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Title: Blueprints neurology / Frank W. Drislane.
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 Contents

Preface
Acknowledgments
Abbreviations

PART I BASICS OF NEUROLOGY

1 The Neurologic Examination

2 Neurologic Investigations

PART II COMMON NEUROLOGIC SYMPTOMS

3 The Approach to Coma and Altered Consciousness

4 Neuro-Ophthalmology

5 The Approach to Weakness

6 The Sensory System

7 Dizziness, Vertigo, and Syncope

8 Ataxia and Gait Disorders

9 Urinary and Sexual Dysfunction

10 Headache and Facial Pain

PART III NEUROLOGIC DISORDERS

11 Aphasia and Other Disorders of Higher Cortical Function

12 Dementia
13 Sleep Disorders

14 Vascular Disease

15 Seizures

16 Movement Disorders

17 Head Trauma

18 Systemic Conditions with Neurologic Manifestations

19 Central Nervous System Tumors

20 Demyelinating Diseases of the Central Nervous System

21 Infections of the Nervous System

22 Disorders of the Spinal Cord

23 Radiculopathy, Plexopathy, and Peripheral Neuropathy

24 Disorders of the Neuromuscular Junction and Skeletal Muscle

25 Pediatric Neurology

Questions
Answers
Appendix: Evidence-Based Resources
Index
 Preface

B lueprints Neurology was first published more than 15 years ago as one of a series of
books designed to help medical students prepare for USMLE Steps 2 and 3. As the
study and practice of Medicine and Neurology and professional board examinations
have evolved over the years, so too has Blueprints Neurology changed to assist students
to learn Neurology in multiple evaluation and examination settings.
Examination preparation remains at the core of the series. To that end, the authors
review the subject matter of the examination before each edition. The authors and
editors work together to organize the most important, current, and factually correct
material into a complete but concise review guide. Our goal remains integrating the
depth of factual knowledge with the breadth of practice information in order to optimize
both understanding and retention. We have been pleased to hear from our readers that
the book is utilized by many medical students during their clinical rotations, as well as
in preparation for shelf and board examinations. Residents in Internal Medicine,
Emergency Medicine, and Family Practice, as well as nurse practitioners and
physicians’ associates have found Blueprints helpful during the Neurology portion of
their training. We believe the book’s applications have broadened with each edition due
to the quality of our authors’ experience and their dedication to highlighting and
clarifying a targeted range of basic but important topics that should be mastered.
Virtually all chapters are authored by experts in the content area, including
neurologists from both academic medicine and busy private practice groups. They have
incorporated suggestions received from medical students, faculty, clinicians, and
program directors with regard to content and organization. Each chapter covers a single
subject area for review; most can be read in under an hour. “Key Points,” highlighted
throughout, facilitate quick review of the key concepts tested most frequently. Most
chapters have Vignettes with characteristic clinical presentations to test one’s review of
the chapter. The 100 Questions at the end of the book are also written in the “Clinical
Vignette” style used in USMLE and Board examinations, as recommended by student
reviewers of the Blueprints series.
This fifth edition of Blueprints Neurology is the most thoroughly updated edition to
date, with several new authors (generally closer in stage of education to the students for
whom the book is written). It includes important updates on areas such as Multiple
Sclerosis, Stroke, Epilepsy, Movement disorders and their genetic bases, Sleep
disorders such as narcolepsy and cataplexy, and new drug and other treatments for each.
Each chapter includes the most recent information and practice principles available and
accepted at the time of publication.
 We hope that readers of Blueprints Neurology will come to see the wonder of the
human nervous system, how important it is to individuals in health and when it fails, and
how the study and practice of Neurology is more helpful to patients than ever before.

Frank W. Drislane, MD
Aimee K. Boegle, MD, PhD
Alexandra Hovaguimian, MD
Courtney McIlduff, MD, MMSc
Andrew W. Tarulli, MD
Louis R. Caplan, MD
 Acknowledgments

W e thank our patients for the opportunity of working with them and learning
Neurology; our colleagues and teachers (and particularly, upon his retirement,
Michael Ronthal, MBBCh) at Beth Israel Deaconess Medical Center Neurology
department for teaching us more fascinating concepts about the nervous system; and our
families for tolerating the many hours spent writing and revising this book.
 Abbreviations

A(β) amyloid-beta
ABP abductor pollicis brevis
Abs antibodies
AβPP amyloid–beta protein precursor
ACA anterior cerebral artery
ACE angiotensin-converting enzyme
AChR acetylcholine receptor
AD Alzheimer disease
ADEM acute disseminated encephalomyelitis
ADHD attention deficit–hyperactivity disorder
ADM abductor digiti minimi
AICA anteroinferior cerebellar artery
AIDP acute inflammatory demyelinating polyradiculoneuropathy
AIDS acquired immunodeficiency syndrome
AION anterior ischemic optic neuropathy
ALS amyotrophic lateral sclerosis
ANA antinuclear antibody
APP amyloid precursor protein
APS antiphospholipid syndrome
ASD anti-seizure drug
AVM arteriovenous malformation
AZT zidovudine
BMD Becker muscular dystrophy
BPPV benign positional paroxysmal vertigo
CBC complete blood count
GMP cyclic guanosine monophosphate
CIDP chronic inflammatory demyelinating polyradiculoneuropathy
CJD Creutzfeldt-Jakob disease
CK creatine kinase
CMAP compound muscle action potential
CMT Charcot-Marie-Tooth disease
CN cranial nerve
CNS central nervous system
COMT catechol O-methyl transferase
CP cerebral palsy
CPAP continuous positive airway pressure
CSF cerebrospinal fluid
CT computed tomography
DH detrusor hyperreflexia
DI detrusor instability
DLB dementia with Lewy bodies
DM dermatomyositis
DMD Duchenne muscular dystrophy
DSD detrusor sphincter dyssynergia
DTRs deep tendon reflexes
DWI diffusion-weighted imaging
EA episodic ataxia
ED erectile dysfunction
EEG electroencephalogram
EMG electromyography
ER emergency room
ESR erythrocyte sedimentation rate
ET essential tremor
EWN Edinger-Westphal nuclei
FDI first dorsal interosseus
FEV1 forced expiratory volume in 1 second
FLAIR fluid-attenuated inversion recovery
FTA fluorescent treponemal antibody
FTD frontotemporal dementia
FVC forced vital capacity
GAD glutamic acid decarboxylase
GBS Guillain-Barré syndrome
GCS Glasgow Coma Scale
GTC generalized tonic–clonic
HD Huntington’s disease
HIV human immunodeficiency virus
HNPP hereditary neuropathy with liability to pressure palsies
HS Horner’s syndrome
HSAN hereditary sensory and autonomic neuropathy
HSV herpes simplex virus
IBM inclusion body myositis
ICA internal cerebral artery
ICP intracranial pressure
ICU intensive care unit
IIH idiopathic intracranial hypertension
INO internuclear ophthalmoplegia
INR international normalized ratio
IVIg intravenous immunoglobulin
LEMS Lambert-Eaton myasthenic syndrome
LGN lateral geniculate nucleus
LMN lower motor neuron
LND light-near dissociation
LP lumbar puncture
MAG myelin-associated glycoprotein
MCA middle cerebral artery
MELAS mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke
MERRF myoclonic epilepsy with ragged red fibers
MFS Miller Fisher syndrome
MG myasthenia gravis
MLF medial longitudinal fasciculus
MMN multifocal motor neuropathy
MND motor neuron disease
MRA magnetic resonance angiography
MRC Medical Research Council
MRI magnetic resonance imaging
MRV magnetic resonance venography
MS multiple sclerosis
MSA multiple system atrophy
MSLT multiple sleep latency test
MuSK muscle-specific kinase
NCS nerve conduction studies
NCV nerve conduction velocity
NFTs neurofibrillary tangles
NIF negative inspiratory force
NMDA N-methyl-D-aspartate
NMJ neuromuscular junction
NMS neuroleptic malignant syndrome
NSAIDs nonsteroidal anti-inflammatory drug
OCD obsessive-compulsive disorder
ON optic neuritis
PANDAS pediatric autoimmune neurologic disorders associated with streptococcal infection
PAS periodic acid–Schiff
PCA posterior cerebral arteries
PCD paraneoplastic cerebellar degeneration
PCNSL primary central nervous system lymphoma
PCR polymerase chain reaction
PD Parkinson’s disease
PDC paroxysmal (nonkinesigenic) dystonic choreoathetosis
PEO progressive external ophthalmoplegia
PET positron emission tomography
PICA posteroinferior cerebellar artery
PKC paroxysmal kinesigenic choreoathetosis
PM polymyositis
PML progressive multifocal leukoencephalopathy
PN peripheral neuropathy
PNS peripheral nervous system
POTS postural orthostatic tachycardia syndrome
PP periodic paralysis
PPD purified protein derivative
PPRF paramedian pontine reticular formation
PS1 presenilin 1
PS2 presenilin 2
PSP progressive supranuclear palsy
PT prothrombin time
PTT partial thromboplastin time
PVR postvoid residual
QSART quantitative sudomotor axon reflex test
RAPD relative afferent pupillary defect
REM rapid eye movement
RF radiofrequency
riMLF rostral interstitial nucleus of the MLF
RPR rapid plasma reagin
rt-PA recombinant tissue-type plasminogen activator
SAH subarachnoid hemorrhage
SCA spinocerebellar ataxia
SCA superior cerebellar artery
SE status epilepticus
SLE systemic lupus erythematosus
SMA spinal muscular atrophy
SNAP sensory nerve action potential
SPECT single-photon emission computed tomography
SSRI selective serotonin reuptake inhibitor
STT spinothalamic tract
TB tuberculosis
TCD transcranial Doppler
TE time to echo
TIA transient ischemic attack
TORCH toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex
TR time to repetition
TSC tuberous sclerosis complex
UMN upper motor neuron
VA visual acuity
VDRL Venereal Disease Research Laboratory
VOR vestibulo-ocular reflex
VP venous pulsation
VPL ventroposterolateral
WD Wilson’s disease
 PART I BASICS OF NEUROLOGY

1 The Neurologic Examination

The care of patients in all specialties has been enhanced by the use of an increasingly
sophisticated array of biomarkers, genetic tests, and imaging modalities. Yet even in the
setting of these critical advancements, the physical examination remains of utmost
importance in Neurology. We glean valuable information from listening to the manner in
which concerns are expressed, observing how patients walk into the clinic or lie in a
hospital bed, and performing maneuvers designed to interrogate the functional integrity
of nervous system components. Ultimately, the examination is a tool we use to pinpoint
the nature and origin of abnormalities. The resultant picture can narrow the list of
possible diagnoses and guide further investigation.

PRINCIPLES
1. It is useful to conduct a complete examination at least once for every Neurology
patient. The neurologic examination may be unique in its length, but it is worthwhile
to complete a thorough assessment at least once with each Neurology patient for
several reasons. First, that examination provides a baseline assessment of neurologic
status—which can be particularly valuable in the hospital, where examinations can
evolve in important and sometimes unforeseen ways. Second, a full examination may
uncover unexpected abnormalities. One might be tempted to skip a full mental status
examination for a patient who can exchange pleasantries normally—only to be
surprised when the patient identifies the year as 1962. Because neurologic problems
can present with discrete deficits, formal testing in each domain is sensible. Third,
abnormalities on basic tests can point out the need for more in-depth, specialized
evaluations. For example, the emergence of diplopia on testing extraocular
movements might prompt a search for fatigable eyelid weakness that can raise
concern for myasthenia gravis. In this way, the neurologic examination becomes
tailored for each individual patient. Fourth, the examination allows one to directly
confirm or refute hypotheses about contributory problems suggested by the history.
Foot drop is more likely to result from a lumbosacral radiculopathy if accompanied
by back pain; a positive straight leg raise test can help corroborate this explanation.
Finally, the examination can show a pattern of abnormalities that provides a clue as
to where in the nervous system the problem lies.
2. The goal is to localize the problem. The nervous system is extensive. Broadly, we
can characterize elements as central or peripheral. The central nervous system
includes the brain and spinal cord. The peripheral nervous system (PNS)
incorporates nerve roots, plexi, peripheral nerves, neuromuscular junctions, and
muscles. Dysfunction originating from each of these locations can translate into
distinctive examination findings (Table 1-1); recognizing characteristic patterns is
often the key to localizing a deficit. Using this approach, the exam can help determine
whether left hand weakness stems from carpal tunnel syndrome, a brachial plexus
injury, cervical radiculopathy, or a middle cerebral artery stroke. These distinctions
are important because the diagnostic steps, prognoses, and therapies differ for each
of these conditions.
3. Findings should be interpreted in the context of the history. In performing a
comprehensive neurologic examination, it is not uncommon to detect incidental
abnormalities. Particularly at the start of one’s career, it can be difficult to discern
whether certain abnormalities are important. One should assign greater weight to
findings related to the presenting symptoms or a patient’s medical history. For
instance, abnormal sensation in a football-shaped region over the anterolateral thigh
may be a key finding in an obese person who developed burning in this area after
wearing tight-fitting pants, but an unimportant (or untrustworthy) discovery in an
individual who presents with an acute change in mental status.

TABLE 1-1. Localizing Patterns of Sensorimotor Abnormalities

Location of Lesion Characteristic Distribution
Brain Right or left hemi-body (face, arm, and leg)
Brainstem Crossed face and limbs (e.g., right face, left limbs)
Spinal cord At a sensory level on one or both sides of the posterior torso (at or above the site
of the lesion)
Nerve root Along an individual nerve root (i.e., a dermatome if a sensory change, or a
myotome if weakness)
Plexus Patchy in affected upper or lower extremity
Peripheral nerves Distal, symmetric sensorimotor changes
(polyneuropathy)
Neuromuscular junction Fatigable weakness
Muscle Proximal, symmetric weakness

KEY POINTS
● A complete neurologic examination is important to identify and characterize patterns of abnormalities.
● The goal of the examination is to localize lesions in the nervous system.
● Findings should always be interpreted in the context of the clinical history.
ELEMENTS OF THE EXAMINATION
The details of the neurologic examination (Table 1-2) should be tailored to fit the
patient’s presenting symptoms and identified abnormalities on a basic exam.

MENTAL STATUS
The mental status exam is performed to identify cognitive deficits related to specific
regions in the brain. The first step is to assess level of consciousness, which can range
from awake and alert to unarousable even with noxious stimulation. Rather than using
medical terms such as stuporous or obtunded in the latter setting, it is more helpful to
describe what external stimuli are required to arouse a patient or maintain wakefulness.
The level of consciousness frames further testing of cognitive function. Attention is
tested, typically by asking patients to recite spans of numbers, months, or words such as
“world,” forward and backward. A specific form of inattention is referred to as neglect.
Patients with dense neglect may fail to describe items on one side of a picture or of their
surroundings or fail to bisect a line properly. Subtle neglect may manifest as extinction
to double simultaneous stimulation; in this scenario, a patient can sense a single visual
or sensory stimulus on either side of the body but reports it on the nonneglected side
alone when bilateral stimuli are presented. In some cases, it is not possible to perform
formal tests of attention because patients become focused on one detail or task and keep
repeating it (“perseveration”). Deficits in attention are important to recognize because
they can compromise the ability to complete other tasks in the mental status examination.
Orientation is tested by asking a patient to identify his or her name and location as well
as the day, date, month, year, and current situation.
Memory is assessed by asking patients to repeat several words immediately and
again after intervals (e.g., 30 seconds and 3 minutes). The examiner should make note of
whether the patient is aware of current events. Language is assessed in several ways:
by listening to the fluency and prosody of spontaneous speech, identifying word
substitutions (i.e., paraphasic errors), and assessing the ability to repeat phrases, read,
write, and name common and uncommon objects. Furthermore, the examiner can ask the
patient to name as many words as possible starting with the letter “F,” “A,” or “S” in 1
minute, paying attention not only to the number of words generated but also to the
manner in which they are named. For example, does the patient recognize whether she
or he repeated words? Were words volunteered in identifiable categories? In addition
to insight into language function, these details provide insight into how well patients can
plan and organize information (i.e., frontal lobe executive function). To assess verbal
comprehension, check to see if patients can follow spoken midline, appendicular, and
cross-body commands.
 TABLE 1-2. Commonly Performed Elements of the Neurologic Examination
Mental Status
Attention Serial backward tasks (months of the year, digit span)
Language Fluency of speech, repetition, comprehension of commands, naming objects, reading,
writing
Memory Recall of words after 5 minutes
Visuospatial function Clock drawing; complex figure copying
Neglect Line bisection, double simultaneous stimulation
Frontal lobe function Generation of word lists; performance of learned motor sequence; test of inhibition
Cranial Nerves
II Visual acuity, fields, pupils, funduscopic exam
III, IV, VI Extraocular movements
V, VII Facial sensation and movement
IX, X, XII Palate and tongue movement
Motor
Bulk Inspection for atrophy
Tone Evaluation for rigidity, spasticity
Power Observational tests (pronator drift, rising from chair, walking on heels and toes), direct
confrontation strength testing
Reflexes
Muscle stretch reflexes Assessment at sites including biceps, brachioradialis, triceps, knee, ankle
Babinski sign Stroking lateral sole of foot
Sensory
Pinprick and temperature Mapping of pinprick, cold sensation
Vibration and joint position Timing appreciation of tuning fork stimulus at joints, assessing perception of location of
sense limbs in space
Romberg sign Unsteady, when standing with feet together, then closing eyes
Coordination
Accuracy of targeting Finger-to-nose, heel-to-shin tests
Rhythm of movements Rapid alternating movements, rhythmic finger or heel tapping
Gait
Stance Evaluation of narrow or wide base
Stride and arm swing Assessment for shuffling, decreased arm swing
Ataxia Evaluation of ability to tandem walk

Calculation ability can be tested by asking patients to perform simple arithmetic

(e.g., the number of quarters in $1.50). One can check for apraxia by asking patients to
pantomime a learned motor task—optimally one that requires use of both hands, for
example, cutting a loaf of bread. Visuospatial function and nonverbal learning can be
tested in a variety of ways. Patients can be asked to draw numbers in a circle to form a
clock; alternatively, they can be asked to copy a complex figure drawn by the examiner
(Fig. 1-1).
FIGURE 1-1. Example of a complex figure to be copied by the patient as test of visuospatial function.

Other tests of frontal lobe function include learning and then repeating a simple
motor sequence of hand postures (i.e., the Luria manual sequencing task). Another test of
appropriate inhibition, the go/no go test, comprises tapping the table when only one
letter (e.g., “B”) is said aloud in a string of letters. Perseveration is also considered a
frontal deficit. If cognitive impairment emerges as a concern, the examiner should
consider looking for the presence of primitive reflexes, which are signs of “frontal
release” or disinhibition. Examples include the palmo-mental, snout, and rooting
reflexes; of note, the examiner should be careful not to overinterpret these reflexes,
because they can occur in normal subjects with age or may not be relevant to the
presenting problem.

KEY POINTS
● The mental status exam should begin with assessment of level of consciousness and attention because these
can affect the interpretation of subsequent tests.
● Memory, language, calculation, praxis, visuospatial, and frontal lobe function are other key elements of the
mental status exam that can suggest focal brain lesions.

CRANIAL NERVES
One way to test cranial nerves is to start at eye level and move down the face in
approximate numerical order (Table 1-3).
Olfaction (I) is rarely tested. When patients report alterations in the ability to smell,
each nostril should be tested separately. A non-noxious stimulus, such as coffee or
vanilla, can be used.
Optic nerve (II) function is assessed in several ways. Visual acuity is investigated
with a near card. Visual fields are tested by having the patient cover one eye and focus
on the examiner’s nose; they are then asked to signal when they can appreciate a small
red object enter the field of view from each of four quadrants when the object is held
halfway between the patient’s eye and the examiner’s (the limits of the patient’s visual
fields should correspond to those of the examiner’s). Direct visualization of the optic
nerve can be achieved by fundoscopy. The afferent limb of the pupillary light reflex is
also mediated by the optic nerve; the efferent limb is subtended by CN III.
Extraocular movements (III, IV, and VI) are tested in three main ways: by having the
patient pursue a moving target (e.g., an examiner’s finger drawing of the letter “H” in
front of the face; i.e., pursuit); by directing the patient’s gaze to various stationary
targets or directions (saccades); and by having the patient fixate on an object while the
head is turned passively (vestibulo-ocular movements). The presence of nystagmus
should be noted.
Muscles of mastication (V) are tested by assessing the strength of jaw opening and
palpating the contraction of the masseter when the jaw is clenched. Facial sensation can
be tested to all modalities over the forehead (V1), cheek (V2), and jaw (V3) regions.
The afferent limb of the corneal reflex is mediated by CN V; the efferent limb is
controlled by CN VII.
Muscles of facial expression (VII) are tested by having patients raise the eyebrows,
squeeze the eyes shut, puff the cheeks, or show the teeth. Though uncommonly tested,
taste over the anterior two-thirds of the tongue is mediated by this nerve and can be
evaluated with sugar or another nonnoxious stimulus.
Hearing (VIII) may be evaluated in each ear simply by whispering or rubbing fingers;
more detailed assessment of hearing loss may be accomplished with the Weber and
Rinne tuning fork (512 Hz) tests. Vestibular function can be tested in many ways,
including evaluation of eye fixation while the patient’s head is turned rapidly or by
observation for a gradual rotation of gait direction while the patient is walking in place
with the eyes closed.

TABLE 1-3. The Cranial Nerves

Nerve Name Exit through the Skull Function
I Olfactory Cribriform plate Olfaction (test using nonnoxious substance)
II Optic Optic canal Vision (acuity, fields, color), afferent limb of
pupillary reflex
III Oculomotor Superior orbital fissure Superior rectus, inferior rectus, medial rectus,
inferior oblique, levator palpebrae, efferent
limb of pupillary reflex
IV Trochlear Superior orbital fissure Superior oblique of contralateral eye
V Trigeminal Superior orbital fissure Muscles of mastication, tensor tympani,
 (V1), foramen rotundum tensor veli palatini, facial sensation, afferent
(V2), foramen ovale (V3) limb of corneal reflex
VI Abducens Superior orbital fissure Lateral rectus
VII Facial Internal auditory meatus Muscles of facial expression, stapedius, taste
on anterior two-thirds of tongue, efferent limb
of corneal reflex
VIII Vestibulocochlear Internal auditory meatus Hearing, vestibular function
IX Glossopharyngeal Jugular foramen Movement of palate, sensation over palate
and pharynx, taste over posterior one-third of
tongue, afferent limb of gag reflex
X Vagus Jugular foramen Movement of palate; sensation over pharynx,
larynx, and epiglottis; efferent limb of gag
reflex; parasympathetic function of viscera
XI Accessory Jugular foramen Sternocleidomastoid and trapezius movement
XII Hypoglossal Hypoglossal foramen Tongue movement

Palate elevation should be symmetric, and the voice should not be hoarse or nasal (IX
and X). Failure of the right palate to elevate implies pathology of the right
glossopharyngeal nerve. The gag reflex is also mediated by these nerves.
Sternocleidomastoid strength is tested by having the patient turn the head against
resistance; weakness on turning to the left implies a right accessory nerve (XI) problem.
The trapezius muscle is tested by having patients shrug the shoulders.
Tongue protrusion should be in the midline. If the tongue deviates toward the right,
the problem lies with the right hypoglossal nerve (XII).

KEY POINTS
● Cranial nerve testing is most easily performed and recorded in approximate numerical order.
● Key elements of the cranial nerve exam include assessment of vision and eye movements, facial movement
and sensation, and movements of the palate and tongue.

MOTOR EXAM
First, bulk is assessed by observing and palpating the muscles and comparing each side
to the other and the patient’s overall muscle bulk to that expected for age.
Tone is one of the most important parts of the motor exam. In the arms, tone is
checked by moving the patient’s arm, flexing and extending at the elbow, moving the
wrist in a circular fashion, and pronating and supinating the forearm rapidly using a
handshake grip. Abnormalities of tone such as spasticity and rigidity are discussed in
subsequent chapters. Tone in the legs can be tested well only with the patient supine.
The examiner lifts the leg up suddenly under the knee; in the presence of increased tone,
the heel comes off the bed. Increased tone can be characterized further as rigid or
spastic. In rigid limbs, the examiner can sense increased resistance throughout the
passive movements, but spasticity is speed dependent, with abnormalities emerging
with quick movements (e.g., elbow extension).
Strength is assessed by both observation and direct confrontation (Fig. 1-2). A
pronator drift may be observed in an arm held supinated and extended in front of the
body. The patient may be asked to rise from a chair without using the arms or to walk on
the heels and toes. The power of individual muscles as assessed by direct confrontation
testing is most often graded according to the Medical Research Council (MRC) scale
(Table 1-4). In some settings, such as the intensive care unit, it is not possible to
perform detailed motor assessments. In this case, the examiner can look to see if there is
symmetry to voluntary limb movements. Another approach is to evaluate whether the
patient can withdraw meaningfully (i.e., pull the examined limb away from a mildly
noxious stimulus such as a pinch).

FIGURE 1-2. Power testing of individual movements. For each movement, the predominant muscle, peripheral
nerve, and nerve root are given. (Reproduced with permission from Ginsberg L. Lecture Notes: Neurology. 8th ed.
Oxford: Blackwell Publishing; 2005:40–41.)
 The presence of involuntary abnormal movements should be noted. For instance,
fasciculations appear as small twitches underneath the skin. Myoclonus and asterixis
can cause a limb to jump or transiently lose tone from a given posture. Chorea has a
writhing quality. Tremor can appear as an alternating movement of the arm, leg, or head.

TABLE 1-4. Medical Research Council Grading of Muscle Power

0 No contraction of muscle visible
1 Flicker or trace of contraction visible
2 Active movement at joint, with gravity eliminated
3 Active movement against gravity
4 Active movement against gravity and some resistance
5 Normal power

KEY POINTS
● The motor exam begins with assessment of bulk and tone (including an assessment for spasticity and rigidity).
● Strength testing involves both functional observation and confrontation testing of individual muscle power.
● Strength is graded on the MRC scale from 0 to 5.

REFLEXES
Muscle stretch (or “deep tendon”) reflexes can be useful aids in localizing or
diagnosing both central and PNS problems (Fig. 1-3).
FIGURE 1-3. Muscle stretch (“deep tendon”) reflexes. (Reproduced with permission from Ginsberg L. Lecture
Notes: Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:44.)

In the arms, the biceps, brachioradialis, and triceps reflexes are most commonly
tested. A pectoral reflex can be assessed by tapping the pectoralis muscle and looking
for adduction of the proximal arm. Thumb flexion stimulated by flicking the distal
phalanx of the middle finger is a positive Hoffmann sign, an indication of hyperreflexia.
In the legs, patellar (knee jerk) and ankle reflexes are commonly tested. The adductor
reflex can also be tested by striking the medial thigh and looking for thigh adduction.
The Babinski sign is sought by stroking the lateral sole of the foot while observing for
extension of the great toe. Clonus, if present, can be elicited by forcibly dorsiflexing the
ankle when it is relaxed. In some cases, an exaggerated jaw jerk can localize a problem
above the level of the cervical spine.

SENSORY EXAM
The sensory examination assesses small-fiber (pinprick, temperature) and large-fiber
(vibration, proprioception) function. Pinprick and temperature information is carried in
the spinothalamic tract. Vibration and proprioception require dorsal column tract
integrity. It is generally helpful to start distally and move proximally when testing each
modality because polyneuropathy, one of the most common causes of sensory
abnormality, generally shows up first in the toes. Nevertheless, it makes sense to test
sensory function more extensively in any affected limb—even if more distal function is
normal—to look for other patterns of abnormality.
Pinprick: Using a sterile instrument (e.g., special pins designed for the neurologic
exam), the examiner starts to prick the toes and gradually moves up the leg to assess
if there is a gradient to sensation. The process can be repeated starting in the fingers
and moving up the arm. If there is concern for a spinal cord lesion, it is important to
perform pinprick along the length of the torso to identify a “level” where sensation
transitions from abnormal to normal. If the patient reports facial symptoms, the pin
should be used to assess sensation in areas representing each branch of the
trigeminal nerve.
Temperature: Using a similar approach, a cold tuning fork can be used to assess
temperature sensation.
Vibration: After striking the 128-Hz tuning fork, the stem is placed against a joint, and
the duration for which the stimulus is appreciated is recorded. In general, this great
toe is tested first, with the examiner testing increasingly proximal joints if the distal
findings are abnormal.
Proprioception: Proprioception, or joint position sense, is tested in an order similar to
that used for vibration assessment. Usually, the examiner starts by holding the sides
of the great toe and asking the patient to report when it is being moved upward and
downward by a few millimeters.
Light touch is often not useful to test in isolation because it relies on a combination of
pathways. By itself it is unlikely to provide clues to localization or diagnosis.

KEY POINTS
● Pinprick and temperature information is carried in the spinothalamic pathway, whereas vibration and joint
position sense are relayed in the dorsal columns.
● It is important to use an organized approach (e.g., always moving distal to proximal along a limb) when testing
sensory function.

COORDINATION
Coordination of the limbs and the trunk should be assessed. Finger-to-nose testing can
identify dysmetria (inaccuracy of targeting) or types of tremor in the arms. Heel-to-shin
testing can elicit incoordination in the legs. To test axial abnormalities, the patient can
be asked to sit upright and unsupported, with the eyes closed.
 Rapid alternating movements, rhythmic finger tapping, and heel tapping are
particularly sensitive to coordination problems. In some disorders, such as Parkinson’s
disease, there can be a hesitation, decremental slowing (i.e., damping), or increasingly
small excursions with repetitive movements. Patients may also have trouble with the
timing, or cadence, of these movements. Dysdiadochokinesis is the term used to
describe difficulty with rapid alternating movements.

GAIT
Ambulation is one of the most important elements of the neurologic examination.
Normal gait requires the proper functioning of many different aspects of the nervous
system, so it is one of the most sensitive ways to detect an abnormality. Furthermore,
some patterns of gait abnormality herald the presence of specific disorders (e.g.,
parkinsonism). Routinely, posture, base, initiation, stride length, turning, arm swing, and
overall balance are considered.
Posture should be upright. The patient with a normal base, or stance, maintains the
feet at about hip-width apart. In general, healthy individuals start walking without any
hesitation. Stride length should be full, with clearance of the feet from the floor. Short-
stepped and shuffling gaits are characterized by decreased stride length and limited
excursion of the feet from the ground. The arms normally swing fully in the opposite
direction from their respective legs during ambulation. Decreased arm swing is often a
feature of extrapyramidal disorders. A normal turn can be executed in two steps;
patients with Parkinson’s disease may take multiple small steps to turn “en bloc.”
Ataxia of gait results in an inability to walk in a straight line; patients may stagger
from one side to the other or list consistently toward one side. Ataxia is typically
associated with a wide-based stance. Ataxia can be brought out most obviously by
having the patient attempt to walk heel to toe (tandem). A Romberg sign is present when
the patient maintains a steady stance with feet together and eyes open but sways and
falls with feet together and eyes closed; its presence usually implies a deficit of joint
position sense, not cerebellar dysfunction.

KEY POINTS
● Gait is one of the most important elements of the neurologic exam because it is sensitive for many deficits,
and certain diseases have characteristic gait disorders.
● Base, initiation, stride length, turning, arm swing, and the ability to perform tandem gait should be assessed.
● A positive Romberg sign suggests a deficit in joint position sense.
 2 Neurologic Investigations

CEREBROSPINAL FLUID ANALYSIS

Cerebrospinal fluid (CSF) bathes the internal and external surface of the brain and
spinal cord. It is produced by the choroid plexus of the ventricles and is absorbed
through the villi of the arachnoid granulations that project into the dural venous sinuses.
CSF is produced continually at a rate of about 0.5 mL per minute; the total volume is
approximately 150 mL. The entire CSF volume is thus replaced about every 5 hours.
Lumbar puncture (LP) at the L3–L4 or L4–L5 interspace is the most commonly used
means of obtaining CSF for analysis. LP is contraindicated by the presence of a space-
occupying lesion that is causing mass effect in the central nervous system (CNS), raised
intracranial pressure, local infection or inflammation at the planned puncture site, or a
significant coagulopathy.

TECHNIQUE
Optimal positioning is the key to a successful and atraumatic LP. LP is best performed
with the patient in the lateral decubitus position with the legs flexed up over the
abdomen. Ideally, a pillow should be placed between the legs, and the patient should lie
on the edge of the bed where there is better support to keep the back straight. The
anterosuperior iliac spine is at the level of the L3–L4 vertebral interspace. The LP may
be performed at this level, one interspace higher, or one to two interspaces lower.
(Remember that the spinal cord ends at the level of L1–L2.) The needle is inserted with
the bevel facing upward, so that it will enter parallel to the ligaments and dura that it
pierces rather than cutting them transversely. The needle is directed slightly rostrally to
coincide with the downward angulation of the spinous processes. The needle is
advanced gently until CSF is obtained. To measure the opening pressure reliably, the
patient’s legs should be extended slightly and note should be made of fluctuation of the
CSF meniscus within the manometer with respiration.

INTERPRETATION OF RESULTS
CSF is a clear, colorless fluid. The glucose content is about two-thirds that of blood,
and it contains up to 40 to 50 mg/dL protein. Fewer than five cells are present, and these
are lymphocytes. The opening pressure measured by LP in the lateral recumbent
position is about 60 to 150 mm H2O.
Xanthochromia refers to the yellow discoloration of the supernatant of a spun CSF
sample. Its presence helps to distinguish an in vivo intrathecal hemorrhage from a
traumatic tap (in which red blood cells [RBCs] have not lysed, so the supernatant is still
colorless).
The implications of various CSF findings are summarized inTable 2-1. CSF findings
in a variety of common conditions are summarized in Table 2-2. Special tests may be
performed as indicated. Some examples include cytology for suspected malignancy,
oligoclonal banding for suspected immune-mediated processes such as multiple
sclerosis, 14-3-3 protein for Creutzfeldt–Jakob disease, and a variety of polymerase
chain reactions and serologic tests to detect infections of the nervous system.

SAFETY, TOLERABILITY, AND COMPLICATIONS

Cerebral or cerebellar herniation may occur when LP is performed in the presence of
either a supratentorial or infratentorial mass lesion. A computed tomography (CT) scan
should be performed prior to an LP when there are examination findings raising concern
for increased intracranial pressure, focal neurologic findings, or severe encephalopathy.
Radiologic contraindications to LP include closure of the fourth ventricle and
quadrigeminal cistern. Low-pressure headache is the most common complication of LP.
It is most effectively prevented by using smaller (higher gauge) LP needles, inserting the
bevel of the LP needle parallel rather than perpendicular to the dural fibers, and
replacing the stylet after obtaining CSF. Should a post-LP headache develop, it is
treated initially by having the patient lie flat and increase his or her intake of liquids and
caffeine. In patients who do not respond to these conservative measures, it may be
necessary to administer an epidural blood patch (see Chapter 10).

TABLE 2-1. Interpretation of CSF Findings

Red Blood Cells
No xanthochromia Traumatic tap
Xanthochromia Subarachnoid hemorrhage; hemorrhagic encephalitis
White Blood Cells
Polymorphs Bacterial or early viral infection
Lymphocytes Infection (viral, fungal, mycobacterial); demyelination (MS, ADEM); CNS
lymphoma
Elevated protein Infection (fungal, mycobacterial); demyelination; tumor (e.g., meningioma,
meningeal carcinomatosis); sarcoidosis; age
Low glucose Bacterial infection; mycobacterial infection
Oligoclonal bands Demyelination (MS); CNS infections (e.g., Lyme disease); noninfectious
inflammatory processes (e.g., SLE)
Angiotensin-converting enzyme May be elevated in neurosarcoidosis
 ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; CSF, cerebrospinal fluid; MS, multiple
sclerosis; SLE, systemic lupus erythematosus

TABLE 2-2. CSF Findings in Common Neurologic Diseases

Disease Cells Protein Glucose Other
(Pleocytosis)
Bacterial meningitis Polymorphs High Low Culture and Gram stain
may be positive
Viral Lymphocytes High Normal Viral PCR may be
meningitis/encephalitis positive
Tuberculous Lymphocytes High Very low Positive for acid-fast
meningitis bacilli
Guillain–Barré None High (degree depends on Normal —
syndrome interval from symptom
onset)
Multiple sclerosis Several lymphocytes Slightly high Normal OCBs usually present
ADEM Lymphocytes or Usually high Normal OCBs usually absent
polymorphs
Subarachnoid Lymphocytes and May be high Normal Xanthochromia
hemorrhage many RBCs
ADEM, acute disseminated encephalomyelitis; CSF, cerebrospinal fluid; OCB, oligoclonal bands; PCR, polymerase
chain reaction; RBC, red blood cell.

KEY POINTS
● A CT scan should be performed prior to LP, especially when there is concern about increased intracranial
pressure or focal neurologic abnormalities.
● LP is performed at or below the L2–L3 interspace.
● Xanthochromia indicates recent intrathecal hemorrhage.

COMPUTED TOMOGRAPHY AND MAGNETIC

RESONANCE IMAGING
TECHNICAL CONSIDERATIONS
CT measures the degree of X-ray attenuation by tissue. Attenuation is defined simply as
the removal (by absorption or scatter) of X-ray photons and is quantified on an arbitrary
scale (in Hounsfield units) that is represented in shades of gray. Differences in the
shades directly reflect the differences in the X-ray attenuation of different tissues, a
property that depends on their atomic number and physical density. Images are usually
obtained in either an axial or a coronal plane. Three-dimensional reconstruction and
angiography are possible with new-generation spiral CT scanners.
Magnetic resonance imaging (MRI) is similar to CT in that radiant energy is directed
at the patient and detected as it emerges from the patient. MRI differs, however, in its
use of radiofrequency (RF) pulses rather than X-rays. The images in MRI result from the
varying intensity of radio-wave signals emanating from the tissue in which hydrogen
ions have been excited by an RF pulse. A detailed understanding of magnetic resonance
physics is not necessary for the interpretation of routinely used MRI sequences. It is
sufficient to understand that the patient is placed in a magnet and that an RF pulse is
administered. Signal intensity is measured at a time interval, known as time to echo
(TE), following RF administration. The RF pulse is administered many times in
generating an image; the time to repetition (TR) is the time between these RF pulses.
Two basic MRI sequences in common usage are T1-weighted (short TE and TR) and
T2-weighted (long TE and long TR) images. Fat is bright on a T1-weighted image,
which imparts a brighter signal to the myelin-containing white matter. Water (including
CSF) is dark on T1 and bright on T2. T2 images are most useful in evaluating the spinal
cord (Fig. 2-1). Gadolinium is the contrast agent used in MRI, and gadolinium-enhanced
images are usually acquired with a T1-weighted sequence. Contrast-enhanced images
are invaluable in determining the presence of brain tumors, abscesses, other areas of
inflammation, and new multiple sclerosis lesions (see Fig. 19-1).

