasthenia
gravis: An open-label pilot study. Neurology,
56: 97–99.
Evoli A, Batocchi AP, Minisci C, et al. (2001)
Therapeutic options in ocular myasthenia
gravis. Neuromuscular Disorders, 11:
208–216.
Gronseth GS, Barohn RJ (2000) Practice parame-
ter: thymectomy for autoimmune myasthenia
gravis (an evidence-base review). Report of the
Quality Standards Subcommittee of the Amer-
ican Academy of Neurology. Neurology, 55:
7–15.Kissel JT, Franklin GM, and the Quality
Standards Subcommittee of the American
Academy of Neurology (2000) Treatment of
myasthenia gravis. A call to arms. Neurology,
55: 3–4.
Pallace J, Newsom-Davis J, Lecky B, and the
Myasthenia Study Group (1998) A ran-
domised, double-blind trial of prednisolone
alone or with azathioprine in myasthenia
gravis. Neurology, 50: 1778–1783.
Task Force of the Medical Scientific Advisory
Board of the Myasthenia Gravis Foundation of
America (2000) Myasthenia gravis: recom-
mendations for clinical research standards.
Neurology, 55: 16–23.
Tindall RSA, Rollins JA, Phillips TJ, et al. (1987)
Preliminary results of a double-blind, ran-
domised, placebo-controlled tiral of cy-
closporine in myasthenia gravis. N. Engl. J.
Med., 316: 719–724.
Clinical research
Task Force of the Medical Scientific Advisory
Board of the Myasthenia Gravis Foundation of
America (2000) Myasthenia gravis: recom-
mendations for clinical research standards.
Neurology, 55: 16–23.
LAMBERT–EATON MYASTHENIC
SYNDROME
General
Seneviratne U, de Silva R (1999) Lambert-Eaton
myasthenic syndrome. Postgrad. Med. J., 75:
516–520.
Original descriptions
Anderson HJ, Churchill-Davidson HC, Rochard-
son AT (1953) Bronchial neoplasm with myas-
thenia: prolonged apnoea after administration
of succinlycholine. Lancet, 2: 1291–1293.
Eaton LM, Lambert EH (1957) Electromyogra-
phy and electrical stimulation of nerves in dis-
eases of the motor unit: observations on a
myasthenic syndrome associated with malig-
nant tumours. JAMA, 163: 117–124.
Lambert EH, Eaton LM, Rooke ED (1956) De-
fect of neuromuscular conduction associated
with malignant neoplasms. Am. J. Physiol.,
187: 612–613.
Treatment
Sanders DB, Massey JM, Sanders LL, Edwards LJ
(2000) A randomised trial of 3,4-diaminopy-
ridine in Lambert–Eaton myasthenic syn-
drome. Neurology, 54: 603–607.
668 Chapter Twenty-four
Muscle Disorders
X-LINKED DYSTROPHINOPATHIES
DEFINITION
Recessive disorders of muscle (Duchenne’s and Becker’s
muscular dystrophy) caused by a mutation in the short arm,
locus 21, of the X chromosome (Xp21), in the enormous
gene that codes for the protein dystrophin.
Dystrophin is a filamentous protein present in striated
and cardiac muscle and other tissues which is expressed at
the periphery of the muscle fiber in the sarcolemmal
membrane. Its function is to support the muscle membrane
during muscle contraction and prevent destruction of
muscle fibers in response to shearing forces.
CLASSIFICATION
Duchenne’s muscular dystrophy (DMD)
The most severe dystrophinopathy, in which practically no
dystrophin is detected in skeletal muscle by immuno-
cytochemistry.
807
808
Becker’s muscular dystrophy (BMD)
A milder allelic form in which some muscle fibers express
dystrophin. First recognized by Becker in 1955 as a distinct
benign form of X-linked myopathy.
EPIDEMIOLOGY (see Table 48)
• Incidence:
– DMD: 1 per 3500 male births.
– BMD: one-fifth to one-tenth that of DMD (i.e. about 1
per 35 000 births).
• Prevalence:
– DMD: 2.5 per 100 000 population (relatively low, com-
pared with incidence, because the disease is usually fatal
before the third decade).
– BMD: higher than that of DMD because of its relatively
benign natural history.
• Age:
– DMD: onset in early childhood (muscle necrosis and
serum enzyme elevation can be found in neonates).
– BMD: onset in teenage years or early 20s.
• Gender:
– Almost all patients are male because the inheritance is as
an X-linked recessive trait.
– Girls are affected very rarely due to autosomal
translocation or if there is only one X chromosome (e.g.
Turner’s syndrome).
807–809 Normal muscle. H&E stain, x30 magnification (807). Note
the arrangement of the muscle fibers in fascicles, the close
interdigitation of the muscle fibers, and the muscle fiber nuclei are
nearly all subsarcolemmal. NADH-tr. x100 (808): a mosaic
arrangement of fibers of various staining intensities.Type 1 fibers are
darkly stained and Type 2 fibers are paler, but this distinction is clearer
in myosin ATPase preparation.Type 2A fibers tend to be darker than
type 2B fibers.The intermyofibrillar substance has a finely granular
appearance. Electron microscopy (809, bar = 1 ␮m).
809
 X-linked Dystrophinopathies 669

810
Table 48 Epidemiology of X-linked dystrophinopathies
DMD BMD
Incidence 1/3500 1/35 000
Onset 2–7 years 3 years–adult
Creatine kinase 50x normal 10x normal
Wheelchair-bound By 12 years of age After 12 years of age
Respiratory failure By 20 years of age After 20 years of age
Dystrophin Absent Reduced (patchy
expression)

PATHOLOGY
Light microscopy (807–811)
• Abnormal variations in fiber size.
• Fiber splitting. 811
• Central nuclei.
• Replacement by fat and fibrous tissues.

Dystrophin immunostaining (812–814)

• DMD: <3% of fibers have dystrophin (813).
• BMD: severe (i.e. in a wheelchair by 15–20 years of age):
3–15% dystrophin; mild (i.e. ambulatory >20 years of
age): >20% dystrophin; partial staining of circumference
of muscle fibers (814).

810 Duchenne muscular dystrophy. Muscle biopsy showing variability of

fiber size, rounded fibers, and distortion of the muscle structure by
extensive deposition of fibrous and fatty tissue between the muscle fibers.

811 Duchenne muscular dystrophy. An area of regenerative activity in 812

muscle: regenerating fibers are usually smaller than surrounding fibers
and contain central, enlarged, vesicular nuclei, with prominent nucleoli.

812–814 Cryostatic sections of human muscle biopsies stained with

fluorescent labelled monoclonal antibodies to dystrophin, a cytoskeletal
protein located at the periphery of muscle fibers beneath the
sarcolemma from: normal muscle (812), showing characteristic even
staining of the sarcolemma; muscle from an individual with Duchenne’s
muscular dystrophy (813) showing virtually no staining of dystrophin
(<3%); muscle from an individual with Becker’s muscular dystrophy
(814), showing only dull green background staining which is reduced in
intensity and varies both between and within fibers.

813 814
670 Muscle Disorders
ETIOLOGY AND PATHOPHYSIOLOGY
• The dystrophinopathies involve X-linked inheritance.
• A mutation in the short arm, locus 21, of the X chromo-
some (Xp21), in the gene that codes for dystrophin.
• Null mutations result in no protein production and a
severe progressive phenotype (DMD), whereas missense
mutations result in phenotypes of intermediate severity
(BMD). The dystrophin gene is the largest gene
associated with a disease that has been identified (2.4
million base pairs). It consists of at least 85 exons with
introns making up 98% of the gene.
• In about one-third of patients, DMD is the result of a
new mutation; one-third of all patients have a family
history consistent with X-linked recessive inheritance, and
one-third are born to unwitting carriers.
• The mutation rate in the gene is unusually high
(7–10 × 10-5/gene/generation), probably because of its
large size.
• Dystrophin links the cytoskeleton to the sarcolemma.
Absence of dystrophin results in loss of dystrophin-
associated glycoprotein and disruption of the linkage
between the cytoskeleton and the extracellular matrix,
leading to sarcolemmal instability and muscle cell necrosis.
CLINICAL FEATURES
DMD
• Progressive symmetric proximal muscle weakness of the
upper and lower limb girdles with hypertrophy of calf
muscles.
• Cardiomyopathy is always present.
• Non-progressive intellectual impairment occurs in at least
10% and up to one-third of patients and is present from
childhood; special schooling is required for some patients.
• Smooth muscle can be affected, causing paralytic ileus,
gastric dilatation and atony of the bladder wall.
Year 2
• Motor developmental delay is noticeable after the first
year.
• Onset of walking may be delayed beyond 18 months of
age.
Year 5
• Difficulty running and climbing stairs, have frequent falls.
• Show tip-toe walking with a waddling gait.
• Gower’s sign: in order to stand up from the floor,
children employ their hands to ‘climb up their legs’
(815, 816).
• They have weakness of lower limbs, pelvic muscles and
lower trunk.
• Hyperlordosis with a prominent abdomen.
• Enlarged but weak calf muscles (pseudohypertrophy),
due to excess fat and connective tissue plus large but
ineffective muscle fibers.
Years 6–9
• Joint contractures of the iliotibial bands, hip flexors, and
heel cords are present.
• Thoracic deformity.
Year 10
Unable to walk or stand and are dependent on a wheelchair.
Mid teens
Loss of upper limb function occurs.
Late teens–early twenties
• Usually fatal.
• Death is usually related to pulmonary infections,
respiratory failure, gastrointestinal complications or
cardiomyopathy.
Carriers
• About 8% of female carriers have limb-girdle myopathies.
• A small number of carriers may also suffer from isolated
cardiomyopathy.
BMD
• Onset is usually after 12 years of age (3–20 years of age).
• Patients show similar clinical features to DMD but
milder, and myocardial and intellectual involvement is
less common.
• Calf pain during exercise and myoglobinuria are common.
• Patients may live up to many decades with mild to
moderate symptoms that can be indistinguishable from
those of limb-girdle dystrophies.
DIFFERENTIAL DIAGNOSIS
• Congenital myopathies of the nemaline and central core
types.
• Limb-girdle muscular dystrophies (see p.674).
• Spinal muscular atrophy (see p.534):
• X-linked and autosomal dominant forms of muscular
dystrophy, e.g. Emery–Dreifuss muscular dystrophy:
– The defective gene for the commoner X-linked
Emery–Dreifuss muscular dystrophy (EDMD), STA at
Xq28, when normal, codes for a 34 kD nuclear
membrane protein named ‘emerin’, which is expressed
in skeletal muscle and myocardium but is still of
unknown function. The gene, LMNA at 1q21, for the
autosomal dominant form of EDMD encodes other
nuclear membrane proteins, laminins A and C.
– Onset in early childhood of progressive humeroperoneal
muscle weakness and wasting, and contractures of elbow
flexors, Achilles tendons and paraspinal muscles. Cardiac
involvement is common with conduction defects, brady-
cardias, and heart blocks. Appropriately timed insertion
of a pacemaker may prevent a fatal conduction defect.
– The diagnosis of EDMD depends on mutation analysis
rather than protein immunohistochemistry (at present).
INVESTIGATIONS
Blood
• Serum creatine kinase: markedly elevated up to the
thousands or tens of thousands of units in DMD, and
also elevated in BMD and female carriers.
• Molecular genetics: DNA analysis in blood leukocytes
using the polymerase chain reaction (PCR) is abnormal
in more than two-thirds of DMD patients.
• Electrophoresis (western blotting) biochemically
demonstrates the deficiency of a particular protein, such
as dystrophin.
 X-linked Dystrophinopathies
Urine
Myoglobinuria after anesthetic exposure (DMD).
EKG
Features of a cardiomyopathy may be present (also in female
carriers).
EMG
Myopathic features occur early in the course. Later, the
number of motor units that are activated decreases and
tissue may even become unexcitable.
Muscle biopsy
Obtain from mildly involved muscles rectus abdominus
rather than from gastrocnemius or deltoid muscles because
of worsening caused by immobilization.
Light microscopy (810, 811)
• Abnormal variations in fiber size.
• Fiber splitting.
• Central nuclei.
• Replacement by fat and fibrous tissues.
Dystrophin immunohistochemistry staining
• Staining uses labelled monoclonal antibodies to
dystrophin, a cytoskeletal protein located at the periphery
of muscle fibers and beneath the sarcolemma.
• In DMD, the majority of fibers fail to show any staining
(813).
• In BMD the intensity of staining is reduced and varies
both between and within fibers, as it does in the rare
female carriers of DMD who manifest symptoms of the
disease (814).
• Staining differentiates benign from malignant myopathies.
Role
With the advent of molecular diagnosis and in cases with
documented family histories, muscle biopsy might not be
required as much as in the past to establish the diagnosis.
In less-documented cases, muscle biopsy can be very useful
in distinguishing DMD, which is a severe disease, from
other diseases that present with similar clinical features but
which have a more favorable prognosis (e.g. congenital
myopathies of the nemaline and central core types).
815
815, 816 A boy with Duchenne muscular dystrophy rising from the
floor, and climbing up his legs (Gowers’ sign). (Courtesy of Professor
BA Kakulas, Neuropathology Department, Royal Perth Hospital,
Australia.)
671
DIAGNOSIS
DMD
The diagnosis can be confirmed by muscle biopsy showing
absence or near absence of dystrophin on immunostaining
(813). DNA analysis in blood leukocytes using PCR is
abnormal in more than two-thirds of DMD patients.
Prenatal diagnosis from chorionic villi is also feasible.
PREVENTION
Prenatal diagnosis and carrier detection
Conventional strategies of detecting female carriers by pedigree
analysis, clinical assessment (some mild muscle weakness),
serum creatine kinase (CK) determination (elevated in about
70% of cases), EMG, and histologic study of muscle biopsy
specimens, are now complemented by dystrophin analysis in
muscle biopsy, PCR analysis of heterozygotes, and restriction
fragment length polymorphism analysis.
Fetal abnormalities can be detected using molecular
techniques in samples of chorionic villi during early pregnancy
(after 8 weeks) or by amniocentesis. Muscle biopsy from fetus
or dystrophin immunostaining can be obtained after 19 weeks
of gestation with ultrasound guidance.
DNA analysis by molecular genetic studies is much more
accurate and thus now essential for detecting female carriers
of DMD and BMD, as well as for prenatal diagnostic
analysis of chorion villus biopsy material.
Genetic counselling
Genetic counselling is important for all families with an
affected male. A known carrier has one chance in two of
giving birth to a DMD boy or to a carrier female. About
one-third of patients, however, do not have family histories.
It is often necessary to know the specific gene mutation
occurring in a family, which is usually accomplished by
initially studying an affected male in the family. However, a
major problem in genetic counselling in DMD is that some
mothers transmitted a mutation to more than one offspring
816
672 Muscle Disorders
which they did not have in their somatic cells (in their
peripheral blood leukocytes). This has been attributed to
germline mosaicism. This means that prenatal testing may
have to be considered in subsequent pregnancies if a mother
has had an affected son, because it cannot be guaranteed
that his dystrophy is the result of a new mutation and is
therefore unlikely to recur.
TREATMENT
A multidisciplinary team approach to ongoing management
(medical, genetic, physiotherapy, occupational therapy,
nursing, social work) is required.
Family and patient education
Physical, emotional, educational and financial implications
should be discussed.
Physiotherapy
• Physiotherapy aims to preserve mobility and prevent
early contractures, which are common in flexor muscles
of hips, knees and ankles.
• Passive range of motion exercises and appropriate
orthotics may prolong ambulation.
• Exercises to maintain strength in functional muscles and
prevent obesity (which further impairs ambulation and
respiratory function) are also helpful.
• Patients who can no longer walk may benefit from splints
(at night, kept in a neutral position), braces, crutches,
and surgery (e.g. scoliosis surgery), and should try to
stand at least 3 hours/day in divided periods. However,
excessive exercise can be detrimental.
Respiratory therapy
• Breathing exercises or playing wind instruments may be
beneficial.
• In the late stages, intermittent positive pressure ventilation
is useful, particularly when CO2 is being retained.
Medication
Prednisolone 0.75 mg/kg/day by oral administration may
be appropriate in special circumstances such as acute
deterioration. Neuromuscular strength may improve after
1 month of treatment and the maximum effect is reached
by 3 months. In controlled studies, the benefits lasted for
3 years. Adverse effects include insomnia, difficult behavior
and gastrointestinal symptoms. The mechanism by which
steroids may stabilize the clinical course of DMD may be
that prednisone slows muscle destruction.
Oxandrolone, an anabolic steroid, may be useful before
initiating corticosteroid therapy because it is safe, accelerates
linear growth, and may slow the progress of weakness.
Avoid anesthetics with halothane and succinylcholine
because patients may develop episodes that resemble
malignant hyperthermia. Adverse effects may be reduced by
using non-depolarizing muscle relaxants.
Gene therapy
• Gene therapy is experimental.
• Myoblast transplant therapy has succeeded in the mdx
mouse model but has failed in patients to date.
• Gene therapy administered through viral vectors or
liposomes is being tested in animal models.
Other strategies for treatment (currently
being researched)
• Elucidate the function of the dystrophin–glycoprotein
complex.
• Restore the link between subsarcolemmal cytoskeleton
and the extracellular matrix by:
– Replacing the missing protein (dystrophin):
Myoblast transfer: not successful to date.
Gene therapy: difficult.
– Up-regulating compensating proteins (utrophin).
– Up-regulating proteins with missense mutations
(sarcoglycans).
• Gene therapy is in the experimental preclinical stage.
PROGNOSIS
DMD
Most boys start using a wheelchairs by age 12 years and die
in their 20s.
BMD
The natural history is much less predictably than that of
DMD but inability to walk occurs later than with DMD.
Patients become confined to a wheelchair at 12–40 years or
later, and many individuals marry, have children, and survive
well into middle age and beyond. Death usually occurs at
30–60 years of age.
FACIO-SCAPULO-HUMERAL
MUSCULAR DYSTROPHY (FSHD)
DEFINITION
An autosomal dominant inherited disorder characterized by
weakness of the facial, scapulohumeral, anterior tibial and pelvic
girdle muscles; sometimes associated with retinal vascular
disease, sensory hearing loss and, in severe cases, even abnor-
malities of the CNS due to a genetic defect on chromosome 4.
EPIDEMIOLOGY
• Prevalence: 1:20 000; the third most common hereditary
disease of muscle (after Duchenne and myotonic
dystrophy).
• Age of onset: any age, but usually 10–50 years of age, and
mostly in the second and third decades. A large proportion
of gene carriers remain asymptomatic for decades.
• Gender: M=F.
PATHOLOGY
Dystrophic muscle
• Disruption of muscle architecture.
• Abnormal variation in fiber size.
• Degeneration and regeneration of muscle fibers.
• Replacement of muscle by fat and fibrous tissue.
ETIOLOGY AND PATHOPHYSIOLOGY
Autosomal dominant inheritance with high penetrance: the
gene is located to the distal chromosome 4q35 where there
are normally between 10 and 100 almost identical tandemly
arranged repeating units each of 3.3 kb, making up an area
that is greater than 35 kb in length. In patients with FSHD,
a number of these repeats are deleted, due to large deletions
 Facio-scapulo-humeral Muscular Dystrophy (FSHD)
of variable size, so that the area is <35 kb in length (as
measured on an electrophoretic gel). No gene has been
identified within the area of this deletion, suggesting that
these deletions execute a position effect on a more
centromeric located gene. In other words, the deletions do
not appear to disrupt a transcribed gene but are thought to
interfere with the expression of a gene or genes located
proximal to the deletions.
CLINICAL FEATURES
• Weakness of the facial, scapulohumeral, anterior tibial,
and pelvic girdle muscles occurs (817, 818).
• The spectrum of clinical severity is wide, even within
families: some have only minimal facial involvement and
normal life expectancy, and others are wheelchair bound
in childhood with marked kyphoscoliosis and ventilatory
failure.
• Although weakness is present in over 95% of affected
individuals by age 20 years, up to one-third of patients
have no symptoms (i.e. do not recognize the weakness),
and most present to medical attention because of
involvement of the shoulder rather than the facial muscles.
• However, the first sign is weakness of certain facial
muscles, including the orbicularis oculi, orbicularis oris,
and zygomaticus, but the actual onset of the weakness can
be difficult to establish because abnormal features may be
interpreted as nothing more than family traits. Bell’s
phenomenon and drooping of the lower lip are present,
and patients may be unable to whistle. The masseter,
temporalis, and extraocular muscles are not involved, and
the bulbar and respiratory muscles are also spared.
817
817, 818 Wasting and weakness of the muscles of the face, upper arms and shoulders with prominent weakness of the pectoral muscles and
winging of the scapulae in a patient with facioscapulohumeral muscular dystrophy.
673
• FSHD also involves the trapezii, rhomboids, and serratus
anterior scapular fixators. Scapular winging is maximized
with forward movement because of the serratus anterior
weakness (see p.616). The pectoralis is very atrophic.
Deltoid and rotator cuff musculature are better preserved.
• Later in the disease, weakness involves the lower limbs,
particularly the anterolateral leg compartment (foot
dorsiflexors) and finally the hip girdles. Truncal weakness
may also occur.
• Side-to-side asymmetry of muscle wasting and weakness
is frequent and often striking.
• Heart muscle is spared usually but a predilection for atrial
tachyarrhythmias exists.
• An exudative retinopathy is present in one-third of cases.
• Retinal vascular tortuosities are usually subclinical in
most cases.
• High frequency sensory hearing loss can be present but
is usually asymptomatic.
• Abnormalities of the CNS are present in severe cases.
DIFFERENTIAL DIAGNOSIS
• Autosomal dominant scapuloperoneal syndromes:
different pattern of involvement and progression.
• Neurogenic disorders.
• Nemaline myopathy.
• Desmin storage.
• Mitochondrial myopathy.
• Polymyositis.
• Centronuclear myopathy.
818
674 Muscle Disorders
INVESTIGATIONS
• Serum CK: may be raised 2–7 times normal, but this
varies by age and gender (elevated in three-quarters of
affected males and two-fifths of affected females).
• EMG: myopathic.
• Muscle biopsy: may reveal minimal myopathic changes
or severe dystrophic muscle, depending in part on the
choice of muscle biopsied. A significant inflammatory
component may be seen.
• Blood: leukocyte DNA analysis: affected individuals have
small restriction fragments of 10–35 kb containing the
deletion, whereas unaffected individuals have restriction
fragments of 50–300 kb.
DIAGNOSIS
• Patients with characteristic facial and shoulder weakness,
and an autosomal dominant family history almost always
have the same molecular defect.
• The 4q35 deletion that causes FSHD can be identified
in 86–95% of cases with the disease (sensitivity), and is
>98% specific for the disease.
• The 5–14% of affected individuals in whom a deletion cannot
be identified is attributed to: (1) technical difficulties with
degraded or partially digested DNA; (2) translocation
between 4q35 and homologous regions on 10q complicating
the interpretation of the Southern blot data and, rarely, (3)
FSHD not linked to 4q (locus heterogeneity). In such cases,
if the clinical suspicion of FSHD remains high, further testing
with other 4q35 and 10q probes as well as more extensive
study of the kindred with linkage analysis may be required.
PRESYMPTOMATIC AND PRENATAL DIAGNOSIS
Restriction enzyme DNA fragments associated with the
gene have been found to be greater than 35 kb in length in
individuals who do not have muscular dystrophy; in affected
individuals fragments are always less than this (as measured
by electrophoretic gel).
Furthermore, there is a general tendency for shorter
fragments (i.e. larger deletions) to be associated with earlier
onset and more severe cases of the disease; in a sporadic case,
for example, this can give an idea of the likely prognosis.
TREATMENT
Myopathy
No specific treatment for the weakness.
Physiotherapy
Posterior plastic ankle orthotics can correct foot drop. A trunk
brace may help patients with prominent lumbar lordosis and
abdomen. A motorized wheelchair with adjustable height
control is invaluable for non-ambulatory patients.
Exudative retinopathy
Photocoagulation may be necessary to prevent retinal
detachment.
PROGNOSIS
• Many patients are only mildly affected; most affected
individuals remain able to work, often adapting remark-
ably well to profound weakness in distinct muscle groups.
• The rate of disease progression is variable but usually very
slow.
• It is severely disabling for >15% who eventually become
dependent on wheelchairs.
LIMB-GIRDLE MUSCULAR
DYSTROPHIES (LGMD)
DEFINITION
A clinically and genetically heterogeneous group of
autosomal-dominant and autosomal-recessive inherited
muscle disorders.
EPIDEMIOLOGY
• Uncommon.
• Age: onset at any age but predominantly between first
and fourth decades.
• Gender: M=F.
ETIOLOGY
• A small minority (<10%) of cases are inherited as an
autosomal dominant trait (type 1) and are relatively mild.
• The majority are inherited as autosomal recessive traits
(type 2) , which is often more severe and resembles DMD.
• At least three dominant subtypes and eight recessive
subtypes have been identified.
• One recessive subtype (LGMD 2A) is caused by a
deficiency of a muscle-specific protease (calpain 3).
• Four other recessive subtypes (LGMD 2C, D, E and F)
are caused by deficiencies of particular sarcoglycans
(dystrophin associated glycoproteins) which form part of
the dystrophin-associated protein complex of muscle
membrane.
The dystrophin-associated complex
• A large oligomeric complex in the sarcolemmal
membrane of skeletal muscle, which provides an
important structural link between the actin-cytoskeleton
and the extracellular matrix in skeletal muscle (819).
• The complex consists of several subcomplexes beneath
the extracellular matrix (laminin-2, α-dystroglycan,
glycoprotein complex [sarcoglycans and β-dystroglycan],
dystrophin and F-actin cytoskeleton).
Laminin-2 (merosin)
• Laminin-2 is located in the extracellular matrix at the
periphery of muscle fibers.
• Absent in children with congenital muscular dystrophy
(onset in newborn) who have a nonsense mutation (no
functioning protein produced).
• Deficient in children and even adults who have a
missense mutation in the merosin gene and produce
merosin but in reduced quantities.
• It is also expressed around blood vessels in the brain.
Hence MRI T2W images show a leukodystrophic
pattern, but the intellect is usually normal.
 Limb-girdle Muscular Dystrophies (LGMD) 675