FIGURE 2-1. T2-weighted MRI of the cervical spine. MRI, magnetic resonance imaging.

Other commonly used MRI sequences are fluid-attenuated inversion recovery

(FLAIR) and susceptibility- and diffusion-weighted imaging (DWI). FLAIR is a strong
T2-weighted image, but one in which the signal from water/CSF has been inverted and
is thus of low rather than high intensity. FLAIR is the single best screening image
sequence for most pathologic processes of the CNS. It is very useful in assessing the
chronic lesion burden in multiple sclerosis (see Fig. 20-2). A susceptibility-weighted
sequence is one that is sensitive to the disruptive effect of a substance on the local
magnetic field. Examples of substances that exert such a susceptibility effect are
calcium, bone, and the blood breakdown products ferritin and hemosiderin. Areas of
increased susceptibility appear black on these images.
DWI demonstrates cellular toxicity with high sensitivity and is most commonly
employed in the diagnosis of acute stroke, where it can be positive within half an hour
of symptom onset. Areas of restricted diffusion appear bright on DWI. Figure 2-2
provides examples of T1, T2, FLAIR, and DWI images.

CLINICAL UTILITY
Head CT is often the initial investigation used in a variety of neurologic disorders,
including headache, trauma, seizures, subarachnoid hemorrhage, and stroke. The
sensitivity of a CT scan for detecting lesions depends on many factors, including the
nature and duration of the underlying disease process. The sensitivity for detecting areas
of inflammation, infection, or tumor may be increased by the administration of
intravenous contrast. Contrast enhancement indicates local disruption of the blood–brain
barrier. CT is the investigation of choice for demonstrating fresh blood.
FIGURE 2-2. Normal T1, T2, FLAIR, and DWI images of the brain. DWI, diffusion-weighted imaging; FLAIR,
fluid-attenuated inversion recovery.

Apart from providing better anatomic definition, MRI is particularly useful for
imaging the contents of the posterior fossa and craniocervical junction, which are seen
poorly on CT because of artifact from surrounding bone. DWI is the most sensitive
technique available for demonstrating early tissue ischemia and is therefore extremely
useful in the evaluation of patients with suspected stroke.

SAFETY, TOLERABILITY, AND COMPLICATIONS

CT scanning employs X-rays and is thus relatively contraindicated during pregnancy.
The use of RF waves in MRI makes this the imaging modality of choice in pregnant
women. There is no cross-reactivity between the iodinated contrast agents used in CT
and the gadolinium used as a contrast agent in MRI. When contrasted imaging is
required, MRI may therefore be preferable when there is a history of allergy to
intravenous contrast. Similarly, gadolinium does not have the nephrotoxicity of
iodinated contrast. MRI is not safe when metal objects (foreign bodies, plates, and
screws) and pacemaker and defibrillator devices are present, unless those materials
have been made MRI compatible. Some people with claustrophobia cannot tolerate
MRI; under these circumstances, CT is preferred.

KEY POINTS
● CT is the imaging modality of choice for demonstrating acute intracranial bleeding.
● MRI is required for adequate imaging of the posterior fossa and craniocervical junction.
● DWI is the most sensitive MRI sequence for demonstrating early cerebral ischemia or infarction.

VASCULAR IMAGING STUDIES

Conventional angiography involves cannulation of the great vessels and injection of
contrast material to obtain an image of the vascular anatomy (Fig. 2-3). This is the most
sensitive and specific imaging study of the intracranial and extracranial circulation.
Risks of the procedure include contrast reaction, stroke caused by plaque dislodged by
the catheter, and bleeding at the cannulation site. Although the risks of the procedure and
developments in magnetic resonance angiography (MRA) (below) have decreased the
use of conventional angiograms, it remains the “gold standard” in vascular imaging.
MRA uses blood flow as a contrast agent and MR technique to define vascular
anatomy (Fig. 2-4). Compared with conventional angiography, MRA is less invasive
and can be performed more quickly and less expensively, but it is not as sensitive or
specific for cerebrovascular disease. MRA is performed commonly on the intracranial
circulation of stroke patients to look for evidence of vascular narrowing or occlusion.
“Fat-suppressed” MRA of the neck is useful for determining the presence of vertebral
or carotid artery dissections. Magnetic resonance venography (MRV) can be used to
demonstrate venous sinus thrombosis and other venous disease.
FIGURE 2-3. Conventional cerebral angiogram demonstrating aneurysm of the right middle cerebral artery
(arrow). ACA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery. (Reproduced with
permission from Yochum TR , Rowe LJ. Yochum and Rowe’s Essentials of Skeletal Radiology. 3rd ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2004.)

FIGURE 2-4. MRA of the circle of Willis. MRA, magnetic resonance angiography.

CT angiography (CTA) of the head is most often used for patients with acute stroke to
determine whether there is a vascular occlusion that might be amenable to mechanical
thrombectomy or intra-arterial tPA (tissue plasminogen activator) . CTA of the neck
may identify carotid artery stenosis or dissection of the carotid or vertebral arteries.
Extracranial Doppler sonography measures blood flow by determining the difference
between emitted and received ultrasound frequencies. It is used commonly to detect
stenosis or occlusion of the extracranial carotid circulation, especially in the planning
stages for carotid endarterectomy. Transcranial Doppler (TCD) detects intracranial
stenosis, emboli, and vasospasm occurring after subarachnoid hemorrhage. Most of the
intracranial circulation, however, is inaccessible to TCD. Although somewhat less
accurate than MRA or conventional angiography, Doppler studies are noninvasive and
essentially without contraindication.

KEY POINTS
● Conventional angiography is the gold standard for evaluating cerebrovascular anatomy.
● CTA is useful in identifying acute vascular occlusions that may be treatable by mechanical thrombectomy or
intra-arterial tPA.
● MRA is less invasive but also less accurate than conventional angiography.
● MRV is useful for assessing the presence of venous sinus thrombosis.

OTHER IMAGING STUDIES

18-fluorodeoxyglucose positron emission tomography (FDG-PET) scans measure
regional brain metabolism. They are most often employed in the presurgical evaluation
of epilepsy patients. Hypermetabolism can be demonstrated during seizures (although
obtaining the scan during a seizure is challenging), whereas hypometabolic regions may
be evident interictally. PET scans can also be useful in differentiating among the
degenerative dementias: Hypometabolism is more prominent in the temporal and
parietal lobes in Alzheimer disease patients, in the frontal and temporal regions in
frontotemporal dementia patients, and in the occipital region in dementia with Lewy
body patients. Amyloid PET imaging is a molecular imaging technique which uses a
radiotracer to detect elevated levels of β-amyloid in the brain in patients with
Alzheimer disease. It can be used to distinguish between patients with Alzheimer
disease, those with other dementias, and normal subjects. Single-photon emission
computed tomography (SPECT) uses a radioactive isotope to demonstrate increased
blood flow during seizures or decreased blood flow in the degenerative dementias.
Dopamine transporter SPECT (DaT scan)is a special kind of SPECT scan in which
a radioisotope that binds to dopamine transporter in the striatum is injected. It can be
helpful to distinguish Parkinson disease from other movement disorders. Magnetic
resonance spectroscopy may be used to demonstrate areas of neuronal damage or
dysfunction and has been studied in the assessment of brain tumors, demyelinating
disease, and infections of the CNS. Peripheral nerve ultrasound is being developed
for the evaluation of focal and general neuropathic symptoms.

ELECTROENCEPHALOGRAPHY
The electroencephalogram (EEG) provides a record of the electrical activity of the
cerebral cortex. EEG patterns are characterized by the frequency and amplitude of the
recorded electrical activity, and the patterns of activity correlate with the degree of
wakefulness or sleep. The normally observed frequency patterns are divided into four
groups: alpha (8–13 Hz), beta (14–30 Hz), theta (4–7 Hz), and delta (0.5–4.0 Hz) (Fig.
2-5). Under normal circumstances, alpha waves are observed over the posterior head
regions in the relaxed awake state with the eyes closed. Lower-amplitude beta activity
is more prominent over the frontal regions. Theta and delta activities are normal during
drowsiness and sleep, and the different stages of sleep are defined by the relative
proportions and amplitudes of theta and delta activities (see Chapter 13).

FIGURE 2-5. Electroencephalogram frequencies.

TECHNIQUE
The standard EEG is recorded from electrodes attached to the scalp in a symmetric
array. The pattern in which these electrodes are connected to each other is referred to as
the montage, of which there are essentially two types: bipolar and referential. In a
bipolar montage, all electrodes are active and a recording is made of the difference in
electrical activity between two adjacent electrodes. In a referential montage, the
electrical activity is recorded beneath the active electrode relative to a distant electrode
or common average signal. The signal recorded by an EEG is a sum of excitatory and
inhibitory postsynaptic potentials of cortical neurons.

CLINICAL UTILITY
Several common patterns of abnormal EEG activity are recognized. A slower frequency
background in all areas indicates a diffuse encephalopathy (often caused by a systemic
process). Focal slow activity in the theta or delta range suggests local dysfunction in the
underlying brain. The slowing cannot specify the etiology, but vascular disease is a
common cause of such findings. Interictal epileptiform findings include sharp-and-
spike-wave discharges, with or without an accompanying slow wave. Electrographic
seizures may take various forms. The most common are rhythmic spike- or sharp- and
slow-wave discharges or rhythmic slow waves. They may be focal or generalized.
Activation procedures can be used to enhance the likelihood of finding abnormal EEG
patterns: Hyperventilation is useful for provoking epileptiform discharges changes in
patients with absence seizures, whereas photic stimulation can induce epileptiform
discharges in patients with myoclonic seizures.
To appreciate the utility of the EEG, it is important to understand its limitations. First,
the patterns of electrical activity recorded by the EEG are rarely specific to their cause.
For example, widespread theta and delta background slowing during the awake state
suggests an encephalopathy but does not indicate the etiology. Second, the EEG records
the electrical activity of cortical neurons. Although subcortical structures influence
cortical activity, the surface EEG may be insensitive to dysfunction of deep structures.
For example, seizures originating in the medial frontal or temporal lobes may not be
readily apparent on the surface EEG. Furthermore, the EEG provides a measure of the
electrical activity of the cortex at the time of the recording and is therefore frequently
normal in paroxysmal conditions such as epilepsy. The interictal EEG, for example,
may be abnormal in only about 50% of adults with epilepsy. The frequency of interictal
EEG abnormalities may be higher in certain forms of epilepsy.

KEY POINTS
● EEG can be used in the evaluation of seizure disorders and encephalopathy.
● Epilepsy is a clinical diagnosis; interictal epileptiform findings are demonstrable in about half of patients with
epilepsy on routine EEG.

EVOKED POTENTIALS
Evoked potentials are electrical potentials or waveforms that are recorded from the
brain, spinal cord, or peripheral nervous system in response to a stimulus. Visual-
evoked potentials are used primarily in the diagnosis of optic neuritis and multiple
sclerosis. A visual target is presented to a patient, and surface potentials are recorded
over the occipital lobes. A delay in the P100 potential suggests dysfunction of the optic
nerve or its connections. Somatosensory-evoked potentials (SSEPs) may be used to
assess peripheral nerve and spinal cord problems. They are also used in the evaluation
of patients with coma and brain death: Bilateral absence of the N20 potentials indicates
a very poor prognosis. SSEPs and motor-evoked potentials are used to monitor
neurologic function during several types of surgery, especially spine surgery. Brainstem
auditory–evoked potentials are useful to assess brainstem dysfunction and are most
often used in surgical planning for patients with vestibular schwannomas and to assess
hearing in infants.

NERVE CONDUCTION STUDIES AND

ELECTROMYOGRAPHY
Nerve conduction studies (NCS) and electromyography (EMG) are electrophysiologic
tools that may aid in the diagnosis of peripheral nervous system disorders.

TECHNIQUE
In performing NCS, an electrical stimulus is applied over a nerve and recordings are
made from surface skin electrodes. For motor studies, the recording electrodes are
placed over the endplate of a muscle innervated by the nerve being stimulated. The
nerve is stimulated in at least two locations (distal and proximal), and the distance
between the two sites of stimulation is measured carefully. The distal latency,
compound muscle action potential (CMAP), and conduction velocity are recorded. The
CMAP is a recording of the contraction of the underlying muscle. The distal latency is
the time interval between stimulation over the distal portion of the nerve and the
initiation of the CMAP. Conduction velocity is calculated by measuring the difference in
latency to CMAP initiation between proximal and distal sites of stimulation. For
sensory studies, the nerve is stimulated at one site and the sensory nerve action potential
is recorded either at a more proximal site (orthodromic study) or at a more distal site
(antidromic study). Repetitive nerve stimulation studies are used to demonstrate either
decremental or incremental CMAP responses in disorders of the neuromuscular junction
(NMJ).
EMG involves the insertion of a needle into individual muscles. Recordings are made
of the muscle’s electrical activity upon insertion (insertional activity), while the muscle
is at rest (spontaneous activity), and during contraction (volitional motor unit
potentials). To increase the strength of muscular contraction, motor units can fire more
quickly (activation) or more motor units can be added (recruitment). Reduced activation
is seen in CNS disease. Reduced recruitment suggests a peripheral nervous system
lesion, whereas early recruitment suggests myopathic disease. For routine EMG studies,
activity is recorded from a group of muscle fibers simultaneously. Single-fiber EMG is
the technique used in the investigation of disorders of the NMJ: increased jitter and
blocking are the single-fiber EMG hallmarks of NMJ disease.

TABLE 2-3. Electromyography in Neurogenic and Myopathic Disorders

Insertional activity
Spontaneous activity
Volitional motor unit potentials
Recruitment
Neurogenic
↑ (active denervation)
↑ (active denervation)
Large amplitude; polyphasic
Reduced
Myopathic
Usually normal (↑ in inflammatory and
necrotizing myopathies)
Usually normal (↑ in inflammatory and
necrotizing myopathies)
Small amplitude; polyphasic
Usually normal early

TABLE 2-4. Nerve Conduction Studies in Demyelinating and Axonal Neuropathies

Demyelinating Axonal
Distal latency Markedly prolonged Normal or mildly prolonged
Conduction velocity Markedly reduced Normal; may be slightly slowed
CMAP amplitude Normal or mildly reduced Reduced
CMAP, compound muscle action potential

CLINICAL UTILITY
NCS and EMG are used primarily to assist in the localization of dysfunction within the
peripheral nervous system and to define pathophysiology more clearly. For example,
NCS and EMG may help to differentiate a C8–T1 radiculopathy from a lower brachial
plexopathy or an ulnar neuropathy in the patient who presents with numbness of the
fourth and fifth fingers and weakness of the hand. Similarly, the combination of motor
NCS, repetitive nerve stimulation, and EMG may help to localize motor dysfunction
(i.e., weakness) to the peripheral nerve, the NMJ, or the muscle (Table 2-3). In a patient
with a polyneuropathy, NCS may help to define the relative degree of motor and sensory
involvement and to distinguish primary demyelinating from axonal disease (Table 2-4).

KEY POINTS
● The goal of NCS and EMG is to localize the neurologic dysfunction within the peripheral nervous system.
● Repetitive nerve stimulation and single-fiber EMG are useful in the diagnosis of disorders of the NMJ.
 PART II COMMON NEUROLOGIC
SYMPTOMS

3 The Approach to Coma and Altered

Consciousness

The neurologic evaluation and management of a patient with coma or altered

consciousness can be intimidating for the student, because such patients are usually
critically ill and may require prompt intervention. The fundamental principles behind
the evaluation of a neurologic problem, however, should not be discarded. On the
contrary, an orderly and hypothesis-based approach may be even more important in a
comatose patient than in others, given the need for timely diagnosis and the relative
limitations of history and examination.

DEFINITION
Coma is defined as a state of unarousable unresponsiveness. Typically, the patient lies
with eyes closed and does not open them even to vigorous stimulation, such as sternal
rub, nasal tickle, or nailbed pressure. Alterations in consciousness short of coma are
often described using terms such as drowsiness, lethargy, obtundation, and stupor, but
these terms tend to be used imprecisely and it is generally best to describe simply how
the patient responded to various degrees of stimulation. The Glasgow Coma Scale
(GCS) assigns a numerical score to a patient’s level of responsiveness and is commonly
used by neurosurgeons in cases of head trauma (see Table 17-1). Its utility lies in its
ease of use by nurses and paramedics, its inter-rater reproducibility, and its prognostic
value following head injury. Although the GCS describes a level of responsiveness, it
does not assist in determining the cause of coma.

KEY POINTS
● Coma is a state of unarousable unresponsiveness.
● It is important to describe a patient’s responses to various degrees of stimulation.
● The GCS, which has prognostic value in patients with head trauma, is reproducible and easy to use.
CLINICAL APPROACH
An algorithm for approaching patients with coma or altered consciousness is presented
i n Figure 3-1. The initial steps of stabilization and evaluation culminate in the
neurologic exam, which is performed with two goals in mind: to assess brainstem
function and to look for focal signs. The differential diagnosis and further investigations
stem from this clinical assessment.
1. Remember the ABCs. In any patient with altered consciousness, the airway,
breathing, and circulation (ABC) should be checked and maintained according to
usual protocols, including intubation and mechanical ventilation if required.
2. Look for obvious clues to etiology. A brief history and general exam should be
performed to search for obvious clues. A history of medical problems such as
diabetes, hepatic failure, alcoholism, or a seizure disorder may be provided by the
family, noted on a medical alert bracelet, or deduced from prescription labels. The
circumstances in which the patient was found can offer clues to the onset or etiology
of depressed consciousness. The general exam may yield telling signs, such as an
odor on the breath, needle tracks on the skin, or a tongue laceration. It is important to
check for meningeal signs in any unconscious patient because both bacterial
meningitis and subarachnoid hemorrhage may lead to depressed consciousness.
FIGURE 3-1. The approach to coma and altered consciousness. [ABC: airway, breathing, and circulation.]

3. Try reversing common reversible etiologies. Most emergency departments make it

standard practice to administer naloxone, thiamine, and dextrose to any patient with
depressed consciousness and no obvious etiology. Note that thiamine should always
be given before glucose because the latter can precipitate Wernicke encephalopathy
if given alone.
4. Check brainstem reflexes and look for focal signs. These are the two primary goals
of the neurologic exam in this setting, because the subsequent diagnostic and
therapeutic steps will depend on these clinical findings.
5. Assess for all medication exposure. All comatose patients should have a toxicology
screen for substances of abuse and other drugs. It is also important to remember what
medications were administered in the emergency setting, including for intubation, as
they can impact the findings of the neurologic exam. Remembering the half-life of the
drug and mechanisms of action will help inform the interpretation of the exam.

KEY POINTS
● The clinical approach to the patient with altered consciousness begins with the ABCs: airway, breathing, and
circulation.
● Look for obvious clues to etiology.
● Try reversing common reversible etiologies.
● Use the neurologic exam to check brainstem reflexes and look for focal signs.

EXAMINATION
It is important to proceed with the neurologic exam of a comatose patient in an orderly
fashion—it is easy to be intimidated or distracted by the array of attached tubes and
lines or by the intensity and anxiety of other clinicians. An appropriate way to begin is
to progress systematically through the sequence of the usual neurologic exam, making
adjustments as necessary for the patient’s altered level of responsiveness.
Mental status testing in these patients begins with assessing the level of
consciousness. An increasing gradient of stimulation should be applied and the patient’s
responses recorded. For example, does the patient lie with his or her eyes closed but
open them slowly when spoken to in a loud voice? Does he or she groan but not open
the eyes when sternal rub is applied? For many patients, further cognitive testing may
not be possible. For those who can be aroused even briefly, however, a short evaluation
of attention, language, visuospatial function, and neglect is in order, because this may
reveal a gross focal finding such as an aphasia or dense neglect of the left side.
Cranial nerves (CNs) should be examined in detail, because this is the portion of the
exam most relevant to the assessment of brainstem function. In an arousable patient,
most CNs can be tested in the usual manner. In a patient who is not arousable enough to
follow commands, several important brainstem reflexes should be tested (Table 3-1),
including the pupillary, corneal, oculocephalic, and gag reflexes. In addition, a
funduscopic examination should always be performed. For many patients with altered
consciousness, testing for a blink to visual threat may be the only way to judge visual
fields. If the patient cannot move his or her face to command, the examiner may be
restricted to looking for an asymmetry at rest, such as a flattened nasolabial fold on one
side. Supraorbital pressure can be used to assess for facial asymmetries, as well as
response to noxious stimuli. Bilateral nasal tickle also tests sensation in the trigeminal
nerve (CN V)—which prompts a response via CN VII. This is less painful than
supraorbital pressure. The presence of an endotracheal tube may make such testing
difficult.

TABLE 3-1. Brainstem Reflexes

Reflex Cranial Nerves How to Test
Involved
Pupillary II (afferent); III (efferent) Shine light in each pupil and observe for direct (same
side) and consensual (contralateral) constriction
Oculocephalic (doll’s eyes) VIII (afferent); III, IV, VI Forcibly turn head horizontally and vertically and observe
(efferent) for conjugate eye movement in opposite direction
(contraindicated if cervical spine injury has not been ruled
out)
Caloric testing (if Same Inject 50 mL ice water into each ear and observe for
necessary)a conjugate eye deviation toward the ear injected
Corneal V1 (afferent); VII Touch lateral cornea with cotton tip and observe for
(efferent) direct and consensual blink
Gag IX (afferent); X/XI Stimulate posterior pharynx with cotton tip and observe
(efferent) for gag
aCaloric testing should be performed if turning the head is contraindicated or does not result in eye movement. The
external auditory canal should be examined first with an otoscope to exclude tympanic perforation or obstruction by
wax. Never assume the eyes are immobile unless caloric testing has been done.

Motor tone should be checked in all extremities. If the patient can cooperate with
some testing, a gross hemiparesis can be ruled out by having the patient hold the arms
extended or legs elevated and observing for a downward drift. Otherwise, the examiner
may be restricted to observing for asymmetry of spontaneous movements (or to asking
caretakers whether all extremities have been seen to move symmetrically). Failing that,
noxious stimuli such as nailbed pressure or a pinch on a flexor surface can be applied to
each limb and the speed and strength of withdrawal noted, although abnormalities here
may result from sensory loss as well as motor dysfunction. Decorticate and decerebrate
posturing, signs of brainstem dysfunction, may be seen either spontaneously or in
response to noxious stimuli (Fig. 3-2).
Muscle stretch reflexes can be tested in the usual manner, and a Babinski sign should
be sought.
Sensory testing in most patients with altered consciousness is limited to testing of
light touch or pain sensation. Noxious stimulation to each limb, as described previously,
may be useful in looking for gross sensory abnormalities. In all cases in which noxious
or invasive testing is needed, it is important to explain to the family and others at the
bedside what the exam maneuvers and their purposes are before performing them, as
noxious stimuli can be distressing for loved ones to watch.
Coordination may be tested in patients who are arousable enough.
 KEY POINTS
● The mental status exam in patients with altered consciousness primarily assesses the level of responsiveness.
● The CN exam includes the testing of important brainstem reflexes, including the pupillary, corneal, and
oculocephalic reflexes.
● The remainder of the examination should be dedicated to looking for focal abnormalities.

FIGURE 3-2. Decorticate (above) and decerebrate (below) posturing. Both indicate brainstem dysfunction,
although decorticate posturing suggests dysfunction slightly more superior than decerebrate posturing. (LifeART image
Copyright © 2012 Lippincott Williams & Wilkins.)

DIFFERENTIAL DIAGNOSIS
In theory, there are two main ways in which consciousness can be depressed: the
brainstem can be dysfunctional or both cerebral hemispheres can be dysfunctional
simultaneously. As examples, acute disease in the brainstem (e.g., pontine hemorrhage)
can lead to coma, as can processes affecting both cerebral hemispheres at once (e.g.,
hypoglycemia). Unilateral cerebral hemispheric lesions, however, can also lead to
coma if they are large or severe enough to cause swelling and compression of the
opposite hemisphere or downward pressure on the brainstem.
Accordingly, most neurologists interpret the information obtained from the exam of
the comatose patient using the following principle: The presence or absence of
brainstem reflexes suggests how deep the coma is, whereas the presence or absence of
focal signs narrows the differential diagnosis and guides the workup.
Thus, in milder cases of depressed consciousness, the pupillary, corneal, and gag
reflexes may all be preserved. In more severe cases, some or all of these brainstem
reflexes may be lost, no matter what the etiology. (Note that if a brainstem reflex is
abnormal in an asymmetric fashion, such as a unilateral unreactive pupil, this would be
interpreted as a focal sign and suggests compression of, or primary disease in, the
brainstem.)
BOX 3-1. Structural Causes of Depressed Consciousness
Acute ischemic stroke
Brainstem
Unilateral cerebral hemisphere (with edema)
Acute intracranial hemorrhage
Intraparenchymal
Subdural
Epidural
Brain tumor (with edema or hemorrhage)
Primary
Metastatic
Brain abscess (with mass effect)

The presence of focal signs either on CN testing or in the remainder of the

examination—including such findings as hemiparesis, aphasia, reflex asymmetry, facial
droop, or a unilateral Babinski sign—suggests a structural cause of depressed
consciousness (Box 3-1). Examples include a large unilateral stroke, abscess, tumor, or
intracranial hemorrhage. The absence of focal signs suggests a diffuse cause of
depressed consciousness, including metabolic, toxic, or hypoxic-ischemic etiologies
(Box 3-2). Examples include coma from fulminant hepatic failure, barbiturate overdose,
or anoxia following cardiac arrest. Remember to review medications that were
administered to the patient prior to the exam when interpreting these findings because
sedatives and paralytics can influence the clinical findings and may mask brainstem
functions transiently.

BOX 3-2. Diffuse Causes of Depressed Consciousness

Metabolic
Electrolyte abnormality
Hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypomagnesemia, hypermagnesemia,
hypophosphatemia
Glucose abnormality
Hypoglycemia, nonketotic hyperosmolar coma, diabetic ketoacidosis
Hepatic failure
Uremia
Thyroid dysfunction
Myxedema coma, thyrotoxicosis
Adrenal insufficiency
Toxic
Alcohol
 Sedatives
Narcotics
Psychotropic drugs
Other exogenous toxins (carbon monoxide, heavy metals)
Infectious
Meningitis (bacterial, viral, fungal)
Diffuse encephalitis
Hypoxic-ischemic
Respiratory failure
Cardiac arrest
Other
Subarachnoid hemorrhage
Carcinomatous meningitis
Seizures or postictal state

KEY POINTS
● In theory, consciousness can be depressed either by dysfunction of the brainstem or dysfunction of both
cerebral hemispheres simultaneously; in reality, large unilateral hemispheric lesions (with pressure on the
other side) qualify as well.
● The presence or absence of brainstem reflexes suggests how deep the coma is.
● The presence of focal signs suggests a structural cause of coma.
● The absence of focal signs suggests a diffuse cause of coma, such as metabolic, toxic, infectious, or hypoxic-
ischemic etiologies.
● Remember to review medications administered to the patient when interpreting the exam.

LABORATORY AND RADIOLOGIC STUDIES

The distinction between structural and diffuse causes of depressed consciousness,
arrived at by interpreting the findings on exam, suggests different pathways of diagnostic
workup.
The presence of focal findings on examination, suggesting a structural cause, demands
urgent head imaging, usually a noncontrast computed tomography (CT) scan. One should
look for signs of a large acute stroke, an intracranial hemorrhage, or a mass lesion that
may have enlarged rapidly or had a hemorrhage within it. Contrast-enhanced CT should
be avoided if an acute hemorrhage is possible. Hemorrhages are readily evident on
noncontrast CT, but contrast enhancement can mimic hemorrhage when it is used. Even
in cases where focal brainstem signs are found, the initial choice of head imaging may
have to be a CT scan rather than magnetic resonance imaging, despite the poor quality of
the former in evaluating the brainstem, because of the possibility of a large cerebral
hemispheric lesion compressing the brainstem and the usually more immediate
availability of CT.
The absence of focal findings on examination, suggesting a diffuse cause, warrants an
extensive workup for causes of metabolic, toxic, or infectious etiologies. Blood testing,
including complete blood count, electrolytes, glucose, liver function tests, and
toxicologic screen, is necessary. In women of reproductive age, it is also prudent to
obtain a pregnancy test, as this impacts medication management. If infection is
suspected, a chest X-ray, urinalysis, and blood or urine cultures may be called for.
There should be a low threshold for obtaining a lumbar puncture (LP). If a basic workup
is unrevealing, one should search for more unusual causes (such as myxedema coma, by
checking thyroid function tests).
Head imaging is usually needed even in these cases of suspected diffuse causes
because it may demonstrate signs of global hypoxic-ischemic injury, diffuse cerebral
edema, or bilateral lesions mimicking a diffuse process, although the urgency is not as
high as for patients with focal findings. Almost without exception, a head CT should be
performed before obtaining an LP in the evaluation of a patient with depressed
consciousness, given the risk of precipitating brain herniation if a large intracranial
mass (particularly in the posterior fossa) is present. If bacterial meningitis is suspected,
empiric antibiotic treatment can be started if CT scanning is delayed.
Frequently, an electroencephalogram (EEG) is ordered in patients with coma or
altered consciousness. Although many of its findings may be nonspecific, the EEG can
help to assess how deep a coma is based on the degree of background slowing. In
addition, there are occasionally more specific patterns on EEG that suggest a particular
diagnosis, such as hepatic encephalopathy or anoxic brain injury. Finally, the EEG can
help diagnose nonconvulsive status epilepticus as a cause of coma in cases in which this
is (or is not) suspected clinically.

KEY POINTS
● If a structural cause of coma is suspected, urgent head imaging, usually with a noncontrast head CT, should
be performed.
● If a diffuse cause is suspected, an extensive workup for metabolic, toxic, or infectious causes should be
undertaken.
● Head imaging in suspected diffuse cases may demonstrate cerebral edema, signs of global hypoxic-ischemic
injury, or bilateral lesions mimicking a diffuse process.
● Almost without exception, head CT should be performed before LP.
● EEG can assess the depth of coma and can occasionally suggest a specific diagnosis.
TREATMENT AND PROGNOSIS
The treatment of coma and altered consciousness depends on the specific diagnosis.
Metabolic, infectious, or toxic etiologies require mostly medical management, whereas
some structural causes of coma may require neurosurgical intervention. Specific
treatments for particular conditions are detailed in later chapters, in particular Chapter
14 for strokes and hemorrhages, Chapter 17 for head trauma, Chapter 18 for systemic
and metabolic disorders, Chapter 19 for brain tumors, and Chapter 21 for central
nervous system (CNS) infections.
When increased intracranial pressure (ICP) is suspected clinically or radiologically,
treatments aimed at lowering ICP should be applied. These include raising the head of
the bed, hyperventilation, and the use of an osmotic diuretic such as mannitol.
Corticosteroids tend to be useful in cases of edema associated with brain tumors. The
lowering of ICP may be a neurologic or neurosurgical emergency if the patient shows
signs of brain herniation, which is discussed in more detail in Chapter 17.
The prognosis of depressed consciousness is mostly dependent on etiology. The
patient with a barbiturate overdose may recover completely, whereas one with a severe
anoxic injury often does not. Age is an important prognostic factor as well. One of the
most frequent reasons for admission to an intensive care unit or for neurologic
consultation is to estimate the prognosis of a patient in coma following cardiopulmonary
arrest. Currently, the standard of care for patients with cardiac arrest is usually to
undergo therapeutic hypothermia (aiming for a core body temperature between 32°C and
34°C) in the acute phase—which has been demonstrated to lead to better neurologic
outcomes compared with normothermia or hyperthermia. In these cases, the
circumstances and duration of the cardiac arrest are important, and published studies
have correlated outcomes with findings on neurologic examination performed at least 24
hours after the arrest.

KEY POINTS
● The treatment of coma or altered consciousness depends on the etiology.
● The lowering of ICP may be a neurologic emergency if the patient shows signs of brain herniation.
● Therapeutic hypothermia is currently the standard of care in the acute phase for most post-cardiac arrest
patients.
● Prognostic factors for coma or altered consciousness include both etiology and patient age.

SPECIAL TOPICS
PERSISTENT VEGETATIVE STATE
Persistent vegetative state is a state in which patients have lost all awareness and
cognitive function but may remain with the eyes open, exhibit sleep–wake cycles, and
maintain respiration and other autonomic functions. Patients may progress into this state
after being in coma for a prolonged period if their vital functions have been supported.

MINIMALLY CONSCIOUS STATE

The minimally conscious state (MCS) is defined by the Aspen Work Group as “a
condition of severely altered consciousness in which minimal, but definite, behavioral
evidence of self or environmental awareness is demonstrated.” Patients can emerge
from a vegetative state into an MCS. The diagnosis of MCS is made by reproducible
behaviors on exam as outlined in Table 3-2 and includes following a simple command,
verbalization, and purposeful behaviors or responses that are environmentally
appropriate. The most common finding is sustained visual fixation and pursuit. Patients
in the MCS may have some limited awareness of self or the environment—which differs
from patients in a vegetative state who do not have evidence of any awareness.

TABLE 3-2. Criteria for the Determination of the Minimally Conscious State
A patient must demonstrate at least one of these features:
• Following simple instructions
• Can give a yes or no answer, either with a verbal response or a motor cue
• Can communicate verbally, and understandably
A patient must exhibit intentional or affective behavior in response to the immediate environment, e.g.:
• Emotional responses (joyous or tearful) that are appropriate to verbal or visual stimuli (and that are not elicited by
neutral stimuli)
• Utterances or gesticulations in response to verbal questions
• Purposeful reaching for objects in which the intention of the movement toward the object is clear
• Sustained gaze fixation on an external visual cue, visual pursuit, adjustment of grasp, or movement in response to the
shape of an object

Imaging modalities have also been used in hopes of identifying reliable biomarkers to
differentiate between the MCS and the persistent vegetative state. Fluorodeoxyglucose
positron emission tomography, functional magnetic resonance imaging, and quantitative
EEG have been shown in some studies to demonstrate differences between these two
conditions when patients are given a cognitive challenge or instruction. Nevertheless,
these diagnostic techniques are not used routinely in most clinical practice as
controversies remain regarding their sensitivity and specificity.

LOCKED-IN SYNDROME
Although a locked-in syndrome can be confused with coma at first glance, a patient with
locked-in syndrome is awake and may be intact cognitively, with no abnormality of
consciousness. Usually a consequence of large lesions in the base of the pons, the
locked-in syndrome leaves patients unable to move the extremities and most of the face.
If all other motor function is lost, patients may be limited to communicating by vertical
eye movements or blinks.

BRAIN DEATH
Death can be declared either when there has been irreversible cessation of
cardiopulmonary function or there has been irreversible cessation of all functions of the
entire brain, including the brainstem. A declaration of death based on the latter criterion
is commonly referred to as brain death. The American Academy of Neurology has
established evidence-based guidelines on the diagnosis of brain death, and many
institutions have specific guidelines for how brain death must be determined based on
these guidelines. In general, the patient must be comatose, with a known and presumed
irreversible cause, have absent brainstem reflexes, and have no spontaneous
respirations even when the PCO2 has been allowed to rise (the apnea test). Other causes
of coma must be excluded, and confounding factors such as hypothermia or CNS-
depressant drugs must not be present.
The clinical diagnosis of brain death does not require ancillary testing such as EEG
or cerebral angiogram. These tests may be omitted when the clinical diagnosis is clear,
because they (very infrequently) give misleading results. Ancillary testing may be used
when there is uncertainty regarding the diagnosis—because of the unreliability of the
neurologic exam or when an apnea test cannot be performed. In brain death, the EEG
should demonstrate an absence of reactivity to somatosensory or audiovisual stimuli.
Cerebral blood flow studies will demonstrate no intracerebral filling above the carotid
or vertebral arteries.

KEY POINTS
● A persistent vegetative state may follow prolonged coma and is characterized by preserved sleep–wake
cycles and maintenance of autonomic function, with the absence of awareness and cognition.
● An MCS is a condition of impaired consciousness with retention of some environmental awareness or self-
awareness.
● Locked-in syndrome, in which awareness and cognitive function are preserved but almost complete paralysis
occurs, is often caused by large lesions in the base of the pons.
● Brain death is a declaration of death based on irreversible cessation of all brain function.
● Prognosis can also be aided using blood flow studies and EEG.

ACUTE CONFUSIONAL STATE

Definition
The terms confusion, delirium, and encephalopathy are often used nonspecifically to
indicate a disturbance of mental status in which the patient is unable to carry out a
coherent plan of thought or action. Most neurologists employ the terms confusion or
encephalopathy, whereas delirium (commonly used by psychiatrists) often implies a
state of confusion characterized by a waxing and waning level of alertness and,
sometimes, agitation.
At its core, an acute confusional state results from a problem of attention. Thus, a
patient’s failure to answer questions in a coherent manner or to carry out an intended
series of actions in an expected way derives from an inability to maintain attention for
long enough to proceed through the cognitive or motor steps required for the task. On
formal mental status testing, therefore, patients with confusion typically do poorly on
standard tests of attention, such as spelling the word “world” in reverse, reciting the
months of the year backward, or completing serial subtractions. Such inattention may be
significant enough to render impossible the performance of more detailed mental status
testing. These cognitive deficits may also fluctuate, as do the levels of alertness. The
term encephalopathy or encephalopathic is therefore used frequently by neurologists to
describe patients who are unable to maintain attention because of a toxic or metabolic
derangement. This is different from patients with progressive dementia syndromes or
attention deficit disorder whose deficits are more fixed. Depending on the underlying
etiology of the acute confusional state, other associated features on neurologic or
general physical examination might aid in the diagnosis—such as asterixis in a patient
with hepatic (or other) encephalopathy.