α-Dystroglycan
• Is a 97 kDa precursor which is encoded by a single gene, Table 49 Classification of limb-girdle muscular
mapped to chromosome 3p21, and has a novel laminin dystrophies
(merosin) receptor, which connects the sarcolemma to Disorder Gene location Gene product
the extracellular matrix.
• It is located outside the cell, and binds the extracellular Autosomal dominant
matrix component laminin-2 with high affinity. LGMD 1A 5q22-q34 (Genetic anticipation, no cardiac
• It is found in muscle and also the neuromuscular involvement)
junction, peripheral nerve, brain, kidney and embryo. 1B 1q11-21 Caveolin-3 (cardiac arrhythmias
may occur early)
Sarcoglycans: α (adhalin), β, γ 1C 3p25 Caveolin-3 (a scaffolding protein)
• These are abnormal in some autosomal recessive forms 1D 6q23
of limb girdle muscular dystrophy (sarcoglycanopathies). 1E 5q31
• The spectrum of disease (sarcoglycanopathies) is similar Autosomal recessive
to DMD and BMD, and determined by the nature of the LGMD 2A 15q15.1-q21.1 Calpain-3
mutations (nonsense vs. missense). 2B 2p13 Dysferlin (cf. Miyoshi myopathy)
• Girls present like DMD or BMD, with gradual onset of 2C 13q12 γ-sarcoglycan
progressive proximal limb weakness (e.g. difficulty 2D 17q12-q21.33 α-sarcoglycan (adhalin)
ascending stairs and running), lumbar lordosis, 2E 4q12 β-sarcoglycan
prominent calf muscles, and tight tendoachilles. 2F 5q33-q34 δ-sarcoglycan
• Cardiomyopathy may occur. 2G 17q11-q12 ?
• CK is high. 2H 9q31-q34.1 ?
• Muscle biopsy dystrophic, but a normal amount of
dystrophin is present. Staining for antibodies to
sarcoglycans reveals a deficiency of one or more of the
sarcoglycans.

Dysferlin
Basal lamina/extracellular matrix
819
• Is localized in muscle membrane but its role is unknown
at present.
• Dysferlinopathies have their onset in late teens or
adulthood.
• Weakness begins in the lower limbs only: distal Laminin-2 Sarcolemma/plasma
(merosin) membrane
(gastrocnemius) weakness (plantar flexion: difficulty Sarcoglycans
standing on toes) and painful calves. α-dystroglycan
• Weakness progresses slowly and may involve the biceps α
(only) in the upper limbs. ε γ
• CK is elevated (1000s). δ β
• Muscle biopsy is dystrophic (necrotizing myopathy).
β-dystroglycan
• Loss of ambulation occurs at 30–40 years of age.
Syntrophins
β-Dystroglycan (inside the cell) Dystrophin
This binds to the cysteine-rich domain of dystrophin. Dystrobrevin

Dystrophin
-COOH
Dystrophin links the cytoskeleton to the sarcolemma.
F-actin
CLASSIFICATION (see Table 49) Intracellular
NH2-

819 Diagrammatic representation of the dystrophin-associated

complex in the muscle fiber membrane. Specific muscular dystrophies
are caused by deficiencies of dystrophin (Duchenne and Becker
muscular dystrophy), a particular sarcoglycan (limb-girdle muscular
dystrophy), or laminin-2 (merosin) (congenital muscular dystrophy).
676 Muscle Disorders

PATHOLOGY Autosomal recessive LGMD

No characteristic histologic features are present (820, 821). Sarcoglycanopathy
• Sarcoglycanopathy generally occurs as childhood-onset,
Dystrophic muscle but may arise in adults.
• Dystrophic muscle shows disruption of muscle architecture. • Calf hypertrophy is common (824, 825).
• Variation in fiber size, with very hypertrophied fibers and • Early involvement of the scapular muscle, deltoid and
small fibers. pelvic girdle.
• Prominent internal nuclei especially in hypertrophied fibers. • Serum CK is normal or mildly elevated.
• Fiber splitting in some fibers, especially in severely
involved fibers and late in disease. Calpainopathy
• Degeneration and regeneration of muscle fibers. • Onset occurs in patients aged 8–15 years generally, but
• Increased fibrous tissue. adult-onset is fairly common.
• Atrophic muscles, scapular winging, sparing of hip
Immunohistochemistry adductors, and Achilles tend contractures are present.
Deficiency of a muscle specific protease (calpain-3) or a • Serum CK is 10 times normal values.
particular sarcoglycan can be found.
Dysferlinopathy
PATHOPHYSIOLOGY • Presentation occurs in late teens or early twenties.
Disruption of the dystrophin–glycoprotein complex in • There is posterior distal lower limb involvement early on,
skeletal muscle leads to several forms of limb-girdle (and with inability to stand on the toes.
other forms of) muscular dystrophy. • Serum CK is massively elevated (may be >100 times
normal values).
CLINICAL FEATURES
General DIFFERENTIAL DIAGNOSIS
• Proximal muscle weakness occurs in pelvic and upper • BMD.
girdle muscles, sparing the face (822, 823). • Emery–Dreifuss muscular dystrophy: contractures are a
• Cardiac involvement may occur. very prominent feature.
• Chronic polymyositis.
Autosomal dominant LGMD • Mitochondrial cytopathy.
Dominant family history. • Metabolic myopathy: adult-onset acid maltase deficiency.
• Endocrine and drug-induced myopathies.
LGMD 1A • MG.
• Onset occurs in patients aged 18–35 years. • Spinal muscular atrophy.
• Affected individuals may have dysarthria and Achilles
tendon contractures. INVESTIGATIONS
• Serum CK is normal or mildly elevated. Blood
• Serum creatine kinase: usually elevated. If normal or mild
LGMD 1B elevation in active disease, suspect autosomal dominant
• Onset occurs in patients aged 4–38 years. LGMD. If elevated >100 times normal in the early
• Cardiac conduction defects are a prominent complication. stages, suspect dysferlinopathy.
• Serum CK is normal or mildly elevated. • Molecular genetics: DNA analysis in blood leukocytes
using PCR.
LGMD 1C (caveolin deficiency) • Electrophoresis (western blotting): biochemically
• Onset occurs in patients aged 5 years. demonstrates the deficiency of a particular protein.
• Serum CK is 4–25 times normal values.

820 821

820, 821 Muscle biopsy specimens in a patient with limb-girdle muscular dystrophy showing variation in fiber size, prominent internal nuclei and
degenerative and regenerative changes.
 Limb-girdle Muscular Dystrophies (LGMD) 677

• Linkage analysis to dominant LGMD loci if dominant DIAGNOSIS

family history and family structure is suitable.
EKG
Features of a cardiomyopathy may be present.
EMG
Myopathic, no specific features.
Muscle biopsy
Light microscopy: dystrophic muscle (820, 821)
• Disruption of muscle architecture.
• Variation in fiber size.
• Degeneration and regeneration of muscle fibers.
• Increased fibrous tissue.
Immunocytochemistry
Use at least two sarcoglycan antibodies as well as dystrophin
antibodies:
• Dystrophin: generally normal, but may be abnormal in
sarcoglycanopathy.
• Sarcoglycans: a specific sarcoglycan
may be absent or reduced. Sarco-
glycans are normal in calpainopathy
and dysferlinopathy.
• Dysferlin.
Direct detection of the mutation is the final proof of
diagnosis and allows carrier detection/prenatal diagnosis.
However, given the complexity of the genes and the
heterogeneity of the mutations, this is best directed by the
results of protein analysis. Therefore, these dystrophies
should be diagnosed using a combination of clinical studies,
protein studies and genetic studies, which may only be
carried out in specialized centers.
TREATMENT
A multidisciplinary team approach (medical, genetic
counselling, physiotherapy, occupational therapy, speech
therapy, psychology, social work) is required.
PROGNOSIS
Variably progressive.
822 823

If abnormalities are detected on

immunocytochemistry with dystrophin
or sarcoglycan antibodies, then the full
range of sarcoglycan antibodies should
be used to attempt to pinpoint the
primary deficiency.

Immunoblotting
Immunoblotting is necessary to examine
calpain-3. Multiplex blotting may also
show which sarcoglycan is primarily
involved.

822, 823 The limb-girdle muscular

dystrophy phenotype: note wasting of the
proximal two-thirds of the deltoids (with
pseudohypertrophy of the distal one-third),
forearm flexors, thigh adductors, and medial
heads of the gastrocnemius muscles.

824 825

824, 825 Calf hypertrophy in a 30 year old

man with a sarcoglycanopathy.
678 Muscle Disorders
MYOTONIC DYSTROPHY
DEFINITION
A autosomal dominant disorder due to a mutation causing
an expanded CTG trinucleotide repeat in the DMPK gene
on chromosome 19. The disease has varied and diverse
expression in many body systems, including skeletal muscle,
brain, eye, heart, thyroid, pancreas and gonads, but the
cardinal clinical features of myotonia, muscle wasting, typical
facies and cataract are almost diagnostic.
EPIDEMIOLOGY
The most common form of muscular dystrophy in adults.
• Incidence: 14/100 000 live births.
• Prevalence: 1 in 20 000.
• Age: any age.
• Gender: M=F.
ETIOLOGY AND PATHOPHYSIOLOGY
• Myotonic dystrophy shows an autosomal dominant
inheritance of an expanded triplet cytosine-thymine-
guanine (CTG) repeat in the DMPK (myotonic
dystrophy protein kinase) gene on chromosome 19
(19q13.2-13.3). Normal individuals have up to about 38
repeats; a disease allele may consist of 50 to several
thousand repeats.
• The length of the trinucleotide repeat correlates directly
with the severity of the disease and inversely with the age
of onset.
• DMPK is a protein-kinase, a ubiquitous enzyme related to
protein phosphorylation. The enzyme is widely distributed
which may explain the generalized multisystem nature of
the disorder. However, the mutation is located in a part of
the DMPK gene that does not code for protein. It remains
unclear how a mutation that does not interrupt the
DMPK protein coding sequence has a dominant effect
with such severe consequences.
PATHOLOGY
Muscle
• Large numbers of internal nuclei, often occurring in long
chains, together with sarcoplasmic masses and ring-fibers
(826).
• Increased variability in fiber size.
• Increased endomysial and interfascicular fibrous tissue.
• Moth-eaten fibers.
• Individual necrotic and regenerating fibers are rare.
• Type 1 fibers appear smaller than Type 2 fibers.
CLINICAL FEATURES
Many patients have predominant systemic symptoms rather
than neuromuscular symptoms, and some are never
diagnosed with myotonic dystrophy.
Skeletal muscle wasting and weakness
Facial muscles
• Hatched and thin face.
• Frontal balding (early).
• Temporalis and masseter atrophy (827–830).
• Ptosis (not as severe as in MG or Kearns–Sayre
syndrome) and occasionally diplopia due to extraocular
muscle involvement.
• Dysphagia (oropharyngeal involvement).
Sternocleidomastoid muscles
Wasting and weakness out of proportion with shoulder and
posterior neck muscles.
Limb muscles
Predominantly distal muscle wasting (831) and weakness
(particularly the hands), which occurs later. Proximal limb
muscles are usually preserved until the late stages.
Consequently, patients usually remain ambulatory, unlike
those with other dystrophies.
Diaphragm
• Hypoventilation.
• Opiates and barbiturates may induce respiratory failure.
• Depolarizing relaxants may increase myotonia.
Skeletal muscle myotonia
• Delayed muscle relaxation occurs after contraction.
• It is often a sign rather than a symptom: patients seldom
complain of stiffness, but do complain of dysarthria
(myotonia of the tongue as well as facial weakness).
• It may be elicited by percussion of the tongue or thenar
eminence, or by failing to release the grip after a
handshake.
• True myotonia is diminished by repetitive muscle
contractions.
Malignant hyperpyrexia
Eyes
Subcapsular cataracts.
Heart
Conduction defects
• Symptomatic primary heart muscle disease is very rare
and hence routine echocardiography is not indicated
(unlike in BMD/DMD) but cardiac conduction
problems (heart block and arrhythmias) are common and
a major cause of morbidity and mortality.
• The perioperative period is a particularly dangerous time
with respect to development of tachyarrhythmias and
heart block; the anesthetist must always be made aware
of the diagnosis of myotonic dystrophy.
• There is a broad correlation between the likelihood of
cardiac disease and both the severity of skeletal muscle
involvement and the length of the trinucleotide repeat.
Brain
Excessive daytime sleepiness
• The most common non-muscular symptom, being
present in 75% of patients.
• Patients may sleep most of the day.
• Sleepiness is broadly correlated with overall disease
severity.
• It is most frequently due to a disturbance of central
mechanisms, but occasionally is due to nocturnal
hypoventilation, with or without obstructive sleep apnea,
as a result of respiratory muscle weakness.
Mental apathy, low intellect, and perhaps progressive dementia
Skull
• Hyperostosis.
• Small pituitary fossa.
 Myotonic Dystrophy 679

Gastrointestinal tract 826

Smooth muscle involvement
• Abdominal pain (55% of patients).
• Dysphagia (45%): skeletal muscle dysfunction in the
upper esophagus and pharynx.
• Vomiting (35%).
• Diarrhea (33%).
• Constipation (33%).
• Coughing when eating (33%).
• Anal incontinence (30%).
• Cholelithiasis.