Differential Diagnosis
The differential diagnosis of acute confusion includes a number of different disorders,
such as aphasia (particularly Wernicke-type), psychosis, and complex partial seizures.
Patients with Wernicke aphasia may appear “confused” but in fact are attentive and able
to carry out coherent series of actions; their deficit lies solely in their ability to
communicate. Although patients with psychosis may also behave as if they are acutely
confused, pure confusional states do not result in frank psychotic symptoms like
hallucinations or delusions. Complex partial seizures can be characterized by behavior
that appears “confused,” but seizures are typically self-limited in duration and may be
associated with clonic motor movements or automatisms such as lip-smacking.

Diagnostic Evaluation
An acute confusional state is most commonly caused by an underlying systemic or
neurologic disorder, including infection, metabolic disturbance, inflammatory condition,
or hypoxic-ischemic state, among many possibilities. Focal brain disorders, particularly
acute right hemispheric lesions, can also lead to confusion. The appropriate diagnostic
workup in a patient with confusion is therefore potentially quite extensive. Blood work
and urinalysis to search for infectious or metabolic disturbances are often warranted. If
there is clinical suspicion for a CNS infection, cerebrospinal fluid (CSF) analysis
should be performed. Neuroimaging should be obtained if the neurologic history or
examination suggests the possibility of an acute focal lesion. An EEG can help to
determine whether there is a widespread dysfunction (encephalopathy), focal
abnormalities, or ongoing seizures. It is unlikely to demonstrate the precise cause of an
acute confusional state but can help to confirm a diagnosis, as characteristic findings of
an encephalopathy may be present, and in some cases the EEG can help diagnose
nonconvulsive status epilepticus.

Treatment and Prognosis

The treatment and prognosis of acute confusional states depend largely on the underlying
etiology. Most cases of confusion arise from a reversible underlying cause and will
resolve if the underlying disorder is treated appropriately. Confusional states arising
from structural neurologic lesions or more chronic underlying disturbances may be less
likely to improve spontaneously.

KEY POINTS
● An acute confusional state, also sometimes called encephalopathy or delirium, is characterized by an inability
to carry out a coherent plan of thought or action.
● Acute confusion is primarily the result of a core problem with attention.
● Systemic infections and metabolic disturbances are common causes of an acute confusional state, although
many possible etiologies exist.

CLINICAL VIGNETTES

VIGNETTE 1
A 52-year-old homeless man is brought into the emergency room (ER) by police
after he was found unresponsive on a sidewalk in the middle of the night. The police
indicate that with vigorous shaking, they were able to get him to open his eyes
briefly, but then he began speaking “nonsense” and fell back asleep quickly. On
arrival to the ER, the patient is afebrile, heart rate is 120, blood pressure is 90/50
mm Hg, and respiratory rate is 12.
1. Which of the following assessments or interventions for an unresponsive patient
 should not be done immediately upon arrival to the ER?
a. Fingerstick blood glucose check
b. Maintenance of airway, breathing, and circulation
c. Evaluation of pupillary and other brainstem reflexes
d. LP for CSF analysis
e. Administration of thiamine
2. Initial screening neurologic exam shows that the patient can only sustain attention
for 10 to 20 seconds after vigorous stimulation before closing his eyes again
and becoming unresponsive. He cannot perform any serial tasks forward or
backward, and only follows a single simple command at a time. He has
prominent horizontal nystagmus when he keeps his eyes open, and wobbles
noticeably when trying to sit up straight. There are no other focal findings. A
social worker who knows the patient from a nearby shelter reports that he has
problems with chronic alcohol abuse. What is the most likely diagnosis?
a. Wernicke encephalopathy
b. Korsakoff syndrome
c. Hepatic encephalopathy from alcoholic cirrhosis
d. Cerebellar degeneration
e. Carcinomatous meningitis (leptomeningeal metastasis)

ANSWERS

VIGNETTE 1 QUESTION 1
Answer D:
Although LP for CSF analysis may be necessary to rule out infectious meningitis, it
should only be performed after the clinician is certain that there is no intracranial
mass, particularly in the posterior fossa. Whereas in certain circumstances, an LP
could be performed after a careful funduscopic examination rules out raised ICP
(e.g., by confirming the presence of venous pulsations), in most situations a
noncontrast head CT should be performed first to rule out a mass or bleeding.
Maintenance of the ABCs, fingerstick blood glucose check, a screening
neurologic exam focused on brainstem reflexes, the identification of clear focal
neurologic deficits, and administration of thiamine are all standard assessments or
interventions that can (and should) be performed immediately for an unresponsive
patient.

VIGNETTE 1 QUESTION 2
2. Answer A:
Wernicke encephalopathy, commonly seen in the setting of thiamine deficiency in
chronic alcoholism, is characterized by an acute confusional state, sometimes
progressing to frank coma, eye movement abnormalities (often nystagmus or
horizontal gaze deficits), and ataxia (in this case an inability to maintain midline
posture). Autonomic signs are frequent. Treatment with parenteral thiamine can
reverse or improve the neurologic impairment to varying degrees.
Korsakoff syndrome is a long-term memory disorder, characterized by
anterograde amnesia and confabulation, that can arise after acute Wernicke
encephalopathy has resolved. Although an alcoholic patient may be at risk for
hepatic encephalopathy or cerebellar degeneration, and carcinomatous meningitis
can cause an acute confusional state, those are not the most likely causes of this
patient’s current clinical presentation.
 4 Neuro-Ophthalmology

Neuro-ophthalmology is a field that helps elucidate the causes of visual symptoms, such
as double vision (diplopia), and signs including pupillary dysfunction and eye
movement abnormalities. Because these symptoms and signs can reflect lesions at
multiple points along a complex path from the eye to the brain, or even more generalized
systemic illnesses, it is important to take a careful history. The presenting details
narrow the differential and guide the choice of specialized tests during the neuro-
ophthalmologic examination. This examination focuses on factors including visual
acuity, visual fields, the optic disc, pupillary function, eye movements, and eyelid
elevation. Sometimes, a combination of findings forms a pattern that reflects a well-
recognized syndrome.
The ability to localize lesions and identify syndromes to generate a plan for
investigation and management depends on understanding the structures that play a role in
visual systems. It is also important to comprehend how they interact with the external
environment. The more anterior parts of the visual system (i.e., the eyes and optic
nerves) allow exploration of visual space. The posterior cerebral hemispheres are
involved in the integration and perception of visual information through higher cortical
function—as discussed in Chapter 11.

ANATOMY OF VISUAL PATHS, PUPILS, AND

OCULOMOTOR NERVES
Light enters the cornea and stimulates the rods and cones in the retina, generating
electrical signals that are transmitted through the optic nerve. Fibers from the nerve of
each eye cross at the optic chiasm before forming the optic tracts. Ninety percent of
retinal axons in these tracts terminate in the lateral geniculate nucleus of the thalamus,
the principal subcortical structure that carries visual information to the cerebral cortex
through the optic radiations. The primary visual cortex is visual area 1, corresponding
to Brodmann area 17 (striate cortex), which receives information from the contralateral
visual hemi-field. This information is then transferred to the associative visual cortex,
including areas 18 and 19, and to higher order centers in the posterior parietal and
inferior temporal cortices, where the perception of motion, depth, color, location, and
form takes place. The visual pathway and associated visual field defects are shown in
Figure 4-1.
Pupil size is determined by parasympathetic and sympathetic influences. The pupil
controls light transmission through the initial part of the visual pathway, including the
optic tract. The optic tract synapses with the Edinger–Westphal nucleus (EWN) in the
rostral aspect of the third nerve nucleus. Efferent parasympathetic fibers from the EWN
travel with the third cranial nerve (CN III). In the cavernous sinus, they run with the
inferior division of CN III and synapse in the parasympathetic ciliary ganglion in the
posterior orbit. Parasympathetic fibers ultimately innervate pupilloconstrictor muscles
in the iris (Fig. 4-2).
Sympathetic fibers effect pupil dilation via a three-neuron route. First-order neurons
project down from the hypothalamus to an initial synapse in the intermediolateral cell
column from C8 to T2 spinal levels (the “ciliospinal center of Budge”). Second-order
neurons then travel from the sympathetic trunk to the superior cervical ganglion located
near the bifurcation of the common carotid artery. Third-order neurons then travel in the
adventitia of the internal carotid artery to join the first division of the trigeminal nerve
to innervate elements of the orbit and eye, including the pupillodilator muscles (Fig. 4-
3).
FIGURE 4-1. Visual pathways (figure, left; Note: this diagram is as if from an MRI scan: right side of brain on
the left and left side of the brain on the right.) and visual field defects associated with lesions along the visual pathway
(table, right). Light entering from the nasal visual field stimulates photoreceptors of the temporal retina, and vice versa.
Photoreceptors transmit signals to bipolar cells and then retinal ganglion cells. Ganglion cell axons form the nerve fiber
layer of the retina and enter the optic nerve (1 and 2). Each optic nerve carries visual information from one eye.
(Arteritic and nonarteritic anterior ischemic optic neuropathy may be associated with altitudinal deficits.) The two optic
nerves form the optic chiasm (3). Fibers from nasal halves of the retina (carrying information from the temporal visual
fields) decussate at the optic chiasm and join temporal fibers (carrying information from the nasal visual fields) from
the contralateral eye to form the optic tracts (4). Each optic tract carries visual information from the contralateral
visual field. Each optic tract synapses with neurons at the lateral geniculate nucleus (LGN) on the same side (some
fibers involved in the light reflex do not reach the LGN but go instead to the pretectal nucleus as part of the pupillary
light reflex). From the LGNs, signals are transmitted through the geniculocalcarine tract (5, 6, and 7). Fibers that carry
visual information from the upper contralateral visual fields travel through Meyer’s loop in the temporal lobes; fibers
carrying visual information from the lower contralateral visual field travel through the parietal lobes. Visual information
from the contralateral visual field reaches the occipital (calcarine) cortex (8). Strokes affecting the PCA may be
associated with macular sparing because the macula is also supplied by the MCA. AMD, age-related macular
degeneration; CRAO, central retinal artery occlusion; CRVO, central retinal vein occlusion; MCA, middle cerebral
artery; PCA, posterior cerebral artery. Reprinted with permission from Chowdhury SH, Chowdhury JH, Cozma AI.
Essentials for the Canadian Medical Licensing Exam: Review and Prep for MCCQE. 2nd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2016. Figure 15-5.
FIGURE 4-2. Eye movement abnormalities related to brainstem lesions of the abducens nerve or nucleus or both,
and of the medial longitudinal fasciculus (MLF), causing deficits of eye movements in the horizontal plane. (The
diagram depicts a coronal view of the brainstem, with midbrain structures above and pontine structures below.) (1)
Lesion of the abducens nerve root: Motor neurons in the abducens nucleus innervate the ipsilateral lateral rectus
muscle, so a patient with a lesion of the abducens root external to the pons has a loss of voluntary lateral gaze in the
eye on the side of the lesion, with paralysis of the lateral rectus muscle. Other movements in the affected eye, and all
movements in the contralateral eye, are normal. The patient will have diplopia. When looking straight ahead, the eye on
the lesioned side will deviate slightly toward the midline (given the unopposed action of the medial rectus in the same
eye). The diplopia is made worse when attempting to look toward the lesioned side in a horizontal plane. (2) Caudal
basilar pontine lesion: Because axons arising from abducens motor neurons pass through the basilar pons, they are
located laterally adjacent to corticospinal fibers. A lesion in this portion of the pons may simultaneously damage the
exiting abducens fibers and corticospinal axons. A patient with this lesion may have a crossed hemiplegia, paralysis of
the lateral rectus muscle on the side of the lesion (with loss of voluntary lateral gaze to that side, and diplopia), and a
paralysis of the arm and leg on the opposite side of the body. (3) Internuclear ophthalmoplegia (INO): In addition
to abducens motor neurons that innervate the ipsilateral lateral rectus muscle, the abducens nucleus also contains
interneurons. The axons of these interneurons cross the midline, enter the MLF, and ascend to terminate on motor
neurons in the oculomotor nucleus that innervate the medial rectus muscle on that side. A lesion in the MLF interrupts
these axons and results in a loss of medial gaze (medial rectus paralysis) in the eye on the side of the lesion during
attempted conjugate eye movements. Other movements in the affected eye and all movements in the contralateral eye
are normal. (Thus, a right INO specifies a lesion in the right MLF and paralysis of the right medial rectus muscle.) (4)
A lesion of the abducens nucleus damages α motor neurons innervating the ipsilateral lateral rectus muscle and the
interneurons that terminate on medial rectus α motor neurons in the contralateral oculomotor nucleus. A patient with
this lesion has loss of horizontal gaze in both eyes during attempted voluntary eye movement toward the side of the
lesion; horizontal gaze toward the contralateral side is normal. (This is basically an abducens root lesion plus an INO.)
(5) The one-and-a-half syndrome is so named because a unilateral pontine lesion may result in a loss of medial and
lateral voluntary eye movement on the side of the lesion (the “one”) and a loss of medial horizontal eye movement on
the contralateral side (the “one-half”). This lesion involves the abducens nucleus on one side (deficits = lateral rectus
paralysis on the side of the lesion, medial rectus paralysis on the contralateral side) and the immediately adjacent MLF
conveying the axons of abducens interneurons originating in the opposite abducens nucleus (deficit = medial rectus
paralysis on the side of the lesion). These lesions are usually large and involve portions of the paramedian pontine
reticular formation, commonly called the horizontal gaze center. Reprinted with permission from Haines DE.
Neuroanatomy: An Atlas of Structures, Sections, and Systems. 8th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2011.

FIGURE 4-3. Parasympathetic pathway mediating pupillary constriction to light. The axons of the retinal ganglion
cells project to the pretectal area. The neurons in the pretectal area send projections to the preganglionic
parasympathetic neurons of the ipsilateral and contralateral Edinger–Westphal nuclei (EWN). The axons of the
neurons in each EWN exit through the ipsilateral oculomotor nerve and project to the corresponding ciliary ganglion.
The postganglionic fibers of the ciliary ganglion innervate the ciliary muscle. CN, cranial nerve.

Eye movements are facilitated by the oculomotor (III), trochlear (IV), and abducens
(VI) CNs. CN III innervates the contralateral superior rectus and ipsilateral medial
rectus, inferior rectus, levator palpebrae, pupil constrictors, and inferior oblique
muscles. CN IV innervates the superior oblique muscle that intorts and depresses the
adducted eye. CN VI innervates the lateral rectus muscle, which abducts the eye. The
medial longitudinal fasciculus (MLF) connects the contralateral abducens nucleus and
paramedian pontine reticular formation (PPRF) with the ipsilateral third nerve nucleus;
it effectively yokes the eyes for coordinated horizontal movements. Vertical eye
movements are controlled by the rostral interstitial nucleus of the MLF (riMLF), which
resides in the midbrain near the CN III nucleus. Fibers controlling upgaze cross in the
posterior commissure to communicate with the contralateral inferior oblique and
superior rectus subnuclei of the CN III complex.

KEY POINTS
● Visual perception depends on the transmission of signals that travel through a multi-step pathway including
the retina, optic nerve, optic chiasm, optic tracts, lateral geniculate nucleus, and optic radiations on their way
to the visual cortex.
● The primary visual cortex receives information from the contralateral visual hemi-field.
● Parasympathetic fibers from the Edinger–Westphal nucleus play an important role in pupil constriction.
● Sympathetic fibers travel in a three-neuron path from the hypothalamus to the intermediolateral cell
column/ciliospinal center and then to the superior cervical ganglion before joining the first division of the
trigeminal nerve to innervate pupil dilators.
● Extra-ocular movements are governed by six muscles served by CNs III, IV, and IV.

HISTORY
As in all branches of medicine, the history is key in characterizing symptoms such as
eye pain, eyelid droop, and visual disturbance. It is important to ask about antecedent
trauma. If there is no identifiable trigger, inquiring about the timing of symptom onset
can be helpful. For example, the sudden onset of visual symptoms makes vascular
causes more likely. Diurnal variations in symptoms can also provide a clue: Patients
with myasthenia gravis often experience worsening double vision and eyelid droop at
the end of the day. Exploring associated symptoms is important: Does the patient have
concomitant limb weakness that could point to a stroke? Review of systems can uncover
diagnostic hints such as prior transient neurologic deficits, which could point to
vascular cause or multiple sclerosis. Similarly, medical and surgical history can be
informative (e.g., diabetes can predispose to sudden, painful dysfunction of CN III, or
less frequently, CN IV or VI). Prior cataract surgery can change pupillary reactivity and
be associated with an eyelid droop. A review of recently used medications is essential
because oral antiseizure drugs, topical agents such as apraclonidine (used for
glaucoma), transdermal scopolamine, inhaled ipratropium, and injected botulinum toxin
can cause symptoms and signs on exam. Habits such as alcohol ingestion are important
to ask about because intoxication and vitamin deficiencies may be relevant. Finally, a
family history of neurologic symptoms (e.g., gait imbalance or incoordination) raises the
possibility of genetic disorders (e.g., spinocerebellar ataxia) that can be accompanied
by visual deficits.

CHARACTERIZING COMMON CHIEF CONCERNS

DIPLOPIA
Neurologists and ophthalmologists commonly evaluate patients who report blurred or
frankly double vision. Double vision results from a misalignment of the eyes, either as a
decompensation of a previous strabismus or more commonly as a symptom of one of
many neurologic disorders. To help narrow the differential, a pertinent history is
important. Four questions are particularly worthwhile: (1) Does the double vision
improve with closure of one eye? The aim is to determine if the lesion is monocular
(involves one eye) or binocular (involves both eyes). Monocular visual loss implies a
problem in the eye, optic nerve, or chiasm. Binocular visual loss reflects a chiasmal or
retrochiasmal lesion. (2) Does the double vision emerge when looking in a particular
direction (e.g., up, down, left, or right)? Answers help determine which extra-ocular
muscles could be weak, as does the next query. (3) Do the two images appear side by
side, one directly above the other, or with a skew? Finally, (4) Does the double vision
worsen when looking at objects up close or far away? Whereas intact medial rectus
(CN III) function is needed for near gaze, CN VI is needed for far gaze.

POSITIVE AND NEGATIVE VISUAL PHENOMENA

Visual disturbances, as with other sensory symptoms, can be described as negative or
positive phenomena. Negative visual phenomena can be described as blackness,
grayness, dimness, or a shade that obscures vision (i.e., amaurosis fugax), as seen in
patients with strokes or transient ischemic attacks. When decreased vision is unilateral
and associated with eye pain that worsens with movement, optic neuritis is an important
consideration. Positive visual phenomena include brightness, shimmering, sparkling,
shining, flickering, or colors, often suggesting migraine or seizures. In the Charles
Bonnet syndrome, simple and complex, nonstereotyped hallucinations (including of
scenes and people) occur in the setting of acquired visual loss. A “release
phenomenon,” it is most common with chronic disease, impaired visual acuity, and
known binocular disease (e.g., glaucoma). Altered perception of the external
environment can also manifest as the illusion of movement (oscillopsia).

KEY POINTS
● Determine if an eyelid abnormality is congenital or acquired using the history and photographs.
● If there is diurnal variation, determine if the application of ice decreases the degree of ptosis, as can be seen
in myasthenia gravis.
● Assess for other historical and clinical signs to characterize the ptosis.

SPECIALIZED EXAMINATION TECHNIQUES:

LOOKING FOR SIGNS AND SYNDROMES
Building on the examination outlined in Chapter 1, more in-depth testing is required to
define neuro-ophthalmologic deficits. Of particular note are structures and function
related to the eyelid, pupil, optic disc, vision, and extra-ocular movements. At least
some elements of the neuro-ophthalmologic examination can be performed in all
patients, whether they are assessed in the intensive care unit or outpatient clinic.

EYELID
Eyelid abnormalities may be the first feature noted when evaluating patients. The
palpebral fissure (the distance between the upper and lower eyelid margins in line with
the pupil) measures 9 to 12 mm in healthy adults. The upper lid comes about 1 mm
down over the cornea and the lower lid up to the intersection of the cornea and sclera.
“Ptosis” generally refers to an abnormal droop of the upper eyelid, such that it covers at
least part of the pupil. Conversely, “upside-down ptosis” refers to elevation of the
lower lid. In addition to abnormal lid closure, one can detect lid retraction with ptosis.
As an initial step, it is important to distinguish whether an eyelid abnormality is
congenital or acquired. Looking at photographs or driver’s licenses can help establish
chronicity. Improvement in acquired forms of ptosis after the application of ice for 2
minutes suggests a neuromuscular junction disorder (myasthenia gravis), although ptosis
can also stem from a primary muscle disease (e.g., myotonic or oculopharyngeal
muscular dystrophy), CN dysfunction (CN III lesion), or a central process. Beyond the
neurologic system, structural changes can involve the eyelid; for example, eyelid
infections can alter lid appearance. Contact lens use and natural aging can lead to the
spontaneous dehiscence of the levator aponeurosis—mimicking ptosis. Lid retraction,
on the other hand, might reflect a CN VII lesion (as can be seen with a Bell’s palsy) or
hyperthyroidism. The latter possibility should prompt assessment of the globe for signs
of concomitant proptosis.

KEY POINTS
● Determining if double vision is worse with both eyes open (i.e., binocular), elicited by a particular direction or
distance of gaze, or associated with images in a particular orientation can help localize the lesion.
● Negative visual phenomena include loss of vision, often due to a vascular cause or inflammation.
● Positive visual phenomena include lights, colors, and hallucinations; potential causes include migraine, seizure,
and the Charles Bonnet syndrome.

PUPIL
Examination of the pupil requires attention to size and reactivity to light and near
objects.
Size: factors affecting resting pupil size include emotional state, age, and intraocular
pressure. When conducting an examination of asymptomatic individuals, one can
encounter a difference in right and left pupil size (anisocoria). Side-to-side asymmetries
can be benign, or “physiologic.” In general, physiologic asymmetries are within 0.4 mm.
Asymmetries can also become apparent when one pupil becomes abnormally small
(miosis) or large (mydriasis). Distinguishing which pupil is abnormal can be
determined preliminarily by assessing the degree of asymmetry in the light and dark. If
the anisocoria is most pronounced in the light, the abnormal pupil is the larger one; it is
pathologically dilated (mydriatic). Mydriasis can be a function of problems anywhere
along the path from the CN III nucleus in the midbrain, along the CN III, to the iris. With
midbrain lesions, the mydriasis is often associated with other signs including weakness,
nystagmus, and loss of consciousness. Drugs (e.g., topical apraclonidine) are also
commonly associated with asymmetric pupillary dilation—if administered unilaterally.
In this case, there is no associated pain, ptosis, or diplopia.
If the anisocoria is more apparent in the dark, the abnormal pupil is the smaller one; it
is pathologically constricted (miotic). It may demonstrate a lag of seconds before
starting to dilate in dark conditions. When this occurs, there is a sympathetic system
defect. Miosis should always prompt a full evaluation for Horner’s syndrome (HS),
which is characterized by unilateral miosis, ptosis, and (depending on the level of the
lesion) impaired ipsilateral facial flushing and sweating (anhidrosis). There are many
different causes of HS (Box 4-1). In each case, the syndrome can be confirmed by the
absence of dilation in response to cocaine eye drops. Hydroxyamphetamine eye drops
can then help to distinguish a preganglionic from a postganglionic third-order neuron HS
(the pupil with a postganglionic HS fails to dilate with hydroxyamphetamine).
Reactivity: To test pupil reactivity, a bright light is flashed alternately for 2 to 3
seconds in each eye. If one pupil appears to dilate when the light is directed toward that
eye, but it constricts appropriately when light is directed toward the other eye, there is a
relative afferent pupillary defect (RAPD). The affected pupil is also known as a
Marcus Gunn pupil. A normal pupil constricts reflexively not only to adjust to light but
also to view objects held at reading distance. A pattern of “light near dissociation”
(LND) occurs when an individual has impaired pupil constriction to light but intact
pupil constriction to objects placed close to the eye. This pattern of “accommodation
without reaction” is commonly affiliated with an Argyll Robertson pupil, which can be
a sequela of syphilis. LND can also be a sign of a tonic (Adie) pupil. A tonically
dilated pupil results from the interruption of the parasympathetic supply from the ciliary
ganglion and can be seen in the setting of problems with the retina, optic nerve, chiasm,
or optic tract. Enhanced contraction of the affected pupil to 0.1% pilocarpine supports
the diagnosis of a tonic pupil.

BOX 4-1. Etiology of Horner’s Syndrome

First-order (or central):
Hypothalamic infarcts, tumor
Mesencephalic stroke
Brainstem: ischemia (Wallenberg syndrome), tumor, hemorrhage
Spinal cord: syringomyelia, trauma
Second-order (or preganglionic):

Cervicothoracic cord/spinal root trauma

Cervical spondylosis
Pulmonary apical tumor: Pancoast tumor
Third-order (or postganglionic):
Superior cervical ganglion (tumor, iatrogenic)
Internal carotid artery: dissection, trauma, thrombosis, tumor
Base of skull: tumor, trauma
Middle ear problems
Cavernous sinus: tumor, inflammation (Tolosa–Hunt syndrome), aneurysm, thrombosis, fistula

KEY POINTS
● If anisocoria is more apparent in the dark, the abnormal pupil is the smaller (miotic) one. Consider a HS when
miosis is accompanied by a mild ptosis and, possibly, facial anhidrosis.
 ● If the anisocoria is more apparent in the light, the abnormal pupil is the larger (mydriatic) one; consider a
CN III lesion.
● An RAPD is dilation of a pupil on direct stimulation of light, with preserved consensual constriction with light
stimulation of the contralateral pupil; the finding raises the possibility of an optic nerve lesion.
● LND occurs when an individual has impaired pupil constriction to direct stimulation by light but intact
constriction to objects placed close to the eye, as can be seen in Adie or Argyll Robertson pupillary defects.

OPTIC DISC
Examination with an ophthalmoscope is essential to assess for disc abnormalities
including pallor, loss of nearby venous pulsations, and blurring of disc margins, as can
be seen with swelling of the optic disc. The term papilledema implies optic disc
swelling from blockage of axoplasmic transport in the optic nerve resulting from
increased intracranial pressure (ICP); it is often painless and bilateral. Papilledema is
unilateral in the Foster–Kennedy syndrome, which refers to ipsilateral optic disc
atrophy (due to compression of the optic nerve by a mass lesion in the frontal lobe) and
papilledema in the contralateral optic disc (due to increased ICP). The termpapillitis
refers to swelling of the optic disc from other local or systemic causes such as viruses
and rheumatologic disorders. It can be associated with painful eye movements and is
generally unilateral. Another cause of unilateral optic disc swelling is anterior ischemic
optic neuropathy (AION), which is painless and further classified as nonarteritic or
arteritic. The nonarteritic form is associated with atherosclerotic risk factors. The
arteritic form is often seen in the setting of giant cell arteritis (GCA).

KEY POINTS
● Papilledema is optic disc swelling from increased ICP; it is often bilateral.
● Papillitis refers to swelling of the optic disc from other local or systemic causes; it is often unilateral.
● Foster–Kennedy syndrome refers to ipsilateral optic disc atrophy and contralateral papilledema, due to a
frontal lobe mass.
● AION is a painless, unilateral condition associated with atherosclerotic risk factors (nonarteritic) or GCA
(arteritic).

VISION
In the very ill patient, it may only be possible to evaluate vision by learning if there is a
preserved ability to “blink to threat.” This phenomenon describes when a patient closes
an eye when an object, such as the examiner’s finger, is presented quickly to a given
visual field. Each eye should be tested for a response.
In a fully conscious patient, visual acuity (VA) can be checked one eye at a time using
a distance chart (e.g., a handheld Snellen chart) with good illumination. If VA is poor,
have the patient read through a pinhole. If the use of the pinhole improves VA, a
problem with refraction has been identified. If the patient is unable to read letters, try
counting fingers, followed by perception of movement, and finally perception of a bright
light. Impairment of VA usually represents a defect in the refractive apparatus of the
eye, in the optic nerve, or both. Rarely, chiasmal or retrochiasmal lesions cause
diminished VA. Color vision can also be tested by using Ishihara plates. Another
method is looking for red desaturation (decreased perception of red color or its
intensity), which often suggests an optic neuropathy or neuritis. Visual field testing at the
bedside is done by confrontation, evaluating each eye individually. While the patient
looks at a fixed target near your own center of visual field (such as your nose), move
your fingers or a small object in the different quadrants and compare the patient’s visual
field to yours.
Vision loss with eye pain that worsens with movement raises concern for optic
neuritis. A loss of color vision out of proportion to the VA loss supports this diagnosis.
Particularly in young patients, these findings suggest demyelinating disorders such as
multiple sclerosis and neuromyelitis optica. In patients older than 50 years, ischemic
optic neuropathies (e.g., as with GCA) are more likely. In immunocompromised
patients, unilateral eye pain and visual loss in the context of sensory change on the
ipsilateral forehead, headache, malaise, and fever should raise the possibility of zoster
ophthalmicus—even before the appearance of characteristic lesions; suspicion for this
diagnosis should be even higher if vesicular lesions are noted on the nose (Hutchinson’s
sign) because the globe is also innervated by the nasociliary branch of the trigeminal
nerve. Box 4-2 shows some causes of visual loss categorized by lesion location.

KEY POINTS
● Test VA and fields one eye at a time.
● Ocular and refractory, rather than neurologic, problems are suggested by improvement in VA when using a
pinhole.
● The combination of vision loss, abnormal color vision, and pain with eye movements in a young patient raises
concern for a demyelinating disorder such as multiple sclerosis or neuromyelitis optica.

EYE ALIGNMENT AND MOVEMENTS: CRANIAL NERVES III,

IV, AND VI
Abnormal eye position and movements can result from lesions in individual extra-
ocular muscles, abnormalities of the neuromuscular junction, or dysfunction of the
oculomotor nerves, their central nuclei, or central connections. The most common cause
of oculomotor nerve dysfunction in older adults is brainstem microvascular ischemia,
commonly associated with hypertension, diabetes mellitus, and atherosclerosis.
Resultant lesions can occur in isolation or in the setting of more serious systemic
illness.

BOX 4-2. Causes of Visual Loss

Retina
Detachment
Infectious: CMV, toxoplasmosis
Toxic: ethambutol
Degenerative: macular degeneration, retinitis pigmentosa
Ischemic: embolic
Optic disc
AION: nonarteritic and arteritic
Optic neuritis
Glaucoma
Papilledema (late)
Sarcoidosis
Tumor
Optic nerve
Demyelination, including multiple sclerosis and neuromyelitis optica
Tumor, including meningioma, glioma, etc.
Thyroid ophthalmopathy
Trauma
Optic chiasm
Tumor: pituitary tumors such as adenoma, craniopharyngioma, and glioma
Sphenoid mucocele
Internal carotid artery aneurysm
Trauma
Demyelination
Vascular
Toxic
Retrochiasmal
Tumor: glioma, meningioma, metastasis
Stroke involving the visual pathway
Demyelination
Degenerative diseases

AION, anterior ischemic optic neuropathy; CMV, cytomegalovirus.

In very sick patients, the examination often consists of observation without the
patient’s active involvement. In this scenario, the examiner can comment on lid position
and pupillary responses and on the direction of gaze at rest and alignment of the eyes in
the primary position. Some helpful terms used to describe eye misalignment are detailed
i n Table 4-1. A patient with a decreased level of consciousness may not be able to
follow directions (e.g., to track the examiner’s finger in the shape of an “H”). It is still
possible, however, to gain insight into how the eyes move through the oculocephalic
maneuver (doll’s eye test). This is performed by making rapid horizontal and vertical
movements of the head. A normal response is for the eyes to remain “looking” forward
(i.e., by rotating in a direction opposite to that of the head movement). The vestibulo-
ocular reflex (VOR) coordinates eye movements with head movement, preventing the
visual image from slipping during movements of the head. Slow, passive head
movements can elicit it. Information from the semicircular canals (rotation) and otoliths
(linear acceleration) travels to the vestibular nuclei. From there, it proceeds to the
abducens (CN VI) nuclei and then through the MLF to CNs III and IV. Abnormalities of
the VOR can result in nystagmus (which is discussed later in this chapter).
In the interactive patient, extra-ocular movements are tested by having him or her
follow a target moving in the shape of an H (as outlined in Chapter 1). If double vision
is a concern, it is important to note if and when the diplopia emerges in the course of
this maneuver. Extra-ocular testing can demonstrate a myriad of lesions that occur in
isolation or in combinations.

CN III Deficit
An oculomotor nerve lesion can cause ophthalmoparesis, pupil dilation, ptosis, or a
combination of these findings. Because parasympathetic fibers run in the outer part of
CN III and the motor fibers are more internal, compression of the nerve initially
produces a dilated pupil without compromising eye movements. Particularly when there
is pain, this finding should raise concern for a posterior communicating artery aneurysm.
On the other hand, vascular problems producing CN III ischemia (e.g., diabetes)
produce a pupil-sparing third nerve lesion in which the pupil is normal and reactive but
there is a deficit of the ocular movements innervated by CN III; pain is common, except
in midbrain lesions. A lesion in the nucleus of the CN III causes bilateral ptosis and
weakness of the contralateral superior rectus, with failure of upward gaze.

TABLE 4-1. Some Terms Used to Define Eye Misalignment

Strabismus Misalignment of the Eyes
Comitant strabismus Misalignment constant in all directions of gaze; each eye has full range of
movement (usually an ophthalmologic problem)
Incomitant strabismus Degree of misalignment varies with the direction of gaze (usually a neurologic
problem)
Phoria Misalignment of the eyes when binocular vision is absent (cover–uncover one
(esophoria, exophoria) eye)
Tropia Misalignment of the eyes when both eyes are opened and binocular vision is
(esotropia, exotropia) possible

CN IV Deficit
A trochlear nerve lesion leads to a lack of intorsion on downgaze, producing an oblique
diplopia, worse on downgaze when the affected eye is adducted. Patients may report
diplopia when reading or going down stairs. They may discover that tilting the head
away from the side of the lesion decreases the double vision. Trauma is a relatively
common cause.

CN VI Deficit
An abducens lesion is associated with inward deviation of the affected eye at rest. This
is because there is a deficit in lateral gaze on the affected side even in primary position.
Raised ICP, for instance, in the setting of pseudotumor cerebri, can be the culprit.
CNs III, IV, and VI travel together through the cavernous sinus along with the first and
second divisions of CN V. Accordingly, conditions such as a carotid-cavernous fistula
are important considerations when pain and altered sensation of the upper face occur
along with impaired eye movements. Chemosis, proptosis, and ecchymosis can be
accompanying features.
As discussed, some extra-ocular movement and alignment abnormalities stem from
primary central nervous system processes. For instance, lesions of the MLF produce an
internuclear ophthalmoplegia (INO) (Fig. 4-4). Adduction during convergence is
preserved because convergence does not depend on the MLF. Bilateral INOs can be
seen in brainstem strokes and demyelination. In the “one-and-a-half syndrome” (caused
by a lesion in the PPRF or CN VI nerve nucleus, also involving the adjacent ipsilateral
MLF; Fig. 4-4), the only possible eye movement in the lateral plane is abduction of the
contralateral eye. Convergence is spared, as well. These syndromes are relatively
common in multiple sclerosis and can also occur because of stroke, in which case there
is often accompanying dysarthria, facial weakness, and ataxia.
FIGURE 4-4. Sympathetic pathway mediating pupillary dilation (oculosympathetic pathway). Hypothalamic fibers
(right side of the diagram) project to the ipsilateral ciliospinal center of the intermediolateral cell column from C8 to T1
spinal levels, which projects “preganglionic” sympathetic fibers to the superior cervical ganglion (left side of diagram),
which in turn projects perivascular “postganglionic” sympathetic fibers via the tympanic cavity, cavernous sinus, and
superior orbital fissure to the dilator pupillae. Interruption of this pathway at any level results in a Horner’s syndrome.
Modified from Fix JD. High-Yield Neuroanatomy. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:67.

A brainstem or cerebellar lesion can also result in a skew deviation. This term
describes when one eye appears higher than the other (i.e., a vertical tropia). The
hypotropic (lower) eye is often on the side of the lesion. Parinaud syndrome is
characterized by an upgaze disturbance, convergence-retraction nystagmus on attempted
upgaze, and LND. It can be produced by dorsal midbrain compression (e.g., by
hydrocephalus or a pineal tumor). Abnormal vertical gaze movements can also be found
in other dorsal midbrain syndromes.
Other eye movements include saccades and nystagmus. Both findings can be normal
or abnormal. Accordingly, clinical context is important for interpretation. Saccades are
normal rapid eye movements that redirect the eyes to a new fixation object. To test
saccades, an examiner asks the patient to fix the eyes on one target and then to another
located along the horizontal or vertical plane. Abnormal voluntary saccades involve
either multiple jumps to reach the visual target (undershoot, hypometric) or jumps
beyond the target (overshoot, hypermetric). One can also look for involuntary saccadic
intrusions (quick jumps rather than a continuous movement) during tests of smooth
pursuit. Inability to produce saccades is called oculomotor apraxia. Abnormal
saccades have limited localizing value and can be seen in conditions including
Parkinson disease. In general, they are associated with supranuclear abnormalities.