Thyroid
Hypothyroidism or hyperthyroidism.

827 828 826 Longitudinal section of muscle

from a patient with myotonic
dystrophy showing long chains of large
numbers of internal nuclei.

827–830 Frontal alopecia, myopathic

facies (e.g. ptosis), and wasting of the
temporalis, masseters, sternomastoids
in a man (827, 828) and a woman
(829, 830) with myotonic dystrophy.
Note that the woman’s head is tilted
backwards to compensate for the
ptosis. She also has an ‘inverted smile’.

831 Wasting of the distal limb

muscles such as the forearm, anterior
tibial and calf muscles in myotonic
dystrophy.

831

829 830
680 Muscle Disorders

Pancreas • Generalized myotonia, worse in the cold and relieved by

Diabetes mellitus. warmth or exercise.
• Patients show diffuse muscle hypertrophy and little if any
Gonads weakness.
Tubular testicular atrophy, impotence and poor libido in men.
N.B. These patients tend to tolerate general anesthetics Sodium channelopathies
poorly. Paramyotonia congenita (autosomal dominant):
• Attacks of myotonia and flaccid weakness, usually precipita-
SPECIAL FORMS ted by cold, but also by hyperkalemia and beta-blockers.
Congenital myotonic dystrophy • Myotonia is relieved by hypokalemia or acetazolamide.
• Present since birth. • There is overlap with the periodic paralyses, since in some
• The abnormal gene is transmitted exclusively through patients the weakness is associated with hyper- or
maternal inheritance. hypokalemia, and hyperkalemic periodic paralysis results
• The fetus shows hydramnios and reduced fetal movements. from mutations in the same sodium channel gene as
• Neonates show respiratory distress, bilateral facial weakness paramyotonia congenita. Hypokalemic periodic paralysis is
and hypotonia. a calcium channelopathy (see p.693).
• In children mental retardation is a major feature; 75% of
patients need special education, and 75% of the remainder Distal myopathy
at mainstream schools require further assistance to achieve Neurogenic
minimum standards in reading and counting. • HMSN 2 (Charcot–Marie–Tooth–2).
• There is a high prevalence of cardiac and gastroinstestinal • Distal spinal muscular atrophy.
involvement: 20% die of cardiac dysfunction and 15% are • Scapuloperoneal syndrome.
still incontinent of feces at age 5 years.
• 25% die before 18 months of age, and 50% survive into the Myopathic
mid-30s. • Myotonic dystrophy.
• Fascioscapulohumeral dystrophy.
Myotonic dystrophy type 2 • Desminopathy.
• Myotonic dystrophy type 2 is linked to the long arm of • Mitochondrial myopathy.
chromosome 3 in a single large family. • Congenital myopathies.
• Clinical features are the same as those with myotonic • Glycogen storage disease.
dystrophy type 1, although the degree of facial and limb • Inclusion body myositis.
weakness and the ptosis are more like that of a mild, rather
than severe, myotonic dystrophy type 1. INVESTIGATIONS
Blood
Proximal myotonic myopathy (PROMM) • Fasting glucose.
• Proximal muscle weakness and myotonia predominates but • Thyroid function tests.
distal weakness may also develop in some individuals with • Serum IgG reduced.
PROMM. • Serum CK: normal or mildly elevated.
• The disease has a similar frequency as classic myotonic
dystrophy. Slit lamp examination
• It is linked to the same region of chromosome 3 as Cataracts.
myotonic dystrophy type 2.
• Patients show a less severe impairment than classic myotonic EKG
dystrophy . • Abnormalities of cardiac conduction are common, even in
• Congenital disease is absent. patients without cardiac symptoms, and progress over time.
• An annual EKG is recommended because EKG changes are
DIFFERENTIAL DIAGNOSIS often a predictor of development of cardiac symptoms.
Myotonia clinically • Ventricular late-potentials may be predictive of ventricular
• Myotonic dystrophy (adults). arrhythmias. However, potentially fatal heart block or
• Myotonia congenita (dominant and recessive forms). rhythm disturbances can occur despite a normal EKG. As
• Paramyotonia congenita ± hyperkalemic periodic paralysis. the perioperative period is a particularly dangerous time with
• Hypothyroid myopathy. respect to development of tachyarrhythmias and heart block,
• Drugs: 20,25-diazacholesterol (lipid lowering agent), the anesthetist must always be made aware of the diagnosis
triparanol (lipid lowering agent), beta-blockers, and of myotonic dystrophy.
depolarizing muscle relaxants (e.g. succinylcholine) may
cause or exacerbate myotonia. 24-hour EKG recording
This is indicated if cardiac symptoms are present or a significant
Non-dystrophic myotonias change occurs on the EKG.
Chloride channelopathies
Myotonia congenita: EMG
• Thompsen’s disease (autosomal dominant): presents in Multiple myotonic discharges.
infancy.
• Becker’s disease (autosomal recessive): present in childhood. Molecular DNA analysis
PCR technique: triplet repeat expansion.
 Polymyositis 681

DIAGNOSIS POLYMYOSITIS
Clinical and EMG, but confirmed by molecular DNA analysis.

TREATMENT DEFINITION
The main goals are prevention and treatment of systemic An acquired proximal inflammatory myopathy characterized
disease. by progressive proximal muscle weakness, elevated serum
creatine kinase, and the presence of inflammatory infiltrates
Myotonia in muscle.
In general, patients do not complain much about myotonia:
• Phenytoin 100–200 mg bd orally can alleviate disabling EPIDEMIOLOGY
and bothersome myotonia with reasonable efficacy and • Prevalence: 1 in 100 000.
safety. • Age at onset: >18 years of age.
• Nifedipine 10–20 mg three times daily may help. • Gender: F≥M.
• Antimyotonic drugs such as quinine sulfate,
disopyramide (100–200 mg three times daily) and PATHOLOGY
procainamide (250–500 mg four times daily) prolong the Acute
PR interval and can impair cardiac conduction. • Predominantly endomysial (in the fascicles) inflammatory
Disopyramide has anticholinergic adverse effects. cell infiltrates (T cells), surrounding or partially invading
Procainamide may cause nausea, diarrhea, skin rash, individual muscle fibers (832).
confusion, and SLE-like syndrome and agranulocytosis. • B cells are infrequent.
• A short course of prednisolone may help particularly • T cells are of the cytotoxic type.
severe cases sometimes. • Single fiber necrosis with phagocytosis.
• ‘Moth-eaten’ fibers.
N.B. Any improvement in myotonia may not necessarily • Atrophy of both fiber types.
realize functional benefit for patients whose symptoms are more • Angular atrophic fibers.
as a result of weakness than myotonia. • Increased central nucleation.
• No perifascicular atrophy or microangiopathy.
Excessive daytime sleepiness due to
central mechanisms Chronic
• Lifestyle advice: take short naps at convenient times, such as • Marked variation in fiber size (833).
after meals, to minimize disruption of daily activities. • Hypertrophied fibers.
• Methylphenidate may be helpful, but there have been no • Central nucleation.
long term studies of risks and benefits. • Fiber splitting.
• Regenerating and necrotic fibers.
Excessive daytime sleepiness due to hypercapnia • Endomysial and perifascicular fibrosis.
Normal assisted ventilation. • Inflammatory cell exudates.
• Focally distributed architectural changes in individual fibers.
Fecal incontinence
Procainamide 300 mg bd. ETIOLOGY AND PATHOPHYSIOLOGY
Idiopathic polymyositis
PROGNOSIS T cell mediated cytotoxicity of muscle fibers.
Sudden death is well recognized, and may be due to heart
block or arrhythmia.

832 833

832 Polymyositis. Inflammatory infiltrate between muscle fibers within 833 Chronic polymyositis, transverse section of muscle, x140, H&E.
the fascicle (endomysial) and adjacent to necrotic fibers and small There is marked variability in muscle fiber size, central nucleation, a
intrafascicular blood vessels. marked increase in fibrous tissue, and a diffuse inflammatory cell
response. Some fibers are conspicuously rounded.
682 Muscle Disorders

Systemic autoimmune or connective tissue diseases Evolution of symptoms

• Mixed connective tissue disease. Weakness usually evolves slowly over months or, frequently,
• Systemic lupus erythematosus. several years, such that gross muscle wasting may be evident
• Rheumatoid arthritis. at the time of diagnosis.
• Scleroderma.
• Polyarteritis nodosa (834). Underlying carcinoma
• Sjögren’s syndrome. No link.

Infection DIFFERENTIAL DIAGNOSIS

Viral myositis • Myositis associated with autoimmune disorders (MCTD,
• HIV. SLE, RA, PSS, PAN).
• Human T-cell lymphotropic virus type 1. • Polymyalgia rheumatica: pain with limitation of
• Benign acute myositis: movement (which may be misinterpreted as muscle
– Influenza A and B. weakness), but the CK is normal and muscle biopsy
– Parainfluenza. shows only minimal abnormalities.
– Adenovirus 2. • Endocrine myopathy: thyroid disease.
• Acute rhabdomyolysis: • Metabolic myopathy: osteomalacic myopathy.
– Influenza A and B. • Toxic myopathy: alcohol, opiates, chloroquine, D-peni-
– Echo 9. cillamine, zidovudine.
– Adenovirus 21. • Muscular dystrophy.
– Herpes simplex. • Myotonic dystrophy.
– Epstein–Barr virus. • MG.
• Epidemic pleurodynia: Coxsackie B5 (also B1, 3 and 4). • Spinal muscular atrophy.
• Neuropathy.
Bacterial myositis
Acute suppurative myositis: INVESTIGATIONS
• Staphylococcus aureus. Blood
• Streptococcus. • Serum CK level: helpful in diagnosis and monitoring
• Yersinia. response to therapy. Levels may be normal or only
• Anerobic organisms. moderately raised (up to five times normal).
• ESR: usually, though not invariably, elevated.
Fungal myositis • Anti Jo-1 antibody, found in 30% of cases, is associated
with lung infiltrates and greater risk of cardiomyopathy.
Parasitic myositis
• Protozoa: EKG
– Toxoplasmosis. Occasionally shows heart block.
– Sarcosporidiosis.
– Trypanosomiasis. EMG
– Amebiasis. • Useful for confirming active or inactive myopathy and
• Cestodes: for excluding neurogenic disorders.
– Cysticercosis.
– Coenurosis.
– Hydatidosis.
– Sparganosis.
• Nematodes
– Trichinosis.
– Toxocariasis. 834
Drugs
• Penicillamine, zidovudine.

CLINICAL FEATURES (see Table 50)

Presentation of symptoms
• Slow onset (weeks to months).
• Usually symmetric weakness of proximal limb muscles,
typically involving the pelvic more than the shoulder
girdle, occasionally with pain and muscle tenderness.
• Weight loss, neck weakness, dysphagia and voice change
are common.
• No skin rash, eye and facial muscle involvement, family
history of neuromuscular disease, history of exposure to
myotoxic drugs or toxins, endocrinopathy, neurogenic 834 Polyarteritis nodosa. In this muscle biopsy there is intimal
disease, or dystrophy is present. thickening and infiltration of the walls of two small arteries by
macrophages and lymphocytes.
 Polymyositis 683

• Shows increased spontaneous activity with fibrillations,
positive sharp waves, and complex repetitive discharges;
and myopathic potentials characterized by short-
duration, low-amplitude polyphasic motor units on
voluntary activation. These findings are non-specific and
occur in a variety of acute, toxic and active myopathic
processes.
• Mixed myopathic and neurogenic potentials (polyphasic
units of short and long duration) may also be present as
a consequence of the regeneration of muscle fibers and
chronicity of the disease.
Muscle biopsy
Endomysial infiltration by mononuclear inflammatory
infiltrates (predominantly T8 lymphocytes), surrounding
and invading muscle fibers (832–834).
DIAGNOSIS
A diagnosis of exclusion, based on clinical features, sup-
ported by laboratory investigations, of which the most im-
portant is muscle biopsy. Patients do not have (1) family his-
tory, (2) exposure to myotoxic drugs or toxins, (3) anoth-
er acquired muscle disease caused by endocrine, metabolic,
or neurogenic disease, (4) certain sporadically occurring dy-
strophies (dystrophinopathies, sarcoglycanopathies, dysfer-
linopathies), and (5) inclusion body myositis.
TREATMENT
• Empirical.
• Treatment has non-selective effects on the immune
system.
• Efficacy has not been proven in randomized trials.
• No treatment is uniformly effective.
• Adverse effects can be serious.
• Encouragement of mobility (particularly in the elderly)
and physiotherapy to prevent contractures are essential.
• A high protein diet is advisable.
• Attention to swallowing, adequacy of ventilation, and
precautions against deep venous thrombosis must be
considered.
Corticosteroids
• Oral prednisolone 1 mg/kg/day on alternate days.
• Combination therapy with methotrexate or azathioprine
can be considered.
• Intravenous methylprednisolone: 0.5 g/day for 3 days
(pulse therapy) if symptoms are not controlled with oral
therapy.
Avoiding complications of corticosteroid treatment
• Keep initial dose of prednisolone <1 mg/kg/day, if
possible, particularly if mild disease, concern about
adverse effects (e.g. postmenopausal) or remission
induced.
• Begin to reduce high dose prednisolone (1 mg/kg/day)
within 4–6 weeks.
• Begin combination therapy at 4–6 weeks as a steroid
sparing agent if the disease is slow to come under control
(i.e. introduce a second line agent earlier rather than
later, as opposed to continuing prednisolone for
2–3 months: too long really).
• Keep maintenance dose <10 mg/day (or 20 mg alternate
days).
• Monitor muscle performance regularly (manual,
myometer or isokinetic dynamometry, and functional
assessment).
• Use prophylactic calcium supplements and biphos-
phonates, particularly in postmenopausal women.

Table 50 Major clinical features of dermatomyositis, polymyositis and inclusion body myositis (IBM)
Clinical features Dermatomyositis Polymyositis IBM
Male: female 1:2 1:1 3:1
Age at onset Any age >18 years >50 years
Site of weakness Limb girdle Limb girdle Asymmetric
Respiratory muscle involvement In severe cases No No
Dysphagia Frequent Rare 40% of patients
Muscle tenderness Frequent Infrequent Infrequent
Skin involvement Frequent No Absent
Involvement of other systems Lung, heart No No
Associations
Connective tissue diseases PSS, MCTD Yes <15% of cases
Autoimmune diseases Uncommon Common Uncommon
Viruses Not proven HIV, HTLV-1 Not proven
Parasites and bacteria No Yes No
Drug-induced myotoxicity Yes Yes No
Carcinoma 20% No No
Familial No No Yes, in some cases
Course Acute/subacute Subacute/chronic Chronic
684 Muscle Disorders

Steroid resistance DERMATOMYOSITIS

Second line agents
• Methotrexate: can be given as a single weekly oral dose.
• Azathioprine 2.5 mg/kg/day. DEFINITION
An idiopathic inflammatory myopathy with characteristic
Third line agents cutaneous manifestations.
• Cyclosporine.
• Cyclophosphamide. EPIDEMIOLOGY
• Plasma exchange. • Prevalence: 1 in 100 000.
• Age at onset: any age, affects children and adults.
Problems in management Comprises 95% of childhood myositis.
• Late diagnosis. • Gender: F>M (2:1).
• Steroid complications: cushingoid features.
• Ocular cataracts or glaucoma. PATHOLOGY
• Diabetes. Inflammatory infiltration of muscle occurs by macrophages
• Infection. and T and B lymphocytes. B cells are frequent, and T cells
• Osteoporosis. are of the helper type. The inflammatory infiltrates are
• Myopathy: predominantly perivascular, or in and around the
– If prednisone >10 mg/day for a long period. interfascicular septa, rather than within the fascicles.
– Detect by declining strength on myometry. Therefore, they do not penetrate the muscle fiber
– Normal CK. membrane. Damage appears to occur through compression,
– Myopathic EMG with spontaneous activity. rather than infiltration, of the fiber.
– Biopsy if uncertain. Microangiopathy: intramuscular blood vessels show
• Steroid resistance. endothelial hyperplasia with tubuloreticular profiles, fibrin
• Relapses: it is not common to be able to withdraw thrombi (particularly in children) and obliteration of
treatment and avoid relapse, but using a small capillaries. Capillary numbers are reduced, there are
maintenance dose also does not seem to prevent relapses. immunoglobulin deposits on vessel walls and blood vessel
• Immunodeficiency. endothelial cells show ultrastructural changes. The capillary
loss and consequent ischemia causes microinfarcts and may
Treatment of relapses be responsible for the sometimes striking perivascular
• Increase dose of prednisolone to 30–50 mg/day. atrophy seen.
• Add methotrexate or azathioprine. The necrotic, degenerating and regenerating muscle
• Add intravenous immunoglobulin if patients do not fibers are mostly in groups involving a portion of a muscle
show prompt improvement over 3 weeks. fasciculus and are often the result of microinfarcts within the
muscle.
Other ‘last resort’ forms of treatment Perifascicular atrophy, characterized by two to 10 layers
• Plasmapheresis. of atrophic fibers at the periphery of the fascicle is found in
• X-ray irradiation. about 90% of children and at least 50% of adults with
• Thoracic outlet drainage. dermatomyositis and is diagnostic of dermatomyositis, even
• Thymectomy. in the absence of inflammation.
• Stem cell transplant.
ETIOLOGY
PROGNOSIS • Unknown in most cases.
The response is less favorable than in dermatomyositis, • Caused or exacerbated by drugs in a few patients:
particularly in those with a long history at presentation. – Hydroxyurea.
Immunosuppressive therapy usually causes improvement – Quinidine.
and prevents further progression but significant improve- – Non-steroidal anti-inflammatory drugs.
ment may not occur in some. Antibody to signal recogni- – Penicillamine.
tion peptide, found in 5% of cases, is associated with a – 3-hydroxy-3-methylglutaryl coenzyme A-reductase
fulminant course and resistance to treatment. The 5-year inhibitors (‘statins’).
survival rate for treated patients is nearly 80%. Up to 30%
of patients may be left with residual muscle weakness. PATHOPHYSIOLOGY
A humorally-mediated microangiopathy (e.g. antibodies
against capillary endothelial cells with complement
activation) with muscle fiber inflammation occurring
secondarily to focal ischemia.

CLINICAL FEATURES
Muscle disease
• Initial symptoms include subacute onset of myalgias,
fatigue and weakness, manifested as difficulty climbing
stairs, raising the arms for actions such as shaving or
brushing hair, rising from a squatting or sitting position,
or a combination of these features.
 Dermatomyositis
• Weakness typically involves the proximal muscles sym-
metrically, and the pelvic more than the shoulder girdle.
• Pain and tenderness on palpation of the muscles is
variable.
• The course is slowly progressive during a period of weeks
to months.
• Difficulty swallowing (dysphagia) or symptoms of
aspiration may reflect involvement of striated muscle in
the pharynx or upper esophagus.
• Dysphonia.
Cutaneous manifestations
• Heliotrope rash (835): a violaceous to dusky erythe-
matous rash, with or without edema, in a symmetric
distribution involving the perorbital skin. The rash may
be mild and only comprise a slight discoloration along
the eyelid margin.
• Gottron’s papules: slightly raised violaceous papules and
plaques, with or without a slight scale and rarely a thick
psoriasiform scale, over bony prominences, particularly
the metacarpophalangeal joints, proximal interphalangeal
joints, and distal interphalangeal joints. Papules may also
be found overlying the elbows, knees, feet, or a combin-
ation of these. Within the lesions there is commonly
telangiectasia.
• An erythematous to violaceous psoriasiform dermatitis
involving the scalp.
• Malar erythema.
• Poikiloderma (which is the combination of atrophy,
dyspigmentation, and telangiectasia) on sun exposed skin
such as the extensor surfaces of the arms, the ‘V’ of the
neck, and the upper back (shawl sign).
• Violaceous erythema on the extensor surfaces.
• Nailfold changes: periungual telangiectases and/or
hypertrophy of the cuticle, and small hemorrhagic
infarcts in the hypertrophic area.
835
835 A blue–purple discoloration of the eyelids, cheeks and nose by a
typically heliotrope and slightly edematous rash of dermatomyositis.
685
Systemic features
• Raynaud’s phenomenon: generalized arthralgias accom-
panied by morning stiffness; a symmetric non-deforming
arthritis involving the small joints of the hands, wrists and
ankles; or both, may be present in up to 25% of patients.
• Esophageal disease, manifested by dysphagia, occurs in
about 15–50% of patients. There are two main forms:
– Proximal dysphagia is caused by involvement of striated
muscle of the pharynx or proximal esophagus, correlates
with severity of the muscle disease, and responds to
steroid treatment.
– Distal dysphagia is due to involvement of non-striated
muscle and is more common in patients who have an
overlap with scleroderma or another collagen-vascular
disorder.
• Pulmonary disease: occurs in about 15–30% of patients,
particularly those with esophageal disease, and is usually
due to an interstitial pneumonitis. Less common causes
include the muscle disease itself (causing hypoventilation
or aspiration), and treatments for the muscle disease (caus-
ing opportunistic infections or drug-induced hypersen-
sitivity pneumonitis). Associated with a poor prognosis.
• Cardiac disease: present in up to 50% of patients but
uncommonly symptomatic. Disorders include conduc-
tion defects and primary end-rhythm disturbances, and
even less commonly congestive heart failure, pericarditis,
and valvular disease. Associated with a poor prognosis.
• Calcinosis of the skin (firm, yellow, or flesh-colored
nodules, usually over bony prominences, and occasionally
extruding through the surface of the skin) or muscle
(generally asymptomatic) is unusual in adults but may
occur in up to 40% of children and adolescents with
dermatomyositis.
Malignancy
• About 20–25% have associated malignancy, before the
onset of myositis, concurrently with myositis, or after the
onset of dermatomyositis.
• Malignancy is more common in older patients
(>50 years) but may even occur in children.
• The site of malignancy can be predicted by the patient’s
age (e.g. testicular cancer in young men, colon and
prostate cancer in elderly men).
• Gynecologic malignancy, particularly ovarian carcinoma,
is common. Nasopharyngeal carcinoma is common
among Asians with dermatomyositis.
Evolution of symptoms
• Symptoms are usually subacute over several weeks.
• Evolution may be rapid with severe weakness, dysphagia
and respiratory muscle involvement, sometimes requiring
ventilatory support. Muscle pain, tenderness, and
swelling, if present, tend to equate with a rapid onset.
SPECIAL FORMS
Childhood dermatomyositis
• Childhood dermatomyositis is more common than
childhood and adolescent polymyositis.
• Onset is usually insidious and mistaken for a viral-type
illness or dermatitis, but a fulminant onset and course
may occur.
• It is commonly characterized as a vasculitis and has
greater potential for calcinosis than adult disease.
686 Muscle Disorders

DIFFERENTIAL DIAGNOSIS Muscle biopsy

Muscle weakness • Biopsies are obtained under local anesthetic from a
• Muscular dystrophy. moderately involved muscle, typically quadriceps or
• Myotonic dystrophy. deltoid (see Pathology, above).
• Steroid myopathy. • Light microscopy shows microvascular injury with
• Neuropathy. perifascicular fiber atrophy, a perimysial inflammatory
infiltrate dominated by B and T4 lymphocytes; deposits
Heliotrope rash and photosensitive of membrane attack complex confirm the role of
poikilodermatous eruption complement.
• Systemic lupus erythematosus: a heliotrope rash is rarely seen.
• Scleroderma: a heliotrope rash is rarely seen. Skin biopsy

Gottron’s papules PROGNOSTIC TESTS

• Systemic lupus erythematosus.
• Psoriasis: distinct histopathology.
• Lichen planus: distinct histopathology.
Scalp erythematous to violaceous
psoriasiform dermatitis
• Psoriasis.
• Seborrheic dermatitis.
Facial erythema
• Systemic lupus erythematosus.
• Rosacea.
• Seborrheic dermatitis.
• Atopic dermatitis.
INVESTIGATIONS
Diagnosis
ESR is usually elevated
Serum muscle enzymes
CK, aldolase, lactate dehydrogenase, alanine aminotrans-
ferase levels:
• CK is the most specific and widely used.
• It is helpful in the diagnosis and monitoring the response
to therapy.
• Levels may be raised up to 20 times normal, particularly
in acute cases, whereas levels may be normal or only
moderately raised (up to five times normal) in polymyo-
sitis, and are often normal in inclusion body myositis.
Serologic tests
• Antinuclear antibody: commonly positive.
• Antibodies to Mi-2, and antinuclear antibody, are specific but
not sensitive, being found in only about 25% of patients.
• Antibodies to Jo-1 are predictive of pulmonary
involvement but are rare.
• Antibodies to Ro (SS-A) are found in rare cases.
EMG
• EMG is useful for confirming active or inactive myopathy
and for excluding neurogenic disorders.
• Shows a myopathic pattern of increased spontaneous activity
with fibrillations, positive sharp waves, and complex repetitive
discharges; and myopathic potentials characterized by short-
duration, low-amplitude polyphasic motor units on voluntary
activation. These findings are non-specific and occur in a
variety of acute, toxic and active myopathic processes.
• Mixed myopathic and neurogenic potentials (polyphasic
units of short and long duration) may also be present as
a consequence of the regeneration of muscle fibers and
chronicity of the disease.
Tests and examinations are determined by the patient’s age
and gender, and commonly include rectal, vaginal and
breast examination for assessment of malignant disease.
Tests include mammography, sigmoidoscopy, EKG, chest x-
ray and pulmonary function tests, barium swallow and
esophageal motility studies, abdominal scanning (ultrasound
or CT), testing for fecal occult blood and basic hematologic
and biochemical studies. Repeat each year for the first
3 years after diagnosis or whenever new symptoms arise.
DIAGNOSIS
Based on clinical features, supported by laboratory investi-
gations, of which the most important is muscle biopsy.
TREATMENT
General
• Bedrest combined with a range-of-motion exercise
programme if patients have progressive weakness.
• Raise the head of the bed and avoid meals before
bedtime in patients with dysphagia.
Muscle disease
Treatment for muscle disease is controversial because of the
absence of controlled clinical trials.
First line therapy
Oral prednisolone 0.5–1 mg/kg bodyweight/day for at
least 1 month after myositis has become clinically and
enzymatically inactive. The dose is then gradually reduced,
generally over a period lasting 1.5 to two times as long as
the period of active intense treatment, but depending on
clinical progress and, to some extent, serum CK levels.
Convert to an alternate day regime after a few months.
N.B. It is easier to manage patients who have presented
acutely or subacutely, in whom the response to treatment is
usually more obvious and a high CK levels falls, than those
with a slowly progressive disorder: if a response occurs at all,
it is slow, and the CK level may have been normal or little
elevated at presentation.
Adjunct or second line therapy
Immunosuppressive agents: about 25% of patients will not
respond to systemic corticosteroids and 25–50% will develop
substantial steroid-related adverse effects. Therefore, early
intervention with steroid-sparing agents, such as methotrexate,
azathioprine (2.5 mg/kg bodyweight), cyclophosphamide,
mycophenolate mofetil, chlorambucil, or cyclosporine may be
effective in inducing or maintaining a remission.
About 50–75% of patients respond to an immuno-
suppressive agent with an increase in strength, a decrease in
enzyme concentrations, or a decrease in corticosteroid dosage.
 Inclusion Body Myositis (IBM)
Other therapy
• High-dose intravenous immunoglobulin has been shown
to be effective for recalcitrant dermatomyositis in a
double-blind, placebo-controlled trial (N. Engl. J. Med.,
1993; 329: 1993–2000). The indications are usually
resistance to steroids and second line agents, adverse
reactions to immunosuppressants and severe relapses.
The regimen may be 0.4 g/kg/day for 5 days followed
by monthly three day courses for up to 6 months (unless
no response within 3 months).
• Largely anecdotal reports have described success with
pulsed methylprednisolone, combination immunosup-
pressive therapy and whole body irradiation.
• Plasmapheresis was ineffective in a placebo-controlled
trial (N. Engl. J. Med., 1992; 326: 1380–1384).
Skin disease
• Patients should avoid sunlight or use a broad-spectrum
sunscreen with a high sun protective factor, if they are
photosensitive.
• Hydroxychloroquine hydrochloric acid 200–400 mg/day
is effective in about 80% of patients when used as a
steroid-sparing agent.
• Chloroquine phosphate 250–500 mg/day can be used
if patients are not responsive to hydroxychloroquine.
• Periodic ophthalmologic examinations and blood counts
are required for patients on continuous antimalarial
therapy.
• Methotrexate 15–35 mg/week can also be used.
PROGNOSIS
Adverse prognostic factors
• Increasing age.
• Severe myositis (frequently correlates with the degree of
weakness and the serum CK concentrations).
• Dysphagia or dysphonia.
• Cardiopulmonary involvement.
• Malignant disease.
• Poor response to corticosteroid therapy.
Prognosis
• If treated early, most patients will respond well, with many
showing full recovery of muscle function. In most cases the
disease will burn itself out, although this may take many
years during which time treatment has to be continued.
• Interstitial lung disease and other pulmonary disorders are
an important but under-recognized cause of late
morbidity. Similarly, cardiac involvement is common with
conduction defects, rarely leading to complete heart block,
arrhythmias and congestive heart failure.
Malignancy
The myositis may follow the course of malignant disease (a
paraneoplastic course) or may follow its own course
independent of treatment of the malignant disease.
836 Eosinophilic (pink) cytoplasmic inclusions and basophilic (blue)
granular inclusions located at the periphery of narrow vacuoles (rimmed
vacuoles) in a muscle fiber of a patient with inclusion body myositis.
687
INCLUSION BODY MYOSITIS (IBM)
DEFINITION
Inclusion body myositis is an idiopathic inflammatory
myopathy.
EPIDEMIOLOGY
• Prevalence: uncommon but the most common cause of
acquired myositis in patients over 50 years of age.
• Age at onset: after 50 years of age.
• Gender: M>F (3:1).
• Race: more common in whites than blacks.
PATHOLOGY
• Inflammatory infiltrates (predominantly T cells)
surrounding or invading individual non-necrotic muscle
fibers (endomysial inflammation) (like that seen in
polymyositis) are often present but rarely extensive.
• Basophilic granular inclusions are distributed around the
edge of slit-like vacuoles (rimmed vacuoles) (836).
• Eosinophilic cytoplasmic inclusions.
• Angulated fibers, often in small groups.
• Intranuclear or intracytoplasmic 15–18 nm tubulo-
filaments in muscle fibers on electron microscopy.
ETIOLOGY AND PATHOPHYSIOLOGY
Sporadic
• Uncertain; autoimmune, viral and degenerative theories
prevail.
• Partly mediated by cytotoxic T cells, with a secondary
inflammatory response to degenerating muscle (which is
why the amount of inflammation is variable and the
response to immunosuppression is poor).
• Multiple mitochondrial DNA deletions are present in
75% of patients.
• Amyloidogenic protein deposition has been reported in
affected muscle and increased cellular prion protein has
also been described.
Hereditary
Autosomal recessive rimmed vacuolar myopathies
Gene locus 9p1-q1.
Autosomal dominant rimmed vacuolar myopathies
• Gene locus 14q.
• Oculopharyngeal muscular dystrophy.
836
688 Muscle Disorders
CLINICAL FEATURES
• Gradual onset.
• Painless weakness of distal and proximal muscles
(particularly long finger flexors [flexor digitorum
profundus], wrist flexors and quadriceps femoris) which
may be asymmetric.
• Dysphagia in up to 30% of cases.
• Muscle wasting can be marked.
• Early loss of deep tendon reflexes.
• Numbness and sensory symptoms may suggest an
associated peripheral sensory neuropathy.
DIFFERENTIAL DIAGNOSIS
• Polymyositis.
• Neuropathy: e.g. diabetic amyotrophy.
INVESTIGATIONS
Blood
• Serum CK level: often normal or mildly raised.
• ESR: normal in 80% of cases.
EMG
• A mixed neuromyopathic pattern may be seen.
• 30% of patients have EMG signs of axonal neuropathy.
Muscle biopsy
Biopsy may show inflammation, predominantly an endo-
mysially-located mononuclear infiltrate with cytotoxic T cells
invading non-necrotic muscle fibers; rimmed vacuoles and
filamentous inclusions in muscle are characteristic. The
inclusions contain ubiquitin and tau protein, and are
pathologically similar to Alzheimer neurofibrillary tangles.
DIAGNOSIS
Highly likely if a clinical phenotype of asymmetric muscle
weakness with prominent wrist flexor, finger flexor and knee
extensory muscle involvement is present. A definitive
diagnosis requires electron microscopy of muscle biopsy
specimens showing muscle fibers with rimmed vacuoles
containing 15–18 nm tubulofilaments and small amyloid
deposits, in addition to light microscopy evidence of
endomysial T cell infiltration of non-necrotic muscle fibers.
An accurate diagnosis is important because inappropriate
treatment can cause adverse effects.
TREATMENT
• Numerous forms of immunosuppressive treatment have
been tried without benefit: most patients are resistant to
immunosuppressive treatment. High-dose steroids are
rarely beneficial clinically despite often reducing a raised
CK.
• In some who are not old and frail, the condition may
stabilize with a 3–6 month trial of prednisolone
combined with methotrexate (or azathioprine).
• Anabolic steroids (e.g. clenbuterol 20 µg/day–20 µg bd)
are being trialled.
• A physiotherapy/strength training program is also
important.
PROGNOSIS
Gradual deterioration is usual, with increasing weakness of
the neck, trunk, and distal arm muscles, and extensive
weakness and wasting in the legs. The disease can progress
to severe generalized weakness and disability.
METABOLIC AND ENDOCRINE
MYOPATHIES
DEFINITION
Metabolic and endocrine myopathies are a large,
heterogeneous group of inherited and acquired disorders of
muscle due to a disturbance of metabolism.
EPIDEMIOLOGY
• Uncommon.
• Age: usually infants and children, but may present in
adulthood (particularly endocrine myopathies).
• Gender: usually M=F.
ETIOLOGY AND PATHOPHYSIOLOGY
Disorders of glycogen metabolism
Acid maltase deficiency
• An autosomal-recessive glycogen storage disorder.
• Caused by a deficiency of lysosomal alpha-glucosidase
which results in impaired lysosomal conversion of
glycogen to glucose so that glycogen accumulates in the
liver, heart, CNS and muscle.
• The genetic abnormality maps to chromosome 17.
McArdle’s disease
• Autosomal recessive.
• Caused by a myophosphorylase (a-1,4-glucan ortho-
phosphate glycosyltransferase) deficiency, which results
in impaired conversion of glycogen to glucose-1-
phosphate in muscle.
• The gene for myophosphorylase maps to chromosome
11q13. At least 16 different mutations have been
identified, the most frequent of which is a nonsense
mutation in exon 1 (R49X), which causes the substi-
tution of an arginine (CGA) with a stop codon (TGA),
and a missense mutation (W797R) in exon 20.
• Glycogen breakdown is impossible during a sudden burst
of muscle activity; ATP generation is compromised;
muscle cell pH is shifted to alkaline.
Phosphofructokinase deficiency
• Autosomal recessive.
• Caused by impaired conversion of fructose-6-phosphate
to fructose-1,6-diphosphate in muscle.
Debranching enzyme system deficiency
• Autosomal recessive.
• Caused by impaired hydrolysis of glycogen to glucose-1-
phosphate.
Disorders of lipid metabolism
• Long chain fatty acids are a major source of muscle
energy and are consumed during muscular activity.
• Carnitine is involved in the transport of free fatty acids
into mitochondria.
Muscle carnitine deficiency
Lipids accumulate in muscle which is deficient in carnitine.
Carnitine-O-palmitoyltransferase deficiency
• Autosomal recessive.
• Caused by impaired transport of free fatty acids into
mitochondria.
 Metabolic and Endocrine Myopathies
• The abnormal gene maps to chromosome 1.
Mitochondrial myopathies (see p.162)
Reduced ATP generation by oxidative phosphorylation.
Endocrine disorders
Thyrotoxic myopathy
Muscle stiffness and weakness.
Thyrotoxic periodic paralysis (see p.694)
Dysthyroid eye disease (exophthalmic ophthalmoplegia) (837)
Hypothyroid myopathy
Muscle weakness
Thyroid hormone has a regulatory role on the transcription
of numerous muscle genes encoding both myofibrillar and
calcium-regulatory proteins.
Steroid myopathy (838)
• About 70% of patients with Cushing’s syndrome have
muscle weakness.
837
837 Dysthyroid eye disease (exophthalmic ophthalmoplegia) showing
left eyelid retraction, and exophthalmos. Dysconjugate vertical eye
movements were present.
838
838 Muscle biopsy of a patient with a steroid myopathy showing Type
II muscle fiber atrophy, which may be seen in disuse, cachexia,
myasthenia gravis as well as a steroid effect. Myosin ATPase stain, pH
9.4.Type 1 fibers are pale and Type 2 fibers are darkly stained. Fibers
showing an intermediate reaction are usually Type 1.
689
• Fluorinated corticosteroids, such as dexamethasone and
triamcinolone, have more myopathic potential. The dose
required to cause myopathy varies among individuals.
Addison’s disease and other forms of hypoadrenalism
May occur as one component of adrenoleukodystrophy (see
p.166).
Acromegaly
Electrolyte disorders
Calcium
• Hyperparathyroidism:
– Primary hyperparathyroidism: adenoma.
– Secondary hyperparathyroidism: typically secondary to
renal disease.
• Osteomalacia.
Potassium
• Iatrogenic usually.
• Secondary periodic paralyses (see p.693).
• Primary hyperaldosteronism.
Malignant hyperthermia
• An autosomal dominant susceptibility to a number of
drugs, particularly anesthestics such as halothane and suc-
cinylcholine. Other drugs include tricyclic antidepressants,
monoamine oxidase inhibitors, methoxyflurane, ketamine,
enflurane, diethyl ether, and cyclopropane.
• Due to a malfunction of the calcium channel of the sarco-
plasmic reticulum (the ryanodine receptor). The abnormal
ryanodine receptor may accentuate calcium release.
• The gene for the ryanodine receptor maps to chromo-
some 19 (13-1).
• Fast, uncontrolled increase in skeletal muscle metabolism
associated with rhabdomyolysis occurs and may occur in
association with dystrophinopathies and central core
congenital myopathy.
CLINICAL FEATURES
Disorders of glycogen metabolism
Acid maltase deficiency
• Infantile form: Pompe’s disease: a generalized glyco-
genosis with severe cardiomyopathy, hypotonia, macro-
glossia, cardiomegaly and hepatomegaly. Death occurs in
infancy.
• Adult form: a slowly progressive myopathy affecting
predominantly the diaphragm (hence respiratory failure),
biceps, shoulder, and thigh adductor muscles. There is
little or no heart disease.
McArdle’s disease
• Males are affected more than females (4:1).
• Onset in childhood or adolescence usually.
• Attacks of exercise intolerance with muscle pain (myalgia)
and stiffness, often precipitated by brief, strong exercises.
• Fatigue.
• Cramps and dark urine (myoglobinuria) usually develop
during adulthood.
• Seizures.
• Renal failure may occur secondary to myoglobinuria.
• Not progressive usually.
690 Muscle Disorders