TABLE 4-2. Nystagmus: Categories, Characteristics, and Causes

Physiologic (Nonpathologic) Characteristics
Nystagmus
Optokinetic Normal response to a continuously moving object
Vestibulo-ocular Elicited by rotations of the patient’s head
Endpoint Few beats elicited by eccentric gaze
Congenital Jerk or pendular; present after birth; remains throughout life
Pathologic or Acquired Characteristics Possible Causes
Nystagmus
Periodic alternating Horizontal jerk nystagmus that Craniocervical junction disorders,
changes direction every 2 to 3 min multiple sclerosis, bilateral blindness,
toxicity from anticonvulsants
Downbeat Present in primary position Craniocervical junction disorders
(Chiari malformation), spinocerebellar
degeneration, multiple sclerosis,
familial periodic ataxia, drug
intoxication
Upbeating Present in primary position Anterior cerebellar vermis and lower
brainstem lesions, drug intoxication,
Wernicke encephalopathy
See–saw One eye elevates and intorts, Trauma, brainstem vascular disease,
whereas the other depresses and multiple sclerosis, third ventricle
extorts tumors (in which case the nystagmus
is associated with bitemporal
hemianopia reflecting chiasmal
involvement)
Gaze-evoked Similar to endpoint nystagmus, but Drug intoxication, cerebellar disease,
amplitude is greater and it occurs in a brainstem or hemisphere lesions
less eccentric position of the eyes
Rebound Transient, rapid, horizontal jerk when Cerebellar or posterior fossa lesions
the eyes are moving to or from an
eccentric position
Vestibular Usually horizontal, with a rotatory Peripheral inner ear disorders,
component Ménière disease, vascular disorder,
drug toxicity

TABLE 4-3. Tips for Differentiating Central from Peripheral Nystagmus

Peripheral (Vestibular) Central (Brainstem)
Direction Unidirectional; fast phase away from Bidirectional or unidirectional
the lesion
Purely horizontal without rotatory Uncommon Common
component
Vertical nystagmus Never present May be present
 Visual fixation Inhibits nystagmus and vertigo Has no effect
Tinnitus or deafness Often present Rarely present
Vertigo Severe Mild
Duration Short, but recurrent May be chronic
Causes Vascular disorders, trauma, toxicity, Vascular, demyelination, and
Ménière disease, vestibular neuronitis neoplastic/paraneoplastic disorders

Nystagmus is a rhythmic to-and-fro movement of the eyes. It can be congenital,

physiologic, or a sign of visual or neurologic dysfunction. It can be slow and
continuous, with movements of equal speed in any direction (pendular), or consists of a
slow drift and quick corrective jerk in the opposite direction (jerk). Jerk nystagmus is
common and is described by the direction and trajectory of the quick movement. Table
4-2 gives a brief description of different forms of nystagmus and possible causes. Table
4-3 describes a few characteristics to help differentiate central from peripheral sources
of nystagmus.

KEY POINTS
● Deficits in extra-ocular movements can help identify lesions of CNs III, IV, and VI.
● A left INO (affecting the left MLF) includes the inability to adduct the left eye in right lateral gaze, plus
nystagmus of the abducting right eye.
● With a one-and-a-half syndrome, the only eye movement in the lateral plane is abduction of the eye
contralateral to the affected PPRF, CN VI nucleus, and MLF.
● Parinaud syndrome includes limited upgaze and can be seen with hydrocephalus and pineal tumors.
● Saccades are rapid eye movements that redirect the eyes to a new fixation object.
● Jerk nystagmus is described according to the direction of the quick, corrective “jerk.”
 5 The Approach to Weakness

Weakness is one of the most common presenting neurologic complaints. Many patients
may tolerate some degree of numbness, tingling, or even pain, but often it is when
weakness sets in that medical attention is finally sought. Similarly, friends or family
members will not notice a patient’s sensory problems, but significant weakness will be
obvious to all.
At the same time, weakness can be one of the most difficult neurologic problems to
sort out, because the pathways that control motor function span the entire axis of the
nervous system. Left leg weakness can arise from a peripheral nerve lesion, a
lumbosacral plexus problem, or a stroke in the right cerebral hemisphere. Each of these
has a different workup, prognosis, and treatment, and it is the job of the physician to use
the history and examination to distinguish among them.

PRINCIPLES
Figure 5-1 presents a flowchart to aid in the diagnosis of weakness. The key steps in the
clinical approach are outlined below.
1. Make sure that true weakness is the complaint. Sometimes patients will use the
term weak to mean a general sense of fatigue; others will say a limb is “weak” when
it is clumsy or numb. Having the patient confirm that decreased strength is the
symptom may be useful. Likewise, a limb that is painful to move may seem “weak”
because of effort; whether there is true underlying weakness may be difficult to
discern. Weakness should be characterized as objectively as possible, representing
the patient’s understanding of the reported symptom in conjunction with the findings
on a detailed physical exam. It is therefore important that patients undergo a
systematic motor exam that quantifies the severity of the weakness and discerns
whenever possible if the weakness is effort dependent or pain limited.
The history of the onset and pattern of progression of the symptoms is also very
important. If the weakness was preceded by a seizure, it may be due to a Todd
paralysis (a transient unilateral weakness that resolves typically within several hours
after a seizure). If the weakness occurred abruptly and is unilateral, this may be more
suggestive of a vascular cause, whereas if the weakness occurred insidiously and is
 progressive, other etiologies should be considered.
2. Identify which muscles are weak. This seems like an obvious point but must be
emphasized. It is not sufficient to know that a patient has left leg weakness. Testing
must be done in enough detail to know which muscles in the left leg are weak or, if
they are all weak, which are weaker than others.
3. Determine the pattern of weakness. This is frequently the crux of the entire
diagnosis. It is the pattern of weakness that will indicate the underlying lesion—
whether left leg weakness is due to a peroneal nerve problem or a right hemispheric
stroke. One must be familiar with the different patterns of weakness and their
implications.
4. Look for associated signs and symptoms. If a leg is weak, determine whether it is
also numb, tingling, or painful. Check the reflexes carefully. Examine the muscles
themselves looking for atrophy and fasciculations. Tone is also important in helping
assess if the problem is peripheral or central. Often the motor deficit overshadows
other problems, whose presence may be helpful in supporting or excluding certain
diagnoses. Patients may also have an acute cause of weakness superimposed upon a
more chronic underlying condition.
FIGURE 5-1. The approach to weakness. EMG/NCS, electromyography/nerve conduction studies; NMJ,
neuromuscular junction.

5. Use laboratory and electrophysiologic tests wisely. Blood tests or neuroimaging

studies can be useful in the appropriate settings, and electromyography/nerve
conduction studies (EMG/NCS) can act as an extension of the clinical exam in
localizing the problem to a particular segment of the peripheral nervous system.
Lumbar puncture (LP) may also be necessary in patients with suspected Guillain–
Barré syndrome. Tests are most useful, however, in the setting of a complete clinical
evaluation and formed diagnostic hypothesis.
 KEY POINTS
● Weakness can be caused by lesions along the entire neuraxis, from brain to muscle.
● The diagnosis rests on determining what the pattern of weakness is, searching for associated signs and
symptoms, and using laboratory tests and EMG/NCS to confirm clinical hypotheses.

DIFFERENTIAL DIAGNOSIS
It is useful to consider the disorders that cause weakness in an anatomic order, from
most distal in the nervous system (primary muscle disorders) to most proximal
(disorders of the cerebral hemispheres). Below, each anatomic category is presented
with the clues that might lead a clinician to suspect a disorder in that location.
Individual diseases in each category are discussed in the later chapters covering
specific neurologic disorders.

PRIMARY MUSCLE DISORDERS

Pattern of Weakness
Primary muscle problems tend to cause weakness predominantly in proximal muscles,
in a symmetric fashion. Distal muscles are affected later or not as severely. In addition,
neck flexors and extensors, which are not affected in most nerve or brain lesions, may
be weak in a muscle disorder.

Associated Signs and Symptoms

Associated signs and symptoms may occasionally include muscle pain if the muscle
disorder is inflammatory, such as polymyositis. By their nature, primary disorders of
muscle should not cause sensory signs or other symptoms. Reflexes are
characteristically preserved unless the process is so severe that the muscles are nearly
paralyzed.

Laboratory Studies
Some disorders of muscle are characterized by an elevated serum creatine kinase (CK)
level. The demonstration of characteristic “myopathic” changes on an EMG can help
confirm a primary muscle disorder.

Differential Diagnosis
Primary muscle disorders, discussed in Chapter 24, include both acquired problems
(myopathies), which can result from inflammatory or toxic etiologies among other
causes, and congenital problems (muscular dystrophies).

KEY POINTS
● Primary muscle disorders typically cause symmetric proximal weakness and can affect neck muscles.
● Sensory signs and symptoms are typically not present in primary muscle disorders.
● Serum CK level is elevated in some muscle disorders, and EMG may show a characteristic “myopathic”
pattern.

NEUROMUSCULAR JUNCTION DISORDERS

Pattern of Weakness
Neuromuscular junction (NMJ) problems can vary in the pattern of weakness they
cause, though most affect proximal limb muscles. Some NMJ disorders can lead to
ptosis as well as weakness of extraocular, bulbar, and neck muscles. The characteristic
feature of NMJ disorders is not the location of weakness, however, but the fluctuation.
The degree of weakness may change from hour to hour. Depending on the specific
disease, strength may be worse after using the muscles or toward the end of the day; it
may improve after resting or in the morning (fatigability). Alternatively, strength may
improve paradoxically after exercise in other conditions.

Associated Signs and Symptoms

By their nature, NMJ problems, which affect only the junction between the motor axon
terminal and the muscle, should not lead to sensory signs or symptoms. Some NMJ
disorders may have associated autonomic features and can also be associated with
malignancies. A detailed review of systems can help identify these features.

Laboratory Studies
EMG/NCS can demonstrate nearly pathognomonic findings for certain NMJ disorders
on specialized testing. Some of the diseases in this category have specific serum
markers, such as anti-acetylcholine receptor antibodies and muscle specific kinase in
myasthenia gravis. These are discussed in further detail in Chapter 24.

Differential Diagnosis
NMJ disorders are discussed in Chapter 24; they include myasthenia gravis and
Lambert–Eaton myasthenic syndrome, among others.
 KEY POINTS
● NMJ disorders can cause weakness of proximal muscles; some characteristically affect extraocular and
bulbar muscles.
● The key to diagnosing NMJ disorders is fluctuation in the degree of weakness.
● Sensory signs and symptoms are not generally present in NMJ disorders.
● EMG/NCS can be nearly pathognomonic in some cases of NMJ disorders.

PERIPHERAL NERVE DISORDERS

Pattern of Weakness
Each muscle in the upper or lower limbs is innervated by an individual peripheral nerve
(Table 5-1). A lesion involving a particular peripheral nerve will lead to weakness in
the muscles innervated by that nerve while sparing other, often neighboring muscles.
Disorders affecting a single peripheral nerve are known as mononeuropathies.
Certain systemic conditions can lead to dysfunction of multiple peripheral nerves in
succession, a disorder known as mononeuropathy multiplex. Finally, when peripheral
nerves are all affected diffusely, in a polyneuropathy, dysfunction typically occurs in
the longest nerves first. Thus, weakness from a polyneuropathy usually appears first in
the distal muscles, symmetrically.

Associated Signs and Symptoms

Mononeuropathies may cause sensory symptoms—such as numbness, tingling, or pain—
in the distribution of the relevant peripheral nerve. Mononeuropathy multiplex is
characteristically associated with pain. Polyneuropathies, depending on etiology,
usually have associated sensory loss and depressed or absent reflexes, particularly in
the distal extremities.

Laboratory Studies
EMG/NCS can confirm the clinical suspicion of a problem localized to the peripheral
nerves. NCS can identify whether the pathologic process affects primarily the axons or
the myelin of the nerve, an essential step in formulating a differential diagnosis. EMG
may yield insight into the relative acuity or chronicity of a nerve disorder.

Differential Diagnosis
Mononeuropathies most commonly occur as a result of entrapment (as in carpal tunnel
syndrome). Mononeuropathy multiplex is associated with systemic vasculitis and other
metabolic or rheumatologic diseases. Demyelinating polyneuropathies can be hereditary
(such as Charcot–Marie–Tooth disease) or acquired (as in Guillain–Barré syndrome),
whereas axonal polyneuropathies have many potential underlying causes from systemic
conditions or ingestions (e.g., alcohol or toxins). Peripheral nerve disorders are
discussed in Chapter 23.

TABLE 5-1. Commonly Tested Movements

Movement Muscle Nerve Root
Shoulder abduction Deltoid Axillary C5
Elbow flexion Biceps Musculocutaneous C5/C6
Elbow extension Triceps Radial C7
Wrist extension Wrist extensors Radial C7
Finger flexion Finger flexors Median, ulnar C8/T1
Finger extension Finger extensors Radial C7
Finger abduction Interossei Ulnar C8/T1
Hip flexion Iliopsoas Nerve to iliopsoas L1/L2/L3
Hip abduction Gluteus medius, minimus Superior gluteal L5
Hip adduction Hip adductors Obturator L3
Hip extension Gluteus maximus Sciatic S1
Knee flexion Hamstrings Sciatic L5/S1
Knee extension Quadriceps Femoral L3/L4
Plantar flexion Gastrocnemius, soleus Tibial S1
Dorsiflexion Tibialis anterior Peroneal L5
Foot eversion Peroneus muscles Peroneal S1
Foot inversion Tibialis posterior Tibial L5
Great toe extension Extensor hallucis longus Peroneal L5

KEY POINTS
● Mononeuropathies lead to weakness in muscles innervated by a single peripheral nerve.
● Polyneuropathies first affect the muscles of the distal extremities symmetrically.
● EMG/NCS can confirm peripheral nerve involvement, identify axonal or demyelinating features, and evaluate
the relative chronicity of a nerve disorder.

NERVE ROOT DISORDERS

Pattern of Weakness
Each nerve root relevant to the upper or lower limbs exits the spinal cord and
eventually traverses a plexus (either brachial or lumbosacral) in which its fibers
separate and become part of multiple different peripheral nerves, which then go on to
innervate multiple different muscles. The result is that most muscles are innervated by
fibers that originate from more than one nerve root, although some muscles are
predominantly innervated by fibers from one nerve root (Table 5-1). In any case, a
lesion of a single nerve root will cause weakness in the muscles innervated
predominantly by fibers from that root, while leaving other, often neighboring muscles
unaffected.
A problem involving a single nerve root is termed a radiculopathy. Some processes
lead to dysfunction of multiple nerve roots at once (polyradiculopathy), leaving a
pattern of weakness that may be more diffuse and difficult to sort out because multiple
muscles related to multiple nerve roots can be weak bilaterally.

Associated Signs and Symptoms

Radiculopathies often have associated tingling or pain, frequently radiating out from the
neck or back. Objective sensory loss is rare in disorders affecting a single nerve root
because there is overlap from neighboring roots. If the nerve root is one that subserves a
particular muscle stretch reflex (Table 5-2), that reflex may be depressed or absent.
Cervical radiculopathies (causing symptoms in the arms) and lumbar radiculopathies
(causing symptoms in the legs) are the most common radiculopathies. Symptoms from
thoracic nerve roots are uncommon.

Laboratory Studies
EMG/NCS can confirm that nerve roots are the culprit in a weak patient and can be
particularly useful for cases where clinical differentiation between a root problem and a
peripheral nerve problem is murky. Single radiculopathies may require magnetic
resonance imaging (MRI) of the spine to rule out structural causes, whereas
polyradiculopathies may require LP to look for infectious or inflammatory conditions.

TABLE 5-2. Commonly Tested Muscle Stretch Reflexes

Reflex Root
Biceps C5
Brachioradialis C6
Triceps C7
Finger flexor C8/T1
Patellar (knee jerk) L4
Hip adductor L3
Ankle jerk S1

Differential Diagnosis
Single radiculopathies can be caused by herniated disks or by reactivation of varicella
zoster virus (shingles), for example. Polyradiculopathies are often inflammatory or
infectious. These disorders are discussed in Chapter 23.

KEY POINTS
● A radiculopathy causes weakness in the muscles innervated predominantly by fibers from one nerve root.
● Radiating pain and tingling are common symptoms.
● If the nerve root subserves a particular muscle stretch reflex, that reflex may be depressed or absent.
● A polyradiculopathy may lead to weakness of multiple muscles related to multiple nerve roots bilaterally.

PLEXUS DISORDERS

Pattern of Weakness
The intricacies of brachial and lumbosacral plexus anatomy (Fig. 5-2) are often quite
intimidating for students, but they need not be, because—ironically—it is their complex
anatomy that makes localizing lesions to a plexus more straightforward than expected.
Put simply, if multiple muscles in a limb are weak and do not conform to the pattern of a
particular nerve root or peripheral nerve, a plexus problem should be suspected. In the
leg, for example, weakness in both hip flexors and hip adductors would have to involve
the L1, L2, and L3 roots or both the nerve to the iliopsoas and the obturator nerve
(Table 5-1); a much more likely explanation is a lesion in the upper part of the
lumbosacral plexus.
FIGURE 5-2. Brachial plexus anatomy. (Reprinted with permission from Moore KL, Dalley AF. Clinically
Oriented Anatomy. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006:776. Figure 6.5.)

Associated Signs and Symptoms

Because the plexus is where multiple nerve roots intermingle their fibers to form
multiple peripheral nerves, it is unsurprising that plexus disorders can have associated
sensory findings (in the distribution of one or more roots or nerves) or dropped reflexes
(subserved by one or more roots).

Laboratory Studies
EMG/NCS is frequently ordered in cases of clinically suspected plexopathies to help
confirm the localization to the plexus, given the less-than-straightforward anatomy. MRI
of the brachial plexus or pelvis (or lumbosacral plexus) may be necessary to rule out
mass lesions.

Differential Diagnosis
Plexopathies can be caused by idiopathic inflammation, radiation, infiltration by
metastases, hemorrhage, or trauma, and are discussed in Chapter 23. Diabetic patients
are prone to develop a characteristic lumbosacral plexopathy known as diabetic
amyotrophy.

KEY POINTS
● A plexus problem should be suspected when multiple muscles in a limb are weak and do not conform to a
particular nerve root or peripheral nerve pattern.
● There may be associated sensory signs or reflex loss in plexus disorders.
● Plexopathies can be confirmed by EMG/NCS and have many potential causes.

SPINAL CORD DISORDERS

Pattern of Weakness
Spinal cord disorders cause weakness in two ways. First, the anterior horn cells located
at the level of the lesion are affected, leading to weakness of the muscles innervated by
the nerve root at that level. This mimics a radiculopathy, with weakness in a particular
nerve root pattern. Second, there is weakness below the level of the lesion because of
the interruption of the descending corticospinal tracts. This weakness occurs in an upper
motor neuron (UMN) pattern (Fig. 5-3).
FIGURE 5-3. Upper motor neuron (UMN) versus lower motor neuron (LMN).

Associated Signs and Symptoms

Depending on the extent of the lesion, there may be sensory findings because of the
interruption of the ascending tracts. There may be a sensory level (loss of sensation
below a particular dermatomal level) on the torso. Bladder and bowel incontinence may
occur.
The findings in patients with a spinal cord lesion may also vary depending on the
mechanism and acuity of the lesion. Patients with acute spinal cord injuries may also
have spinal shock which is manifested by loss of reflexes, flaccid paralysis, and loss of
sensory functions below the level of the injury. They may also have neurogenic shock
because of the impaired autonomic function resulting in hypotension, bradycardia, and
hypothermia.
In the later phases of a spinal cord injury, the neurologic findings change
significantly. Muscle stretch (“deep tendon”) reflexes below the level of a spinal cord
lesion are increased, and there may be Babinski signs. Spasticity ensues, and patients
with lesions above T6 may develop autonomic dysreflexia after the first month from the
onset of the injury. This condition is characterized by paroxysmal profound
hypertension, bradycardia, flushing, and headache. It can be triggered by almost any
physical or metabolic stimuli and results in significant morbidity and cardiovascular
mortality for patients with spinal cord injuries.

Laboratory Studies
MRI of the spine can rule out structural etiologies or demonstrate intrinsic inflammation
within the cord. LP may be needed to evaluate infectious, inflammatory, or neoplastic
causes of cord dysfunction.

Differential Diagnosis
Spinal cord disorders are discussed in Chapter 22; they may stem from inflammation
(transverse myelitis), infarction, compression, or other causes. Amyotrophic lateral
sclerosis causes degeneration of both the corticospinal tracts and anterior horn cells.

KEY POINTS
● Spinal cord disorders lead to weakness in a UMN pattern below the lesion and weakness in a nerve root
pattern at the level of the lesion.
● The pattern of weakness and associated findings such as tone and reflexes may vary depending on the acuity
and mechanism of the spinal cord lesion.
● There may be sensory loss below the level of the lesion because of the interruption of ascending tracts.
● Reflexes below the level of the lesion are typically increased, and Babinski signs may be present.
● Autonomic dysreflexia may develop in patients with lesions above T6 about a month after the initial spinal
cord trauma.
● Bladder and bowel incontinence may occur.

DISORDERS OF THE CEREBRAL HEMISPHERES AND

BRAINSTEM

Pattern of Weakness
Lesions in the cerebral hemispheres lead to weakness of the contralateral body in a
UMN pattern (Fig. 5-3). Knowledge of the homunculus of the motor strip (Fig. 5-4)
explains why lesions in the parasagittal part of the cerebral hemisphere cause weakness
primarily in the leg, whereas lesions more laterally in the hemisphere cause weakness
primarily in the face and arm. Deep hemispheric lesions, as in the internal capsule, may
lead to weakness of all three parts of the contralateral body (face, arm, and leg),
because motor fibers from all areas of the motor strip join together as they travel toward
the brainstem.
Lesions in the base of the pons may lead to weakness of the ipsilateral face and
contralateral arm and leg (crossed signs), because descending motor fibers to the face
have crossed at that level but those to the body have not.

FIGURE 5-4. The homunculus of the motor strip.

Associated Signs and Symptoms

Lesions of the cerebral hemispheres frequently have associated cognitive signs, such as
those described in Chapter 11. Left hemisphere lesions may cause aphasia or apraxia,
whereas right hemisphere lesions may cause neglect or visuospatial dysfunction.
Lesions of the brainstem may cause cranial nerve problems, such as extraocular
movement disorders.

Imaging Studies
Imaging of the brain is important to evaluate almost all of the potential etiologies in this
category. The choice of MRI or computed tomography depends on the suspected
etiology and relative acuity.

Differential Diagnosis
The differential diagnosis includes such diverse etiologies as stroke (Chapter 14),
demyelinating disease (Chapter 20), traumatic injury (Chapter 17), brain tumor (Chapter
19), and infection (Chapter 21).

KEY POINTS
● Cerebral hemisphere lesions lead to weakness of the contralateral side in a UMN pattern.
● Parasagittal lesions lead primarily to leg weakness, more lateral lesions lead primarily to face and arm
weakness, and deep lesions may lead to weakness of all three parts.
● Cerebral hemisphere lesions may have accompanying cognitive signs, such as aphasia or neglect.
● Brainstem lesions may have accompanying cranial nerve findings.
 6 The Sensory System

The sensory system is that part of the nervous system responsible for processing sensory
information, including the somatosensory and special senses: smell, vision, taste,
hearing, and vestibular sensation. Abnormalities of sensation can be characterized by an
increase, decrease, impairment, or loss of feeling. The diagnosis of sensory problems
requires an understanding of the anatomy and an analysis of the presentation, location,
characteristics, and distribution of symptoms.

ANATOMY OF THE SENSORY PATHWAYS

The first step in any sensory pathway is activation of a sensory receptor by a specific
stimulus. Information from the receptor is then carried to the central nervous system
(CNS) by the afferent nerves (peripheral or cranial) known as first-order neurons. Pain
and temperature sensation is carried by thinly myelinated (A-δ) and unmyelinated
slowly conducting (C) fibers that synapse as they enter the dorsal horn of the spinal
cord. From there, axons from the second-order neurons cross and travel contralaterally
in the spinothalamic tract (STT), also called the anterolateral system (Fig. 6-1).
Proprioception, vibration, and light touch run ipsilaterally in heavily myelinated (A-α
and A-β) fibers in the dorsal column system, reaching the second-order neuron at the
level of the medulla in the nuclei gracilis and cuneatus. Axons from these nuclei cross in
the lower medulla to form the medial lemniscus (Fig. 6-2).
There is a somatotopic arrangement of fibers in these tracts.
• STT: At the level of the spinal cord, sacral segments are located laterally and cervical
segments medially.
• The dorsal columns: The most medial fibers convey input from sacral areas, whereas
lateral fibers convey information from the arms. At the level of the medial lemniscus,
the upper body fibers become medial and those of the lower body lateral.
Facial sensation is carried to the brainstem by the trigeminal nerve. The STT and the
trigeminal tract terminate in the thalamus, ventroposterolateral and ventroposteromedial,
respectively, with further cortical projections through the third-order neurons to the
postcentral cortex in a somatotopic arrangement similar to that seen in the motor cortex,
with the face in the lowest area of the parietal lobe and the leg in the parasagittal
parietal area. Fine sensory discrimination and localization of pain, temperature, touch,
and pressure require normal functioning of the sensory cortex (Fig. 6-3).

EXAMINATION OF THE SENSORY SYSTEM

The sensory examination is the most subjective, and sometimes the most difficult,
component of the neurologic examination; it requires the patient’s cooperation.
Inattention or aphasia may complicate interpretation of the sensory examination. The
evaluation of different primary sensory modalities, including temperature, pain (or
pinprick), light touch, vibration, and proprioception, is necessary to characterize
sensory loss and its extent. In some instances, it is difficult to demonstrate sensory
abnormalities in a patient with sensory symptoms. In others, the examination may show
sensory findings in an asymptomatic patient. Whatever the situation, the sensory
examination must be organized and methodical.
Touch sensation is tested using a very soft stimulus, such as a wisp of cotton. Pain
sensation is tested with a pin. Thermal modalities are tested using objects with a
temperature range between 10°C and 50°C because beyond those limits the stimulus
becomes painful. Moving the great toe (or a finger) up and down, by just a few
millimeters, and asking the patient to indicate the direction of movement (with the eyes
closed) tests proprioception or joint position sense. Vibration sense requires a tuning
fork (128 Hz) to be applied to the toes and other bony prominences.
FIGURE 6-1. The anterolateral system. VPL, ventroposterolateral.

The next step is to record the sensory symptoms and findings using accepted
definitions. It is best to record the patient’s own words when possible. Not only the
presence or absence of sensation but also slight differences and gradations should be
recorded. The following list defines some of the terminology used to describe sensory
abnormalities:
FIGURE 6-2. The posterior column—medial lemniscal system. VPL, ventroposterolateral.

• Paresthesias are abnormal sensations described by the patient as tingling, prickling,

pins, and needles, and so on.
• Dysesthesias are abnormal and often unpleasant sensations in response to touch.
• Hyperesthesia is increased sensitivity to sensory stimuli. The opposite is
hypoesthesia.
• Allodynia is pain provoked by normally innocuous stimuli.
• Dissociated sensory loss is a pattern of neurologic dysfunction of a single sensory
tract (either posterior columns or STTs) in which the loss of proprioception and fine
touch is not associated with loss of pain and temperature, or vice versa. For
example, in syringomyelia, a condition in which the central canal of the spinal cord
 expands, the STT is compromised early. This leads to loss of pain and temperature
sensation in the dermatomes involved but preservation of posterior column function
and, therefore, a normal response to light touch and normal proprioception. Such
dissociated sensory loss occurs frequently with central cord syndromes (see Chapter
22).

FIGURE 6-3. Somatotopic map (“homunculus”) of the sensory cortex. Reprinted with permission from Jensen S.
Nursing Health Assessment. 1st ed. Baltimore, MD: Lippincott Williams & Wilkins; 2010. Figure 24.3.

APPROACH TO THE PATIENT WITH SENSORY

LOSS
As with any aspect of the neurologic examination, the approach to sensory symptoms
begins with a careful history. Patients complaining of sensory dysfunction can report
negative symptoms, positive symptoms, or both. Negative symptoms include numbness,
loss of cold or warm sensation, blindness, and deafness. Positive symptoms include
pain, paresthesias (tingling, pins, and needles), visual sparkles, and tinnitus. Listening to
the patient’s experience will help guide the physical examination and may even provide
insight into potential causes. For example, negative symptoms usually imply disruption
of nerve excitation (such as in a stroke), whereas positive symptoms refer in general to
excitation or disinhibition (as seen with seizures or migraine).
Once the history is obtained, the next task is to establish the presence or absence of a
neurologic lesion or deficit. If a lesion is identified, the extent or location of the lesion
and its effect on different sensory modalities should be mapped out by a careful and
detailed sensory examination. This is important because different pathologic processes
can affect different sensory symptoms and lead to specific patterns of sensory loss.
Although in theory it is easy to distinguish peripheral nerve injury from disease in
other locations, this is often not possible or at best imprecise in practice. Nevertheless,
the history and complete physical examination together may help the clinician more
definitively determine the neuroanatomic level at which the symptoms are produced,
that is, at nerve, plexus, root, cord, or other CNS locations. In general, compression of a
peripheral nerve causes sensory loss in the territory of that specific nerve. Root
problems produce a dermatomal pattern of sensory loss (Fig. 6-4). Spinal cord disease
leads to a characteristic loss of sensation below a certain spinal level (sensory level).
With brainstem lesions, the sensory abnormalities may occur on the ipsilateral side of
the face and contralateral side of the body. Central sensory loss involving the thalamus
or sensory cortex will generally affect the contralateral face, arm, and leg.
Because there are many primary neurologic diseases as well as systemic illnesses
that can present with sensory symptoms, putting the sensory examination into the context
of the remainder of the physical examination may make potential etiologies more
obvious. Sometimes, the sensory problems are accompanied by other signs such as
weakness, neglect, visual field cuts, cognitive or behavioral problems, or seizures that
may help to determine the location of the lesion.
FIGURE 6-4. Sensory dermatomes. Reprinted with permission from Hoppenfeld JD. Fundamentals of Pain
Medicine: How to Diagnose and Treat your Patients. 1st ed. Baltimore, MD: Lippincott Williams & Wilkins; 2014.
Figure 2.12.

Examples of different patterns of sensory loss and the location of the respective
neurologic problem are shown in Table 6-1. This table serves as a guide to the process
of localization and diagnosis based on clinical symptoms and the neurologic
examination, without the need for further technologic resources.

TABLE 6-1. Patterns of Sensory Loss According to Localization

Site of the Sensory Findings Other Neurologic Examples
Lesion Abnormalities
Peripheral Loss of LT, T, PP, and Distal muscle weakness, Peroneal neuropathy; median
nerve proprioception in the affected muscle atrophy, areflexia neuropathy (carpal tunnel
area; associated weakness in syndrome); ulnar neuropathy
 muscles innervated by that nerve
Root Variable loss of all sensory Weakness in a myotomal L5 radiculopathy; C6
modalities in a dermatomal distribution, atrophy, radiculopathy
distribution segmental hyporeflexia
Plexus Sensory loss in the distribution of Weakness and atrophy that Brachial plexopathy due to
two or more peripheral nerves cannot be localized to a trauma, inflammation, tumor
single nerve or root, infiltration
areflexia
Spinal cord • Sensory level: bilateral loss of allParaplegia, tetraplegia. Myelopathy; central cord
sensory modalities Initially areflexia, then syndromes; Brown-Sequard
• Sensory dissociation hyperreflexia below the syndrome; vitamin B12 deficiency
• Contralateral hypoesthesia and lesion; Babinski sign (subacute combined
ipsilateral loss of degeneration)
proprioception (Brown-
Sequard syndrome)
• Proprioceptive loss and
corticospinal tract involvement
Brainstem Ipsilateral facial numbness and Alternating hemiplegia; Posterior circulation strokes;
contralateral body numbness cranial nerve findings; brainstem tumor
ataxia
Thalamus Hemibody anesthesia May have motor findings Lacunar stroke; hemorrhage
Posterior limb Hemibody anesthesia Hemiplegia Lacunar stroke; hemorrhage;
of internal tumor
capsule
Cortex All modalities affected on the Sensory neglect; Parietal stroke; hemorrhage;
contralateral side agraphesthesia AVM
Psychogenic Hyperesthesia for one modality in Any Psychogenic (this is a diagnosis
one area with anesthesia for of exclusion)
another modality in the same
area; changing sensory findings;
nonphysiologic sensory level
changes (abrupt midline changes,
vibration asymmetry over the
forehead, etc.)
AVM, arteriovenous malformation; LT, light touch; PP, pinprick; T, temperature.

The last step in evaluating these sensory abnormalities is to determine the cause.
There are many primary neurologic diseases as well as systemic diseases that can
present with sensory symptoms; many are explored in more detail in Chapter 23 on
peripheral neuropathies.

KEY POINTS
● STT is the pathway for pain, temperature, and light (poorly localized) touch. Mnemonic: STT (sting,
temperature, touch).
● The dorsal columns carry well-localized touch, pressure, vibration, and conscious proprioception.
● Nonconscious proprioception is conveyed by the spinocerebellar tracts.
● Damage to a peripheral nerve produces a sensory deficit in the territory innervated by that nerve. Damage to
a nerve root may produce a dermatomal loss of sensation. Damage to the brachial or lumbar plexus
produces sensory loss in multiple nerve territories.
● Spinal cord lesions often produce an identifiable sensory level on examination. Brainstem lesions cause
crossed sensory loss. Thalamic and cortical lesions produce contralateral hypoesthesia or anesthesia.
● Examples of sensory dissociation include syringomyelia (loss of pain and temperature sensation, with
preserved proprioception); Brown-Sequard syndrome (loss of proprioception on the side ipsilateral to the
lesion, and loss of pain and temperature sensation on the contralateral side); and subacute combined
degeneration (loss of proprioception, but preserved pain and temperature sensation).
 7 Dizziness, Vertigo, and Syncope

The word dizziness is used by patients and sometimes clinicians to describe many
different symptoms ranging from room spinning and light-headedness to disorientation,
complex partial seizures, and anxiety. As a result, the differential diagnosis for self-
reported “dizziness” is very broad. As with all of medicine, obtaining a clear history of
what “dizziness” really means to the patient, followed by a careful neurologic
examination, is vital to establish the diagnosis and avoid unwarranted testing. The
following sections detail different types of dizziness, including the key features and
underlying etiologies.

VERTIGO
Vertigo is a type of dizziness in which a patient perceives motion when there is no
actual motion. This is most commonly a sensation of the room spinning in a clockwise
or counterclockwise direction. Vertigo can also be a sensation of motion, as if on a
boat. Some patients also experience a sensation of propulsion, as if they are being
pulled or pushed in a direction. Vertigo is a descriptive term, not a diagnosis. Stating
that a patient has vertigo is no more specific than saying that a patient has fever or chest
pain. The specific cause of the vertigo must be established in order to establish a
diagnosis.
Vertigo is caused by an asymmetric impairment in the vestibular system. This can
occur at any point along the vestibular pathway from the vestibular nerve or labyrinth to
the central vestibular structures. Vestibular disorders can therefore be divided into
peripheral and central categories, based on the cause.
The specific details of the onset, quality, duration, triggers, and associated symptoms,
as well as the patient’s medical history, aid in guiding the differential diagnosis.
Vertigo is often associated with nausea. Patients may describe a staggering gait or
that they must hold on to nearby objects to avoid falling. Depending on the etiology,
patients may also have symptoms of diplopia (double vision). Vertigo may be constant
or intermittent, depending on the cause. The duration of symptoms and associated
features aid in narrowing the diagnostic possibilities. The examination is used to
evaluate further and establish the diagnosis. These are critical steps that allow a
clinician to triage or distinguish an emergency cause of vertigo such as a brainstem
stroke from a benign etiology, for example, benign paroxysmal positional vertigo
(BPPV).

PERIPHERAL VERTIGO
There are many causes of peripheral vertigo, each with key features that allow the
clinician to determine it.
BPPV is a common form of vertigo. It is caused by an otolith (also called a canalith)
of calcium carbonate debris in the semicircular canal. The semicircular canals are
within each inner ear and are lined with cilia and endolymph. Each time the head
moves, the endolymph moves, which in turn causes the cilia to move and send signals to
the central vestibular structures. When an otolith is in the semicircular canal, it disrupts
the movement of the endolymph and creates a sensation of spinning. The vertigo occurs
only when the person moves the head. The spinning sensation resolves, usually in under
a minute, if the patient is perfectly still. Bending over, looking up, or rolling over in bed
are common triggers. The vertigo may be accompanied by nausea and sometimes
emesis. Importantly, BPPV is not associated with diplopia, weakness, sensory
symptoms, or hearing loss.
Otoliths can form in the horizontal and anterior (superior) semicircular canals but are
most common in the posterior canal. The orientation and position with which the
nystagmus is elicited are slightly different depending on the location of the otolith.
Episodes of BPPV often occur in bouts; patients may have recurrent episodes for
several days in a row which then resolve, but BPPV may recur frequently if untreated.
BPPV patients have normal neurologic examinations, without evidence of ataxia or
sustained nystagmus. The gait remains normal. The diagnosis may be corroborated by
doing the Dix–Hallpike maneuver (Fig. 7-1). The maneuver is 50% to 80% sensitive,
but some patients are unable to cooperate. During the test, the patient should be
observed in each position for 30 to 45 seconds. Nystagmus usually appears within a few
seconds and extinguishes after less than 1 minute. The nystagmus is typically upbeating
and torsional. When the patient is repositioned in the upright position, the nystagmus
recurs with the same cadence. The maneuver is performed with each side of the head
turned downward; the side tested which provokes the nystagmus is the one with the
otolith. With each repetition of the maneuver, the clinical response becomes less
intense. During the maneuver, nystagmus is not always visible to the examiner, but the
patient may still experience vertigo. This is referred to as “subjective BPPV” and still
responds to treatment.
BPPV is treated with vestibular therapy aimed at repositioning the otolith, usually by
doing the Epley maneuver (Fig. 7-2). Of note, patients with otoliths in the horizontal and
anterior canals may require different repositioning maneuvers.
FIGURE 7-1. Dix–Hallpike maneuver. This bedside maneuver helps to diagnose BPPV. From Furman JM, Cass
SP. Benign paroxysmal positional vertigo. N Engl J Med. 1999;341(21):1590–1596. Copyright © 1999 Massachusetts
Medical Society. Reprinted with permission from Massachusetts Medical Society.
FIGURE 7-2. The Epley maneuver. Reprinted with permission from Krebs C, Weinberg J, Akesson E.
Lippincott’s Illustrated Review of Neurscience. 1st ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.