Phosphofructokinase deficiency: Hypothyroid myopathy

• Clinically similar to McArdle’s disease. • More common in women.
• A mild hemolytic tendency is sometimes present. • Aching and painful muscles.
• Cramps.
Debranching enzyme system deficiency • Enlarged muscles.
• Infancy: growth retardation, hepatomegaly, mild • Muscle weakness (rare).
myopathy, and seizures which tend to improve after • Myedema (ridging of muscle on percussion).
puberty. • Respiratory muscle weakness may be present.
• Adults: mild weakness of hands and legs. Cardiomyopathy • Slow-recovery reflexes.
is a late complication.
Steroid myopathy
Disorders of lipid metabolism • Proximal muscle weakness, earlier and worse in the lower
Muscle carnitine deficiency limbs than upper limbs, and sometimes painful. Wasting
Myopathy develops in infants or children. is late.
• Difficulty climbing stairs.
Carnitine-O-palmitoyltransferase deficiency
• Most patients are male and present in adolescence. Addison’s disease and other forms of hypoadrenalism:
• Intermittent attacks occur without warning; precipitated • Myalgia and muscle cramps.
by prolonged exertion, fasting or a high fat diet. Muscle • Proximal muscle weakness.
cramps, muscle pain, and dark urine (myoglobinuria) are • Painful flexion contractures in the legs sometimes.
present, with normal muscle strength during attacks. • Fatigue and lassitude.
• Exposure to cold, viral infections, and general anesthesia • Postural hypotension.
can also precipitate rhabdomyolysis. • Confusional state, stupor and coma.
• Renal failure (due to myoglobinuria) and respiratory
failure may ensue. Acromegaly
• Patients have a normal capacity to perform short, • Increased muscle bulk.
demanding exercise. • Improved strength initially but later muscle wasting and
weakness occur.
Endocrine disorders • Non-specific headache.
Typically mild to moderate proximal muscle weakness. • Associated entrapment neuropathy (e.g. carpal tunnel
syndrome).
Thyrotoxic myopathy • Sensorimotor peripheral neuropathy (sometimes with
• Common. enlarged nerves).
• Proximal muscle weakness and some wasting occurs; • Visual field defects.
occasionally the bulbar and respiratory muscles only are • Hypopituitarism.
affected (cf. myasthenia, p.657). • Obstructive sleep apnea.
• Fatigue. • Complications of diabetes and hypertension.
• Heat intolerance.
• Normal or augmented reflexes. Electrolyte disorders
• Fasciculations sometimes (cf. motor neuron disease, Hyperparathyroidism and osteomalacia
p.534). Proximal and often painful muscle weakness, mainly affecting
• Associated with hypokalemic periodic paralysis and the legs and associated with mild wasting.
myasthenia gravis.
Hypokalemia and hyperkalemia
Thyrotoxic periodic paralysis (see p.694) Cause of generalized weakness.
• Very rare.
• Orientals particularly are affected. Malignant hyperthermia
• During general anesthesia or after exposure to a causal
Dysthyroid eye disease (exophthalmic ophthalmoplegia) (837) drug.
• Can be quite asymmetric. • Rapid elevation of temperature which may rise to 43°C
• Difficulty of upgaze initially (inferior rectus infiltrated (109°F).
early). • Tachycardia.
• Diplopia. • Muscle rigidity (e.g. begins with trismus).
• Lid retraction. • Areflexia.
• Exophthalmos. • Coma.
• Conjunctival and lid edema.
• Exposure keratopathy. DIFFERENTIAL DIAGNOSIS
• Ptosis often. Muscle cramps or pain on exercise
• Little pain (grittiness or fullness). • Disorders of glycogenolysis or glycolysis (e.g. McArdle’s
• Eventually raised intraocular pressure and blindness may disease).
occur. • Carnitine-O-palmitoyltransferase deficiency.
• The patient is usually but not necessarily thyrotoxic. • Mitochondrial myopathies, including zidovudine toxicity.
• Toxic myopathy caused by clofibrate and related drugs.
• Hypothyroid myopathy.
 Metabolic and Endocrine Myopathies
Myoglobinuria
Myoglobin is found in muscle and if there is severe and
acute muscle injury it is released into the blood and appears
in the urine (myoglobinuria). The urine is colored brown
in severe cases and reacts to benzidine; if there is neither
hematuria nor hemoglobinemia a positive test strongly
suggests myoglobinuria. The muscle enzymes are always
raised and the muscles are tender, weak and sometimes
swollen. In severe cases acute renal failure occurs.
• Disorders of glycogenolysis or glycolysis (e.g. McArdle’s
disease).
• Carnitine-O-palmitoyltransferase deficiency.
• Duchenne muscular dystrophy after anesthetic exposure.
• Acute alcoholic myopathy.
• Acute viral myositis and other acute fulminating
inflammatory myopathies.
• Malignant hyperthermia crisis.
• Neuroleptic malignant syndrome (see p.133).
• Status epilepticus.
• Excessive exercise.
• Heat stroke.
• Crush injury of muscle.
• Snake bite.
Myotonia clinically
• Myotonic dystrophy (adults).
• Myotonia congenita (dominant and recessive forms).
• Paramyotonia congenita ± hyperkalemic periodic
paralysis.
• Hypothyroid myopathy.
Respiratory insufficiency (possible and prominent)
• Acid maltase deficiency (adult-onset).
• Acute myopathy after administration of high-dose
corticosteroids and muscle paralysing agent (e.g. status
asthmaticus).
• Myotonic dystrophy.
• Nemaline myopathy.
• Centronuclear myopathy.
• Myopathy with cytoplasmic bodies.
Thyrotoxic myopathy
• Hypokalemic periodic paralysis.
• Myasthenia gravis.
• Motor neuron disease.
Malignant hyperthermia
Neuroleptic malignant syndrome (see p.133): also present
with high fever, rigidity, tachycardia, and rhabdomyolysis,
but it is of slower onset over days to weeks, not familial, and
usually triggered by drugs that block central dopaminergic
pathways, such as phenothiazines, lithium and haloperidol,
or can occur after discontinuation of L-dopa (levodopa) for
Parkinson’s disease.
INVESTIGATIONS
Disorders of glycogen metabolism
Acid maltase deficiency
• Serum CK: slightly elevated.
• EMG: non-specifically myopathic but myotonic
discharges may occur (although patients do not have
myotonia).
• Blood leukocyte or urine: acid maltase deficiency.
691
• Muscle biopsy: vacuolar myopathy with high glycogen
content, and acid maltase deficiency.
• Chorionic villi biopsy: for prenatal diagnosis.
McArdle’s disease
• Serum CK: elevated after exercise.
• Urine: myoglobinuria occasionally.
• EMG: myopathic.
• Forearm ischemic exercise produces no increase in
venous lactate levels.
• Muscle biopsy: subsarcolemmal deposits of glycogen at
the periphery, undetectable histochemical reaction of
phosphorylase.
Phosphofructokinase deficiency
Forearm ischemic exercise produces no increase in venous
lactate levels.
Debranching enzyme system deficiency
• Infancy: fasting hypoglycemia and ketonuria.
• Adults: serum CK: elevated.
• Forearm ischemic exercise produces no increase in
venous lactate levels.
• Muscle biopsy: excess glycogen.
Disorders of lipid metabolism
Muscle carnitine deficiency
• Normal blood level of carnitine.
• Muscle biopsy: accumulation of lipid which is deficient
in carnitine.
Carnitine-O-palmitoyltransferase deficiency
• Urine: myoglobinuria.
• Serum CK: normal but often raised following the attacks.
• Muscle biopsy at the time of an attack: may show lipid
accumulation and little CPT activity.
Endocrine disorders
Typically a myopathic EMG and the non-specific finding of
Type II fiber atrophy on muscle biopsy.
Thyrotoxic myopathy
• Serum CK: normal.
• EMG: myopathic.
Thyrotoxic periodic paralysis (see p.694)
Plasma potassium is usually low but can be normal.
Dysthyroid eye disease (exophthalmic ophthalmoplegia)
• Thyroid function tests: the patient is usually but not
necessarily thyrotoxic.
• Thyroid antibodies: often positive.
• Response to thyrotrophin releasing hormone: abnormal.
• CT scan of the orbits: enlarged extraocular muscles.
Hypothyroid myopathy
• Serum CK: may be grossly elevated.
• Thyroid function tests: low thyroxine. TSH may be
elevated if primary hypothyroidism.
• Urine myoglobin: rhabdomyolysis may be present.
692 Muscle Disorders

Steroid myopathy Dysthyroid eye disease (exophthalmic ophthalmoplegia)

• Serum CK: normal. • Restore the euthyroid state.
• EMG: normal insertional activity and no spontaneous • Tarsorrhaphy to protect the cornea.
activity. • Surgical correction of diplopia if necessary.
• Muscle biopsy (838). • Severe cases: high doses of corticosteroids, cyclosporine,
and even orbital decompression have been used to save
Addison’s disease and other forms of hypoadrenalism sight.
Serum electrolytes: hyponatremia and hyperkalemia.
Hypothyroid myopathy
Acromegaly Restore the euthyroid state.
Serum CK: sometimes elevated.
Steroid myopathy
Hyperparathyroidism and osteomalacia • Change to a non-fluorinated steroid.
Serum CK: usually normal. • Reduce steroid dose to the lowest possible therapeutic
level.
Malignant hyperthermia • Administer the steroid on an alternate daily basis if
• Arterial blood gases: metabolic acidosis. needed.
• Serum CK: precipitous rise, sometimes to 10 000 times • Adequate diet and exercise should assist recovery.
the normal values.
• Blood coagulation profile: disseminated intravascular Hyperparathyroidism
coagulation. • Primary hyperparathyroidism: remove the adenoma.
• Urine: myoglobinuria. • Secondary hyperparathyroidism (typically to renal
disease):
DIAGNOSIS – Partial parathyroidectomy.
The diagnosis usually depends on histochemistry or – 1,25 dihydroxycholecalciferol.
biochemical assay of muscle biopsy material. – 1-alpha tocopheral.
• Osteomalacia: vitamin D therapy.
PREVENTION
Malignant hyperthermia Malignant hyperthermia
• Screen the relatives of affected patients by muscle biopsy; Treatment depends on the severity, which is often related to
abnormal muscle contracture in vitro is induced by the dosage and duration of anesthesia.
caffeine or halothane.
• Barbiturate, nitrous oxide, and opiate non-depolarizing Mild cases
relaxant anesthesias should not induce malignant Discontinue the anesthetic.
hyperthermia.
More severe cases
TREATMENT • Dantrolene 2 mg/kg i.v. every 5 min, up to 10 mg/kg:
Correct the metabolic defect if possible. inhibits calcium release from the sarcoplasmic reticulum.
• Correct associated hyperkalemia (not with calcium).
Disorders of glycogen metabolism • Increase ventilation.
Acid maltase deficiency • Correct the acid–base disturbance: give i.v. sodium
• No specific therapy at present but promising results of bicarbonate 2–4 mg/kg.
myophosphorylase gene transfer in myoblasts in vitro • Cool the patient: cooling blankets and cold i.v. fluids
have been reported in McArdle’s disease. until temperature reaches 38°C (100°F).
• Inspiratory exercises are useful. • Volume load with diuretics if myoglobinuria is present.
• Give steroids for the acute stress reaction.
McArdle’s disease
Oral creatine supplementation may improve skeletal muscle PROGNOSIS
function. In most cases, the weakness reverses when the metabolic
defect is corrected but improvement may take weeks to
Disorders of lipid metabolism months.
Carnitine-O-palmitoyltransferase deficiency The prognosis for malignant hyperthermia is more
No specific therapy. guarded but mortality can be greatly diminished by
recognizing the syndrome and treating it appropriately.
Endocrine disorders
Thyrotoxic myopathy
• Correct the hyperthyroidism
• Symptomatic therapy with beta-blockers.
• Glucocorticoids can be used in thyroid storm to block
the peripheral conversion of T4 to T3.

Thyrotoxic periodic paralysis (see p.694)

Correct the thyrotoxicosis and plasma potassium if low.
 Hypokalemic Paralysis 693

HYPOKALEMIC PARALYSIS • Uterosigmoidostomy.

• Laxative abuse.

DEFINITION CLINICAL FEATURES

A rare but treatable clinical syndrome, representing a
heterogeneous group of disorders, characterized by acute
systemic weakness and low serum potassium.
EPIDEMIOLOGY
• Rare.
• Age: youth and young adults predominantly.
• Gender: M>F.
ETIOLOGY AND PATHOPHYSIOLOGY
• Symptomatology results from the increased ratio between
intra- and extracellular potassium concentrations, which
modifies membrane polarization and thereby alters the
function of excitable tissues such as nerve and muscle.
• Most cases are due to alteration in the transcellular
distribution of potassium and the others to actual potassium
depletion from renal or extrarenal losses.
• Muscular weakness, particularly of the lower extremities is
present, which can be severe and generalized with marked
potassium depletion (e.g. virtually total paralysis including
respiratory, bulbar and cranial musculature).
• Deep tendon reflexes may be decreased or absent.
• Consciousness and sensation are preserved.
• Underlying etiology may be determined from the age of
onset, race, family history, medications and underlying
disease states.
SPECIAL FORMS
Familial (primary) periodic paralysis (FPP)
Epidemiology
• Age of onset: early in life (e.g. puberty), rarely after 25 years
of age.
• Gender: M>F.
• Race: Caucasians typically.

Causes of hypokalemia Etiology and pathophysiology

Transcellular shift of K (no depletion) • Autosomal dominant inheritance (2/3 of all cases of
• Familial or primary hypokalemic periodic paralysis (most periodic paralysis).
cases). • Mutations in the gene (on chromosome 1q32) encoding
• Thyrotoxic periodic paralysis (839, 840). the skeletal muscle voltage-gated calcium channel α-1
• Barium poisoning. subunit (CACNL1A3) account for most cases.
• Insulin excess. • Mutations in the gene coding for the skeletal muscle
• Alkalosis. voltage-gated sodium channel α subunit (SCN4A)
account for a minority of cases.
Actual K depletion • Weakness occurs in association with hypokalemia (but can
Renal losses: also occur with normokalemia, or hyperkalemia).
• Excessive mineralocorticoids (primary and secondary However, alterations in potassium regulation are well
aldosteronism, liquorice ingestion, glucocorticoid excess). documented. Total body potassium stores remain adequate,
• Renal tubular diseases (renal tubular acidoses, leukemia, but serum potassium decreases due to potassium migration
Liddle’s syndrome, antibiotics, carbonic anhydrase inhibitors). into muscle cells which causes the muscles to become
• Diuretics. electrically inexcitable.
• Magnesium depletion. • The exact method of potassium translocation is not known
but is secondary to an abnormality in muscle membrane.
Extra-renal losses: (? An increase in muscle membrane sodium or calcium
• Dietary deficiency. permeability associated with an inherited defect within
• Diarrhea. skeletal muscle voltage-gated sodium or calcium
• Rectal villous adenoma. channels.)
• Fistulas. Continued overleaf

839 840

839, 840 Thyrotoxic patient presenting with periodic paralysis. Exophthalmos due to thyrotoxicosis (839). Lateral view of the neck showing
thyroid goiter (840).
694 Muscle Disorders
Etiology and pathophysiology (continued)
• Also associated with paramyotonia congenita, myotonia
congenita, and generalized myotonia (i.e. both hyper-
kalemia and hypokalemia can cause paralysis).
Clinical features
• Episodic attacks of muscle weakness with no stiffness.
• Precipitants: decrease in blood potassium levels, rest, sleep,
carbohydrate intake or insulin administration (attacks
almost never occur during vigorous physical activity).
• Frequency: varies from daily to yearly.
• Duration: from 3–4 hours to a day or more.
Differential diagnosis
Hyperkalemic familial periodic paralysis:
• Usually starts in infancy or childhood.
• Attacks can be precipitated or induced by fasting, cold,
pregnancy and potassium loading.
• Muscles can be stiff and in some patients there is myotonia
of the eyelids, tongue, thumb and forearm muscles.
• During attacks the serum potassium is often raised
(above 5.0 mmol/l [0.5 mEq/l]), as is the urine
excretion of potassium and the CK level.
• Associated with a genetic abnormality at chromosome 17q.
Diagnosis
Low serum potassium during a paralytic attack, and
exclusion of secondary causes of hypokalemia.
Treatment
• Oral potassium 0.2–0.4 mmol/kg (0.2–0.4 mEq/l),
repeated at 15–30 minute intervals depending on the
response of the patient (muscle strength), EKG, and
serum potassium level.
• If the patient is unable to swallow, or is vomiting,
intravenous potassium chloride 20 mmol per 100 ml
normal saline hourly, while monitoring clinical status and
serum potassium, may be necessary.
• Glucose in the diluent should be avoided as it can cause
a further intracellular shift of potassium and reduction in
serum potassium levels.
Prophylaxis against recurrent periodic attacks
• Acetazolamide 250–750 mg/day (agent of choice), or
spironolactone 100–200 mg/day or triamterine.
• Acetazolamide abolishes attacks in most patients, perhaps
because of the metabolic acidosis it produces. As
acetazolamide lowers serum potassium, it may be
necessary in some patients to supplement potassium and
to avoid high carbohydrate meals.
• Chronic acetazolamide therapy may be associated with
renal calculus (for which patients should be monitored).
Thyrotoxic periodic paralysis (TPP)
Epidemiology
• The most common acquired form of periodic paralysis.
• Age of onset: second to fourth decades (similar to
thyrotoxicosis).
• Gender: M>F (20:1).
• Race: Orientals (90% of cases), Caucasians, native
American Indians, Blacks, and Aborigines.
• Family history of TPP: rare.
Etiology
Any cause of thyrotoxicosis but usually Graves disease.
Attacks only occur during hyperthyroidism.
Pathogenesis
Uncertain; perhaps a decrease in activity of the calcium pump.
Clinical features
Similar to FPP, but also signs of hyperthyroidism, which are
frequently, but not always subtle (839, 840). Paralytic
attacks can be induced by the thyrotoxic state, and
carbohydrate and insulin administration but only if the
patient is hyperthyroid, and not euthyroid.
Treatment
• Acute attack: potassium administration. Concurrently,
begin to correct the hyperthyroid state and avoid preci-
pitating factors (e.g. extreme exertion, heavy carbo-
hydrate intake, and alcohol ingestion).
• Prophylaxis: beta-adrenergic blocking agents reduce the
frequency and severity of attacks while measures to control
thyrotoxicosis are being instituted. As serum potassium
levels are normal between paralytic attacks, prophylactic
potassium administration is unlikely to be helpful.
Furthermore, acetazolamide is not helpful (unlike in FFP),
and may even exacerbate attacks of paralysis in TPP.
Barium poisoning
• A rare cause of hypokalemic paralysis.
• Most cases are due to suicidal or accidental ingestion of
barium.
• The mechanism of hypokalemia is transcellular shift of K+.
• The paralysis is treated with potassium replacement.
DIFFERENTIAL DIAGNOSIS
CNS
• Cataplexy.
• Sleep paralysis associated with narcolepsy.
• Multiple sclerosis.
• Transient ischemic attack of the brain.
• Hyperventilation syndrome.
• Poliomyelitis.
Peripheral nerve
Guillian–Barré syndrome (see p.588).
Neuro-muscular junction
• Myasthenia gravis (see p.657).
• Lambert–Eaton myasthenic syndrome (see p.664).
• Botulism.
• Diphtheria.
Muscle
• Polymyositis.
• Dermatomyositis.
• Acute inflammatory myopathy (viral/parasitic).
Metabolic/toxic
• Electrolyte abnormalities.
• Porphyria.
• Medications (e.g. opiates).
• Alcoholism.
• Hypoglycemic disorders.
• Endocrine disorders.
 Further Reading 695

INVESTIGATIONS
• Serum potassium.
• EKG.
• Thyroid function tests.
DIAGNOSIS
• Consider the diagnosis of hypokalemic paralysis in any
patient presenting with a sudden onset, areflexic, pure
motor weakness involving one or more limbs, without
alteration in level of consciousness or sphincter function.
• Serum potassium is <3.5 mmol/l (3.5 mEq/l) during an
attack (usually much lower).
• EKG shows U waves, ST segment sagging, and flattening
and inversion of T waves, but these changes do not
correlate well with the severity of the hypokalemia.
• Response of muscle power to provocative testing with glu-
cose, insulin, potassium, and cold: for patients whose at-
tacks are infrequent, but potentially hazardous and patients
must be carefully monitored during their performance.
TREATMENT
• Identify and treat the cause (e.g. correction of the
hyperthyroid state).
• Replace potassium: oral potassium 0.2–0.4 mmol/kg
(0.2–0.4 mEq/l), repeated at 15–30 minute intervals
depending on the response of the patient (muscle
strength), EKG, and serum potassium level.
• Avoid precipitating factors (e.g. extreme exertion, heavy
carbohydrate intake and alcohol ingestion).
PROGNOSIS
• Generally favorable, if appropriately diagnosed and
managed.
• Deaths from respiratory failure and arrhythmia have been
reported.