Vestibular Neuritis and Labyrinthitis

Vestibular neuritis (aka vestibular neuronitis) is believed to be caused by an infectious
or autoimmune injury to the vestibular portion of the VIIIth cranial nerve (although there
is no clear evidence of inflammation, and the exact etiology remains unknown). Patients
present with acute-onset vertigo, often associated with nausea, emesis, and mild gait
ataxia. When the patient also has acute hearing loss, the syndrome is called
labyrinthitis. Patients should not have additional symptoms of focal weakness or
sensory changes. Rarely, patients may report diplopia, but this symptom is more
concerning for a brainstem infarct or hemorrhage.
On examination, patients have spontaneous unilateral horizontal or torsional
nystagmus. The nystagmus can be suppressed with gaze fixation (having the patient
fixate on a target). Patients may also have some gait ataxia and typically fall away from
the side of the lesion. The head impulse test (HIT) (Fig. 7-3) is used to identify whether
there is vestibular impairment, but it does not definitely exclude a central cause.
 Vestibular neuritis can mimic a brainstem infarct or, less commonly, a demyelinating
lesion (described later). The decision to proceed with a stroke workup is often based
on the age and vascular comorbidities of the patient. A magnetic resonance imaging
(MRI) of the brain with thin cuts through the brainstem is often warranted in patients
with a high risk of stroke.
In patients with an acute onset of symptoms, treatment with a corticosteroid taper can
reduce the duration of symptoms. Additional symptomatic treatment with antiemetics
and antihistamines may also be helpful.

Ménière disease
Ménière disease is a constellation of symptoms of vertigo, sensorineural hearing loss,
and tinnitus. It is believed to be caused by surplus endolymph. The exact cause is
unknown, but there are theories that endolymph homeostasis is impaired. It is most
common in adults between the ages of 20 and 40 years. Patients may also report gait
unsteadiness and nausea, vomiting, or both. Patients typically have phases of
exacerbation and remission of the vertigo. Hearing loss remains and often progresses to
deafness.

FIGURE 7-3. Head impulse test (HIT) (sometimes referred to as the head thrust test) is a test of vestibular
function that can be easily done in bedside examination. It tests the vestibulo-ocular reflex (VOR) and can help to
distinguish a peripheral process (e.g., vestibular “neuritis”) from a central one (e.g., a cerebellar stroke). With the
patient sitting, the physician instructs him to maintain his gaze on the examiner’s nose. The physician holds the patient’s
head steady in the midline (Panel 1) and then turns the head rapidly to about 20 degrees from the midline. The normal
response (intact VOR) is for the eyes to stay locked on the examiner’s nose. The abnormal response (impaired VOR)
is for the eyes to move with the head (Panel 2) and then to snap back in one corrective saccade to the examiner’s
nose (Panel 3). The HIT is usually “positive” (i.e., a corrective saccade is visible) with a peripheral lesion and
“normal” (no corrective saccade) with a central lesion (because the VOR pathway does not pass through the
cerebellum). Occasionally, patients with small brainstem strokes have a positive test because the VOR pathway does
pass through the brainstem.
Because it is the “positive” HIT that is reassuring and the “negative” test worrisome, it is important to use the test
only in patients with an acute vestibular syndrome (AVS). If one were to use the HIT in patients with pneumonia or a
fractured wrist, it might be “negative” (or worrisome for a central nervous system event). Therefore, it is critical that it
be applied only to patients presenting with an AVS. Reprinted with permission from Wolfson AB. Harwood-Nuss’
Clinical Practice of Emergency Medicine. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014. Figure 14.1.
Ménière disease is diagnosed by the history, while excluding other causes, especially
central causes of vertigo (see below). Treatment addresses the symptoms. Patients are
counseled to avoid triggers and to have a diet low in sodium and caffeine.

Acoustic Neuroma
An acoustic neuroma (vestibular schwannoma) is a tumor that grows in the vestibular
portion of the vestibulocochlear nerves (cranial nerve VIII). Its cells are derived from
Schwann cells, usually in the internal auditory canal. The tumor can extend into the
posterior fossa and can even cause mass effect on the brainstem. Acoustic neuromas are
among the most common tumors in the cerebellopontine angle. They are most common in
adulthood and are usually unilateral. They are also common in patients with
neurofibromatosis type 2, occurring bilaterally in this condition.
Acoustic neuromas may be asymptomatic and identified as incidental findings on
neuroimaging. When patients are symptomatic, they often present with hearing loss and
tinnitus. Frank vertigo (i.e., room spinning) is not a common symptom, but feelings of
unsteadiness and imbalance are often reported. If there is significant mass effect, the
tumor may compress adjacent cranial nerves, and patients may report symptoms of
trigeminal neuralgia, a facial nerve palsy, or both.
On examination, patients typically have sensorineural hearing loss on the affected
side, but the remainder of the examination is typically normal unless there is significant
mass effect impacting other cranial nerves. Patients have hearing impairment on
audiometry. The diagnosis is established with an MRI (Fig. 7-4). Treatment is usually
surgical resection. In patients who are not surgical candidates, stereotactic radiotherapy
may be attempted to reduce the tumor burden. Tumor recurrence is uncommon.
FIGURE 7-4. Magnetic resonance imaging (MRI) of vestibular schwannoma. (A) T1-weighted axial MRI before
contrast shows large hypointense mass within the cerebellopontine angle exerting mass effect on the brainstem. (B)
T1-weighted axial MRI postcontrast shows a vestibular schwannoma with expansion of the internal auditory meatus.
Reprinted with permission from Louis ED, Mayer SA, Rowland LP. Merritt’s Neurology. 13th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2015. Figure 102.1.

Medications
There are numerous medications that cause dizziness as a side effect. Frank vertigo from
medications is uncommon, but aminoglycosides are the exception and can cause both
cochlear and vestibular toxicity. Patients who develop this side effect have hearing loss
from cochlear involvement and vertigo and disequilibrium from the vestibular nerve
damage. These side effects are most common in patients on long-term therapy. The exact
incidence of ototoxicity from aminoglycosides is not known.

KEY POINTS
● Peripheral vertigo can be due to several different etiologies.
● Careful history and examination are needed to narrow the differential.
● Focal neurologic deficits such as involvement of other cranial nerves, sensory deficits, or weakness are
atypical and warrant workup for a central cause.

CENTRAL VERTIGO
Central vertigo is a category of vertigo that is caused by a lesion in the brainstem or
cerebellum. Patients with central vertigo develop abrupt onset sustained vertigo. It is
not positional and is typically sustained during the acute phase. Central vertigo is most
commonly due to cerebellar infarcts or hemorrhages, but in younger patients, central
vertigo may be due to a demyelinating lesion such as from multiple sclerosis. Migraine
may also cause vertigo but are a diagnosis of exclusion.
Central vertigo is often associated with focal symptoms and findings on examination.
The patient’s eye movements should be examined carefully for spontaneous or gaze-
evoked nystagmus. In addition, a horizontal or vertical misalignment (skew deviation)
may be seen. Patients may have a head tilt if they have a IVth nerve (trochlear nerve)
palsy, and ptosis may be present. Other cranial nerve deficits as well as focal weakness
and sensory changes suggest a central etiology. Hearing loss (as tested with Weber and
Rinne tests) is more suggestive of a peripheral etiology but does not exclude a central
cause.

Cerebral Infarct or Hemorrhage

When vertigo is due to a cerebellar infarct or hemorrhage, the patient typically reports
abrupt onset vertigo and may report a headache. The brainstem is a dense structure with
many nuclei and nerves abutting one another, so most brainstem strokes are associated
with symptoms in addition to vertigo—often referred to as “neighborhood signs.”
Patients may report nausea, vomiting, ataxia, dysphagia, dysarthria, dysmetria, or
combinations of these.
A classic example of a stroke syndrome that causes vertigo is the Wallenberg (or
lateral medullary) syndrome caused by a stroke in the lateral medulla due to a
vertebral or posterior inferior cerebellar artery occlusion. The stroke not only causes
vertigo but is also associated with diplopia and multidirectional nystagmus. Patients
with a Wallenberg syndrome may also have
• Ipsilateral Horner syndrome
• Dissociated sensory loss, that is,
• ipsilateral loss of pain and temperature sensation over the face, with
• contralateral loss of pain and temperature over the limbs and trunk
• Nystagmus: sometimes, direction changing, and not suppressible with visual fixation
• Ipsilateral loss of the corneal reflex
• Hoarseness and dysphagia
• Ipsilateral limb ataxia
• Dysmetria and dysarthria (sometimes)
Abrupt onset of sustained vertigo from vestibulitis can mimic a brainstem or
cerebellar stroke. Brief vertiginous episodes from a transient ischemic attack (TIA) can
also mimic BPPV, at least by history. The additional associated symptoms and findings
on examination help localize the lesion. In addition, the patient’s medical history,
including vascular risk factors, age, and trauma history, is vital in formulating a
differential diagnosis. Isolated vertigo without other symptoms or findings on
examination is rarely due to a stroke. If there is any concern for a central cause of
vertigo, imaging with MRI of the brain should be obtained. If there is specific concern
for a stroke, blood vessel imaging with a magnetic resonance angiography (MRA) or
computed tomography angiography (CTA) should also be ordered. Treatment is based
on management of risk factors for stroke. Symptomatic treatment with antihistamines and
antiemetics may also help.

Demyelinating Lesions
Demyelination in the cerebellum and brainstem can cause acute vertigo. Possible
neighborhood signs depend on the location of the lesion. Patients with central vertigo
from multiple sclerosis or other demyelinating diseases usually have central oculomotor
signs, as described earlier. The diagnosis is established with an MRI of the brain with
and without contrast. The treatment is usually immune therapy for multiple sclerosis.
Symptomatic treatment with antihistamines and antiemetics may also be required.

Migraine
Patients with migraine may experience vertigo with a migraine attack or as an aura
preceding a migraine. There are two specific types of vertigo associated with migraine.
Vestibular migraine (previously called migraine-associated vertigo) is defined as a
headache that meets criteria for a migraine (with or without aura) associated with
symptoms of vertigo. The vertiginous symptoms range from vertigo triggered by head
movement to feelings of motion—either internally or feeling that the external space is
spinning. Symptoms can last for minutes to hours but rarely last weeks.
Migraine with brainstem aura (previously called basilar migraine) is defined as a
fully reversible aura involving at least two brainstem symptoms, including vertigo,
tinnitus, hyperacusis, diplopia, dysarthria, ataxia, decreased level of consciousness, or
combinations of these. Symptoms evolve gradually over 5 to 60 minutes. The auras must
be accompanied or followed by a headache that meets criteria for migraine. Importantly,
patients do not have focal weakness during these auras.
Vertigo because of migraine is generally a diagnosis of exclusion and usually
warrants neuroimaging to exclude other central causes of vertigo. Treatment is focused
on aborting the migraine with typical regimens and treating associated symptoms of
nausea and emesis as needed.

KEY POINTS
 ● Central causes of vertigo should be evaluated as an emergency with neuroimaging.
● The history and associated focal neurologic deficits will aid in localization and differentiation from a peripheral
cause of vertigo.
● Treatment is based on symptomatic management and addressing the structural cause.
● Table 7-1 outlines key features of both peripheral and central vertigo.

TABLE 7-1. Characteristics of Causes of Vertigo

Causes Duration Triggers Hearing Neurologic Diagnostic
Symptoms Symptoms Workup
BPPV Seconds Head movements None None Dix–Hallpike
Vestibular Days–weeks May be preceded Labyrinthitis + No cranial nerve HIT test
neuritis and by an upper hearing loss deficits
labyrinthitis respiratory
infection
Ménière disease Minutes–hours Unknown + Hearing loss None Audiometry:
+ Tinnitus sensorineural
hearing loss
Acoustic Does not typically None + Hearing loss May be present if MRI of the
neuroma cause vertigo + Tinnitus there is mass internal auditory
effect on the canal
brainstem
Brainstem infarct, Hours–days; may Stroke risk Variable Typically present MRI of the brain
hemorrhage, or be intractable factors (excluding
demyelinating MS lesion)
lesion
Migraine with Hours–days Migraine triggers ± Tinnitus Headache MRI of the brain
brainstem aura meeting criteria is normal
for migraine and
reversible
brainstem
symptoms
Vestibular Hours–days Migraine triggers ± Tinnitus Headache None
migraine meeting criteria
for migraine
BPPV, benign paroxysmal positional vertigo; HIT, head impulse test; MRI, magnetic resonance imaging; MS,
multiple sclerosis.

LIGHTHEADED
Lightheadedness is a sensation of feeling faint and is essentially synonymous with
presyncope. It may precede syncope. Lightheadedness is often associated with
diaphoresis, flushing, pallor, or combinations of these. Patients may also have
symptoms of tunnel vision or palpitations. The most concerning acute cause of
presyncope is cerebral hypoperfusion. This can be due to significant hypovolemia, or
cardiac or autonomic etiologies. Unlike with seizures, patients with syncope do not
have alteration of awareness when they regain consciousness (i.e., there is no postictal
confusion). Patients are generally aware of their circumstances and are able to respond
appropriately within seconds of regaining consciousness (although they may be
bewildered by what has happened).

HYPOVOLEMIA
Hypovolemia can be due to severe dehydration, but the most concerning etiology is
severe internal hemorrhage. Acute blood loss is typically identified as the patient
remains hypotensive in all positions and is typically tachycardic. The hemoglobin and
hematocrit levels are very low. Treatment is based on volume repletion while
simultaneously identifying and resolving the cause of the bleeding.

CARDIAC ARRHYTHMIAS
Malignant cardiac dysrhythmias can also cause Lightheadedness. These can be either
tachy- or bradyarrhythmias. Patients may have symptoms of palpitations or chest pain,
but these may be absent. The symptoms are typically not posturally induced (i.e.,
patients feel light-headed in any position) but patients may report feeling worse when
standing. The diagnosis is made by capturing an event on electrocardiogram (ECG) or
longer cardiac telemetry. This may require brief cardiac monitoring, but if the symptoms
are very infrequent, implantable cardiac monitoring may be warranted. Treatment is
based on addressing the underlying dysrhythmia.

AUTONOMIC CAUSES
There are both normal variants and pathologic causes of autonomic presyncope.
Autonomic causes are distinctive from the other causes of presyncope and syncope, as
they generally do not cause symptoms unless the patient is standing.
Neurally mediated syncope (also called vasovagal syncope) is a normal variant
where patients activate an autonomic reflex in which generally parasympathetic activity
is preserved but sympathetic activity is insufficient. Patients therefore typically have
simultaneous bradycardia and hypotension, resulting in cerebral hypoperfusion and
presyncope, syncope, or both. There is typically a prodrome of rapid onset
Lightheadedness, flushing, diaphoresis, and pallor. Some patients also feel nauseated
and have tunnel vision. Sitting or lying down with legs elevated helps ameliorate the
symptoms, but the event is typically self-limited and resolves within a few minutes.
Symptoms are most commonly triggered by postural changes from supine to standing,
especially after prolonged recumbency. Pain, seeing blood, venipuncture, and
micturition are common triggers. People who develop neurally mediated syncope from
pain or blood drawing can develop symptoms even when supine but do not typically
have a full syncopal event when supine. Episodes of presyncope and syncope from
neurally mediated syncope are intermittent and typically triggered. They are self-
resolving and brief. Carotid hypersensitivity is another cause of syncope and
presyncope, triggered by stimulation of the baroreceptors in the carotid sinus, resulting
in bradycardia and hypotension.
The diagnosis can often be made based on history alone, but if there are atypical
features or other factors that warrant additional evaluation, a head-up tilt table test
may be helpful. In this test, the patient’s supine blood pressure and heart rate are
measured when the patient is at rest. The patient is then tilted in reverse Trendelenburg
with the head elevated at a 60-degree angle or higher. The blood pressure and heart rate
are monitored continuously, and the pattern of the blood pressure, heart rate, and
patient’s symptoms is used to identify neurally mediated syncope, orthostatic
hypotension, and a postural tachycardia. Patients who have a normal tilt table test may
still have neurally mediated syncope if their symptoms are intermittent and not captured
during the monitoring.
Orthostatic hypotension is another autonomic cause of presyncope. It is defined as a
drop in the blood pressure within 3 minutes of standing when transitioning from supine
to standing. Criteria include a drop in systolic blood pressure by ≥ 20 mm Hg and in
diastolic blood pressure by ≥ 10 mm Hg. The diagnosis can be established at the
bedside by performing orthostatic vital signs. A head-up tilt table test may also be used.
Some patients have delayed orthostatic hypotension, where the blood pressure drops
after more than 3 minutes of standing.
Orthostatic hypotension can be caused by endocrinopathies, so screening for adrenal
insufficiency may be warranted. Aortic stenosis, pericarditis, and myocarditis can also
cause orthostatic hypotension; an echocardiogram may be needed to assess for structural
cardiac etiologies. There are also many systemic disorders that can cause an autonomic
neuropathy. Diabetic autonomic neuropathy is common, especially in patients with long-
standing or poorly controlled diabetes. This can result in orthostatic hypotension, in
addition to other autonomic impairments. Neurodegenerative conditions such as
Parkinson disease can also cause orthostatic hypotension. There are no tests to identify
the underlying cause, so a detailed history, neurologic examination, and screening for
comorbidities are necessary.
Treatment of orthostatic hypotension is directed at removing any medications that
contribute to the problem, as well as preventing progression of any comorbidity such as
diabetes or cardiac valvular disease that can exacerbate it. Symptomatic management is
based on increasing the volume through a high-fluid and sodium intake, if appropriate
for the patient’s other medical management. Compression stockings may be helpful. In
patients with persistent symptoms despite these strategies, medications such as
fludrocortisones, midodrine, or droxidopa may be helpful as they raise the blood
pressure. When patients are treated with these medications, they must be monitored
carefully for supine hypertension.

POSTURAL TACHYCARDIA
Postural tachycardia is defined as a sustained increase in the heart rate by ≥ 30 bpm
within 10 minutes of standing. It may be caused by hypovolemia or medication side
effects. Some patients with postural tachycardia have a syndrome known as postural
tachycardia syndrome (POTS) and have symptoms of presyncope, as well as fatigue
and cognitive concerns. The cause of POTS is unknown, but it has been associated with
systemic and inflammatory conditions that cause small fiber neuropathies. Treatment is
similar to that of orthostatic hypotension, and patients are counseled to increase their
oral fluid and sodium intake. If behavioral measures are not sufficient, pressure support
with midodrine, fludrocortisones, or beta-blockers may be helpful. Cardiovascular
conditioning is very important to help patients improve their orthostatic tolerance.

METABOLIC CAUSES
There are numerous metabolic derangements that can also cause nonspecific light-
headedness. Hypoglycemia is a common cause in patients with diabetes, especially in
those using insulin. The diagnosis can be established by having the patient check the
blood glucose during the event.
Many medications cause side effects of light-headedness. This may be a nonspecific
symptom, but there are also numerous medications that cause hypotension (not only
antihypertensives) and may cause light-headedness. It is important to review carefully
all the patient’s medications, including over-the-counter remedies and herbal treatments,
to assess for such potential triggers.
Some patients have symptoms of orthostatic intolerance (i.e., feeling light-headed
or presyncope) without significant changes in blood pressure or heart rate. These
symptoms can be due to focal stenosis of the basilar artery or bilateral vertebral
arteries, or even less commonly the carotid arteries bilaterally, but vascular stenosis
alone is a very uncommon cause of symptoms of orthostatic intolerance.

KEY POINTS
● Light-headedness is a term used to describe feelings like presyncope.
● There are numerous etiologies. Cardiac causes are the most important to consider.
● Management of the symptom is based on identifying and treating the underlying cause when possible.
● Increased oral volume, cardiac conditioning, and, sometimes, medications are warranted for management of
orthostatic hypotension.
CONCLUSION
Dizziness and light-headedness are terms that patients may use to describe many
different symptoms. The quality of the symptoms, the history, and examination are vital
in clarifying the etiology. The most urgent concern is for cardiovascular etiologies such
as stroke, TIA, or dysrhythmia. If the dizziness or light-headedness is not consistent with
vertigo or presyncope, other causes including metabolic derangement, medication effect,
seizures, and anxiety should be considered.

CLINICAL VIGNETTES

VIGNETTE 1
A 54-year-old woman is seen in the emergency room (ER) for evaluation of new-
onset dizziness. She describes severe but short-lived paroxysms of dizziness,
sometimes accompanied by nausea. The episodes occur in both the upright and
recumbent positions. Movement exacerbates the dizziness. She reports no other
neurologic symptoms other than long-standing headaches that have not changed in
character or frequency. She recalls that, years ago, she may have had similar
symptoms that resolved spontaneously after her doctors were unable to find a clear
cause. The ER physician reports a normal neurologic examination and requests a
neurology consultation because he is concerned about the possibility of
“vertebrobasilar ischemia.”
1. The best first thing to do is:
a. Reassure the ER physician that isolated dizziness is almost never caused by
vertebrobasilar ischemia and advise him that the patient may be discharged
from the ER.
b. Ask the ER physician to order a stat head computed tomography (CT) scan to
exclude a cerebral hemorrhage.
c. Order a brain MRI with magnetic resonance angiography to evaluate for a
posterior circulation stroke.
d. Carefully review the history of symptoms with the patient and perform a
detailed neurologic examination, including the Dix–Hallpike maneuver.
e. Perform the Epley maneuver to aid with the diagnosis of vestibular neuronitis.
2. You review the patient’s history and determine that she is describing a
hallucination of movement (i.e., vertigo). You concur that there are no other
symptoms. You perform the Dix–Hallpike maneuver. Which of the following
descriptions is most typical of the nystagmus you would expect if the patient has
benign positional paroxysmal vertigo?
 a. A combined vertical and torsional nystagmus
b. A combined horizontal and torsional nystagmus
c. A purely vertical nystagmus
d. A purely torsional nystagmus
e. A purely horizontal nystagmus
3. You confirm the diagnosis of posterior canal BPPV based on a history of vertigo
provoked by changes in head position relative to gravity and demonstration of
the characteristic nystagmus on the Dix–Hallpike maneuver. You decide to treat
the patient using which of the following?
a. Meclizine
b. The Epley maneuver
c. “Tincture of time”
d. Physical therapy
e. Lorazepam

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer D
The first step in evaluating a patient with dizziness is to clarify what is meant by
“dizzy,” as different people mean very different symptoms when using this term.
Although vertebrobasilar ischemia may rarely cause isolated vertigo (i.e., with no
other symptoms to suggest brainstem dysfunction), you should review the history
with the patient and ask specifically about symptoms such as dysarthria, dysphagia,
diplopia, and facial sensory symptoms. A careful neurologic examination is
important, paying specific attention to the presence of any neurologic deficit—
including nystagmus, other cranial nerve deficits, ataxia, or focal sensory findings.
The Dix–Hallpike maneuver should also be performed because, in the context of an
appropriate history, it can be highly diagnostic. Head CT or brain MRI is not
appropriate without a clear clinical differential diagnosis that warrants such scans;
they may or may not be appropriate once the clinical evaluation has been completed.
The Epley maneuver is a therapeutic (not diagnostic) procedure.

VIGNETTE 1 QUESTION 2
2. Answer A
The nystagmus produced by the Dix–Hallpike maneuver, with BPPV based in the
posterior canal, typically includes two important features: (1) a short latency
(usually 5 to 20 seconds) between completion of the maneuver and the onset of a
subjective rotational vertigo along with objective nystagmus and (2) a provoked
subjective vertigo and nystagmus, first increasing in severity and then resolving
within about 60 seconds of the onset of symptoms. The fast component of the
nystagmus is characteristically mixed vertical and torsional. The nystagmus may be
observed again after the patient sits up and the head is in an upright position.

VIGNETTE 1 QUESTION 3
3. Answer B
The Epley maneuver is appropriate for patients with posterior canal BPPV, the most
common form of this illness. The key elements of the Epley maneuver include
starting with the head turned 45 degrees toward the affected side; moving the patient
swiftly to a supine position with the head tilted 30 degrees backward off the edge of
the bed; followed by subsequent progressive rotation of the head and body toward
the unaffected side, before sitting upright (Fig. 7-2); each positioning movement is
separated by a 30-second pause. The goal of the Epley maneuver (or any other
canalith repositioning procedure) is to move canaliths from the posterior
semicircular canal to the vestibule, thereby relieving the stimulus in the semicircular
canal responsible for the vertigo. Ideally, symptoms are at least partially
reproduced with each successive position and then finally resolve.
 8 Ataxia and Gait Disorders

The staggering steps of a young child learning to walk are a classic example of ataxia, a
condition in which the control of motor movements is impaired in the absence of muscle
weakness. The term ataxia is of Greek origin, with “a taxis” meaning “without order or
arrangement.” The precision of movement is controlled by an intricate sensory and
motor feedback system, with key processing of this information occurring in the
cerebellum. As such, disorders affecting the modulation of information entering or
leaving the cerebellum may affect the specific components of movement including rate,
direction, force, and rhythm. Depending on the pathologic cause, ataxia can be diffuse,
unilateral, or bilateral. It can affect the upper limb, lower limb, and truncal, ocular, or
bulbar muscles. Although ataxia can cause significant difficulties with walking, it is not
the only type of gait abnormality. This chapter will review common causes of ataxia and
gait disorders.

ATAXIA
DIAGNOSTIC APPROACH
Ataxia is not a diagnosis, but rather a neurologic examination finding. There are many
ways in which ataxia may manifest clinically. Patients may complain of clumsiness, gait
difficulties, speech or swallowing difficulties, or other problems. Because of the
diverse array of symptoms, several terms are used to describe specific aspects of ataxic
movements. They include the following:
1. Dysarthria: speech characterized by poor articulation. Although not specific for ataxic
disorders, ataxic disorders can lead to slurred, slow, hesitating, and effortful speech.
2. Dysmetria: incoordination of movement characterized by under- or overshooting the
intended position of the limb or eyes. Dysmetric movements appear jerky and erratic.
3. Dysdiadochokinesia: impaired ability to perform movements that require a rapid
change of motion, leading to an inability to keep a steady rate or rhythm.
4. Gait ataxia: broad-based and staggering steps because of incoordination of the legs.
5. Intention tremor: a tremor with an increasing amplitude at the end of a voluntary
movement, due to impaired control of the proximal limb muscles.
6. Nystagmus: periodic, rhythmic oscillation of the eyes. Nystagmus can vary
significantly based on the underlying cause. It can be present in primary gaze or in
specific directions of gaze.
7. Truncal ataxia: instability of the truncal muscles, often manifested by oscillatory
movements of the trunk when sitting or standing.
8. Pseudoathetosis: involuntary, slow, writhing movements of the digits or distal limbs
when the eyes are closed; this results from loss of proprioception.
Given the number of disorders that cause ataxia, the presence and distribution (focal,
diffuse, unilateral, etc.) of the physical examination findings are key to making a clinical
diagnosis. These findings, however, remain tied to the patient’s history. By
understanding the nature of the ataxia (temporary, progressive, or episodic), the acuity
and age of onset, and family history, the differential diagnosis can be pared down
significantly.

ATAXIC DISORDERS
Ataxia is a hallmark of cerebellar disease. As there are many disorders that affect the
cerebellum, it is often the nonataxia-associated symptoms and examination findings that
help differentiate the origin of the ataxia (Table 8-1). Similarly, the time course of
symptom onset and progression aids substantially in diagnosis. Differentiated by time
course, several common causes of ataxia are summarized here and in Box 8-1.

TABLE 8-1. Associated Symptoms and Signs in Cerebellar Ataxia

Associated Symptom or Sign Diagnostic Possibilities
Vomiting Cerebellar stroke, posterior fossa mass
Fever Viral cerebellitis, infection, abscess
Malnutrition Alcoholic cerebellar degeneration, vitamin E deficiency
Depressed consciousness Cerebellar stroke, childhood metabolic disorders
Dementia Creutzfeldt–Jakob disease, inherited SCA
Optic neuritis Multiple sclerosis
Ophthalmoplegia Wernicke encephalopathy, MFS, multiple sclerosis, cerebellar stroke, posterior
fossa mass
Extrapyramidal signs Wilson disease, Creutzfeldt–Jakob disease, olivopontocerebellar atrophy
Hyporeflexia or areflexia MFS, Friedreich ataxia, alcoholic cerebellar degeneration, hypothyroidism
Downbeat nystagmus Foramen magnum lesion, posterior fossa mass
MFS, Miller Fisher syndrome; SCA, spinocerebellar ataxia.

ACUTE ONSET ATAXIA

Cerebellar strokes, either with infarction or hemorrhage, typically present as acute
onset ataxia. Depending on where in the cerebellum the infarct has occurred, clinical
symptoms may include truncal ataxia (seen with lesions of the cerebellar vermis) or
ipsilateral limb ataxia (with cerebellar hemisphere lesions). In many cases, there is
associated vomiting, vertigo, nystagmus, and dysarthria. In cases where hemorrhage or
postinfarction swelling leads to compression of the brainstem, impaired levels of
consciousness may occur. Because of this potential complication, cerebellar strokes are
considered medical emergencies.

BOX 8-1. Differential Diagnosis of Ataxias

Acute or subacute onset

Cerebellar hemorrhage or infarction
Postinfectious or infectious cerebellitis
Toxic (phenytoin, barbiturates, alcohol)
Multiple sclerosis
Episodic ataxia
Acute or subacute with progressive course
Paraneoplastic cerebellar degeneration
Alcoholic or nutritional degeneration
Posterior fossa mass
Chronic onset and progressive course
Autosomal dominant spinocerebellar degeneration
Autosomal recessive cerebellar degenerative disorders
Creutzfeldt–Jakob disease
Hypothyroidism
Wilson disease
Ataxia telangiectasia
Friedreich ataxia

Postinfectious cerebellitis is another acute-to-subacute ataxic syndrome typically

affecting young children between the ages of 2 and 7 years. Symptoms often follow a
viral infection, and there is a strong association with varicella. Symptoms of dysmetria,
gait ataxia, and dysarthria often accompany fever, headache, and vomiting. Fortunately,
symptoms typically resolve over the course of weeks with supportive therapy. Often,
antivirals and steroids are used for treatment.
The clinical triad of ataxia, areflexia, and ophthalmoplegia is the hallmark feature of
Miller Fisher syndrome (MFS). This, too, is often a postinfectious process. It is
thought that MFS is mediated by anti-GQ1b antibodies, which are found in the serum of
more than 90% of patients with this disorder. Typically classified as a variant of
Guillain–Barré syndrome, the illness is responsive to treatment with intravenous
immunoglobulin (IVIG).
Paraneoplastic cerebellar degeneration (PCD) is a disorder caused by the
development of autoantibodies. Pancerebellar symptoms of nystagmus, dysarthria, gait,
limb, and truncal ataxia often present acutely to subacutely, with progression in their
intensity over weeks. The disorder can lead to severe disability and often precedes the
diagnosis of malignancy. Associated with several cancer types (most notably ovarian
and small cell lung cancer), PCD is treated both by treatment of the underlying cancer
and by treatment with immunomodulatory therapies such as IVIG or rituximab. There are
at least nine autoantibodies associated with PCD, although only 60% to 70% of patients
have antibody positivity. Anti-Yo antibody, also known as Purkinje cell cytoplasmic
antibody type 1 (PCA-1), is the most common autoantibody in PCA.

SLOWLY PROGRESSIVE ATAXIC SYNDROMES

Alcoholic Cerebellar Degeneration

Chronic, long-term alcohol consumption is the most common cause of acquired
cerebellar degeneration. Alcohol abuse disproportionately affects the cerebellum and,
in particular, the vermis. This leads to gait and truncal ataxia that progresses over the
course of months to years. As similar syndromes and cerebellar pathology have been
seen in severe malnutrition, it is felt that alcoholic cerebellar degeneration may be due,
in part, to thiamine deficiency. In addition to abstinence from alcohol, treatment is often
focused on vitamin supplementation.

Friedreich Ataxia
Friedreich ataxia (FRDA) is a multisystem disorder and the most common hereditary
ataxia, affecting approximately 1:50,000 individuals worldwide. It is caused by a
trinucleotide repeat expansion in the gene that encodes a protein called frataxin. The
disease typically presents in childhood with gait ataxia, which slowly spreads to
involve the trunk and arms. In addition to the ataxia, the physical examination is often
notable for the distinct combination of absent reflexes, neuropathy, and upgoing toes.
Patients with FRDA are also susceptible to cardiomyopathy, diabetes, and hearing loss.
The disorder is progressive, and there is currently no treatment.

Autosomal Dominant Spinocerebellar Ataxia

The spinocerebellar ataxias (SCAs) are a diverse group of inherited ataxic disorders,
with nearly 40 genetically distinct disorders identified to date. These syndromes are
dominantly inherited and vary significantly in their age of onset. The classic
presentation is that of frequent falls and slurred speech in early adulthood. Depending
on the genetic subtype, patients may also have extrapyramidal, pyramidal, cranial nerve,
or cognitive symptoms. As for the underlying genetic etiologies, the most common forms
of SCA are due to polyglutamine repeats in causative genes. Machado–Joseph disease,
also known as SCA3, is the most common SCA worldwide. Less common forms of
SCA are related to ion-channel genes and genes involved in signal transduction.
Treatment is currently supportive.

Episodic Ataxia
Recurrent, brief episodes of ataxia, vertigo, nausea, and vomiting are the features of
inherited episodic ataxia (EA) syndromes. These disorders typically present in
childhood. Although some forms of EA have complete resolution of symptoms between
spells, these disorders can be associated with interictal symptoms as well as
progressive weakness and ataxia. The two most common forms of EA are EA-1 and
EA-2. The attacks of EA-1 are brief (seconds to minutes) but can occur as frequently as
30 times per day. Myokymia (muscle twitching) is common between events. EA-1 is
caused by mutations in the voltage-gated potassium channel gene KCNA1. EA-2 is the
most common EA syndrome. Caused by mutations in the calcium channel gene
CACNA1A, EA-2 is characterized by longer episodes of ataxia (lasting hours) with
interictal nystagmus and mildly progressive baseline ataxia. Treatment with
acetazolamide can significantly reduce attacks of ataxia.

KEY POINTS
● Sudden onset ataxia occurring with vomiting and depressed consciousness suggests a cerebellar stroke.
● Postinfectious cerebellitis is a common cause of ataxia in children.
● P CD is a pancerebellar syndrome and is most often associated with small cell lung cancer and gynecologic
malignancies.
● Alcoholic cerebellar degeneration typically affects the vermis and is manifested in gait and truncal ataxia.
● The inherited EAs are caused by mutations in calcium and potassium channel genes.
● The autosomal dominant SCAs are a heterogeneous group of slowly progressive degenerative disorders with
nearly 40 different genetic causes.

OTHER GAIT DISORDERS

The prevalence of gait difficulties increases with age, with more than 60% of patients
over the age of 80 having some degree of gait impairment. Because successful
ambulation is dependent on a number of factors including muscle tone and strength,
sensation, and healthy joint mechanics, nonneurologic disorders such as osteoarthritis
and impaired vision can also lead to gait disorders. When ambulatory difficulties are
present, direct observation of the gait is key to understanding potential contributors.
There are some aspects of gait that, when impaired, may yield enough information on
physical examination to diagnose particular neurologic causes (Table 8-2). Below are
pathologic gaits attributed to specific neurologic conditions or locations within the
nervous system.

TABLE 8-2. Etiology of Various Abnormal Gaits

Gait Disorder Anatomic Location Pathology
Hemiplegic Brainstem, cerebral Stroke, tumor, trauma
hemisphere
Paraplegic Spinal cord Demyelination (e.g., with multiple sclerosis), transverse myelitis,
compressive myelopathy
Bihemispheric Diffuse anoxic injury
Akinetic-rigid Basal ganglia Parkinson disease; other parkinsonian syndromes
Frontal Frontal lobes Hydrocephalus, tumor, stroke, neurodegenerative disease
Waddling Hip-girdle weakness Hereditary and acquired myopathies, muscular dystrophies
Slapping Large fiber Vitamin B12 deficiency, tabes dorsalis
neuropathy, dorsal
columns

SPASTIC GAIT
Impairment of upper motor neurons leads to spasticity of the muscles, limiting leg
flexion at the ankle, knee, and hip. The increased tone leads to a narrow base,
circumduction of the legs, with dragging of the toes. Tightness of hip adductors causes
“scissoring,” where the legs cross the midline with each step. Depending on the location
of the lesion, one or both legs can be affected.

AKINETIC-RIGID GAIT
This gait is characterized by a stooped posture, with the head and neck forward, and
slow, shortened steps (“marche à petits pas”). Initiating steps may be difficult, but once
the patient starts walking, there may be a quickening of the steps, known as festination.
Typical of Parkinson disease, this gait may also be seen in other parkinsonian
syndromes or conditions.

FRONTAL GAIT
Described as “magnetic,” a frontal gait is recognized by the impairment in lifting the
feet off the ground despite having normal strength and ability to move the limbs
appropriately when sitting or lying down. Other features of a frontal gait disorder
include a slightly wide base and impaired gait initiation. Frontal gait disorders are
related to impaired communication between the frontal cortex and the deeper structures
required for gait (basal ganglia, brainstem, etc.). This type of gait abnormality may be
due to a number of conditions, including vascular disease and hydrocephalus.

WADDLING GAIT
A normal gait requires the ability to stabilize the hips with each step. This is
accomplished by contracting the hip abductors on the weight-bearing leg while the other
leg rises from the ground. Failure of these muscles to contract effectively leads to a tilt
of the hip-girdle toward the nonweight-bearing leg during ambulation. A waddling gait
is characteristic of many myopathies that tend to disproportionately affect proximal
muscles.

SENSORY ATAXIA
Key to normal walking is the ability for the brain to know where the feet are in space.
Impairment in this sense of proprioception leads to a wide base—to compensate for the
loss of balance. In addition, the foot tends to hit the ground with the heel, with a
subsequent “slapping” of the forefoot leading to a characteristic “slapping” sound.
Limiting other sensory input (dark environment) or uneven surfaces tends to exacerbate
sensory ataxia.

PSYCHOGENIC GAIT
As with many organ systems, the nervous system can be a site of symptoms reflective of
a psychogenic process. When somatization affects gait, the abnormalities seen on
examination rarely fit a traditional or specific gait disorder. Often, the gait demonstrates
variable or inconsistent features. The legs and arms may move in an exaggerated fashion
when walking is attempted, with a tendency to “nearly fall” but without actually falling.
This type of gait is often referred to as astasia-abasia.

KEY POINTS
● Hemiparetic gait suggests hemispheric dysfunction, such as with a stroke.
● Diplegic gait is seen with a myelopathy and bilateral periventricular lesions, as in cerebral palsy.
● Paraparetic gait typically suggests spinal cord disease.
● Akinetic-rigid gait is a feature of parkinsonian syndromes.
● Frontal gait suggests hydrocephalus, neurodegenerative processes, or subcortical disease.
● Waddling gait suggests proximal muscle (hip-girdle) weakness.
● Slapping gait indicates large fiber sensory or dorsal column dysfunction.
● Gait that worsens with eyes closed is often indicative of a sensory or vestibular component to the gait
disorder.
● Astasia-abasia is the term for dramatically impaired gait due to psychogenic causes.
CLINICAL VIGNETTES

VIGNETTE 1
A 14-year-old girl is seen in the outpatient Neurology clinic for evaluation. She
describes a 3-year history of slowly progressive gait ataxia and slurred speech.
There is no family history of a similar disorder. Examination shows limb and gait
ataxia, slurred speech, nystagmus, absent ankle reflexes, hammering of the toes and
high arched feet, and diminished vibration sense in the toes.
1. The most likely cause in this child is:
a. Wilson disease
b. Postinfectious cerebellitis
c. FRDA
d. EA-2
e. MFS
2. Which inheritance pattern is most consistent with FRDA?
a. Autosomal dominant
b. Autosomal recessive
c. X-linked recessive
d. X-linked dominant
e. Maternal (mitochondria)
3. Which of the following systemic problems is not encountered in FRDA?
a. Hearing loss
b. Glucose intolerance and diabetes
c. Hypertrophic cardiomyopathy
d. Cardiac arrhythmias
e. Infertility

ANSWERS

VIGNETTE 1 QUESTION 1
Answer C:
FRDA is a debilitating neurologic disorder characterized by damage to the
cerebellum and the peripheral nerves. Onset is typically between the ages of 10 and
15 years. Characteristic findings include ataxia, slurred speech, dysphagia,
weakness, spasticity, loss of sensation, and skeletal deformities. Wilson disease
may also cause childhood onset ataxia, but is less likely here, given the evidence for
a polyneuropathy (absent ankle reflexes, diminished vibration sense, and foot
deformities indicative of a chronic process); there are isolated reports of
polyneuropathy in Wilson disease, but this is unusual. The slowly progressive
symptoms argue against a postinfectious cerebellitis (usually acute or subacute in
onset). EA is unlikely in view of the temporal course of symptoms. MFS may
include ataxia and evidence of neuropathy, but is typically acute or subacute in
onset, and it is usually characterized by ophthalmoplegia, which was not present in
this child.

VIGNETTE 1 QUESTION 2
Answer B
FRDA is an autosomal recessive disorder caused by a mutation in the FXN gene.
The inheritance is autosomal (rather than X-linked) recessive because the FXN gene
lies on chromosome 9, not on the X-chromosome. FXN produces a protein called
frataxin. The most common mutation is an expanded GAA trinucleotide repeat.
Normally, there are 5 to 33 GAA repeat units; in people with FRDA, the GAA
trinucleotide repeat is expanded to at least 66 units. The abnormally long
trinucleotide repeat disrupts the production of frataxin, severely reducing the amount
of this protein in cells.
Having made a presumptive diagnosis of FRDA, you recognize the multisystem
nature of this disease and the need to screen for systemic manifestations of the
disease.

VIGNETTE 1 QUESTION 3
Answer E:
Sensorineural hearing loss occurs in 13% of individuals with FRDA. Diabetes
mellitus occurs in up to 30%; patients without diabetes may have impaired glucose
tolerance. Hypertrophic cardiomyopathy is found in about two-thirds of patients
with FRDA; the electrocardiogram is abnormal in the majority. Infertility is not a
feature of FRDA.
 9 Urinary and Sexual Dysfunction

The complex neural mechanisms involved in bladder regulation make this process
sensitive to a wide variety of neurologic diseases affecting the central and peripheral
nervous systems, including but not limited to stroke, dementia, Parkinson disease,
multiple sclerosis (MS), and diabetes. Understanding the anatomy and physiology of the
normal bladder is important for both diagnosis and management of impaired bladder
control.

BLADDER CONTINENCE
ANATOMY AND PHYSIOLOGY
Bladder control is maintained at different levels of the nervous system and involves
sensory pathways as well as voluntary and involuntary motor pathways. Several
neuroanatomic connections important for bladder control create “circuits” with key
components located in the brain, spinal cord, and peripheral nerve ganglia. These neural
circuits coordinate the activity of smooth muscle (involuntary control of the bladder and
urethra) and striated muscle (voluntary control of the external urethral sphincter) leading
to urinary storage or micturition (voiding) (Fig. 9-1).
Voluntary micturition is controlled by a circuit connecting the dorsomedial frontal
lobes to the medial (M) region of the pontine micturition center (PMC). Through learned
behavior, the frontal lobes provide volitional control of micturition by initiating a
decrease in urethral pressure. This is followed by increased contraction of the detrusor
muscle, leading to voiding. The nearby lateral (L) region of the PMC, on the other hand,
produces a powerful contraction of the urethral sphincter (promoting storage).
Urinary storage and voiding is also controlled by reflexes at the spinal level, which
affect the PMC signaling. For example, afferent signals of bladder distention trigger
sympathetic outflow in the hypogastric and pudendal nerves to promote urethral
constriction and continence. During elimination of urine, efferent firing in the pelvic
nerves triggers the spinobulbospinal reflex that passes through the PMC and promotes
parasympathetic outflow to the bladder and urethra, allowing for bladder emptying (Fig.
9-1).
Lesions affecting the coordinated effort of the PMC produce a loss of inhibitory
control over spinal reflexes. Then, when the bladder becomes distended, the micturition
reflex is automatically activated at the spinal level, without the patient’s awareness or
control, and detrusor hyperreflexia (DH) and incontinence occur. Likewise, lesions
affecting the peripheral input and spinal reflexes can lead to a variety of urinary
symptoms including urinary retention, incontinence, hesitancy, and overflow urinary
incontinence.

DIAGNOSTIC EVALUATION
The first objective in the evaluation of bladder dysfunction is to determine if the
problem is neurologic or not and, if it is, localize the lesion causing the urinary
difficulties. A detailed history is essential. It is important to obtain information about
initiation; voiding problems such as frequency, stream characteristics, urine volume,
fullness, and urgency; effects of posture, cough, Valsalva maneuver, and medications;
and associated bowel and sexual dysfunction.
Thorough physical and neurologic examinations are necessary. The examiner seeks
signs of frontal lobe dysfunction, parkinsonian features, a sensory level, myelopathy,
and so forth. Laboratory evaluation includes urinalysis to rule out infection.
Measurement of the post-void residual (PVR) by bladder ultrasound or catheterization
is important in the characterization of bladder dysfunction. The PVR is the residual
volume in the bladder after voiding. A normal PVR is less than 50 mL. Urodynamic
studies can clarify the characteristics of incontinence, determine the underlying
neurologic abnormality, categorize vesicourethral dysfunction, and provide a basis for
appropriate therapy.
FIGURE 9-1. The control of bladder function. (Copyright © 2012 Dr. Juan Acosta, MD.)

Some urodynamic studies include the following:

• Cystometry: Provides information about bladder compliance, capacity, and volume at
first sensation and at urge to void; voiding pressure; and the presence of uninhibited
detrusor contractions.
• Cystourethroscopy: Assesses the integrity of the lower urinary system and identifies
important urethral and bladder lesions.
• Neurophysiologic studies: These include electromyography (EMG) of the sphincter
and pelvic floor muscles. Urodynamic findings in various types of neurogenic
bladder dysfunctions are listed in Table 9-1.
 KEY POINTS
● The M region in the pons is the site of activation of micturition.
● History and a complete neurologic examination are important in the evaluation of bladder incontinence.
● P VR should be less than 50 mL. Increased P VR implies poor bladder emptying. Sphincter dyssynergia and
atonic bladder are common neurogenic causes of elevated PVR.

TABLE 9-1. Urodynamic Findings in Neurogenic Bladder

Type Capacity Compliance Others
Spastic bladder Decreased Reduced Uninhibited detrusor
contractions
Atonic bladder Increased Increased Low voiding pressure and
flow rate

CLASSIFICATION
Based on the patient’s symptoms, urinary incontinence can be classified as follows:
Urge incontinence is an involuntary loss of urine associated with a strong desire to
void (urgency), usually associated with detrusor instability (DI). When the DI is the
result of a neurologic problem, the term detrusor hyperreflexia is used and its
clinical expression is a spastic bladder. DH is common in patients with strokes,
frontal lobe dysfunction, suprasacral spinal cord lesions, and MS. It is usually
accompanied by detrusor-sphincter dyssynergia (DSD), which is inappropriate
contraction of the external sphincter with detrusor contraction. This can result in
urinary retention, vesicoureteral reflux, and subsequent renal damage.
Stress incontinence is an involuntary loss of urine during coughing, sneezing, laughing,
or other physical activities that increase intraabdominal pressure (in the absence of
detrusor contraction or an overdistended bladder). This is common in multiparous
women who have cystoceles or weakened muscles of the pelvic floor. Other causes
include urethral hypermobility, significant displacement of the urethra and bladder
neck, and intrinsic urethral sphincter deficiency caused by congenital weakness in
patients with myelomeningocele or epispadias. This can also be seen in patients
who have had prostatectomy, local trauma, or radiation.
Mixed incontinence is a combination of urge and stress incontinence.
Overflow incontinence is an involuntary loss of urine associated with overdistention of
the bladder, typically reflecting a lower motor neuron problem. Patients report
constant dribbling and urge or stress incontinence symptoms. Causes of overflow
incontinence include an underactive or acontractile (atonic) detrusor because of
drugs, diabetic neuropathy, lower spinal cord injury or radical pelvic surgery
 (interrupting innervation to the detrusor muscle), or urethral or bladder outlet
obstruction, leading to overdistention and overflow.

KEY POINTS
● Spastic bladder implies an upper motor neuron problem caused by lesions involving the frontal lobes, pons, or
suprasacral spinal cord. Symptoms include incontinence with urgency and frequency. Urodynamics show
decreased capacity and reduced compliance.
● Stress incontinence is rarely a neurologic problem.
● Atonic bladder implies a lower motor neuron lesion at the level of the conus medullaris, cauda equina, or
sacral plexus; or it may reflect peripheral nerve dysfunction. It is characterized by overflow incontinence
and increased capacity and compliance.
● Sphincter dyssynergia produces an increased PVR, with fluctuating voiding pressures and varying flow rate.
● A small PVR is good; a large PVR with a spastic or atonic bladder is not. It can cause increased intrabladder
pressure with deleterious effects on the ureters and kidneys.

INCONTINENCE IN THE NEUROLOGIC PATIENT

SUPRASPINAL DISEASES AND INJURY
Supraspinal diseases usually result in a hyperreflexic bladder, causing urge
incontinence, reduced bladder capacity, and a small PVR, with no deleterious effects on
the upper urinary tract because voiding is unobstructed.

Cerebrovascular Disease
Large strokes (particularly frontal or pontine) produce an upper motor neuron bladder
(hyperreflexic and small, with urgency and frequency). Urinary incontinence after a
stroke is common and is associated with overall poor functional outcome.

Parkinson Disease
Voiding dysfunction occurs in 40% to 70% of patients with Parkinson disease. DH is
the most common finding. Pseudodyssynergia occurs as a consequence of sphincter
bradykinesia. Urologic causes, such as benign prostatic hypertrophy, are frequently
associated.

SPINAL CORD DISEASES

Spinal cord diseases account for more than 70% of patients with neurogenic bladder
dysfunction. Following disconnection from the pons, the sphincter tends to contract
when the detrusor is contracting (dyssynergia). Spinal cord injury produces DH, loss of
compliance, and DSD. New reflexes emerge to drive bladder emptying and cause the
DH. During spinal shock, the bladder is acontractile, but gradually, over weeks, reflex
detrusor contractions develop in response to low filling volumes.

Multiple Sclerosis
About 75% of patients with MS have bladder dysfunction. The types of bladder
complaints can vary, often reflecting a combination of cortical, brainstem, and spinal
disease. Many patients report irritative bladder symptoms, with DH and DSD occurring
in 50% to 90% of MS patients with bladder complaints.

PERIPHERAL NERVE DISEASES

Because of the bladder’s extensive autonomic innervation, its dysfunction is most often
seen in those generalized polyneuropathies involving small (autonomic) nerve fibers.
Urodynamic studies show impaired detrusor contractility, decreased bladder sensation,
decreased flow rate, and increased PVR. A classic example is diabetic cystopathy, in
which a progressive loss of bladder sensation and impairment of bladder emptying
eventually result in chronic low-pressure urinary retention. The situation is similar in
other types of neuropathies such as amyloidosis, immune-mediated polyneuropathies
(25% of Guillain–Barré patients have bladder symptoms), and inherited neuropathies.
Injury to pelvic nerves (e.g., by local radiation or surgery) can produce similar
symptoms.

KEY POINTS
● Stroke and spinal cord disease usually produce an upper motor neuron bladder or spastic bladder, with or
without sphincter dyssynergia.
● Small-fiber neuropathies can produce a neurogenic atonic bladder with a high PVR.

TREATMENT
Therapy for a neurogenic bladder includes pharmacologic and nonpharmacologic
approaches. Some behavioral techniques that may help with the treatment of this
condition include toileting assistance, bladder retraining, and pelvic muscle
rehabilitation.
Pharmacologic agents are available to treat bladder dysfunction. The choice of
therapy is based on an understanding of the underlying mechanism of the dysfunction and
therefore the site of the neural injury. Table 9-2 summarizes treatments for urinary
incontinence.
 KEY POINTS
● Therapy of urinary incontinence is individualized and often requires adjustments.
● The main management goals are preservation of upper urinary tract function and improvement of the
patient’s urinary symptoms that impair quality of life.

SEXUAL DYSFUNCTION
The sexual response cycle of excitement, plateau, orgasm, and resolution requires the
integrated and coordinated activity of the somatic and autonomic nervous systems
innervating the reproductive system. Sexual dysfunction affects both men and women
and can be caused by a multitude of psychological and physiologic conditions. Whereas
knowledge regarding female sexual physiology is less advanced than that of male sexual
physiology, approximately 40% of women and 30% of men experience sexual
dysfunction of one cause or another.

ANATOMY AND PHYSIOLOGY

Similar to the bladder, a combination of spinal reflexes consisting of sympathetic,
parasympathetic, and somatic innervation contributes to the regulation of the sexual
phases. Because of the differences in anatomy, the exact physiology differs between men
and women, but the general principles are the same and there are, in general, more
similarities than differences. The motor and sensory fibers that innervate the penis and
clitoris are carried in the pudendal nerve. The parasympathetic nerves involved in
erection in men and the sexual response in women originate in the sacral segments S2–
S4 and innervate their respective organs via the pelvic nerves. Activation of the
postganglionic parasympathetic neurons leads to arterial engorgement and thus,
expansion of the cavernous spaces (erection in men and clitoral and vaginal
engorgement in women). Parasympathetic activity also leads to increased prostatic and
vaginal secretions. Local tissue mediators such as nitric oxide and cyclic guanosine
monophosphate (cGMP) are primarily released by parasympathetic activity,
contributing to sustained engorgement. The sympathetic innervation of the sexual organs
arises from cells in the T11 to L2 levels of the spinal cord and travels through the
hypogastric plexus. Sympathetic activity causes vasoconstriction and loss of erection
and is important in ejaculation and orgasm.

TABLE 9-2. Treatment of Urinary Incontinence

CAUSES OF SEXUAL DYSFUNCTION
The etiology of sexual dysfunction can be multifactorial. Neurogenic causes include
neuropathy, myelopathy, cauda equina lesions, and central nervous system dysfunction.
Other causes include vascular disease, pelvic trauma, and endocrine disorders such as
hypothyroidism, hypogonadism, and hyperprolactinemia. Chronic illness such as liver
and kidney disease, psychological conditions, and drugs (i.e., antihypertensives,
anticholinergics, antidepressants, sedatives, alcohol, and narcotics) can also impair
sexual function.

DIAGNOSTIC EVALUATION
The evaluation of a patient with sexual dysfunction includes a complete history and
physical examination. Neurologic examination may provide evidence of cerebral, spinal
cord, or peripheral nerve dysfunction. Laboratory evaluation includes an endocrine
panel with levels of sex hormones, including prolactin, testosterone, and gonadotropins.
Sleep studies can be helpful; erection usually occurs with each episode of rapid eye
movement sleep. EMG and somatosensory-evoked potentials can help detect and
analyze myelopathy or peripheral nerve disease. Vascular studies evaluate the response
of the penis to the injection of vasoactive agents such as papaverine.

TREATMENT
The management of sexual dysfunction requires recognition of the etiology and treatment
of the underlying disease. Endocrine, metabolic, vascular, and psychogenic causes must
be treated when present. If drugs are responsible, changes in medication may be
beneficial. At present, there are no Food and Drug Administration–approved therapies
for female sexual dysfunction. Pharmacologic therapy of male erectile dysfunction
includes selective inhibitors of cGMP-specific phosphodiesterases like sildenafil and
vardenafil, intraurethral suppositories, and intracavernosal injections of alprostadil. A
full discussion of available medical and surgical treatments is beyond the scope of this
chapter.

KEY POINTS
● Sexual dysfunction is often multifactorial and can be caused by a variety of neurologic diseases, including
strokes, MS, and diabetes.
● Various medical and surgical therapies are available depending on the underlying cause of the sexual
dysfunction.
 10 Headache and Facial Pain

Headache disorders are among the most prevalent medical problems worldwide. The
World Health Organization estimates that 50% to 75% of all adults between the ages of
18 and 65 have headaches. This high prevalence results in significant disability and lost
productivity: headache disorders are the third highest cause of years lost to disability
worldwide.
Accordingly, headaches are one of the most common reasons patients present to
physicians in primary care settings, in the emergency department (ED), or in
neurologists’ offices. For clinicians evaluating a patient with headaches, the first
responsibility is to diagnose the type of headache correctly, and then treat appropriately,
because most headache disorders have excellent treatments available, which can reduce
the burden of disability.
Headache disorders fall into two categories, primary headache disorders (those
caused by the headache disorder itself, not due to other causes) and secondary
headache disorders, those caused by (or “symptomatic of”) another underlying medical
problem. The pain can be due to the involvement of pain-sensitive structures in the
head, including cranial nerves, cervical nerve roots, blood vessels, meninges, scalp,
temporomandibular joint (TMJ), teeth, pericranial and cervical muscles, and paranasal
sinuses.
Patients may also have multifactorial headaches, so a detailed history and
examination are necessary to identify the contributing factors. Headache disorders may
remain refractory to treatment or have an insufficient response to treatment if these
comorbidities are not identified and addressed.

DIAGNOSIS
A detailed history and examination are vital in understanding the headache’s cause.
There are no biomarkers currently available for primary headache disorders.

KEY POINTS FOR THE HISTORY

When obtaining the history the following information must be elicited:
• Onset
• Precipitants and triggers
• Duration
• Location (unilateral or bilateral; frontal, lateral, vertex, or occipital)
• Quality and severity
• Frequency
• Alleviating and exacerbating factors
• Positional influences (better or worse when supine)
• Waking the patient from sleep, or occurring upon awakening
• Associated with menses
• Associated symptoms
Additional aspects of the history important in evaluating a patient with headache are:
• Analgesic use
• Caffeine use
• Medical history
• Current or recent pregnancy
• Medications (including asking specifically about contraceptive use, over-the-counter
treatments, and supplements)
• Social history, including detailed screening for illicit drugs
• Family history
• Sleep, including a history of insomnia and snoring; symptoms of obstructive sleep
apnea
The semiology of the headache helps to differentiate a primary from a secondary
headache disorder. The history also allows a clinician to identify red flags that suggest
a secondary headache disorder (Box 10-1).

KEY POINTS FOR THE NEUROLOGIC EXAM

Patients with primary headache disorders usually have normal general medical and
neurologic examinations, although an acutely symptomatic patient with an autonomic
cephalalgia may have signs strongly suggesting that disorder. Some patients with
chronic headaches have findings of TMJ tenderness on palpation, evidence of dental
wearing, or pain with palpation of the cervical muscles or the occipital ridge to suggest
comorbid causes of headache such as cervicalgia.
In the era of the smartphone, patients may bring pictures of themselves to a clinician
for review if they have paroxysmal symptoms and signs (such as ptosis or lacrimation),
which can aid in the diagnosis.
Patients should have a general medical and neurologic exam to assess for secondary
causes of headache. Attention to vital signs is important: Patients with significant
hypertension may be susceptible to developing certain secondary headaches outlined
below; fever may suggest an underlying infection, including a central nervous system
(CNS) infection. A cardiovascular exam can evaluate for arrhythmia or carotid stenosis,
which can cause secondary headache syndromes. A detailed head and neck exam
includes evaluating for nuchal rigidity, cervical myofascial pain, occipital Tinel sign
(evaluated by eliciting tenderness or tingling when palpating near the occipital
protuberance along the occipital nerve), and palpation of the TMJ, assessment of dental
wearing or chipping to suggest bruxism, and observing the oropharynx for narrowing
that could suggest obstructive sleep apnea.

BOX 10-1. Red Flags

• Acute onset or progressive worsening from baseline

• New or different headache
• Systemic symptoms:
Fever, weight loss
• Risk factors:
Malignancy
Immunosuppression
IV illicit substance use
Hypercoagulability, including pregnancy
• Smoking
• Age>50, or no prior headache history
• Features of increased ICP:
Waking patient from sleep
Worsening with Valsalva maneuver
Supine worsening of pain
• Focal features:
Seizures
Mental status abnormality
Cranial nerve deficits
Weakness
Sensory changes (loss of sensation, paresthesias; location and pattern of spread)
• Precipitants:
Trauma
Newly prescribed medications
Infection

A full neurologic exam should also be performed, with emphasis on the funduscopic
exam to assess for papilledema. The cortical sensory exam can suggest cortical
dysfunction that may occur with venous sinus thrombosis. Focal neurologic deficits,
including field cuts, cranial nerve palsies, weakness, or sensory symptoms, often
suggest a secondary headache.
 KEY POINTS
● Headaches are divided into primary and secondary headache disorders.
● There are no biomarkers for primary headache disorders.
● Diagnosis is made primarily on a detailed history and examination.
● Always screen for red flags in the history.
● Screen specifically for pregnancy, contraceptive use, immune status, illicit substance use, and medications.

PRIMARY HEADACHE DISORDERS

Primary headache disorders are those not due to another medical condition. Diagnosis
is established by history and exam. Migraine is by far the most prevalent primary
headache disorder. Table 10-1 outlines common primary headache disorders based on
key features of the history. Figure 10-1 shows the common locations of pain in the
primary headache disorders, compared to that of headaches caused by sinus disease.

MIGRAINE

Migraine Without Aura

It is estimated that one in seven adults worldwide has migraine. It impacts women more
than men in a 2:1 ratio. Migraine may start in childhood and manifest occasionally with
abdominal symptoms (“abdominal migraine”). Motion sickness in children is a risk
factor for the development of migraine.

TABLE 10-1. Key Features of Primary Headache Disorders

Episodic Episodic Episodic Paroxysmal SUNCT and
Migraine Tension Cluster Hemicrania SUNA
Sex Female > male Female > male Male > female Female > male Male > female
Location Unilateral > Bilateral (band Unilateral (behind Unilateral (behind Unilateral (behind
bilateral around the head) or around the or around the or around the
eye) eye) eye)
Quality Throbbing, Dull pressure or Stabbing, burning, Stabbing, burning, Stabbing, burning
pulsatile tightening (vice- boring throbbing
like)
Severity Moderate to Moderate Severe Severe Severe
severe
Attack duration 4–72 h 30 min–7 d 15–180 min 2–30 min 1 s–10 min
Attack frequency Variable Variable From 1 every >5/d to 40/d From 1/d to 200/d
other day to 8/d
 Autonomic No No Yes Yes Yes
features
SUNCT, short-lasting unilateral neuraliform headache attacks with conjunctival injection and tearing; SUNA, short-
lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms.

Migraine headaches are most likely to develop in adolescence and early adulthood.
They can be episodic or chronic. The disability and lost productivity from migraine are
substantial, because it impacts people in their prime working years.
Migraine has numerous identified triggers, including weather changes, menses, and
caffeine (both withdrawal and overuse). Many patients identify foods and drinks such as
alcohol (most commonly red wine), soft cheeses, and nitrite-heavy foods, such as
processed meats, as precipitants, but data are sparse in this area and many migraine
attacks occur without identifiable triggers.
To diagnose migraine, a patient must have at least five attacks with the following
characteristics:
1. The headache lasts for 4 to 72 hours if untreated.
2. It must include at least two of the following features:
a. Throbbing
b. Unilateral headaches
c. Worsening with activity, such as walking
d. Moderate to severe pain
3. It must be associated with at least one of the following:
a. Nausea, vomiting, or both
b. Photophobia and phonophobia

FIGURE 10-1. Location of pain associated with primary headache disorders. Left to right: sinus headache,
cluster headache, tension headache, migraine headache. (Used with permission of A.D.A.M.)
Migraine with Aura
Migraine headaches are often preceded by focal neurologic symptoms known as auras.
These are also called classic migraine or complicated migraine. Auras are defined as
fully reversible neurologic symptoms with a gradual onset, usually followed by a
headache. The aura usually lasts for 5 to 60 (often 20) minutes and is typically
unilateral. It usually resolves without lingering neurologic deficits. Patients are
diagnosed with this disorder when they have an aura followed by a headache that meets
the criteria for migraine, as above. Some auras occur without a headache (“acephalgic
migraine”), but these symptoms usually require additional investigation for a definite
diagnosis.
Visual auras are by the far the most common. Some include a “fortification
spectrum” (zigzag lines off the central vision, usually spreading gradually) or a
scintillating (or flickering) scotoma (an area of decreased visual acuity surrounded by
preserved vision).
Migraine auras can also involve sensory symptoms, most commonly paresthesias
(tingling or pins-and-needles sensation). The paresthesias often “march” or spread
gradually over the course of several minutes along a limb or extend from an arm to the
leg or face.
Migraine auras can also include a gradual onset of weakness, a variant known as
hemiplegic migraine when severe. Hemiplegic migraine may be sporadic but there is
also a syndrome of familial hemiplegic migraine, sometimes associated with well-
characterized genes.
Migraine auras are believed to be due to “cortical spreading depression” in which
there is a spread of hyperpolarization of the cortex followed by a wave of
depolarization. Imaging studies have shown decreased regional cerebral blood flow in
the cortex during migraine aura, but not to the level of worrisome ischemia.

COMPLICATIONS ASSOCIATED WITH MIGRAINE

Status Migrainosus
When migraine lasts for more than 72 hours, the condition is known as status
migrainosus. This is often caused by abortive medication overuse (often referred to as
rebound headache) and frequently requires intravenous (IV) treatment or a brief course
of oral steroids to break the headache cycle.

Stroke Risk Associated with Migraine

Patients with migraine with aura have an increased cardiovascular risk when compared
to healthy controls. The use of estrogen-based contraceptives is therefore
contraindicated in patients with migraine with aura, as the combination results in a
substantially increased stroke risk.

Migraine and Menses

Women of reproductive age frequently have exacerbations of migraine during menses,
most commonly 1 to 2 days prior to the onset of bleeding, often persisting for up to 3
days into bleeding. This is thought due to the withdrawal of estrogen that occurs with
menses. Some women have migraine at the time of menstruation only, a condition known
as pure menstrual migraine. Most, however, have a few episodic headaches at other
times of the month, or menstrually related migraine. It is important to identify the
relationship of menses to migraine because there are specific treatments that may be
helpful for patients with a clear exacerbation around their menses.

Chronic Migraine
Patients who have a headache more than 15 days/month for more than 3 months are
diagnosed with chronic migraine. Some patients with chronic migraine do not have
typical features of migraine with all headaches, but they must have at least 8 days of
headache consistent with migraine to be diagnosed with chronic migraine. If the
headaches are not consistent with migraine, other diagnoses must be considered.
Patients often describe a history of gradually progressive episodic migraines that
increase in frequency to the point of meeting criteria for chronic migraine. With frequent
headaches, many patients with chronic migraine have some component of medication
overuse headache (MOH). Importantly, patients with chronic migraine can revert to
episodic migraine after effective treatment.

MIGRAINE TREATMENTS
Migraine treatments are divided into two categories.

Abortive Treatments
Abortive treatments, also called rescue medications, are medications used to stop a
migraine at the onset. All abortive treatments are most effective if the patient is treated
at the onset of the headache. Delay in treatment results in more prolonged disability, so
patients must be counseled on the appropriate use of abortive treatments.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans (serotonin 1b/1d
agonists) are the mainstays of abortive treatments. Many patients respond well to
NSAIDs alone. For some patients, however, they are insufficient; some patients have
contraindications to using NSAIDS. In these cases, triptans can be highly effective.
There are numerous different types, with different rates of onset of action and half-lives.
There are two long-acting triptans (naratriptan and frovatriptan) and five fast-acting
triptans (almotriptan, eletriptan, sumatriptan, rizatriptan, and zolmitriptan). There are
also numerous different formulations, including oral pills, disintegrating tablets, nasal
sprays, and injectables.
Historically, ergotamines were prescribed as abortive treatments, but they carry a
higher cardiovascular risk and have been largely replaced by triptans. Triptans and
NSAIDS can be combined when needed and may have a synergistic effect in treating
migraine pain. Caffeine is also often added to many migraine treatments because it can
help abort the pain; many over-the-counter “migraine preparations” contain caffeine.
Triptans are currently not known to be safe in pregnancy and have a cardiovascular
risk. They also interact with selective serotonin reuptake inhibitors and serotonin–
norepinephrine reuptake inhibitors, with a low risk of serotonin syndrome. Patients must
be counseled on side effects of all treatments. Identifying the right abortive treatment
requires careful consideration of the patient’s headache features, comorbidities,
concurrent medication use, cost, and family planning goals.
Using abortive treatments on a chronic basis more than twice a week can result in
MOH, so patients should be counseled to not use any of these treatments chronically
more than twice a week to prevent this complication.

Adjuvant Treatments
Because nausea and emesis are frequently associated with migraine, many patients
benefit from antiemetics. Interestingly, prochlorperazine and metoclopramide are more
effective than ondansetron, both in alleviating the nausea and in reducing the severity of
the pain. Antiemetics may also be useful in preventing patients from vomiting their
abortive therapies. They are frequently used in emergency room (ER) and urgent care
settings for patients with severe or refractory migraine. They are often combined with
ketorolac and diphenhydramine for patients with status migrainosus.

Preventive Treatments
Preventive treatments, also called prophylactic treatments, are used for patients with
chronic migraine or frequent and disabling headaches that do not respond sufficiently to
abortive treatments. Preventive therapy aims to reduce the frequency and severity of
migraine, although patients are unlikely to become completely headache-free and should
be counseled accordingly. All prophylactic treatments take some time to have an effect;
patients should remain on a treatment for at least a month (barring significant side
effects or other concerns) before assuming that the treatment is ineffective.
There are three primary categories of preventive oral medications: antihypertensives,
antiseizure medications, and antidepressants. Within each category, there are specific
drugs with the most evidence of efficacy (Table 10-2). In addition to oral therapies,
onabotulinum toxin A (often referred to simply as Botox) was also approved as
migraine prophylaxis for chronic migraine in 2010. In 2018, a new class of preventative
therapy for chronic migraine, Calcitonin Gene-Related Peptide (CGRP) antagonists was
approved by the FDA. Erenumabis is an injectable human monoclonal antibody that
antagonizes CGRP receptor function..
As with abortive treatments, selecting the right prophylactic medication requires
careful consideration of the patient’s comorbidities, concomitant medications, cost, and
family planning goals. Patients must be counseled about treatment options and side
effects, including teratogenicity and impact on contraceptives. Patients who require
preventive therapy also require abortive treatments. Some abortive treatments interact
with prophylactic medications (such as antidepressants and triptans) which should be
taken into consideration.

TABLE 10-2. Migraine Prophylaxis Oral Medications

Antihypertensives Antiseizure Drugs Antidepressants
Metoprolol Sodium valproate Amitriptyline
Propranolol Topiramate Venlafaxine
Timolol
Medications in bold have level A evidence for efficacy. Medications in italics have level B evidence for efficacy.

Lifestyle Modifications
Lifestyle factors are important to identify. A comorbid sleep disorder (insomnia,
obstructive sleep apnea, etc.) makes patients more susceptible to migraine. Skipping
meals, insufficient fluid, excessive caffeine intake, and lack of exercise make
susceptible patients more prone to migraine attacks. Patients should be counseled on
these factors.

KEY POINTS
● Migraines are episodic headaches that commonly cause unilateral, throbbing headaches, often associated with
photophobia, phonophobia, and nausea; they often worsen with exertion.
● Migraine auras are focal transient neurologic symptoms, most commonly visual, that fully resolve and are
usually followed by the headache.
● Patients with “migraine with aura” should not take estrogen-based contraceptives, as the combination
increases the risk of stroke.
● Migraine treatments are divided into abortive and prophylactic therapies.
● Abortive treatments are most commonly NSAIDs and triptans.
● Prophylactic treatments are mostly antihypertensive, antiseizure, and antidepressant drugs.

TENSION-TYPE HEADACHE
Tension-type headaches (often referred to as tension headaches, stress headaches, or
ordinary headaches) are the next most prevalent primary headache disorders, occurring
in 30% to 70% of adults worldwide. Pain is usually bilateral and described as pressure
or tightness. It is usually mild to moderate and lasts for under an hour to several days.
Unlike migraine, it is not associated with photophobia, phonophobia, nausea, or
vomiting. The examination is generally normal, but some patients have pericranial
tenderness to palpation of the scalp, neck, or shoulder muscles.
Tension-type headaches can be episodic or chronic (occurring more than 15
days/month). Interestingly, patients with infrequent tension-type headaches generally do
not seek medical attention, because they do not have significant disability from their
symptoms. Patients with frequent or chronic tension-type headaches benefit from
treatment.

TENSION-TYPE HEADACHE TREATMENT

Treatment for tension-type headaches is divided into abortive and preventive therapies.

Abortive Treatments
Many patients with tension headaches do not require abortive treatments because the
pain is generally mild and does not interfere with the patient’s functioning. For those
with moderate to severe pain, NSAIDs are the mainstay of treatment. Aspirin and
acetaminophen may also be used, but the latter is often less effective than NSAIDs.
Patients should be counseled about the development of MOH and advised to not use
analgesics more than twice a week for long periods.

Preventive Treatments
Antidepressants are the first-line preventive therapy for chronic tension headache. The
tricyclic amitriptyline is the most studied to date and has good evidence for efficacy.
Other antidepressants, including mirtazapine and venlafaxine, are second-line therapies.
Muscle relaxants such as tizanidine are helpful sometimes, particularly in patients with
a cervicogenic component.

Adjuvant Treatments
Tension headaches are often reported to be triggered by stress (physical or emotional);
addressing these triggers, if chronic, is important. Biofeedback (a mind–body technique
used to teach patients greater body awareness and how to control some physical
reactions to pain and stress) can be effective. Poor posture and neck muscle spasm are
also frequent contributors to chronic tension-type headaches, and physical therapy can
help.
 KEY POINTS
● Tension headaches are bifrontal and are pressure or squeezing pain.
● They are generally not as severe as migraine.
● They are not associated with migraine features such as photophobia, phonophobia, or nausea.
● Episodic tension-type headaches, when moderate to severe, are treated with NSAIDs.
● Chronic tension-type headache is often treated with amitriptyline.

TRIGEMINAL AUTONOMIC CEPHALALGIAS

Trigeminal autonomic cephalalgias (TACs) are the third major category of primary
headache disorders. They are characterized by unilateral pain associated with cranial
autonomic symptoms. The diagnosis is made by careful evaluation of the pattern of the
pain and its associated features. (See Table 10-1 for a summary of the different
headache characteristics.)

CLUSTER HEADACHE
Cluster headaches are severe headaches characterized by unilateral pain involving the
orbit, supraorbitally, at the temple, or combinations of these (Fig. 10-1). Cluster periods
are bouts of recurrent attacks of pain, generally lasting weeks to months. These periods
are followed by remission lasting anywhere from months to years. The pain is often
excruciating. During an attack, patients are often restless and pacing, unlike in migraine
where activity exacerbates the pain. The pain must be associated with one of the
following cranial autonomic symptoms:
• Conjunctival injection, lacrimation, or both
• Nasal congestion, rhinorrhea, or both
• Eyelid edema
• Forehead and facial sweating or flushing
• Sensation of fullness in the ear
• Miosis, ptosis, or both
Cluster headaches typically last between 15 and 120 minutes. During a cluster
period, headaches can occur several times a day or as infrequently as every other day.
Cluster headaches are relatively uncommon but are three times more likely to occur
in men. The age of onset is typically in early to mid-adulthood (20–40 years of age).
The cause is unknown, but activation of the posterior hypothalamic gray matter has been
seen in some patients during attacks. Alcohol, histamines, and nitroglycerin are triggers
in susceptible patients. A Horner syndrome caused by carotid dissection may mimic a
cluster headache (Fig. 10-2) but does not usually have the pain characteristics of this
primary headache disorder.