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696

Index
Page numbers in bold type indicate major anemia 222 atrophy
discussions of topics anencephaly 139 lobar 414–16
aneurysms 251 multiple systems (MSA) 263, 435–7,
atrial septal 211 474, 576
A cavernous sinus syndrome 354, 355 olivopontocerebellar (OPCA) 435
abducens nerve 18, 500 saccular 250 see also muscular atrophy
neuropathy 499–504 angiitis attention, assessment of 14
abetalipoproteinemia 531 allergic 597 attention deficit disorder (ADD) 131,
abscess granulomatous 228, 352 133
intracranial 284–7 hypersensitivity 227, 228 auditory nerve 19
spinal epidural 555–7 necrotizing 227, 228 autonomic neuropathy 573–8, 582, 590,
absences (petit mal epilepsy) 68 see also giant cell arteritis; vasculitis 610
accessory nerve see spinal accessory nerve anosmia 482 axillary nerve 620
accommodation reflex 575, 576 anterior compartment syndrome 651, 652 axillary neuropathy 620–1
acid maltase deficiency 688, 689, 691, anterior interosseous syndrome 628, 629 axonal degeneration 36, 582–3
692 anterior ischemic optic neuropathy axonopathy 580
acoustic neuroma 108, 383–4 (AION) 487–8
acquired immunodeficiency syndrome anterior spinal artery syndrome 560
(AIDS) 323, 324 anterior tarsal tunnel syndrome 651, 652 B
dementia complex 301 antiphospholipid antibodies (APAs) 218 back pain 550–1, 552
myelopathy 564 antiphospholipid syndrome 218–24 see also slipped disc
see also human immunodeficiency virus antithrombin III 223–3 bacterial infections
(HIV) anxiety 589 botulism 123
acromegaly 690, 692 aortic valve sclerosis/calcification 211 intracranial abscess 284–7
acute disseminated encephalomyelitis arachnoid cysts 570 leprosy 544, 604–6
(ADEM) 337–9 arachnoiditis, spinal 557–8 Lyme disease 316–17
acute idiopathic facial paralysis (Bell’s Argyll Robertson (AR) pupils 314, 576 meningitis 273–8
palsy) 515–16 Arnold–Chiari malformation 136–9, 530 myositis 682
acute inflammatory demyelinating see also Chiari malformations neurosyphilis 312–15
polyradiculoneuropathy arteriosclerosis 202 tetanus 287–8
(AIDP) 588–92, 602, 603 arteriovenous fistula 246 tuberculous meningo-encephalitis
acute motor axonal neuropathy (AMAN) arteriovenous malformation (AVM) 153, 281–3
590 154, 156, 245–9, 251 Whipple’s disease 289–90
acute motor-sensory axonal neuropathy dural 564 ballism 123
(AMSAN) 590 spinal 246, 443, 530 Baltic myoclonus 88, 89
acute suppurative myositis 682 arteritis 299 Bassen–Kornzweig disease 531
acute transverse myelitis 561–3 giant cell (GCA) 105, 234–7, 597 Becker’s muscular dystrophy (BMD) 668,
Addison’s disease 689, 690, 692 temporal (TA) 237 670–2
adenomas, pituitary 379 arylsulfatase A (ASA) deficiency 169 Behçet’s disease 597
growth hormone-producing 380 asterixis 127, 454 Bell’s palsy 515–16
macroadenomas 382 astrocytoma 364, 368, 370, 371 benign paroxysmal positional vertigo
microadenomas 382 anaplastic 364, 370, 371 110
adrenoleukodystrophy (ALD) 166–8, spinal cord 570 berry aneurysms 250
530 ataxia 127, 165, 436, 530 bilateral vestibular failure 108
adrenomyeloneuropathy (AMN) 166–8, autosomal dominant cerebellar 437–41 Binswanger’s disease 262
530, 564 early onset, of unknown etiology bladder dysfunction 578
adult-onset globoid cell leukodystrophy 442–3 multiple sclerosis 342, 348
(Krabbe disease) 171–2, 530 Friedreich's 441–4 normal pressure hydrocephalus 473–4
AIDS see acquired immunodeficiency multiple sclerosis 349 bladder function 574
syndrome progressive myoclonic 88 blindness see visual disturbances
akinetic mutism 54 with isolated vitamin E deficiency 442 blood pressure 574
akinetic seizures 68–9 ataxia telangiectasia 358, 444–6 see also hypertension
alcohol withdrawal 120 atherogenesis 204 Borrelia burgdorferi 316
allergic granulomatosis 597 atheroma 204 botulism 659
Alzheimer’s disease (AD) 263, 407–14, atherosclerosis 202, 204 bradyarrhythmia
416, 431, 474 atherosclerotic ischemic stroke 202–8 Parkinson’s disease 422
ammonia, liver failure and 454 plaque rupture 205 syncope 59
amnesia, transient global 187 atherothrombosis 205, 206 brain abscess 284–7
amyloid angiopathy 238 see also thromboembolism; thrombosis brain death 51–2, 54, 451
amyloidosis 544, 607, 608, 609 athetosis 123 brain imaging see imaging
amyotrophic lateral sclerosis (ALS) 534, atonic seizures 68–9 brain tumors 357–63
536, 537 atrial fibrillation 210–11 metastases 358, 396, 397, 398
anal reflex 22 atrial septal aneurysm 211 see also specific tumors

brainstem auditory evoked potentials
(BAEPs) 40–1
brainstem myoclonus 127
breath-holding attacks 71
bulbar palsy 524, 528, 536, 538
progressive 534, 537
bulbocavernosus reflex 21
C chronic paroxysmal hemicrania (CPH)
calcaneal neuropathy 647, 648, 650
calpainopathy 676
Campylobacter jejuni 589
CANOMAD syndrome 607
carbon monoxide poisoning 450, 452
carcinoma
choriocarcinoma 389
embryonal 388
naevoid basal cell 358
cardioembolic stroke 209–15
carnitine-O-palmitoyltransferase deficiency
688–9, 690, 691, 692
carotid artery dissection 224–6
carpal tunnel syndrome (CTS) 630–2
cataplexy 57, 58, 175
cauda equina syndrome 141, 474
cavernous malformation 246
cavernous sinus syndrome 354–5
bilateral 355
cavernous sinus thrombosis 258
cavernous sinus/superior orbital fissure
506, 508
central cord syndrome 568
central motor conduction 37
central pontine myelinolysis 457–9
cerebellar herniation 136
cerebral circulation imaging see imaging
cerebral infarction 192, 202, 299
cerebral ischemia 256
cerebral venous thrombosis 257–60
cerebrospinal fluid (CSF)
circulation disorders 468–80
hydrocephalus 468–72
idiopathic intracranial hypertension
(IIH) 477–80
normal pressure hydrocephalus
(NPH) 473–6
circulation physiology 468
examination 31–3
complications 32
indications/contraindications 32
normal values 32–3
technique 31
ceruloplasmin deficiency 159
cervical dystonia 115
cervical spondylosis 544, 545–9
cervical spondylotic myelopathy/radicu-
lopathy 545–9
Charcot joints 314
Charcot–Marie–Tooth (CMT) disease
584, 585–6, 587
type 1 585
type 2 585, 586
Chiari malformations
type I 136, 138, 541, 542, 544
type II 136, 138–9, 541, 544
type III 136, 541
type IV 137
chickenpox 299
childhood
dermatomyositis 685
juvenile myasthenia 659
juvenile myoclonic epilepsy (JME)
86–7
migraine 98
chloride channelopathies 680
Index
cholestanolosis 442
cholesterol reduction, stroke and 200
cholinergic crisis 664
chorea 122–4, 127, 418, 420
choriocarcinoma 389
choroid plexus papilloma 366
chronic inflammatory demyelinating
polyneuropathy (CIDP) 590, 593–5,
602, 603, 608
104, 105
chronic progressive external
ophthalmoplegia (CPEO) 164, 165
Churg–Strauss syndrome 597
cigarette smoking, stroke and 200
cingulate herniation 44
cisternography 26
clinical history see neurologic history
clonus 127
Clostridium tetani 287
cluster headache 103–5
cluster-tic syndrome 104
coagulation disorders 222–3
colloid cyst 366
color vision 15
optic neuropathy and 484
see also visual disturbances
coma 44–50, 54
communication, assessment of 15
compartment syndrome 652
anterior 651, 652
lateral 651, 652
compound muscle action potential
(CMAP) 35, 37
compression neuropathies 612
carpal tunnel syndrome 630–2
femoral neuropathy 640
gluteal neuropathy 644
lateral cutaneous nerve of the thigh
neuropathy 637
median neuropathy 628
peroneal neuropathy 651, 652
plantar interdigital neuropathy 648,
649
posterior cutaneous nerve of the thigh
neuropathy 639
pudendal neuropathy 655
radial neuropathy 624
saphenous nerve 640
sciatic neuropathy 645
ulnar neuropathy 633
computerized tomography (CT) 23–4
CT angiography 28
CT cisternography 26
CT myelography 29
see also specific conditions
confusion 44, 48
consciousness 44
contrast angiography 26–8
coordination assessment 20, 22
corneal response 18
coronary heart disease 211
cortical myoclonus 126
cranial dystonia 115
cranial nerves 15–19
palsy 354
see also specific nerves
cranial neuropathies see neuropathy;
specific nerves
craniopharyngioma 377–9
Creutzfeldt–Jakob disease (CJD) 330–5,
416, 440
amyotrophic form 332
Brownell–Oppenheimer variant 331
Heidenhain variant 331
new variant CJD 332, 334
697
cryoglobulinemia 607, 608, 609
Cryptococcus neoformans meningitis
318–20
cysticercosis 326–9
intraparenchymal 327
racemose 327
cysts
arachnoid 570
colloid 366
cytomegalovirus (CMV) 589
D
Dandy–Walker syndrome 138, 140
deafness 518
debranching enzyme system deficiency
688, 690, 691
degenerative diseases
Alzheimer’s disease (AD) 407–14
ataxia telangiectasia 444–6
autosomal dominant cerebellar ataxias
437–41
axonal degeneration 36, 582–3
diffuse Lewy body disease (DLBD)
430–1
Friedreich’s ataxia 441–4
frontotemporal dementia (FTD)
414–16
hepatolenticular degeneration 157–61
Huntington’s disease (HD) 417–20
multiple systems atrophy (MSA) 435–7
Parkinson’s disease (PD) 420–30
progressive supranuclear palsy (PSP)
432–4
subacute combined degeneration of the
spinal cord 443, 531
Déjérine–Sottas syndrome 585
delirium 44, 48
delusions, olfactory 482
dementia 175, 264, 411–14, 418–19
Alzheimer’s disease 263, 407–14
familial 412
frontotemporal dementia (FTD)
414–16
HIV-associated 301–3, 308
Huntington’s disease 418
Lewy body type 263
normal pressure hydrocephalus 473
Parkinson’s disease 263, 423
pseudo-dementia 412
vascular 261–5, 416, 474
demyelination
acute inflammatory demyelinating
polyradiculoneuropathy (AIDP)
588–92, 602, 603
chronic inflammatory demyelinating
polyneuropathy (CIDP) 590, 593–5,
602, 603, 608
delayed post-anoxic 450
multifocal demyelinating
leukoencephalomyelitis 299
segmental 36–7
depression 416, 420
Alzheimer’s disease 414
multiple sclerosis 349
Parkinson’s disease 429
dermatomyositis 402, 403, 684–7
childhood 685
dermoid tumors 390
diabetic amyotrophy 612
diabetic neuropathy 544, 610–13
diabetic radiculo-plexopathy 612, 641
diastematomyelia, rachischisis 141, 142
diencephalon, herniation 45
diffuse Lewy body disease (DLBD)
430–1
698
diplopia 501–2
disseminated intravascular coagulation
224, 403
dizziness see vertigo
dorsal scapular nerve 615
neuropathy 615–16
double vision, multiple sclerosis 342
see also visual disturbances
Down’s syndrome 410
driving, epilepsy and 76
drop attacks 62, 71
Duchenne’s muscular dystrophy (DMD)
668, 670–2
dysferlinopathy 676
dyskinesias 129–30
Parkinson’s disease 423, 428–9
paroxysmal 129, 130
tardive 129, 130
dysosmia 482
dysraphism 139–42
dysthyroid eye disease 690, 691, 692
dystonia 113–18, 121, 123, 127, 175
cervical 115
cranial 115
dopa-responsive 531
laryngeal 115
myoclonic 116
paroxysmal 116
E juvenile myoclonic epilepsy (JME) (Janz
eclampsia 76
edema, cerebral 358
cytotoxic 358
vasogenic 358, 362
electroencephalography (EEG) 33–5
definition 33
interpretation 35
recordings 34
role 35
technique 33–4
see also specific conditions
electromyography (EEG) 38–40
abnormal muscle activity 38–40
normal muscle activity 38
see also specific conditions
embolism 186, 209
cardiogenic 192, 209–15
pulmonary, Guillain–Barré syndrome
592
spinal cord infarction 559
systemic 216
thromboembolism 190, 206, 207
Emery–Dreifuss muscular dystrophy
(EDMD) 670
empty sella syndrome 380–1
encephalitis 324
subacute and chronic 279–80
toxoplasmic 323–6
tuberculous meningo-encephalitis
281–3
viral 292–5, 338
encephalomyelitis 300
acute disseminated (ADEM) 337–9
limbic 402
postinfectious 293, 337–9
varicella-zoster virus 299–300
encephalomyelopathy, mitochondrial 531
encephalopathy 88, 126, 134, 258
delayed post-anoxic 450, 451
hepatic (HE) 452–7
hypertensive 265–7
hyponatremic 458–9
hypoxic 449–52
metabolic 126, 454
porto-systemic 452, 453
Index
encephalopathy (continued) fasciculations 127
progressive myoclonic 88, 126 febrile convulsions 70
radiation-induced 565–6 femoral nerve 640
static myoclonic 125–6 femoral neuropathy 640–1, 642
subcortical arteriosclerotic (SAE) 474 fibrillation potentials 38
toxic 126, 455 Foster–Kennedy syndrome 493
encephalotrigeminal vascular syndrome Friedreich’s ataxia 441–4
151–2 frontotemporal dementia (FTD) 414–16
endocarditis fundoscopy 16
infective 215–18 fungal infections
marantic 403 meningitis 276, 318–20
enhanced physiologic tremor (EPT) 120 mucormycosis of the nervous system
Enterobacter 284 321–3
entrapment neuropathies 612
lateral plantar neuropathy 648
medial plantar neuropathy 647 G
median neuropathy 628 gait
radial neuropathy 624 assessment 22
saphenous nerve 640 hereditary spastic paraparesis and 530
tibial neuropathy 647 multiple sclerosis and 342
ependymoma 364, 365–6, 368–9, 370, Parkinson’s disease and 422
371 slipped disc and 550
spinal cord 570 galactosylceramide ß-galactosidase
epidermal nevus syndrome 152 deficiency 171
epidermoid tumors 389 gastroparesis 578
epidural hemorrhage germ cell tumors of the CNS 388–92
acute 178 germinoma 388, 392
spinal epidural hematoma 554–5 Gerstmann–Straussler–Scheinker syndrome
epilepsy 57, 65–82, 70–1, 83, 86, 88 416
classification 65–6 giant cell arteritis (GCA) 105, 234–7,
597
syndrome) 86–7 Glasgow coma scale 47
myoclonic epilepsy with ragged-red glaucoma 105
fibers (MERRF) syndrome 164, 165 glioblastoma 364, 368, 370, 371
progressive myoclonic epilepsies (PME) glioblastoma multiforme 364
86, 87–90, 126 glioma 358, 364–71
special forms of 70 optic nerve 148, 372–3
status epilepticus (SE) 82–5 gliomatosis cerebri 366
stroke and 201 glossopharyngeal nerve 19
see also seizures palsy 522
epileptic myoclonus 124–5 glossopharyngeal neuralgia 522
episodic paroxysmal hemicrania (EPH) glossopharyngeal neuropathy 520–2
104 gluteal nerve
erythrocyte abnormalities 222 inferior 643, 644
essential thrombocythemia 222 superior 643–4
essential tremor (ET) 119–22, 423 gluteal neuropathy 643–4
evoked potentials 40–2 glycogen metabolism disorders 688,
brainstem auditory evoked potentials 689–90, 691, 692
(BAEPs) 40–1 GM2 gangliosidoses 172
somatosensory evoked potentials Gottron’s papules 685, 686
(SSEPs) 42 Gradenigo’s syndrome 506, 507
visual evoked potentials (VEPs) 40 grand mal epilepsy 69
see also specific conditions granuloma
examination see neurologic examination non-caseating 352
exophthalmic ophthalmoplegia 690, 691, spinal 531
692 granulomatosis
allergic 597
Wegener’s 597
F granulomatous angiitis 228, 352
F-waves 37 Grave’s disease 659
Fabry’s disease 544, 584 growth hormone excess 380
facial nerve 19 Guillain–Barré syndrome (GBS) 588–92,
facial neuropathy 511–14 596, 598
facial sensation 18
facio-scapulo-humeral muscular dystrophy
(FSHD) 672–4 H
fainting see syncope H-reflex 37
familial adult myoclonic epilepsy (FAME) Haemophilus influenzae 273–4, 278
86 Hallervorden–Spatz disease 162
familial amyloid polyneuropathy 584 hallucinations
familial hemiplegic migraine (FHM) 96, hypnagogic 57
97 olfactory 482
familial periodic paralysis (FPP) 693–4 headache 91–105, 236
familial spastic paraparesis 529 classification 91
family history 12–13 cluster headache 103–5
fasciculation potentials 38–9 history/examination 91–2, 94
 Index 699