FIGURE 10-2. Cluster headache. Horner syndrome. Note mild unilateral ptosis (on the patient’s right side),
anisocoria with a smaller pupil on the side of the ptosis, and redness from associated cluster headache. The common
“upside-down” ptosis (i.e., elevation) of the lower lid is masked by coexisting eyelid laxity and blepharitis, which can be
confounding factors in older adults.

Cluster headaches may be episodic or chronic. Chronic cluster headache is defined

as intractable cluster headaches with less than 1 month of remission before the
recurrence of symptoms. Fortunately, less than 15% of cluster patients have chronic
cluster.

CLUSTER HEADACHE TREATMENTS

Abortive Treatments
A first-line abortive treatment for cluster headaches is 100% oxygen, delivered at 12 to
15 L/min. Patients may receive this treatment in an urgent care or ED setting and if
effective, be prescribed a home oxygen tank. For patients who do not respond, or who
do not have access to home oxygen, triptans are prescribed. Sumatriptan and
zolmitriptan are effective as abortive therapies. In the past, dihydroergotamine (DHE)
was prescribed as an abortive treatment, but triptans are favored over DHE given their
safety profile. Patients with cluster headache are very susceptible to MOH and must be
counseled appropriately. Occipital nerve blocks can also be effective to abort a cluster
cycle.

Preventive Treatments
Preventive treatments for cluster headache are similar to those used for migraine and
include antihypertensive, antiseizure, and psychiatric medications. Verapamil is the
first-line therapy for cluster headache prophylaxis. If not tolerated or if there are
contraindications, glucocorticoids (prednisone or dexamethasone) are also effective.
Lithium and topiramate are often used as second-line agents or as add-on therapy when
needed.
SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE
ATTACKS
Short-lasting unilateral neuralgiform headaches are unilateral, moderate to severe
headaches. Pain is around the orbit or temple but may also occur in the trigeminal
distribution and therefore be mistaken for trigeminal neuralgia (see section Facial Pain).
The headache is a stabbing pain or recurrent stabbing sensation lasting from 1 second to
10 minutes. Patients with a lesion in the posterior fossa may present with symptoms
suggestive of short-lasting unilateral neuralgiform headache, so brain imaging with
magnetic resonance imaging (MRI) is important to establish that this is a primary and
not secondary headache disorder.
There are two forms (see below), differentiated by the types of associated autonomic
symptoms (which always occur on the same side as the headache):
• Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and
tearing (SUNCT): Autonomic symptoms include both conjunctival injection and
lacrimation.
• Short-lasting unilateral neuralgiform headache attacks with cranial autonomic
symptoms (SUNA): Autonomic symptoms include at least one of the following:
• Forehead or facial sweating or flushing
• Ptosis or pupillary miosis
• Eyelid edema
• Nasal congestion, rhinorrhea, or both
• Ear fullness
• Either conjunctival injection or lacrimation, but not both
Both SUNCT and SUNA can be episodic or chronic. The chronic forms are
diagnosed by persistent symptoms lasting more than a year, or for less than a year but
with less than 1 month of remission.

Abortive Treatment
SUNCT and SUNA are challenging disorders to treat, given the brevity of symptoms.
Intravenous lidocaine has helped abort the cycle in some patients.

Preventive Treatment
Antiseizure medications including topiramate, gabapentin, and lamotrigine are used as
preventive therapy in patients with frequent or recurrent symptoms. Occipital nerve
blocks can also be helpful, especially when systemic medications are contraindicated or
not tolerated.

HEMICRANIA
The final TAC is hemicrania, a unilateral headache, differentiated from the other TACs
both by the duration of symptoms and by its unique response to indomethacin. Patients
present with a unilateral orbital or temporal headache associated with one or more
autonomic symptoms on the same side as the headache (the symptoms and signs are the
same as for SUNCT and SUNA).
There are three variants of hemicranias, differentiated by the duration of symptoms:
• Episodic paroxysmal hemicrania:
• Recurrent attacks separated by at least one pain-free month.
• Attacks last between 2 and 30 minutes but can recur within a day.
• Chronic paroxysmal hemicrania:
• Recurrent attacks without remission, or less than 1 month of remission before
recurrence.
• Attacks last between 2 and 30 minutes but can recur within a day.
• Hemicrania continua:
• Intractable pain and autonomic symptoms consistent with hemicranias, lasting for
more than 3 months.
All three forms respond to indomethacin, and this response to treatment is required to
make the diagnosis. Hemicrania is more common in women and typically occurs in mid-
adulthood (30–40 years of age). As with other TCAs, MRI to exclude a lesion in the
posterior fossa is also advised to exclude a secondary headache syndrome.

Abortive and Preventive Treatment

Indomethacin is the definitive treatment for hemicranias. An indomethacin trial is both
diagnostic and therapeutic. The dose is titrated gradually over 10 days to a maximum of
225 mg a day, divided into three doses, until the patient has a therapeutic response. If
there is no response, the diagnosis is not consistent with hemicrania and other etiologies
must be considered.

KEY POINTS
● TACs are unilateral headaches with pain around the orbit or temple.
● They are associated with autonomic symptoms on the same side as the headache.
● The differences among TACs are based on the duration of symptoms and associated features.
● Lesions in the posterior fossa should be excluded before making a diagnosis of a TAC.

OPIOIDS IN HEADACHE MANAGEMENT

Opioids are not more effective than alternate therapies and are generally strongly
discouraged for use in headache medicine. Most headache conditions are recurrent
disorders, so use of opioids in this setting risks development of a secondary opioid use
disorder. Opioids also tend to cause MOH.

SECONDARY HEADACHE DISORDERS

Secondary headache disorders are headaches caused by a medical condition or
medication. They have a broad differential for causes, ranging from preeclampsia and
pheochromocytoma to fever and medication side effects. Most secondary headaches are
associated with other features in the history, examination, or laboratory assessment,
which aid in the diagnosis. Treatment is based on addressing the underlying disorder.
There are six major categories of secondary headaches that may present with headache
only and must be considered.

VASCULAR CAUSES
There are numerous vascular causes of headache. All cerebral hemorrhages can cause
headache. This includes subarachnoid hemorrhage (SAH), intraparenchymal
hemorrhage, and subdural and epidural hematomas. These hemorrhages may be
spontaneous (associated with stroke or hypertension) or traumatic. Patients with
intracerebral hemorrhages typically present with what is referred to as a thunderclap
headache; the onset is abrupt and severe. Emergency imaging, usually with a
noncontrast head computed tomography (CT), is needed to evaluate any abrupt-onset
headache (Fig. 10-3). Cerebral vessel imaging is also warranted if a SAH is identified,
to assess for an aneurysm. Cerebral hemorrhages are discussed further in Chapter 14.
Ischemic strokes are often associated with headaches. Their semiology is
nonspecific, but typically abrupt in onset. Patients may have focal neurologic deficits
which aid in the diagnosis. Cerebral thrombosis, either arterial or venous, can also
cause headache. Patients with venous sinus thrombosis often have headaches with
features of increased intracranial pressure (ICP). Thrombosis should be considered
particularly in patients with hypercoagulability states, including pregnancy. The
diagnosis is made on imaging, including that of cerebral vessels (Fig. 10-4).
FIGURE 10-3. Examples of intracerebral hemorrhages on CT scans. (A) Epidural hemorrhage. (B)
Subdural hemorrhage. (C) Intraparenchymal hemorrhage. (D) Subarachnoid hemorrhage. Arrows point to the subdural
hematoma.
FIGURE 10-4. Deep venous sinus thrombosis in a pregnant woman. Sagittal image from a magnetic
resonance venogram (MRV) demonstrating occlusion of the deep venous system, including the straight
sinus (red arrow). The superior sagittal sinus (green arrow) and right transverse sinus (blue arrow) and
sigmoid sinus (orange arrow) are patent.

Cerebral vasculitis frequently causes a nonspecific headache. When part of a

systemic vasculitis, it is considered a secondary angiitis. If the vasculitis occurs in the
cerebral vessels alone, it is referred to as primary CNS angiitis. In addition to
headache, patients often have paroxysmal focal neurologic deficits. Cerebral arterial
vessel imaging and lumbar puncture (LP) are often required to make this diagnosis;
peripheral vessel biopsies may be necessary.
Giant cell arteritis (GCA), also called temporal arteritis, is a peripheral cranial
arterial vasculitis that often presents with a unilateral headache. Patients are generally
above the age of 50 and report additional symptoms including vision changes
(amaurosis fugax), jaw claudication, fever, and scalp tenderness. Involvement of the
branches of the external carotid artery, including the ophthalmic artery, can result in
blindness if not readily identified and treated promptly. Patients usually have elevated
inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). Empiric
steroids should be started in any patient with a high clinical concern. Temporal artery
biopsy is the gold standard, but GCA can cause “skip lesions” and may require serial
biopsies to identify the pathology.

INFECTIOUS OR INFLAMMATORY CAUSES

Intracranial infections, such as encephalitis and meningitis, usually present with
headache and often with fever. They may also have nuchal rigidity and altered mental
status. As the infection progresses, seizures and focal neurologic deficits may occur.
Infections can be bacterial, viral, fungal, or parasitic; the headache semiology does not
help to differentiate the underlying cause. LP is the crucial diagnostic test and necessary
in any patient for whom there is concern for a CNS infection. There are often other signs
of infection, and the headache has a temporal correlation to the infection (see also
Chapter 21 on CNS infections). CNS inflammatory and autoimmune conditions such as
sarcoidosis and lupus frequently present with headache.

NEOPLASTIC CAUSES
Intracranial neoplasms may present with headaches, especially when there is significant
mass effect. The headache semiology may be nonspecific but may have features of
intracranial hypertension, including wakening the patient from sleep, being worse when
supine, and worse with Valsalva maneuver. The headache may occur early or late with
neoplasms and with any type of primary cancer (see also Chapter 19 on CNS
neoplasms).

TRAUMATIC CAUSES
Head and neck injuries often result in headache. To be attributed to trauma, the
headache must develop with a temporal association to the injury. The severity of the
injury does not necessarily correlate with the severity of the headache; even minor head
injuries or whiplash may cause headaches. There is no specific headache semiology that
helps with the diagnosis. In patients with a history of significant head or neck injury, it
is important to assess for an intracranial hemorrhage or dissection of cervical vessels—
which may require additional treatment.
INTRACEREBRAL PRESSURE DISORDERS
Intracranial hypertension and hypotension can cause headaches, but with markedly
different semiologies.
Intracerebral hypertension may be “idiopathic” (most common in obese young
women) or due to medications or systemic disorders. The headache is often described
as worse when supine or sleeping (awakening the patient from sleep), or with Valsalva
maneuver. It improves with standing. Patients often have other associated features,
including papilledema, pulsatile tinnitus, or visual symptoms. Patients should have
imaging to exclude a mass lesion or venous sinus thrombosis. If the imaging is
unrevealing, the diagnosis is made with an LP when the patient is in the lateral
decubitus position with legs extended. Intracerebral pressure (ICP) is elevated if above
200 mm cerebrospinal fluid (CSF). Acetazolamide is the first-line treatment for
idiopathic intracranial hypertension (IIH). Patients require monitoring of their visual
fields, and treatment for obesity is warranted when present.
Intracerebral hypotension may be spontaneous or traumatic. This headache
improves when the patient is supine but worsens with standing. The pain is often most
severe at the vertex and can be associated with neck pain or tinnitus. It is frequently
traumatic—occurring after an attempted epidural puncture or LP. Generally, the dural
leak causing the headache heals gradually, without intervention, but when symptoms
persist or when the headache etiology is unclear, brain MRI may be helpful; it may
show evidence of sagging (Fig. 10-5). The definitive diagnosis is made with an LP
showing an opening pressure below 60 mm CSF. If a patient remains symptomatic from
intracranial hypotension, a blood patch may be attempted to cover the dural leak (if it
can be found).
FIGURE 10-5. Intracranial hypotension. Gadolinium-enhanced MRI scan of a patient with intracranial
hypotension. There is widespread, symmetric meningeal enhancement (arrows).

MEDICATION CAUSES
Medications associated with headaches are numerous. They range from hormonal
therapies, including contraceptives, to nitric oxide. Withdrawal of a medication or other
treatment may also cause a headache; the most common example is a caffeine
withdrawal headache. Headache semiology is nonspecific, but the temporal association
to medication change helps establish the diagnosis.
Medication overuse headache (MOH), also referred to as rebound headache or
drug-induced headache, is a chronic headache occurring in patients with a primary
headache disorder. The baseline headache disorder is typically markedly exacerbated
(i.e., more frequent, severe, or both) when the medication is overused. MOH is
diagnosed when patients use an abortive therapy 10 or more times per month for more
than 3 months with an increase in headaches.

KEY POINTS
● The history and associated signs and symptoms aid in the diagnosis of secondary headaches.
● Emergency cerebral imaging (usually a CT scan) should be obtained in patients with a thunderclap headache.
● In patients with suspected meningitis or encephalitis, an LP is needed to make the diagnosis.

FACIAL PAIN
In addition to the causes of primary and secondary headache disorders outlined above,
there are structural causes of headache and facial pain, as well as neuropathic causes.

HEAD AND NECK DISORDERS

There are many different structural disorders that can cause headache. Treatments are
based on the specific causes identified, and these disorders may occur simultaneously
with other primary or secondary headache disorders.
Sinusitis is commonly associated with a headache. It may be bifrontal or unilateral.
Acute sinusitis is often associated with other symptoms of a respiratory tract infection.
Temporomandibular joint disorder (TMD) is another common cause of headache and
may be unilateral or bilateral. On exam, there may be evidence of dental wearing
(chipped and flattened teeth) and discomfort on palpation of the joint. Cervicogenic
headaches are also common and may be identified by palpation of myofascial trigger
points in the neck. Cervical range of motion is often reduced.

TRIGEMINAL NEURALGIA
The pain of trigeminal neuralgia is shock-like, occurring in one or all branches of the
trigeminal nerve. The pain is usually paroxysmal and recurrent. It may be triggered by
common activities such as brushing hair or teeth. It may be idiopathic or due to
structural causes such as a mass or vascular lesion, or a demyelinating lesion of
multiple sclerosis. Carbamazepine is a common first-line treatment.

SUMMARY
Migraines, tension headaches, and TACs are the three most common types of primary
headache disorders. The International Headache Society maintains an evidence-based
categorization of primary and secondary headache disorders. If a headache history and
pattern is not consistent with a primary headache disorder, the clinician should consider
a secondary headache disorder, review the rare types of primary headache disorders, or
consider that the headache may be a combination of more than one headache disorder.

CLINICAL VIGNETTES

VIGNETTE 1
A 28-year-old woman is seen in the ER for the recent onset of daily headaches. She
describes the headaches as holocranial, aggravated by straining to defecate and
worst first thing in the morning when she wakes up. She has also noticed tinnitus in
her right ear. The headaches are not preceded by an aura, but she has had a few brief
episodes of transient blurring of vision in the right eye. Examination shows height of
5′2″, weight of 120 lb, and blood pressure 112/70 mm Hg. There is no neck
stiffness. There is binocular double vision on rightward gaze with slight limitation
of abduction of the right eye. Visual fields are normal on bedside confrontation
testing, and the optic discs have a normal appearance. Neurologic examination is
otherwise normal.
1. Which of the following is the most likely diagnosis?
a. Migraine
b. Tension-type headache
c. Low-pressure headache
d. Idiopathic intracranial hypotension
e. Chronic daily headache
 2. You suspect a diagnosis of IIH, but recognize that there is an important
differential diagnosis of secondary headache syndromes to exclude. Which of
the following evaluations or investigations is least appropriate?
a. Formal ophthalmologic evaluation
b. Brain MRI
c. Imaging of the cerebral venous sinuses
d. LP
e. Transcranial Doppler (TCD) ultrasound
f. Pregnancy test
3. Formal visual fields are normal. MRI of the brain is normal, and there is no
evidence for venous sinus thrombosis. Opening pressure at the time of LP was
29 cm H2O, but CSF contents are normal. You confirm the diagnosis of IIH.
Which of the following therapeutic options is not routine for patients with IIH?
a. Carbonic anhydrase inhibitors (e.g., acetazolamide, topiramate)
b. Endovascular venous sinus stenting
c. Optic nerve sheath fenestration
d. Repeated LP
e. Lumboperitoneal shunting

ANSWERS

VIGNETTE 1 QUESTION 1
Answer D:
There are two characteristics to this patient’s headaches that suggest raised
intracranial pressure: They are most severe first thing in the morning, and there is an
exacerbation with Valsalva maneuver. Moreover, the double vision on lateral gaze
with limited abduction of the right eye suggests a partial VIth nerve palsy that may
be a sign of raised intracranial pressure. Her visual symptoms are likely to be
transient visual obscurations, reflecting intermittent hypoperfusion of the optic nerve
head. IIH is high on the differential diagnosis, despite a normal body mass index. In
patients with this history, it is also important to screen for exposure to medications
that can cause or worsen increased intracranial pressure, such as tetracycline
derivatives.

VIGNETTE 1 QUESTION 2
Answer E:
Formal ophthalmologic evaluation should be performed to obtain more detailed
information about the visual fields and to look carefully for signs of early
papilledema. MRI of the brain is appropriate to exclude structural or mass lesions,
and some form of imaging of the venous sinuses is appropriate because venous sinus
thrombosis is an important mimic of IIH. The diagnosis of IIH requires that the CSF
is normal in content (e.g., without white blood cells), hence the importance of a LP.
TCD ultrasound does not have a role in the evaluation of patients with suspected
IIH. All premenopausal women presenting to the ED with headache should undergo
a pregnancy test to inform decisions regarding work-up and treatment.

VIGNETTE 1 QUESTION 3
Answer B:
Carbonic anhydrase inhibitors such as acetazolamide and topiramate are the primary
medical treatments for patients with IIH based on their mechanism of action—
reduced production of CSF. Repeated LPs to promote CSF drainage may also be
effective. Optic nerve sheath fenestration (ONSF) may be appropriate for patients
with papilledema who have visual loss but no or minimal headache and have been
refractory to other treatments. For those with papilledema, visual loss, and
headache, a lumboperitoneal shunt may be appropriate. Aggressive management
with ONSF or shunting is typically used to prevent or treat catastrophic or rapidly
progressive visual loss. Endovascular venous sinus stenting has been proposed
(based on the observations that it may reduce cerebral venous pressure, reduce
intracranial pressure, and improve symptoms), but the risk of serious complications
is high, so this procedure is not considered routine for the management of IIH. It
should be noted that in patients with comorbid obesity, weight loss is also essential
for treatment.
 PART III NEUROLOGIC DISORDERS
11 Aphasia and Other Disorders of
Higher Cortical Function

The behavioral neurology syndromes, including the aphasias, are some of the most
interesting clinical syndromes to both physicians and laypersons. Popular writings of
Oliver Sacks that describe these disorders of higher cortical function are commonly
cited as reasons to enter the field of neurology on residency applications. The
intellectual appeal of such syndromes is not difficult to understand: The higher cognitive
functions are what allow us to carry out essential social activities. From a historical
perspective, disorders of language and other cortical functions were among the first to
be described as being caused by dysfunction of discrete areas of the brain, giving rise to
the concept of cerebral localization in the 19th century.

APHASIA
Aphasia is an acquired disorder of language due to brain dysfunction. It is distinguished
from dysarthria, which is a disorder of the mechanical production of speech. Disorders
of attention may also masquerade as language disorders, but mental status assessment of
the inattentive patient will show dysfunction that extends beyond language. Patients with
hearing difficulties may also be misdiagnosed as having aphasia, especially older
patients who may not have their hearing aids during hospitalization.

DIAGNOSIS
For the purposes of this chapter, the left hemisphere will be considered the dominant
hemisphere for language; this is true in greater than 90% of right-handed people and in
50% of left-handed people. There are several forms of aphasia (Table 11-1) that are
classically caused by lesions in specific areas of the brain (Fig. 11-1) and can be
distinguished from each other by focused examination of the elements of language such
as fluency, comprehension, repetition, and the presence and types of paraphasic errors
(Table 11-2). Anomia (an inability to name an object) is seen to some degree in almost
all aphasias, so testing confrontation naming is one of the most sensitive screening tests
for aphasias—but it is not specific for determining which type of aphasia the patient
has. Common items such as a watch or coat are high-frequency objects that are
relatively easy for patients to name. Components of these items such as a watch dial or
lapel of a coat, however, are lower frequency words and, thus, more sensitive for mild
anomia. It is important to note, however, that impaired naming of low-frequency items
might also reflect a general knowledge deficit related to the patient’s educational
background rather than to an acquired language disorder.

KEY POINTS
● Aphasia is an acquired disorder of language due to brain dysfunction.
● Other causes of impaired communication—including problems with hearing, attention, initiative, or articulation
—are not truly aphasias.
● Anomia is seen in almost all types of aphasia.

BROCA APHASIA
Broca aphasia is primarily a disorder of fluent language production. Patients cannot
produce phrases of more than a few words, and speech is often described as
telegraphic: “me go store.” Content-rich words such as nouns and verbs predominate,
whereas connector words such as conjunctions and prepositions are notably absent.
Overly used phrases such as “how are you” tend to be preserved in patients with a
Broca aphasia. Paraphasic errors (word substitutions) occur often and are usually of the
phonemic type, in which sound substitutions are made (e.g., “spool” rather than
“spoon”). Patients are aware of and frustrated by their inability to communicate.
Comprehension is relatively preserved compared to fluency, but patients have difficulty
understanding sentences with complex syntax, such as when the passive voice is used.
For example, patients with a Broca aphasia will not be able to understand a sentence
such as “on top of the pen, place the paper” but may do better with a sentence such as
“put the paper on top of the pen.” Repetition is poor: It may be preserved at the level of
individual words, but longer phrases and those with any grammatical complexity prove
challenging to repeat.

TABLE 11-1. Aphasias

Type Fluency Comprehension Repetition Commonly Lesion
Associated Location
Signs
Broca Impaired Relatively Impaired Right hemiparesis Broca’s area
preserved (especially face) (inferior frontal)
Wernicke Preserved, but Impaired Impaired Right upper Wernicke’s area
often nonsensical quadrantanopia (superior
or “jargon temporal)
aphasia”
 Conduction Preserved Preserved Impaired Many paraphasic Arcuate
errors fasciculus, insula,
temporal isthmus
Transcortical Impaired Preserved Preserved. In Right hemiparesis Subcortical,
motor some cases adjacent to Broca
repetition is the area
only verbal output
Transcortical Preserved Impaired Preserved – Subcortical,
sensory adjacent to
Wernicke area
Global Impaired Impaired Impaired Severe right Large left
hemiparesis, gaze hemisphere lesion
deviation to left
Subcortical Variable Variable Variable, often Hypophonia, Left basal
preserved often in patients ganglia, thalamus
with basal ganglia
lesions

FIGURE 11-1. Higher cortical (language) centers in the left hemisphere.

Anatomically, a Broca aphasia is associated with lesions in the left posterior–

inferior frontal region, also known as Broca’s area. The most common cause of a Broca
aphasia is infarction in the superior division of the left middle cerebral artery, but other
causes including hemorrhage, tumor, and encephalitis can also produce a Broca aphasia.
Because this area of the cerebral cortex is adjacent to the motor cortex, patients with a
Broca aphasia often have right-sided weakness that is worse in the face and arm than it
is in the leg.

TABLE 11-2. Examination of Language Function

Function Testing
Fluency Listen to patient’s spontaneous speech to see if words are strung together into
 phrases of at least seven words. Overused phrases (e.g., “how do you do?”) do
not count.
Repetition Least challenging: Ask patient to repeat single words
Most challenging: Ask patient to repeat syntactically complex sentences, such as
“no ifs, ands, or buts about it”
Comprehension Least challenging: Ask patient to follow simple midline commands, such as “close
your eyes” or “open your mouth”
Most challenging: Ask patient to follow multistep appendicular commands that
cross the midline, such as “point to the ceiling, then touch your left ear with your
right hand”
Paraphasic errors Listen to patient’s spontaneous speech and observe for word substitutions.
Phonemic paraphasic errors are substitutions of sounds (e.g., “stadler” instead of
“stapler”). Semantic paraphasic errors are substitutions of words in related
categories (e.g., “lamp” instead of “flashlight”).
Naming Least challenging: Ask patient to name high-frequency objects, like watch or tie
Most challenging: Ask patient to name low-frequency objects or parts of objects,
like dial of watch or lapel
Reading Ask patient to read written material aloud and to follow written instructions
Writing Ask patients to write a sentence of their choosing or a sentence dictated by the
examiner Simply having patients write their names does not count (it is an
overlearned task)

KEY POINTS
● Broca aphasia is primarily a disorder of language production.
● Verbal output in Broca aphasia is nonfluent and telegraphic, with phonemic paraphasic errors.
Comprehension is impaired but is relatively preserved for simple phrases. Repetition is poor.
● Anatomically, Broca aphasia is caused by lesions in the left posterior–inferior frontal lobe (Broca’s area).

WERNICKE APHASIA
Wernicke aphasia is often described as a “receptive aphasia” in which the primary
deficit is in understanding spoken language. Patients have difficulty following basic
commands, even at the single word level. Although patients with Wernicke aphasia are
fluent, they also have difficulties with verbal expression: Their speech is often
nonsensical and is described as taking on the character of a “word salad” or “jargon
aphasia.” They make many paraphasic errors, mostly of the semantic type (word
substitutions based on word meanings such as “chair” for “table”). Some of these
paraphasic errors are completely new words, termed neologisms. Repetition is poor,
even at the single word level. Patients with a Wernicke aphasia often have little insight
into their deficits and comport themselves as if they do not have a communication
problem.
The classical anatomic locus in a Wernicke aphasia is in the posterior part of the
superior temporal gyrus in the left hemisphere, known as Wernicke’s area. Stroke in the
inferior division of the middle cerebral artery is the most common cause, but other
causes including hemorrhage, tumor, and inflammation can also produce a Wernicke
aphasia. Often, patients with a Wernicke aphasia have no other clinical deficits, but a
contralateral homonymous superior quadrantanopia may be present, and there may be
mild contralateral weakness or sensory loss.

KEY POINTS
● Wernicke aphasia is primarily a disorder of language comprehension.
● Speech is fluent and often excessive, but difficult to understand because patients have excessive paraphasic
errors, including neologisms.
● The lesions that typically cause a Wernicke aphasia are in the posterior part of the superior temporal gyrus
(Wernicke’s area).

OTHER APHASIAS
Conduction aphasia is characterized by poor repetition and frequent paraphasic errors.
Patients have difficulty correcting errors during spontaneous speech and they make
successive approximations while searching for a target word. Fluency and
comprehension are both preserved. The classical localization of conduction aphasia is
the arcuate fasciculus, which is a white matter tract that connects Wernicke’s area to
Broca‘s area. In practice, however, conduction aphasia is due to lesions in various
locations within the temporal lobe, parietal lobe, or insula.
Transcortical motor aphasia, like Broca aphasia, is a disorder in which language is
nonfluent with relatively preserved comprehension. Repetition is spared and, in some
cases, is the only verbal output that a patient has. The lesions that cause a Broca aphasia
are usually in the frontal white matter adjacent to Broca’s area. Anterior cerebral artery
strokes may cause transcortical motor aphasia, which distinguishes them from most
vascular aphasic disorders, which are due to strokes in the territory of the middle
cerebral artery.
Transcortical sensory aphasia is similar to Wernicke aphasia in that fluency is
preserved but comprehension is poor. Unlike in a Wernicke aphasia, however,
repetition is relatively spared. Lesions that produce transcortical sensory aphasia are
usually in the subcortical white matter underlying Wernicke’s area. Acute-onset
transcortical sensory aphasia is rare compared to other aphasia syndromes. The aphasia
that develops more chronically as part of Alzheimer disease often resembles a
transcortical sensory aphasia.
Global aphasia is characterized by nonfluent verbal output with poor comprehension
and repetition. It may range from complete mutism to minor deficits in each of the
aspects of language. The most common cause of global aphasia is a large left
hemisphere infarction due to ipsilateral internal carotid artery occlusion. Other deficits
including contralateral hemiplegia and ipsilateral eye deviation often accompany a
global aphasia.
In a mixed transcortical aphasia, repetition is spared but fluency and comprehension
are impaired. This aphasia is also known as isolation of the speech area and is due to
large left hemisphere lesions that spare the extrasylvian cortex. This is another rare
aphasia, which is most often seen in patients who have sustained global hypoxic injuries
or carbon monoxide poisoning.
Subcortical aphasias are due to lesions in the deep left hemisphere including the
basal ganglia and thalamus. They are often difficult to classify using typical methods,
although more anterior lesions tend to produce more problems with fluency and
posterior lesions tend to produce more problems with comprehension.

KEY POINTS
● Aphasias that involve the perisylvian cortex such as a Broca aphasia, a Wernicke aphasia, conduction
aphasia, and global aphasia produce impaired repetition. Aphasias that spare the perisylvian cortex, such as
the transcortical aphasias, spare repetition.
● In conduction aphasia, the primary problem with spontaneous speech is the multitude of paraphasic errors,
whereas on formal language assessment, repetition is the main deficit identified.

DISORDERS OF WRITTEN COMMUNICATION

Aphasic disorders affect all aspects and applications of language, not just spoken
language. Reading and writing deficits tend to parallel spoken language deficits,
although deficits are often amplified when patients attempt to read or write. Aphemia is
a disorder in which the opposite is true: Some patients with restricted left frontal lobe
infarctions lose fluency, often to the point of mutism, but their ability to write is
preserved. Patients with such strokes often recover quickly, unlike patients with a Broca
aphasia.
Alexia without agraphia is a syndrome in which patients cannot read but are able to
write. In fact, they are usually not able to read something they have just written. This
syndrome is usually caused by a left posterior cerebral artery infarction involving the
left occipital lobe and adjacent splenium of the corpus callosum. The left occipital
lesion produces a right homonymous hemianopia, and the callosal lesion disconnects the
visual cortex in the right occipital lobe from the language centers in the left temporal
and parietal lobes. Thus, the patient is not able to transmit any visual signals intact to
the language centers. The parietal lobe itself, where much of the writing function
resides, is preserved so patients are still able to write.

APRAXIA
Apraxia is the inability to carry out a learned motor task in response to the stimulus that
normally produces it, in the absence of a disorder of one of the component cognitive or
motor functions such as language, attention, or strength. Patients with apraxia have
difficulty interacting with the environment and more specifically, with using tools. They
may use the right tool for a task with the wrong action or be completely unable to use it.
The traditional terminology for the apraxias, devised by Liepmann, divides them into
ideomotor, ideational, and limb-kinetic forms. This nosology, however, can be
confusing, and it is probably more useful to simply describe what a patient can and
cannot do.
Examination for apraxia should assess both conceptual and actual use of tools. First,
ask the patient to pretend to perform an action without physically holding the tool that
would be used for that action, for example, “pretend to hold a toothbrush and brush your
teeth.” Next, pantomime the use of the toothbrush and ask the patient to do the same.
Finally, give the patient a toothbrush and see how he or she uses it. With each step, look
for problems with orientation or action of the imaginary or real tool with respect to its
target. Test several actions including saluting, hammering with a nail, and cutting with a
knife. Both hands need to be examined in isolation and in conjunction. Also, it is helpful
to determine whether a patient can identify if an action is being performed properly—by
having the examiner perform the task correctly and then incorrectly, and asking which
one was correct. Some patients have oral rather than limb apraxia that may be identified
by asking the patient to whistle or blow out a match.
Apraxia is usually due to left hemisphere lesions. Isolated lesions of the left parietal
lobe produce difficulty with both performing and recognizing appropriate actions. Left
frontal lesions, mostly in the supplementary motor area, produce difficulty with
performing actions, but patients can typically recognize when the examiner is
performing the action correctly or incorrectly. Lesions in the body of the corpus
callosum or right frontal lobe may produce isolated left-hand apraxia by disconnecting
the praxis centers in the left hemisphere from the motor control areas of the left hand in
the right hemisphere.

KEY POINTS
● Apraxia is the inability to carry out a learned motor task in response to the stimulus that normally produces it,
in the absence of a disorder of one of the component cognitive or motor functions such as language,
 attention, or strength.
● Bedside testing of apraxia should include asking a patient to pantomime use of a tool, imitate the examiner
using a tool, and use the tool physically.
● Lesions that produce apraxia involve the frontal or parietal lobes of the left hemisphere, the callosal region, or
the frontal lobe of the right hemisphere.

AGNOSIA
Agnosia is the inability to recognize an object despite preservation of the primary
sensory modality. The agnosias are a rare group of disorders that are most commonly
described in relation to vision. Apperceptive agnosia is an inability to recognize a
visual form. For example, a patient will not recognize what a fork is or that it is a
utensil used for eating. The patient will not be able to copy a picture of a fork.
Associative agnosia is an inability to recognize an object, although the patient is able to
describe it and copy a picture of it. Although there is some variability, apperceptive
agnosia most often occurs with left occipitoparietal lesions, whereas associative
agnosia most often occurs with left occipitotemporal lesions. Prosopagnosia is an
inability to recognize faces and is usually caused by either right-sided or bilateral
occipitotemporal lesions of the fusiform gyrus.

KEY POINTS
● Agnosia is a very rare disorder in which a patient cannot recognize an object despite preservation of the
primary sensory modality.
● Examples of agnosia include apperceptive agnosia, associative agnosia, and prosopagnosia.

GERSTMANN SYNDROME
Gerstmann syndrome is the tetrad of agraphia (inability to write); acalculia (inability to
perform arithmetical calculations); right–left confusion; and finger agnosia (inability to
recognize one’s own fingers or the fingers of the examiner). It is a rare syndrome caused
by lesions in the left parietal lobe, specifically the angular and supramarginal gyri. The
term Gerstmann syndrome should be used when the clinical tetrad is complete and not
accompanied by other deficits: disorders of attention may produce difficulty with all of
the components of the syndrome as well as other cognitive abnormalities.
 KEY POINTS
● Gerstmann syndrome is characterized by the combination of agraphia, acalculia, right–left confusion, and
finger agnosia.
● Lesions in the angular and supramarginal gyri of the left hemisphere may produce a pure Gerstmann
syndrome.

NEGLECT AND RIGHT HEMISPHERIC

SYNDROMES
Neglect is a disorder of directed attention that is usually due to right hemisphere
lesions. Patients lack awareness of what is happening in the left half of space, even in
their own left limbs. Neglect may affect visual, auditory, and tactile modalities, and in
some patients all of these modalities are affected simultaneously. In its most severe
form, a patient with neglect denies that the left side exists, and when presented with his
own hand says that it is the examiner’s hand. In milder forms, neglect may be detected
on targeted mental status examination only (Fig. 11-2). For example, asking a patient to
bisect a line may result in the line being bisected well to the right of the midline,
ignoring much of the left half of the line. A target cancellation test in which a patient is
asked to cross out target letters (“cross out all the As”) will also show evidence for
neglect: The patient will not cross out letters on the left side of the page. Finally,
extinction to double simultaneous stimulation, in which a patient detects only a right-
sided stimulus such as a brief touch on the right hand when both hands are touched
simultaneously, is another subtle manifestation of neglect.
Neglect is often accompanied by other behavioral abnormalities due to right
hemisphere dysfunction. Anosognosia is a patient’s inability to recognize that there is
anything wrong, for example, not knowing that the left side is paralyzed and stating that
there are no problems. Anosodiaphoria is a lack of concern about a deficit; the patient
recognizes that the deficit is present but does not seem disturbed by it. Aprosodia is a
loss of the rhythmic and dynamic components of language, resulting in a monotone voice
with very little fluctuation in tone and volume.
The most common source of neglect is a large right hemispheric lesion involving both
the frontal and parietal lobes, particularly an infarction in the distribution of the right
middle cerebral artery. Patients with frontal lesions may exhibit more prominent signs
of motor neglect, in which they do not use the left hand as much as the right hand. When
severe, neglect is usually associated with a left hemiparesis or hemiplegia and gaze
deviation to the right side.
 KEY POINTS
● Neglect is a disorder in which there is inattention paid to one hemispace, usually the left.
● Patients with severe neglect may not be able to describe things presented to them from the left side, including
their own limbs.
● Milder neglect may be manifested by poor line bisection, difficulty with target cancellation, and extinction to
double simultaneous stimulation.
● Neglect is usually caused by lesions in the right parietal and frontal lobes.

FIGURE 11-2. Drawing illustrating neglect of the left side.

CLINICAL VIGNETTES

VIGNETTE 1
You are called to the emergency room to evaluate a 78-year-old man brought in by
his family. They report that he was fine the night before but awoke in the morning
with a paucity of verbal communication. When you evaluate him, he seems awake
and alert, looking around at his environment, but he offers little spontaneous speech.
When you ask him questions, he responds with two or three word phrases only. He
is able to repeat complex phrases. Comprehension is largely intact.
1. Which of the following terms best describes this type of language disorder?
a. Broca aphasia
b. Transcortical motor aphasia
c. Wernicke aphasia
d. Conduction aphasia
 e. Transcortical sensory aphasia
2. Which is the most likely location for the acute lesion responsible for this
aphasia?
a. Arcuate fasciculus
b. Superior temporal lobe
c. Perisylvian cortex
d. Insula
e. Frontal lobe
3. Which of the following is almost invariably a manifestation of all aphasias?
a. Anomia
b. Anosognosia
c. Apraxia
d. Prosopagnosia
e. Acalculia

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
The reduced verbal fluency with relatively preserved comprehension suggests a
more anteriorly located aphasia. Repetition would be impaired in a Broca aphasia,
but normal, as in this case, with a transcortical motor aphasia. Wernicke and
transcortical sensory aphasia are incorrect as both are characterized by impaired
comprehension. Conduction aphasia is characterized primarily by impaired
repetition.