headache (continued) Horner’s syndrome 16, 225, 494–6 imaging, brain (continued)
idiopathic intracranial hypertension cavernous sinus syndrome 354 single photon emission computed
477 syringomyelia 542 tomography (SPECT) 26
muscle contraction/tension-type human immunodeficiency virus (HIV) cerebral circulation 26–8
101–3 589 contract angiography 26–8
subarachnoid hemorrhage 250, 252, concurrent infection with neurosyphilis CT angiography 28
254 315 magnetic resonance angiography
thunderclap headache 99, 258 HIV myelopathy 564–5 (MRA) 28
see also migraine HIV neuropathy 601–4 ultrasound 28
hearing loss 518 HIV-associated cognitive/motor spine 29–30
heart rate 574, 577 complex (HIV-CMC) (HIV dementia) CT myelography 29
heliotrope rash 685, 686 301–3, 308 magnetic resonance imaging 30
hemangioblastoma 152 Huntington’s disease (HD) 416, 417–20 myelography 29
capillary 393 juvenile Westphal variant 418 see also specific conditions
spinal cord 570 hydrocephalus 468–72 inclusion body myositis (IBM) 687–8
hemangioma 152 acoustic neuroma and 383 infantile paralysis 309–11
hematoma communicating 468 infantile spasms 69
spinal epidural 554–5 ex-vacuo 469 infarction
subdural 177–80 normal pressure hydrocephalus (NPH) cerebral 192, 202
hematomyelia 544 469, 473–6 diffuse white matter 262
hemifacial spasm 127 obstructive 468, 474 migrainous 98
hemiplegic migraine 97 rachischisis and 142 pituitary apoplexy 268
familial (FHM) 96 subarachnoid hemorrhage and 255–6 spinal cord 558–61
hemorrhage hydromyelia 541 vascular dementia and 262
epidural 178 hygroma, subdural 178 venous 260
intracerebral 192, 198, 299 hyperglycemic neuropathy 610 see also stroke
primary (PICH) 238–44 hyperkalemia 690 infective endocarditis 215–18
subarachnoid 178, 192, 198 hyperparathyroidism 690, 692 inflammatory disorders
subdural hematoma 177–80 hyperprolactinemia 380, 381 acute disseminated encephalomyelitis
vascular dementia and 262 hypersensitivity angiitis 227, 228 (ADEM) 337–9
see also stroke hypertension acute inflammatory demyelinating
hemorrhagic stroke idiopathic intracranial 477–80 polyradiculoneuropathy (AIDP)
intracerebral hemorrhage 192, 198, primary intracerebral hemorrhage and 588–92, 602, 603
299 238 cavernous sinus syndrome 354–5
primary intracerebral hemorrhage stroke and 200 chronic inflammatory demyelinating
(PICH) 238–44 hypertensive encephalopathy 265–7 polyneuropathy (CIDP) 590, 593–5,
subarachnoid hemorrhage 178, 192, hyperthyroidism 659 602, 603, 608
198, 249–56 hyperviscosity 222 multiple sclerosis (MS) 340–9
heparin-induced thrombocytopenia 224 hypnic headache 104 neurosarcoidosis 350–3
hepatic encephalopathy (HE) 452–7 hypoadrenalism 380, 689, 690, 692 see also specific disorders
hepatolenticular degeneration 157–61 hypoglossal nerve 19 intracerebral hemorrhage 192, 198
hereditary hemorrhagic telangiectasia palsy 527–8 intracranial abscess 284–7
(HHT) 153–6 hypoglossal neuropathy 526–8 intracranial pressure
hereditary neuralgic amyotrophy 587, hypoglycemia 62 monitoring 470, 475–6
596 hypogonadism 380 raised 359, 362, 384
hereditary neuropathies 584, 605 hypokalemia 690, 693 hydrocephalus 469
Guillain–Barré syndrome (GBS) hypokalemic paralysis 693–5 papilledema 492
588–92, 596, 598 familial periodic paralysis (FPP) 693–4 intravenous digital subtraction
hereditary motor and sensory thyrotoxic periodic paralysis (TPP) 694 angiography (IV DSA) 26–7
neuropathy (HMSN) 584, 585–6 hyponatremia 256, 592 ischemic stroke
type 1 585, 586 hypopituitarism 380 atherosclerotic 202–8, 221–2
type 2 585, 586 hypoprolactinemia 380 lipohyalinosis/microatheroma 204, 238
hereditary neuropathy with liability to hyposmia 482 cardioembolic 209–15
pressure palsies (HNPP) 587–8 hypothyroid myopathy 690, 691, 692 thrombophilic 218-24
hereditary spastic paraparesis (HSP) hypothyroidism 380 isotope cisternography 26
529–31, 538, 564 hypoxia 449, 450–1
heredopathia atactica polyneuritiformis spinal cord infarction 559
584 hypoxic encephalopathy 449–52 J
herniation hysteria 589 Jansky–Bielschowsky disease 89
cerebellar 136 Janz syndrome 86–7
cingulate 44 jaundice, neonatal 175
diencephalon 45 I jaw jerk 19
uncal 46 idiopathic intracranial hypertension (IIH) JC virus (JCV) 307
herpes simplex virus encephalitis (HSE) 477–80 jugular foramen syndrome 524
295–8 IgA paraproteinemic neuropathy syn- juvenile myasthenia 659
herpes zoster infection 599–601 dromes 607, 609 juvenile myoclonic epilepsy (JME) 86–7
facial paresis 513 IgM paraproteinemic neuropathy syn-
varicella-zoster virus encephalomyelitis dromes 607, 608, 609
299–300 imaging K
hexosaminidase A deficiency 172, 442, brain 23–6 Kayser–Fleischer (K–F) ring 158
538 computerized tomography (CT) Kearns–Sayre syndrome (KSS) 164
hexosaminidase B deficiency 538 23–4 Kennedy’s syndrome 532, 533, 537
history see neurologic history magnetic resonance imaging (MRI) Korsakoff’s psychosis 460, 461, 462
HIV see human immunodeficiency virus 24–6 Krabbe’s disease 171–2, 530
Hoffmann–Tinel sign 648 positron emission tomography (PET) Kuf’s disease 89
Holmes–Aidie syndrome 497–8 26 Kugelberg–Welander disease 532, 538
700
L magnetic resonance imaging (MRI)
Lafora body disease 88, 89
Lambert–Eaton myasthenic syndrome
(LEMS) 401, 402, 403, 659, 664–7
laryngeal dystonia 115
late waves 37
late-onset GM2 gangliosidosis 172–3
lateral compartment syndrome 651, 652
lateral cutaneous nerve of the thigh 637
neuropathy 637–8
lateral plantar neuropathy 648
lathyrism 564
Leber’s hereditary optic neuropathy
(LHON) 489, 491–2
Leigh’s disease 165
leprosy 544, 604–6
lepromatous 604
multibacillary 604, 606
paucibacillary 604, 606
tuberculoid 604
leukemia 222
leukocyte abnormalities 222
leukodystrophy 167, 442, 530
adrenoleukodystrophy (ALD) 166–8
adult-onset globoid cell (Krabbe’s
disease) 171–2, 530
metachromatic (MLD) 169–70, 530
leukoencephalitis, acute hemorrhagic 338
leukoencephalomyelitis, multifocal
demyelinating 299
leukoencephalopathy, progressive
multifocal (PML) 307–9
Lewy body type dementia 263, 436
diffuse Lewy body disease (DLBD)
430–1
light reflex 574, 576
limb-girdle muscular dystrophies (LGMD)
674–7
limbic encephalomyelitis 402
lipid metabolism disorders 688–9, 690,
691, 692
lipohyalinosis 204, 238
lipoma, spinal cord 570
Lisch nodules 148
Listeria monocytogenes meningitis 274
liver disease 159, 453, 454
lobar atrophy 414–16
locked-in syndrome 54, 55–6
long thoracic nerve 616
long thoracic neuropathy 616–17
Louis–Bar syndrome 444–6
lower limb examination 21–2
lumbar puncture 31–3
complications 32
indications/contraindications 32
normal values 32–3
technique 31
lumbar radiculopathy 641, 642
lumbar spondylosis 552
lumbosacral plexopathy 641
lumbosacral polyradiculopathy 141
lupus anticoagulant (LA) 220, 221
Lyme disease 316–17
lymphoma 385–8, 564
M migrainous neuralgia 103–5
McArdle’s disease 688, 689, 691, 692
Machado–Joseph disease (MJD) 438–9
macrocytosis 465
magnesium depletion 460
magnetic resonance angiography (MRA)
28
magnetic resonance imaging (MRI)
brain 24–6
spine 30
Index
(continued)
see also specific conditions
malignant angioendotheliosis 222
malignant hyperthermia 689, 690, 691,
692
Marcus Gunn pupil 575
mass lesions see tumors
masticatory muscles 19
measles virus 304
medial plantar neuropathy 647–8, 649
median nerve 627
median neuropathy 627–9
carpal tunnel syndrome 630–2
medulloblastoma 366–7
Meige syndrome 115
MELAS (mitochondrial
encephalomyopathy, lactic acidosis, and
stroke-like episodes) syndrome 163,
164, 165
memory, assessment of 15
Ménière’s disease 109, 111–12
meningioma 374–6
olfactory groove 375
parasagittal fronto-parietal 375
sphenoidal wing 375, 376
spinal cord 570
tuberculum sellae 375, 376
meningitis
acute aseptic (viral) 276, 291–2
Mollaret’s meningitis 291
acute pyogenic (bacterial) 273–8
acute syphilitic 313
fungal 276, 318–20
malignant 279
protozoal 276
subacute and chronic 279–80
tuberculous 276
serous 281
meningocele 140, 141, 142
meningoencephalitis 338, 352
tuberculous 281–3
meningoencephalocele 140, 141
meningomyelocele
Arnold–Chiari malformation 136–9,
530
rachischisis 141, 142
menstrual migraine 98, 100–1
mental state assessment 14–15
mesial temporal sclerosis (MTS) 68
metachromatic leukodystrophy (MLD)
169–70, 530
metastatic lesions 396–400
brain 358, 396, 397, 398, 400
meningeal 396, 397, 398, 399, 400
skull/dural 396, 397
spinal cord 567, 570
microatheroma 204
migraine 71, 95–101, 104–5, 108, 109
aura 71, 96, 97, 98, 187
childhood 98
familial hemiplegic (FHM) 96, 97
hemiplegic 97
menstrual migraine 98, 100–1
ophthalmoplegic 97
vertebrobasilar 97
Miller Fisher syndrome (MFS) 590
mini-mental state examination 14, 15,
411
miosis 496
mitochondrial DNA (mtDNA) 162–3
mitochondrial (oxidative phosphorylation)
diseases 89, 162–6, 531
mitral valve
prolapse 211
mitral valve (continued)
sclerosis/calcification 211
Miyoshi myopathy 586
Mollaret’s meningitis 291
monoclonal gammopathy of uncertain
significance (MGUS) 606, 607, 609
mononeuritis multiplex 602, 603, 604
mononeuropathies
axillary neuropathy 620–1
carpal tunnel syndrome (CTS) 630–2
dorsal scapular nerve neuropathy
615–16
femoral neuropathy 640–1, 642
focal limb mononeuropathies 612
gluteal neuropathy 643–4
lateral cutaneous nerve of the thigh
neuropathy 637–8
long thoracic neuropathy 616–17
median neuropathy 627–9
multiple 544, 587, 598
musculocutaneous neuropathy 621–2
obturator neuropathy 642–3
peroneal neuropathy 650–3
posterior cutaneous nerve of the thigh
neuropathy 639
pudendal neuropathy 655–6
radial neuropathy 623–6
sciatic neuropathy 644–6, 652
suprascapular neuropathy 618–19
sural neuropathy 654–5
tibial neuropathy 647–50
ulnar neuropathy 632–6
Morton’s metatarsalgia 648, 649, 650
Morton’s neuralgia 649
motor nerve conduction studies 35
motor neuron disease (MND) 138, 531,
534–40, 544, 636, 652
familial 537
movement disorders 71, 113–35
chorea 122–4
dyskinesias 129–30
dystonia 113–18
essential tremor (ET) 119–22
Huntington’s disease 418
myoclonus 124–8
neuroleptic malignant syndrome (NMS)
133–5
Tourette syndrome (TS) 130–3
mucormycosis of the nervous system
321–3
multi-sensory dizziness/disequilibrium
108, 109
multifocal demyelinating
leukoencephalomyelitis 299
multifocal motor neuropathy 608
with conduction block 538, 593
multifocal neurologic syndrome 343
multinucleated giant cell myelitis 564
multiple mononeuropathy 544, 587, 598
multiple myeloma 606, 608, 609
multiple sclerosis (MS) 108, 340–9, 443,
458, 492
acute transverse myelitis and 563
optic neuritis and 489, 491
multiple systems atrophy (MSA) 263,
435–7, 474, 576
muscle carnitine deficiency 688, 690, 691
muscle contraction-type headache 101–3
muscle disorders
dermatomyositis 684–7
facio-scapulo-humeral muscular
dystrophy (FSHD) 672–4
hypokalemic paralysis 693–5
inclusion body myositis (IBM) 687–8
limb-girdle muscular dystrophies
(LGMD) 674–7
 Index 701

muscle disorders (continued) myotonia congenita 680 neuropathy (continued)

myotonic dystrophy 678–81 myotonic dystrophy 678–81 facial 511–14
polymyositis 681–4 congenital 680 femoral 640–1, 642
X-linked dystrophinopathies 668–72 proximal myotonic myopathy glossopharyngeal 520–2
see also muscular atrophy; myopathy (PROMM) 680 gluteal 643–4
muscle power 20, 21 type 2 680 hereditary see hereditary neuropathies
muscle tone 20, 21 HIV neuropathy 601–4
muscular atrophy Holmes–Aidie syndrome 497–8
peroneal 584 N Horner’s syndrome 494–6
progressive 534, 537 nevoid basal cell carcinoma 358 hyperglycemic 610
post-polio 311 narcolepsy 56–8 hypoglossal 526–8
spinal (SMA) 532–4, 536, 537–8, 626, necrotizing angiitis 227, 228 lateral cutaneous nerve of the thigh
636, 652 Neisseria meningitidis 273–4 637–8
musculocutaneous nerve 621 neonatal myasthenia 659, 664 long thoracic 616–17
musculocutaneous neuropathy 621–2 nephrotic syndrome 224 median 627–9
myasthenia gravis (MG) 657–64 nerve conduction studies 35–7 multifocal motor neuropathy 608
juvenile myasthenia 659 central motor conduction 37 with conduction block 538, 593
neonatal myasthenia 659, 664 late waves 37 multiple mononeuropathy 544, 587,
ocular myasthenia 659, 663 motor nerves 35 598
penicillamine-induced myasthenia 659 pathologies 36–7 musculocutaneous 621–2
myasthenic crisis 664 repetitive stimulation studies 37 obturator 642–3
Mycobacterium bovis 281 sensory nerves 35–6 ocular motor neuropathies 499–504
Mycobacterium leprae 604 see also specific conditions olfactory 481–2
Mycobacterium tuberculosis 281 neuralgia optic 344, 483–6, 494
mydriasis 498 glossopharyngeal 522 anterior ischemic (AION) 487–8
myelinopathy 580 migrainous 103–5 Leber’s hereditary (LHON) 489,
myelitis 324 Morton’s 649 491–2
acute ascending necrotizing 562 post-herpetic 601 papilledema 492–4
acute transverse 561–3 trigeminal 104, 509–11 paraneoplastic syndromes 402–3
multinucleated giant cell 564 neuralgic amyotrophy 595–7, 629 paraproteinemic 606–9
myelography 29 hereditary 587, 596 peripheral 579–83
myeloma neuroborreliosis 316–17 peroneal 650–3
multiple 606, 608, 609 neurofibrillary tangles 408 plantar 648, 649
osteosclerotic 607, 608, 609 neurofibromas 148 lateral 648
myeloneuropathy 465, 466 spinal cord 570 medial 647–8, 649
myelopathy 562 neurofibromatosis (NF) 147–50, 358, plantar interdigital 648, 649, 650
cervical 474 605 posterior cutaneous nerve of the thigh
HIV myelopathy 564–5 type 1 (NF-1) 147–8, 150 639
paraneoplastic syndromes 402 type 2 (NF-2) 147, 148, 150 pudendal 655–6
radiation 561, 564, 565–6 neuroleptic malignant syndrome (NMS) radial 623–6
spinal cord tumors and 568 133–5 sciatic 644–6, 652
spondylotic 636 neurologic examination 13–23 spinal accessory nerve 525–6
see also myelitis; spinal cord cranial nerves 15–19 suprascapular 618–19
myeloradiculitis 282 general assessment 13–14 sural 654–5
myocardial contusion 212 lower limbs 21–2 syncope and 59
myoclonic dystonia 116 mental state (higher mental function) tibial 647–50
myoclonic epilepsy with ragged-red fibers 14–15 trigeminal 505–8
(MERRF) syndrome 164, 165 spine 15 ulnar 632–6
myoclonic seizures 68, 124–5 upper limbs 20–1 vagus nerve 523–4
myoclonus 123, 124–8, 290 neurologic history 11–13 vasculitic 544, 597–8
Baltic 88, 89 family history 12–13 vestibular-cochlear 517–20
brainstem 127 medications 12 see also polyneuropathy
cortical 126 systems review 12 neurosarcoidosis 350–3
epileptic 124–5 neuroma neurosyphilis 312–15
nocturnal 127 acoustic 108, 383–4 asymptomatic 312
myoglobinuria 691 plexiform 148 concurrent HIV infection 315
myokymia 39 neuromuscular junction disorders 40, 590 neurovascular syndromes 181–269
myopathy 40, 403 Lambert–Eaton myasthenic syndrome antiphospholipid syndrome 218–24
distal 652, 680 (LEMS) 401, 402, 403, 659, 664–7 arteriovenous malformation (AVM)
metabolic and endocrine myopathies myasthenia gravis (MG) 657–64 153, 154, 156, 245–9, 251
688–92 neuromyotonia 659 central nervous system vasculitis
hypothyroid 690, 691, 692 neuronal ceroid lipofuscinosis 89 227–33
steroid 689, 690, 692 neuronopathy 37, 580 cerebral venous thrombosis 257–60
thyrotoxic 689, 690, 691, 692 neuropathy 165, 581 classification 181–3
Miyoshi 586 acute idiopathic facial paralysis (Bell’s dissection of the carotid and vertebral
proximal 644 palsy) 515–16 arteries 224–7
see also muscle disorders; muscular acute motor axonal neuropathy giant cell arteritis (GCA) 105, 234–7
atrophy (AMAN) 590 hypertensive encephalopathy 265–7
myositis acute motor-sensory axonal neuropathy infective endocarditis 215–18
bacterial 682 (AMSAN) 590 pituitary apoplexy 268–9
dermatomyositis 402, 403, 684–7 amyloid 608, 609 primary intracerebral hemorrhage
inclusion body (IBM) 687–8 autonomic 573–8, 582, 590, 610 (PICH) 238–44
parasitic 682 axillary 620–1 stroke 192–201
polymyositis 402, 403, 681–4 calcaneal 647, 648, 650 atherosclerotic ischemic stroke
viral 682 diabetic 544, 610–13 202–8, 221–2
myotonia 39, 678, 680, 681, 691 dorsal scapular nerve 615–16 cardioembolic stroke 209–15
702 Index
neurovascular syndromes (continued) palsy (continued)
subarachnoid hemorrhage (SAH) 178, cranial nerves 354
192, 198, 249–56 glossopharyngeal nerve 522
transient ischemic attacks (TIA) 70, hypoglossal nerve 527–8
178, 186–92 progressive supranuclear (PSP) 263,
vascular dementia 261–5 432–4
new variant CJD (nvCJD) 332, 334 pseudobulbar 524, 536–7, 538
Niemann–Pick disease type C (NP-C) supranuclear horizontal gaze palsy 502
174–5 supranuclear vertical gaze palsy 175,
NINDS–AIREN criteria for vascular 433, 502
dementia 264 see also paralysis
nocturnal myoclonus 127 papilledema 478, 492–4
normal pressure hydrocephalus (NPH) papillitis 489
469, 473–6 papilloma, choroid plexus 366
nutritional deficiency paralysis
vitamin B12 deficiency 463–7, 474, acute idiopathic facial (Bell’s palsy)
564 515–16
vitamin E deficiency 442, 531 hypokalemic 693–5
Wernicke–Korsakoff syndrome 460–2 familial periodic paralysis (FPP)
nystagmus 518, 519 693–4
thyrotoxic periodic paralysis (TPP)
690, 691, 692, 694
O infantile 309–11
obsessive–compulsive disorder 131, 133, respiratory 450
416 rucksack paralysis 596
obtundation 44 sleep paralysis 58
obturator nerve 642 see also palsy
obturator neuropathy 642–3 paramyotonia congenita 680
ocular motor neuropathies 499–504 paraneoplastic syndromes 400, 401–5
ocular myasthenia 659, 663 paraproteinemias 222
oculomotor nerve 18, 500 paraproteinemic neuropathies 606–9
neuropathy 499–504 parasympathetic nervous system 574
olfactory nerve 15 Parkinsonian tremor 120
olfactory neuropathy 481–2 parkinsonism 424
oligodendroglioma 364–5, 368, 370, 371 Parkinson’s disease (PD) 420–30, 431,
olivopontocerebellar atrophy (OPCA) 433, 436, 474
435 dementia 263
one-and-a-half syndrome 504 parosmia 482
ophthalmoplegia 355, 502 paroxysmal dyskinesias 129, 130
exophthalmic 690, 691, 692 paroxysmal dystonias 116
internuclear 503 paroxysmal facial pain 509–11
progressive external 659 paroxysmal nocturnal hemoglobinuria
ophthalmoplegic migraine 97 222
opsoclonus 519 Parsonage Turner syndrome 595
optic nerve 15–16 patent foramen ovale 212
glioma 148, 372–3 penicillamine-induced myasthenia 659
optic neuritis 489–91 perception, assessment of 15
optic neuropathy 344, 483–6, 494 perilymph fistula 108
anterior ischemic (AION) 487–8 peripheral neuropathy 579–83
Leber’s hereditary (LHON) 489, permanent vegetative state (PVS) 52–5
491–2 peroneal muscular atrophy 584
organ of Corti 517 peroneal nerve 650
Osler–Rendu–Weber syndrome 153–6 peroneal neuropathy 650–3
osteomalacia 690, 692 pheochromocytoma 62
osteosclerotic myeloma 607, 608, 609 phosphofructokinase deficiency 688, 690,
oxidative phosphorylation diseases 691
162–6 Pick’s disease 414–16
pinealomas 368, 390, 392
pituitary apoplexy 268–9, 381
P pituitary tumors 379–83
pachymeningitis, syphilitic 443 plantar interdigital neuropathy 648, 649,
pain 650
history 12 plantar neuropathy 648, 649
multiple sclerosis 342, 349 lateral 648
neuropathy 582 medial 647–8, 649
on exercise 690 plantar reflex 21
Parkinson’s disease 423 platelet abnormalities 222
paroxysmal facial pain 509–11 POEMS syndrome 606, 608
slipped disc 550 poikiloderma 685, 686
trigeminal neuralgia 509 poliomyelitis (infantile paralysis) 309–11,
trigeminal neuropathy 506 596
see also headache acute anterior horn cell poliomyelitis
palsy 310
Bell’s 515–16 non-paralytic poliomyelitis 310
bulbar 524, 528, 536, 538 post-polio progressive muscular atrophy
progressive 534, 537 311
poliomyelitis (infantile paralysis)
(continued)
post-polio syndrome 311
polyarteritis nodosa 597
polycythemia rubra vera 222
polymyalgia rheumatica (PMR) 236, 237,
682
polymyositis 402, 403, 681–4
polyneuropathy 582, 610
acute inflammatory demyelinating 602,
603
chronic inflammatory demyelinating
(CIDP) 590, 593–5, 602, 603, 608
distal 649
familial amyloid 584
locked-in syndrome 56
polyradiculopathy
lumbosacral 141
progressive 602, 604
porphyria 584
acute intermittent 544
positron emission tomography (PET) 26
post-herpetic neuralgia 601
post-polio progressive muscular atrophy
311
post-polio syndrome 311
posterior cutaneous nerve of the thigh
639
neuropathy 639
posterior spinal artery syndrome 560
postinfectious encephalomyelitis 293,
337–9
postural hypotension 64, 428, 576, 577,
578
pregnancy
epilepsy and 76, 87
myasthenia and 664
prothrombotic states 222, 224
primary CNS lymphoma 385–8
primary intracerebral hemorrhage (PICH)
238–44
primary lateral sclerosis 534, 537
primary nerve cell degeneration 37
primary orthostatic tremor 120
primary progressive aphasia 416
prion disease 330–5
progressive bulbar palsy 534, 537
progressive multifocal
leukoencephalopathy (PML) 307–9
progressive muscular atrophy 534, 537
progressive myoclonic ataxia 88
progressive myoclonic encephalopathies
88, 126
progressive myoclonic epilepsies (PME)
86, 87–90, 126
progressive polyradiculopathy 602, 604
progressive supranuclear palsy (PSP) 263,
432–4
prolactinoma 380
pronator teres syndrome 628, 629
prosthetic heart valves 211
protein C 223
protein S 223
prothrombotic states 218–24
protozoal infections
meningitis 276
myositis 682
toxoplasmic encephalitis 323–6
proximal diabetic neuropathy 612
proximal myotonic myopathy (PROMM)
680
pseudobulbar palsy 524, 536–7, 538
pseudopapilledema 478
pseudoseizures 71
pseudotumor cerebri 477
ptosis 495, 496, 502, 504

pudendal nerve 655
pudendal neuropathy 655–6
pulmonary arterial venous malformation
212
pupillary responses 16, 574–5, 576, 577
accommodation reflex 575, 576
light reflex 574, 576
relative afferent pupillary defect 575,
576
pyriformis syndrome 645
R semicircular canals 517
rachischisis 139–42
radial nerve 623
radial neuropathy 623–6
radiation-induced encephalo-myelo-
radiculopathy 561, 564, 565–6
radiculopathy 636, 646, 649, 652
cervical spondylotic 545–9
lumbar 641, 642
lumbosacral polyradiculopathy 141
radiation-induced 565–6
spinal cord tumors and 568
raised intracranial pressure 359, 362, 384
hydrocephalus 469
papilledema 492
Ramsay Hunt syndrome 513
Raynaud’s phenomenon 685
reflex tachycardia 577
reflexes 20, 21–2
anal reflex 22
bulbocavernosus reflex 21
H-reflex 37
plantar reflex 21
pupillary 16, 574–5, 576, 577
accommodation reflex 575, 576
light reflex 574, 576
trigeminovascular reflex 96
Refsum’s disease 584, 605
repetitive stimulation studies 37
respiratory failure, Guillain–Barré
syndrome 591
respiratory insufficiency 691
respiratory paralysis 450
resuscitation, coma 50
retinitis pigmentosa 165
rheumatic vascular disease 211
rheumatoid arthritis 597
Ross’ syndrome 498
rubral tremor 120
rucksack paralysis 596
S multiple sclerosis 348
saccades 499
saccular aneurysms 250
saccule 517
sagittal sinus thrombosis 258
Sandhoff disease 172
saphenous nerve 640, 641
sarcoglycanopathy 676
sarcoidosis 350–3, 598
Schilder disease 167
schizophrenia 57, 416
schwannoma, spinal cord 570
sciatic nerve 644
sciatic neuropathy 644–6, 652
sclerosis
amyotrophic lateral (ALS) 534, 536,
537
aortic valve 211
diffuse cerebral sclerosis of Schilder
167
mesial temporal (MTS) 68
mitral valve 211
Index 703
sclerosis (continued) spinal cord (continued)
primary lateral 534, 537 epidural hematoma 554–5
tuberous 143–6, 358 hereditary spastic paraparesis (HSP)
see also atherosclerosis; multiple sclerosis 529–31, 538, 564
Segawa’s disease 115 infarction 558–61
segmental demyelination 36–7 infection 344, 546, 550, 561, 564
seizures 68–70, 187 inflammation 344
akinetic 68–9 see also myelitis
atonic 68–9 subacute combined degeneration 443,
brain tumors and 359, 362 531
myoclonic 68, 124–5 syringomyelia 541–4, 636
see also epilepsy tethered cord syndrome 142
tumors 344, 443, 530, 544, 546, 550,
senile plaques 408 567–71
sensation metastatic lesions 567, 570
assessment 21 see also myelopathy
hereditary spastic paraparesis and 530 spinal cord syndrome
multiple sclerosis and 342 acute non-compressive 344
sensory nerve action potential (SNAP) 36 chronic non-compressive 344
sensory nerve conduction studies 35–6 spinal muscular atrophy (SMA) 532–4,
serotonin syndrome 134 536, 537–8, 626, 636, 652
sexual dysfunction, multiple sclerosis 342, spinal venous infarction syndrome 560
348 spine, examination of 15
shingles 299–300 see also imaging
shock 450 splenomegaly 175
short-lasting unilateral neuralgiform spondylosis 545
headache with conjunctival injection cervical 544, 545–9
and tearing (SUNCT) syndrome 104 lumbar 552
shoulder disorders 619, 620 spondylotic myelopathy 636
Shy–Drager syndrome (SDS) 435 stance assessment 22
sialidosis 89 Staphylococcus aureus 284, 555
sick sinus syndrome 211 startle reflexes 127
sickle cell (SC) disease 222 static myoclonic encephalopathies 125–6
single photon emission computed status epilepticus (SE) 82–5
tomography (SPECT) 26 Steele–Richardson–Olszewski syndrome
sinoatrial disease 211 432
sinus arrhythmia 577 steroid myopathy 689, 690, 692
sinusitis 105 strabismus 502
idiopathic cavernous 354, 355 Streptococcus milleri 284
sleep disorders 58, 62, 131 Streptococcus pneumoniae
narcolepsy 56–8 intracranial abscess 284
sleep apnea 57 meningitis 273–4, 278
sleep paralysis 58 striatonigral degeneration (SND) 435,
sleepiness, excessive 678, 681 436
see also narcolepsy stroke 192–201, 266, 458, 652
slipped disc, acute 550–3 ischemic stroke
smoking, stroke and 200 atherosclerotic ischemic 202–8,
sodium channelopathies 680 221–2
somatosensory evoked potentials (SSEPs) lipohyalinosis/microatheroma 204,
42 238
spasmodic torticollis 115 cardioembolic 209–15
spasticity thrombophilic 218-24
hereditary spastic paraparesis (HSP) hemorrhagic stroke
529–31, 538, 564 intracerebral hemorrhage 192, 198,
299
speech disturbance primary intracerebral hemorrhage
transient ischemic attack 186 (PICH) 238–44
vagus nerve neuropathy 524 subarachnoid hemorrhage 178, 192,
Spielmeyer–Vogt disease 89 198, 249–56
spina bifida aperta 141 stroke-like syndrome 258
spina bifida occulta 140, 141 Strumpell–Lorrain syndrome 529
spinal accessory nerve 19 stupor 44, 48
neuropathy 525–6 Sturge–Weber disease 151–2
spinal artery syndrome subacute sclerosing panencephalitis (SSPE)
anterior 560 304–6
posterior 560 subarachnoid hemorrhage (SAH) 178,
spinal cord 192, 198, 249–56
acute slipped disc 550–3 subcortical arteriosclerotic encephalopathy
acute transverse myelitis 561–3 (SAE) 474
arachnoiditis 557–8 subdural empyema 284–7
arteriovenous malformation 246, 443, subdural hematoma 177–80
530 subdural hygroma 178
cervical spondylotic myelopathy/ suffocation 450
radiculopathy 545–9 sulcocommissural artery syndrome 560
compression 545, 550, 557, 560, 567 supinator syndrome 624, 625
epidural abscess 555–7 supranuclear horizontal gaze palsy 502
704
supranuclear vertical gaze paresis 175,
433, 502
suprascapular nerve 618
suprascapular neuropathy 618–19
sural nerve 654
sural neuropathy 654–5
sweating 574, 577
sympathetic nervous system 573–4
syncope 59–64, 70
syphilis 312–15
concurrent HIV infection 315
meningovascular 312, 313–14
pachymeningitis 443
syringobulbia 541, 542
syringomyelia 541–4, 636
syrinx 541
systemic lupus erythematosus 597
T neuropathy 499–504
tabes dorsalis 312, 314
tachyarrhythmia
reflex tachycardia 577
syncope 59
Taenia solium 326
Tangier disease 544
tapeworm infection 326–9
myositis 682
tardive dyskinesia 129, 130
tarsal tunnel syndrome 647, 648, 649,
650
anterior 651, 652
Tay–Sachs disease 172
telangiectases 153, 154, 246
ataxia telangiectasia 358, 444–6
hereditary hemorrhagic telangiectasia
(HHT) 153–6
temporal arteritis (TA) 237
tension-type headache 101–3
teratomas 389, 390
tetanus 287–8
tethered cord syndrome 142
thiamine deficiency 460
thromboembolism 190, 206, 207
see also atherothrombosis; embolism
thrombophilia 218–24
thrombosis 205, 206, 219
cavernous sinus 258
cerebral venous 257–60
deep cerebral vein 259
cortical venous 258
prothrombotic states 218–24
sagittal/transverse sinus 258
venous sinus 260, 478
thrombotic thrombocytopenic purpura
(TTP) 223
thunderclap headache 99, 258
thymoma 660, 663
thyrotoxic myopathy 689, 690, 691, 692
thyrotoxic periodic paralysis (TPP) 690,
691, 692, 694
thyrotoxicosis 120
tibial nerve 647
tibial neuropathy 647–50
tic douloureux 509–11
tics 123, 127, 130–3
tinnitus 518
Tolosa–Hunt syndrome 354
Tourette syndrome (TS) 130–3
toxoplasmic encephalitis 323–6
transient ischemic attacks (TIA) 70, 178,
186–92
of the eye 187–8
spinal 560
see also stroke
transverse sinus thrombosis 258
Index
tremor 123, 127
enhanced physiologic tremor (EPT)
120
essential tremor (ET) 119–22, 423
intention/terminal tremor 119
multiple sclerosis 349
Parkinsonian tremor 120
position-specific/task-specific tremors
120
primary orthostatic tremor 120
rubral tremor 120
Treponema pallidum 312, 315
trigeminal nerve 18–19
trigeminal neuralgia 104, 509–11
trigeminal neuropathy 505–8
isolated trigeminal sensory neuropathy
508
trigeminovascular reflex 96
trochlear nerve 18, 500
Tropheryma whippelii 289
tuberculoma 281
tuberculosis 555
tuberculous meningitis 281
tuberculous meningo-encephalitis 281–3
tuberous sclerosis 143–6, 358
tumors 352, 357–405, 521
acoustic neuroma 383–4
brain tumors 357–63
cavernous sinus syndrome 354, 355
craniopharyngioma 377–9
germ cell tumors of the CNS 388–92
gliomas 364–71
optic nerve 372–3
intracardiac 212
meningioma 374–6
metastases to the CNS 396–400
spine 567, 570
pituitary tumors 379–83
primary CNS lymphoma 385–8
spinal cord 344, 443, 530, 544, 546,
550, 567–71
von Hippel–Lindau disease (VHL)
392–4
see also specific tumors
Turcot’s syndrome 358
U optic neuritis and 490–1
ulnar nerve 632–3
ulnar neuropathy 632–6
ultrasound 28
uncal herniation 46
Unverricht–Lundborg disease 88, 89
upper limb examination 20–1
utricle 517
V
vagus nerve 19
vagus nerve neuropathy 523–4
Valsalva maneuver 577
varicella-zoster virus encephalomyelitis
299–300
see also herpes zoster infection
vascular dementia 261–5, 416, 474
NINDS–AIREN criteria 264
vascular diseases see neurovascular
syndromes
vascular malformations 238, 246
see also arteriovenous malformation
vasculitic neuropathy 544, 597–8
vasculitis 597
central nervous system 227–33
vegetative state 52, 451
venous infarction 260
venous sinus thrombosis 260, 478
vertebrobasilar dissection 224–7
vertebrobasilar ischemia 61, 108
vertebrobasilar migraine 97
vertigo 107–10, 519
benign paroxysmal positional 110
Ménière’s disease 109, 111–12
multiple sclerosis 342
vestibular neuronitis 111
vestibular-cochlear neuropathy 518
vestibular neuronitis 111
vestibular-cochlear nerve 19, 517
vestibular-cochlear neuropathy 517–20
viral infections
acute aseptic meningitis 291–2
cytomegalovirus (CMV) 589
encephalitis 292–5, 338
herpes simplex virus encephalitis (HSE)
295–8
herpes zoster infection 599–601
facial paresis 513
varicella-zoster virus
encephalomyelitis 299–300
HIV see human immunodeficiency virus
myositis 682
poliomyelitis (infantile paralysis) 309–11
progressive multifocal leukoen-
cephalopathy (PML) 307–9
subacute sclerosing panencephalitis
(SSPE) 304–6
visual acuity 15, 486
multiple sclerosis and 341–2
optic neuritis and 490
optic neuropathy and 484
papilledema 493
visual disturbances 236, 486, 488
idiopathic intracranial hypertension
477, 480
monocular blindness 487–8, 490
multiple sclerosis 349
ocular motor neuropathies 501–2
optic neuritis 489
optic neuropathy 483–4
anterior ischemic (AION) 487
Leber’s hereditary (LHON) 489, 491-2
transient ischemic attack 196
visual evoked potentials (VEPs) 40
visual fields 16
optic neuropathy and 484, 485
papilledema 493
vitamin B12 deficiency 463–7, 474, 564
vitamin E deficiency 442, 531
von Hippel–Lindau disease (VHL) 358,
392–4
von Recklinghausen’s neurofibromatosis
147, 605
W
Waldenström’s macroglobulinemia 222,
607, 608, 609
Wallerian degeneration 36, 580
Wegener’s granulomatosis 597
Werdnig–Hoffman (WH) disease 532,
538
Wernicke–Korsakoff syndrome 460–2
Wernicke’s disease 460, 461
West’s syndrome 69
Whipple’s disease 289–90
Wilson’s disease (WD) 157–61
writer’s cramp 115
X
X-linked dystrophinopathies 668–72