VIGNETTE 1 QUESTION 2
2. Answer E:
Broca aphasia localizes to the inferior frontal lobe, Wernicke to the superior
temporal lobe, and conduction aphasia to a variety of locations including the arcuate
fasciculus, temporal isthmus, and insula. Transcortical aphasias spare the
perisylvian arcuate fasciculus. Transcortical motor aphasia localizes to the frontal
lobe adjacent to Broca area and transcortical sensory aphasia to the inferior
temporal lobe.

VIGNETTE 1 QUESTION 3
3. Answer A:
Anomia is an inability to name, the sine qua non of aphasias. When testing language,
it is always wise to test the patient’s ability to name both high- and low-frequency
objects. Anosognosia, prosopagnosia, apraxia, and acalculia are nonlinguistic
disorders of higher cortical function. Anosognosia signifies a patient’s lack of
awareness of his or her neurologic deficit; it typically reflects a nondominant
hemisphere dysfunction. Apraxia is the inability to carry out a learned motor task
despite preservation of the primary motor, sensory, and coordination functions
needed for the task. Prosopagnosia is a specific form of agnosia (inability to
recognize objects), in which there is an inability to recognize faces. Acalculia is an
inability to calculate.
 12 Dementia

Dementia is the term to describe intellectual and cognitive deterioration of sufficient

severity to interfere with normal functioning. Dementia is not a specific disease and can
variably affect multiple aspects of cognitive function including memory, orientation,
visuospatial perception, language, and higher executive functions, for example,
planning, organizing, and sequencing. This differs from delirium, which implies an often
acute and reversible, global disturbance of mental function (discussed further in Chapter
3).

EPIDEMIOLOGY
Dementia is most common in the elderly but can occur at a younger age, particularly in
those with a hereditary predisposition. Approximately 5% of people between the ages
of 65 and 70 years have dementia; this increases to more than 45% above age 85 years.
Alzheimer disease (AD) accounts for 50% to 70% of cases of dementia.
Cerebrovascular disease may account for an additional 15% to 20%, and the other
causes presented in Box 12-1 account for most of the rest. The societal financial burden
of dementia is substantial, with recent studies estimating more than $150 billion spent in
the United States annually on dementia-related care, a cost on par with those of cancer
and heart disease.

CLINICAL MANIFESTATIONS
There is some degree of cognitive slowing that accompanies normal aging. In general,
however, most patients with actual dementia have more significant and progressive
difficulties, often affecting short-term memory, followed by an indolent deterioration of
cognitive function that may involve language, praxis, and personality. Many dementing
illnesses manifest characteristic symptoms and clinical findings that are helpful in
establishing an etiologic diagnosis.
DIAGNOSTIC EVALUATION
The initial recognition of dementia is difficult. Normal aging can mimic some of its
features. Rarely is the patient aware of cognitive deterioration; in most cases, the family
brings the patient to the doctor months or years after problems have started. Recent
research has demonstrated, however, that subjective cognitive decline reported by older
adults can be an early indicator of dementia, even in the absence of objective cognitive
dysfunction. Thus, the most important information in the diagnosis of dementia is the
clinical history (including reports by relatives) and the physical examination, especially
a very detailed mental status examination. Diagnosis of the cause of dementia consists
of matching the major clinical features of the individual patient with the characteristics
of known dementing illnesses. Of note, it is important to rule out an underlying
depression as the cause for cognitive symptoms, as the associated cognitive
abnormalities of depression can mimic dementia (“pseudodementia”). In addition,
depending on the clinical history and examination, laboratory studies may be helpful in
finding reversible causes of dementia. Box 12-2 summarizes some tests to consider in
the workup of cognitive dysfunction.

KEY POINTS
● Symptoms and signs of dementia include memory loss, abnormalities of speech, difficulties with problem
solving and abstract thinking, impaired judgment, personality changes, and emotional lability.
● The diagnosis of the cause of dementia requires a detailed history and neurologic and physical examination.

BOX 12-1. Causes of Dementia

Degenerative
Alzheimer disease
Lewy body dementia
Frontotemporal dementia
Progressive supranuclear palsy
Parkinson disease
Huntington disease
Spinocerebellar degeneration
Amyotrophic lateral sclerosis with frontotemporal dementia
Olivopontocerebellar atrophy
Metabolic
Hypothyroidism
Vitamin B12 deficiency
Wilson disease (copper deficiency)
Hypercalcemia
 Addison disease
Lipid storage diseases and leukodystrophies
Toxic
Drug intoxication
Alcohol
Arsenic, mercury, and lead intoxication
Infectious
HIV
Syphilis
Subacute sclerosis panencephalitis (postmeasles)
Vascular
Vascular dementia
Vasculitis
Structural, traumatic, autoimmune, and inflammatory
Chronic traumatic encephalopathy
Chronic subdural hematoma
Hydrocephalus
Neoplastic and paraneoplastic
Other
Undetermined
Mixed (Alzheimer plus vascular)

CAUSES OF DEMENTIA
ALZHEIMER DISEASE
In 1907, Alois Alzheimer, a German clinician and neuropathologist, published the
landmark case of a 51-year-old woman with deterioration of her mental state. Her
autopsy showed the classic pathology of Alzheimer disease (AD): neurofibrillary
tangles (NFTs) and senile plaques in the cerebral neocortex and hippocampus.

BOX 12-2. Tests to Consider in a Patient with Dementia

Hematologic screening, including erythrocyte sedimentation rate
Vitamin B12 and folate
Blood calcium
Liver function tests, including ammonia
Electrolytes
Serum urea nitrogen and creatinine levels
Infection workup, including syphilis, HIV, tuberculosis, etc.
Thyroid function tests
EEG should not be ordered routinely in a dementia assessment. Its use is justified when the patient has
evidence of fluctuations in cognitive status that could be seizures. The EEG may be useful at the initial
presentation in patients with suspected CJD
 Computed tomography or MRI of the brain: It rules out structural abnormalities such as tumor, subdural
hematoma, and hydrocephalus and evaluates cortical atrophy
Neuropsychological assessment: It is useful in early stages to establish the diagnosis of dementia and to use as
a comparison tool in the progression of the disease
Brain biopsy: It is only indicated in specific cases such as CJD, HIV, CNS vasculitis, and so on, to confirm the
diagnosis and find or exclude possible treatable causes.

CJD, Creutzfeldt–Jakob disease; CNS, central nervous system; EEG, electroencephalography; HIV, human
immunodeficiency virus; MRI; magnetic resonance imaging.

Clinical Manifestations
“Doctor, my mother is 75 years old, and over the last 3 years I have noted that she is
having more difficulty with her memory. She remembers her marriage 50 years ago, but
she does not remember that we were here yesterday. She asks the same questions
repeatedly and forgets my answers. She is unable to balance her checkbook, and
yesterday she could not find the way home from the drugstore.” This history illustrates
the characteristic features of AD. At the beginning of the illness, the examination shows
no difficulty with language, reasoning, or performance of normal social and personal
behaviors. Only those close to the patient notice small slip-ups, suggesting that
something is wrong (becoming lost while driving, misplacing objects, the kitchen stove
left unattended, missed appointments, loss of social and interpersonal interactions).
Later, the patient has more difficulty with activities of daily life.
As the disease progresses, other aspects of cognitive function are lost, including the
ability to speak, understand, and make decisions. Characteristically, in contrast to
patients with vascular dementia, elementary neurologic functions (motor, visual,
somatosensory, and gait) remain normal until very late in the disease. Psychiatric
manifestations are common at this time: personality changes (apathetic or impulsive),
aggressive behavior (physical or verbal), paranoid thoughts and delusions (persecution,
things being stolen), sleep disturbances (the word “sundowning” is used to describe
worsening psychiatric manifestations during the evening and night), hallucinations
(uncommon, and often a side effect of medications), and depression.
The disease course is relentlessly progressive. The average length of time from onset
of symptoms until diagnosis is 2 to 3 years, with subsequent nursing home placement
after 3 to 6 years. AD patients typically spend 3 years in nursing homes before death.
Thus, the total duration of AD is typically 9 to 12 years.

Epidemiology
Recent estimates suggest that more than 2 million people have AD in the United States
alone, with nearly 4% of people older than 65 years incapacitated by severe AD.
Because of increased life expectancy, the population at risk for AD is the fastest-
growing segment of society. Annually, approximately 100,000 people die of AD and
more than $25 billion is spent on the institutional care of patients with AD.

Etiology and Risk Factors

Many factors are associated with an increased frequency of AD, including age, female
sex, cerebrovascular disease, diabetes, and severe head trauma.
There are also many putative genetic risk factors. The gene for ApoE4 (on
chromosome 19) is associated with both early- and late-onset AD of both sporadic and
familial varieties. Early-onset AD has been associated with many different mutations in
presenilin genes PSEN1 and PSEN2 on chromosomes 14 and 1, respectively. Adults
with Down syndrome have a high risk of AD, in part because of the triplication of the
gene for amyloid precursor protein (APP) located on chromosome 21. Another mutation
in a gene on chromosome 12 that encodes α2-macroglobulin has been associated with
AD. The ApoE alleles and the α2-macroglobulin mutation predispose individuals to
early onset of sporadic AD, and even more to late-onset AD. Other mutations in APP,
PS1, and PS2 are associated with early onset of AD in the third through sixth decades.

Diagnostic Evaluation
With the exception of those patients with identified mutations in known causative genes
(APP, PSEN1, and PSEN2), the diagnosis of AD is a clinical one and can only be
confirmed with brain biopsy. The diagnosis is suggested by the clinical features and by
the insidiously progressive course. Investigations are designed to exclude other causes
of dementia (Box 12-2). Elevated tau protein and low amyloid-beta (Aβ)-42 levels in
the cerebrospinal fluid (CSF) have been suggested as early diagnostic markers for AD.
Magnetic resonance imaging (MRI)-based volumetric measurements may show
reduction of up to 40% in the size of the hippocampus, amygdala, and thalamus.
Functional neuroimaging, such as positron emission tomography (PET) and single-
photon emission computed tomography (SPECT) used to quantify cerebral metabolism
and blood flow, may help to differentiate AD from other dementias. In AD, PET and
SPECT scans show bilateral temporoparietal hypometabolism, but this is not specific
enough to be diagnostic.

Pathology
The major pathologic features of AD are brain atrophy, senile plaques, and NFTs,
associated with a substantial gliosis and loss of neurons in the cerebral cortex. NFTs
represent intracellular accumulation of phosphorylated tau protein. Senile plaques are
extracellular deposits of amyloid surrounded by dystrophic axons. How exactly each of
the known gene mutations associated with AD causes these changes is not established.
In the case of APP, mutations are known to cause increased Aβ production and change
the normal structure of the protein, altering its recognition by metabolizing enzymes,
therefore leading to a progressive accumulation of the peptide. Other pathophysiologic
mechanisms have been proposed, including inflammatory, oxidative, metabolic,
nutritional, and immune processes.

Treatment
At present, there is no satisfactory treatment for patients with AD. Therapy consists of
the following:
• Preventing associated symptoms: This includes treatment of depression, agitation,
sleep disorders, hallucinations, and delusions.
• Preventing or delaying progression: This includes therapy with acetylcholinesterase
inhibitors such as donepezil or rivastigmine, as well as memantine, an N-methyl-D-
aspartate (NMDA) receptor antagonist.
• Prophylaxis: Until now, there have been no successful single-drug clinical trials
demonstrating decreased dementia incidence. This may be due, in part, to the
heterogeneity of the underlying cause of AD, prolonged time course of the illness,
and the likely presence of a protracted, preclinical disease state. In addition to
clinical trials focusing on lifestyle-related interventions (i.e., physical activity, diet),
trials investigating preventative and disease-modifying drugs may one day provide
therapeutic options for the aging population. Table 12-1 provides information
regarding therapy for AD.

TABLE 12-1. Alzheimer Disease Therapy

Medication Mechanism of Action Comments
Donepezil (Aricept) Cholinesterase inhibitor Rare: hepatic toxicity. Common:
diarrhea and abdominal cramps.
Rivastigmine (Exelon) Cholinesterase inhibitor GI disturbances during dose
adjustment. Rare: hepatic toxicity.
Memantine (Namenda) NMDA receptor antagonist Dizziness, headache, confusion
Galantamine (Razadyne) Cholinesterase inhibitor GI side effects, weight loss
GI, gastrointestinal; NMDA, N-methyl-D-aspartate.

KEY POINTS
● AD is the most common neurodegenerative disease of the brain and accounts for 50% to 70% of all
instances of dementia.
● Risk factors for developing AD include older age, cerebrovascular disease, head trauma, female sex, and
family history.
● Potentially treatable causes of dementia should be excluded through laboratory testing and brain imaging.
● The average duration of AD is typically 9 to 12 years from symptom onset. Patients typically succumb from a
combination of neurologic and medical problems.
VASCULAR DEMENTIA
This dementia (previously referred to as multi-infarct dementia) may develop in patients
with cerebrovascular disease. There are two recognized types: macrovascular, related
to large infarcts, and microvascular, in which the pathophysiologic mechanism of brain
injury is subcortical ischemia associated with cerebral small vessel disease (lacunes or
deep white matter changes on MRI). Dementia related to extensive microvascular
changes of the white matter is called Binswanger disease. Vascular dementia has the
same risk factors as cerebrovascular disease, including hypertension, diabetes, age,
embolic sources, and extensive large artery atherosclerosis. It is common for vascular
dementia and other diseases (AD, Lewy body disease) to coexist in the same patient.
For this reason, it is unclear exactly how commonly dementia can arise from a purely
vascular etiology.

Clinical Manifestations and Diagnostic Evaluation

The criteria for diagnosis of vascular dementia include presence of dementia and two or
more of the following: focal neurologic signs on examination; onset that is abrupt,
stepwise, or stroke-related; or brain imaging showing multiple strokes, lacunes, or
extensive deep white matter changes. Most patients with vascular dementia are
hypertensive, diabetic, or both. The diagnosis requires investigation of the cause of
stroke. Cardiac and hypercoagulable workups should be considered in selected cases.

Treatment
The prevention and treatment of vascular dementia are essentially the same as
prevention and treatment of stroke (see Chapter 14).

KEY POINTS
● Vascular dementia may be a common cause of dementia, but it often coexists with other causes.
● Vascular dementia is associated with microvascular disease (Binswanger), lacunar infarcts, and large
strokes.

DEMENTIAS ASSOCIATED WITH

EXTRAPYRAMIDAL FEATURES
This group of dementias includes a wide array of neurodegenerative syndromes,
including but not limited to Lewy body dementia (LBD), frontotemporal dementias
(FTDs), progressive supranuclear palsy (PSP), corticobasal degeneration, striatonigral
degeneration, Huntington disease (HD), and Wilson disease. Some important examples
of these diseases are discussed here.

DEMENTIA WITH LEWY BODIES

Friedrich Lewy first described the cytoplasmic inclusions found in the substantia nigra
in Parkinson disease (PD) in 1912, but it was not until 1961 that these later-named
“Lewy bodies” were noted in the cortex of patients with dementia. LBD is now thought
to be the second leading cause of dementia (rather than vascular dementia). The clinical
picture of LBD is that of a parkinsonian dementia syndrome; it is considered to be on a
spectrum with PD dementia.

Clinical Manifestations
LBD patients typically present with early progressive cognitive decline, frequently
beginning after age 55. Visual hallucinations, often manifesting as small children or
animals, tend to be a prominent feature. Unlike in AD, cognitive domains such as
attention and visuospatial skills are typically affected earlier than memory difficulties.
The extrapyramidal symptoms can also be slightly different in that rest tremor is less
common, and signs are often symmetric. Bradykinesia and gait impairment are more
common than rest tremor. Marked fluctuations of alertness, delusions, and an
extraordinary sensitivity to neuroleptics (i.e., marked worsening with drugs like
haloperidol) are also key features of LBD.

Diagnostic Evaluation
The pathologic hallmark of this disease is the Lewy body, an eosinophilic intracellular
inclusion of the protein alpha synuclein. In LBD and PD, widespread limbic and
cortical Lewy bodies are found, to the point that it can be difficult, based on autopsy, to
distinguish pathologically from which clinical syndrome a patient suffered. Other
pathologic abnormalities can also be present, including varying degrees of AD-type
abnormalities such as NFTs and amyloid plaques.

Treatment
Management of LBD can be complex, because treatment of the parkinsonian syndrome
may worsen neuropsychiatric dysfunction and treatment of the neuropsychiatric disorder
may exacerbate the parkinsonian syndrome. Low doses of atypical neuroleptics such as
risperidone and quetiapine have been used to treat behavioral symptoms.
 KEY POINTS
● LBD may be the second most common type of dementia.
● Fluctuations of alertness, visual hallucinations, and an extraordinary sensitivity to neuroleptics are the three
key distinguishing features of dementia with Lewy bodies.
● Death typically ensues after 10 to 15 years.

FRONTOTEMPORAL LOBAR DEGENERATION

Frontotemporal lobar degeneration (FTLD) is the underlying pathology associated with
a heterogeneous group of degenerative disorders that collectively account for up to 20%
of dementias. Together, these disorders are a leading cause of dementia in patients
presenting before 65 years of age. First described at the turn of the previous century in
reports by Arnold Pick and Alois Alzheimer, FTLDs are pathologically notable for
marked, preferential degeneration of the anterior temporal and frontal lobes, with
prominent tau accumulation.

Clinical Manifestations
Unlike AD, FTLD often presents with behavior changes and nonmemory cognitive
deficits of the early, prominent involvement of the frontal or temporal cortices. The
range of clinical symptoms caused by FTLD can vary such that there are at least three
distinct clinical syndromes. These are behavioral variant frontotemporal dementia
(FTD), semantic variant primary progressive aphasia (PPA), and nonfluent/agrammatic
variant PPA. In addition, there are forms of FTD associated with parkinsonism and with
motor neuron disease.

Diagnostic Evaluation
As noted earlier with LBD, the clinicopathologic correlations of FTDs vary
significantly, likely because of the heterogeneity of the underlying cause of the FTLD.
There are multiple known genetic mutations associated with FTLD, and nearly 40% of
patients with FTD have a first-degree relative with dementia. The inheritance of FTD
has been linked to numerous genetic mutations, including mutations in chromosome 9
open reading frame 72 (C9ORF72), microtubule-associated protein tau, fused in
sarcoma (FUS), TAR DNA-binding protein-43 (TDP-43), and granulin. Interestingly,
mutations in C9ORF72, FUS, and TDP-43 are also associated with inherited motor
neuron disease amyotrophic lateral sclerosis (ALS) and FTD-ALS overlap syndromes,
a point that again illustrates the complexity with which these genetic mutations lead to
neurologic disease.
 KEY POINTS
● FTLD includes multiple clinical disorders affecting the frontal and temporal lobes prominently.
● FTD is a common cause of early-onset dementia (before age 65 years).
● Personality changes early in the disease are common in FTD, in contrast to the findings in AD.
● Nearly 40% of patients with FTLD have a first-degree family member with a history of dementia.

PROGRESSIVE SUPRANUCLEAR PALSY

PSP is a rare, progressive syndrome first described in 1964. Initially, it was felt to be a
type of Parkinson’s disease, but several features led to its classification as a distinct
disorder. Today, it is estimated that PSP may account for 2% to 3% of dementias. No
clear predisposing or genetic factors have been identified.

Clinical Manifestations
PSP typically presents in mid- to late adulthood. Its main features are supranuclear gaze
palsy, that is, an impairment of vertical eye movement; prominent postural instability;
and falls. Additional features of PSP include dysarthria, dysphagia, extrapyramidal
rigidity, gait ataxia, and dementia. As such, there are many subtypes of PSP based on the
prominent clinical abnormalities. Dementia may occur early or develop later, and
frontal lobe abnormalities predominate. Patients become apathetic. In early stages, PSP
may be mistaken for AD.

Diagnostic Evaluation
PSP remains a clinical diagnosis. Similar to AD, PSP is a tauopathy, but unlike the
cortical accumulation of tau in AD, there is a predominantly subcortical disease burden
in PSP, with atrophy of the dorsal midbrain, globus pallidus, and subthalamic nucleus.
The course is progressive, with a median survival of 6 to 10 years.

KEY POINTS
● PSP is a form of subcortical dementia with prominent extrapyramidal features.
● The characteristic clinical findings are limitation of vertical gaze, abnormal gait, and frequent or early falls.
● Median survival is 6 to 10 years.

HUNTINGTON DISEASE
Huntington disease (HD) is an autosomal dominant neurodegenerative disease with
typical clinical onset between the ages of 35 and 45 years. Key clinical manifestations
include chorea, behavioral changes, personality changes (frequently obsessive-
compulsive disorder), and dementia. Diagnosis is by family history, clinical signs, early
caudate atrophy (often very prominent) on brain imaging, and demonstration of more
than 40 CAG repeats in the HD gene on chromosome 4. Management is usually with
dopaminergic antagonists, including neuroleptic drugs, for the chorea. Despite these
therapies, the clinical decline is relentless. Genetic counseling for the family is
fundamental. See Chapter 16, Movement Disorders, for further discussion of HD.

KEY POINTS
● HD is characterized by chorea, dementia, and personality and behavioral changes.
● The clinical course is relentless, and death occurs 10 to 20 years after onset. Suicide is not rare in at-risk and
early-onset HD patients.

PARKINSON DISEASE
PD may produce subcortical dementia. Cognitive impairment develops in about 30% of
patients with idiopathic PD. The distinction from other types of dementia is based on the
natural history and the presence of associated symptoms. The clinical manifestations
include those of subcortical dementia, with marked psychomotor involvement. For more
information regarding PD, see Chapter 16, Movement Disorders.

DEMENTIAS CAUSED BY INFECTIOUS AGENTS

PRION-RELATED DISEASES
Prion-related diseases include Creutzfeldt–Jakob disease, or CJD (familial and
sporadic); Gerstmann–Sträussler–Scheinker syndrome; and fatal familial insomnia.
These so-called transmissible spongiform encephalopathies are a group of disorders
characterized by spongy degeneration, neuronal loss, gliosis, and astrocytic
proliferation resulting from the accumulation in the brain of a mutated protease-resistant
prion protein.
CJD is the most common of these disorders. It is characterized by a rapidly
progressive dementia with pyramidal signs, myoclonus, cerebellar or extrapyramidal
signs, and periodic sharp waves in the electroencephalogram (EEG). MRI with
diffusion-weighted images may show evolving cortical and basal ganglionic
abnormalities during the course of the disease. CSF is typically normal, but the presence
of protein 14-3-3 is relatively sensitive and specific for CJD. There is no therapy. This
syndrome evolves over weeks to months, and death usually occurs within a year.

KEY POINTS
● CJD is rare.
● CJD presents as a rapidly progressive dementia, often with focal neurologic signs and myoclonus.
● EEG and MRI are not diagnostic, but they become more specific in the setting of the appropriate clinical
history.

HUMAN IMMUNODEFICIENCY VIRUS–ASSOCIATED

DEMENTIA COMPLEX
Most patients with human immunodeficiency virus (HIV) disease have central nervous
system (CNS) involvement. This virus can produce an encephalitis and also makes the
individual susceptible to CNS infections such as toxoplasmosis, tuberculosis, and
syphilis, which can also cause dementia. HIV-associated dementia complex is a clinical
entity recognized in HIV patients (usually with low CD4 cell counts) and is
characterized by progressive deterioration of cognitive function.

Clinical Manifestations
Patients report memory problems, difficulty with concentration, and poor attention. The
pathophysiologic bases for this cognitive impairment have not been clarified.

Diagnostic Evaluation
MRI usually shows cortical and subcortical atrophy. White matter changes may also be
prominent.

Treatment
Highly active antiretroviral therapy (HAART) should be used and has reduced the
incidence of HIV-associated dementia in recent years.

KEY POINTS
● HIV-associated dementia is common in HIV patients with low CD4 cell counts.
● Therapy includes HAART.
METABOLIC CAUSES OF DEMENTIA
Vitamin B12 deficiency may present as a progressive dementing illness. Usually,
however, there are many other neurologic features and signs on physical examination,
including dysfunction of the spinal cord (subacute combined degeneration) and
peripheral nervous system, such that the diagnosis becomes evident even prior to the
development of dementia. The most common neurologic symptoms are those of
neuropathy (paresthesias in hands and feet, sensory ataxia, visual loss, orthostatic
hypotension) and memory loss. Other systemic manifestations include anemia and a sore
tongue. Appropriate replacement of vitamin B12 should suffice in the treatment. Other
metabolic causes of dementia are reviewed in Box 12-1.

CLINICAL VIGNETTES

VIGNETTE 1
A 71-year-old woman is brought into the neurologist’s office by her husband
because he has noticed that she has been forgetting things over the past 2 years. She
herself does not notice any particular memory problems, but he notes that she has
forgotten to pay the bills on several occasions, needs to use the global positioning
system device in the car to navigate, even to fairly familiar locations, and often
struggles to remember recent news events and conversations, despite watching TV
news every night. She still recalls remote biographical information such as details
of their wedding and her childhood but cannot remember much about a recent trip
they took together.
1. Which of the following diagnostic assessments is not appropriate initially as part
of an outpatient evaluation for the patient’s symptoms?
a. Screening for depression
b. EEG
c. Neuropsychological testing
d. Serum B12 testing
e. Neuroimaging
2. Neurologic examination shows that the patient has intact attention, but can learn
only 2 items from a list of 10 despite multiple repeated attempts. Some
hesitancy with word-finding and a few semantic paraphasic errors are noted in
the patient’s language, and she demonstrates some difficulties with copying a
complex figure. There are no focal abnormalities on the remainder of her
neurologic examination. A screening questionnaire does not suggest depression;
 brain MRI shows mild cerebral atrophy; and serum B12 and thyroid-stimulating
hormone are within the normal range. Which of the following would be an
appropriate treatment to consider for this patient?
a. Warfarin
b. Vitamin D
c. Donepezil
d. Carbidopa/levodopa
e. Clonazepam

VIGNETTE 2
A 59-year-old man presents with a year-long history of decline in function. He has
not been able to keep his job because of problems with concentration and his
supervisor’s concern about his lack of reliability and professionalism. He has had
odd visual hallucinations and episodes in which he has been very sleepy and
confused during the day. In the past couple of months, his gait has become slower
and stiffer. Neurologic examination demonstrates mild limb rigidity, bradykinesia,
and decreased arm swing. Upon presenting to an emergency room during a
prolonged episode of confusion, he was given haloperidol, which led to a severe
encephalopathy with stupor and extreme rigidity.
1. Which of the following is the most likely diagnosis?
a. CJD
b. PD
c. Normal pressure hydrocephalus
d. Dementia with Lewy bodies
e. AD
2. Further history from the patient’s wife indicates that he has had episodes in
which he has been thrashing around in bed violently, for which he has no
memory in the morning. Occasionally, he reports vivid dreams after these
events in which he is being chased by others down a long corridor. Which of
the following would be an appropriate pharmacologic treatment to consider for
these nighttime episodes?
a. Phenytoin
b. Methylphenidate
c. Clonazepam
d. Carbidopa/levodopa
e. Modafinil

ANSWERS
VIGNETTE 1 QUESTION 1
1. Answer B:
The patient is presenting with symptoms consistent with dementia. Initial steps in
evaluation include ruling out mimics of dementia (such as depression with
“pseudodementia”), establishing the severity and nature of cognitive deficits using
detailed mental status or formal neuropsychological testing, and ruling out
reversible or structural causes of cognitive decline (such as B12 deficiency,
hypothyroidism, or subdural hematomas or mass lesions). In this case, the patient’s
lack of awareness of her own symptoms, in the setting of concern by her spouse, is
more suggestive of true dementia rather than depression, but screening for
depression should still be performed. Neuropsychological evaluation to quantify
cognitive deficits is appropriate. B12 deficiency and subdural hematomas should be
ruled out because they might require specific interventions. EEG would generally
only be recommended in the setting of suspected seizures; periodic discharges on an
EEG can be seen in CJD, but this diagnosis is not otherwise suggested by the
patient’s history and time course of illness.

VIGNETTE 1 QUESTION 2
2. Answer C:
The most likely diagnosis is AD, with memory problems, visuospatial problems,
and a milder language problem that is similar to a transcortical sensory aphasia.
Treatments for AD include acetylcholinesterase inhibitors (such as donepezil) and
memantine (an NMDA receptor antagonist). The other pharmacologic agents listed
do not have a specific role in AD.

VIGNETTE 2 QUESTION 1
1. Answer D:
The constellation of cognitive impairment, parkinsonian signs, fluctuations in
alertness, and visual hallucinations is highly characteristic of dementia with Lewy
bodies. This is a degenerative disorder that is diagnosed pathologically by the
widespread presence of Lewy bodies within cortical neurons and is differentiated
from idiopathic PD by the timing of cognitive versus motor symptoms and the early
psychotic features. Dementia with Lewy bodies differs from AD in that a more
subcortical pattern of dementia is often present, with less effect on memory and
more on comportment and executive function. An exquisite sensitivity to the adverse
effects of neuroleptics is a notable feature of dementia with Lewy bodies; these
agents must be used with extreme caution if this diagnosis is suspected.
VIGNETTE 2 QUESTION 2
2. Answer C:
The most likely diagnosis for these episodes is rapid eye movement (REM) sleep
behavior disorder, a condition most common in elderly men, characterized by the
“acting out” of dreams during REM sleep. The usual atonia of REM sleep is
defective in this condition. REM sleep behavior disorder can occur in association
with dementia with Lewy bodies and PD and can even be the presenting symptom of
these conditions. Confirmation of the diagnosis is usually obtained through
polysomnography. Current treatment options for REM behavior disorder include
melatonin and clonazepam.
 13 Sleep Disorders

PHYSIOLOGY OF SLEEP
Sleep is a process necessary for life and is considered essential for restoration of
energy, consolidation of memory and learning, and maintenance of the immune system.
From a physiologic perspective, sleep can be divided into four stages: rapid eye
movement (REM) sleep and three stages of nonrapid eye movement (nREM) sleep.
REM sleep is distinguished not only by rapid eye movements, as its name indicates, but
also by atonia of all skeletal muscles other than the extraocular muscles and diaphragm.
The three stages of nREM sleep are distinguished from each other by
electroencephalogram (EEG) features. Stage N1 is a transitional state between
wakefulness and sleep and is characterized electrophysiologically by attenuation of the
posterior dominant background rhythm on EEG. Stage N2 is intermediate sleep and
features sleep spindles and K complexes. Stage N3 is also known as deep or slow wave
sleep and is characterized by an EEG background that consists of more than 20% of the
record in the delta frequency (0.5–2 Hz) range.
A typical night of sleep contains four to six cycles lasting approximately 90 minutes
each, with an orderly progression between stages as shown in Figure 13-1. Note that
stage N1 sleep is absent after the first sleep cycle and that both N3 and REM sleep
follow stage N2. Infants spend approximately 50% of sleep in REM, with this
percentage decreasing to the typical young adult value of 20% to 25% between ages 2
and 5 years. Healthy older adults have a decrease in REM sleep to 15% to 20% of the
night. As illustrated in Figure 13-1, REM sleep accounts for a greater percentage of
sleep as the night progresses.
Certain drugs and toxins may alter the proportion of the night spent in the various
stages of sleep. For example, benzodiazepines suppress stage N3, whereas
antidepressants and alcohol suppress REM sleep.

KEY POINTS
● Sleep is divided into four stages: REM sleep and three stages of nREM sleep.
● Sleep spindles and K complexes characterize stage N2 sleep.
 ● Adults spend between 20% and 25% of their sleep in REM.

POLYSOMNOGRAPHY
Apart from the history and physical examination, polysomnography (PSG) is the most
important step in the evaluation of a patient with a suspected sleep disorder. The PSG
consists of a limited EEG montage, which records brain activity and helps with the
staging of sleep, electro-oculography to monitor eye movements, surface
electromyography electrodes attached to the chin and legs to monitor skeletal muscle
activity, transducers to measure airflow and chest movements, pulse oximetry to
measure oxygen saturation, and electrocardiogram to monitor cardiac activity. Standard
PSG may be augmented by video monitoring to investigate for parasomnias such as
REM sleep behavior disorder and somnambulism.

FIGURE 13-1. Stages of sleep. Rapid eye movement (REM) sleep and the three stages of non-REM sleep
alternate throughout the night in cycles that last approximately 90 minutes. There are typically four to six cycles each
night in a healthy young adult.

CIRCADIAN RHYTHMS AND SLEEP-PHASE

DISORDERS
The body is governed by roughly 24-hour cycles of sleep and activity known as
circadian rhythms. These rhythms are coordinated by the suprachiasmatic nucleus of the
hypothalamus, with important inputs from melatonin produced by the pineal gland.
Pathologic circadian rhythms include advanced sleep-phase disorder in which patients
sleep or awaken earlier than they desire and delayed sleep-phase disorder in which
sleep onset is delayed until early morning, with consequent awakening later than
desired. Diagnosis of a circadian rhythm disorder is made by keeping a sleep log.
Bright light therapy and melatonin can treat sleep-phase disorders by resetting circadian
rhythms.
RESTLESS LEGS SYNDROME/PERIODIC LIMB
MOVEMENTS OF SLEEP
Restless legs syndrome (RLS) is a common sleep disorder characterized by an urge to
move the legs, usually during periods of rest or inactivity. Patients describe
uncomfortable crawling sensations in the legs, with worsening discomfort if the legs
remain still, and relief when they are moved. Typically, restless legs symptoms occur in
the evening or at night. They are often accompanied by periodic limb movements of
sleep, which are repetitive involuntary movements of the toe, ankle, knee, and hip that
last 2 to 3 seconds and are followed by slow recovery of the normal leg position. These
movements can awaken the patient, but generally are more bothersome to the bed
partner. RLS is more common in women, and in some families an autosomal dominant
inheritance pattern is probable.
Diagnosis of RLS is made by clinical history. PSG may help to confirm the diagnosis
but is often not necessary. Laboratory evaluation of RLS should include measurement of
ferritin levels, as many patients with RLS have iron deficiency.
The dopamine agonists ropinirole and pramipexole are often the preferred initial
treatments for RLS. Typically, they are administered 2 to 3 hours prior to symptom
onset in the evening. Many patients require an afternoon dose. Side effects of dopamine
agonists include nausea, lightheadedness, and sometimes sleep attacks (falling asleep
suddenly in the daytime). The most important side effect of dopamine agonists for RLS
patients, however, is augmentation in which symptoms develop progressively earlier
in the day. If augmentation becomes a severe problem or RLS symptoms worsen despite
treatment with dopaminergic agents, other options include gabapentin, pregabalin
(which may be less likely to produce augmentation than dopaminergic agents),
levodopa, opioids, and benzodiazepines. Rotigotine is a transdermal dopamine agonist,
which may produce less augmentation. Correction of iron deficiency can help to relieve
symptoms, although dopaminergic agents are often required even after this is
accomplished.

NARCOLEPSY/CATAPLEXY
The four components of the narcolepsy/cataplexy syndrome are excessive daytime
sleepiness with narcolepsy, cataplexy, sleep paralysis, and hypnagogic hallucinations.
Narcolepsy is the irresistible urge to sleep, often taking the form of sleep attacks, that is,
falling asleep suddenly in the daytime. Cataplexy is characterized by the sudden loss of
muscle tone, often in the setting of laughter or other strong emotions, and is the most
specific feature of the syndrome. Hypnagogic hallucinations are those that occur
immediately upon falling asleep.
Onset of narcolepsy/cataplexy syndrome usually occurs in the late teens or twenties.
The pathophysiology of narcolepsy/cataplexy is related to loss of hypocretin-secreting
neurons in the hypothalamus. A cerebrospinal fluid hypocretin level <110 pg/mL is
diagnostic for the syndrome in the appropriate clinical setting. More typically, however,
the diagnosis is established by performing a special type of PSG known as the multiple
sleep latency test (MSLT). An MSLT involves several short naps and monitoring of the
latency to sleep onset and latency to REM onset. Sleep latency of less than 8 minutes,
with more than two episodes of REM at sleep onset, is diagnostic for
narcolepsy/cataplexy.
Modafinil, an alerting agent with an unclear mechanism of action, is typically the first
agent employed for patients with narcolepsy. Amphetamines such as methylphenidate
and dextroamphetamine are also employed, but less frequently due to safety concerns
and potential for abuse. Cataplexy is most often treated with the gamma-aminobutyric
acid metabolite sodium oxybate. Tricyclic antidepressants such as clomipramine and
selective serotonin reuptake inhibitors including fluoxetine and venlafaxine are also
options for treating cataplexy.

KEY POINTS
● The clinical tetrad of narcolepsy/cataplexy is excessive daytime sleepiness with narcolepsy, cataplexy, sleep
paralysis, and hypnagogic hallucinations.
● Shortened sleep onset latency and REM at sleep onset are features identified on MSLT in patients with
narcolepsy/cataplexy.
● Modafinil has become the agent of choice for the treatment of narcolepsy.
● Sodium oxybate, tricyclic antidepressants, and selective serotonin reuptake inhibitors are used to treat
cataplexy.

PARASOMNIAS AND DYSSOMNIAS

Parasomnias are abnormal behaviors that occur during sleep or sleep–wake transition.
There is a wide variety of these disorders, and only a few of the more common ones
will be discussed here.

AROUSAL DISORDERS
These parasomnias are characterized, as their name suggests, by abnormal arousals
from sleep. In confusional arousals, patients awaken with disorientation, slow speech,
and incoordination. Sleep terrors involve rapid awakening from sleep with fearful
behavior, often beginning with a scream, and are associated with autonomic
hyperactivity such as facial flushing, diaphoresis, and tachycardia. Patients with sleep
terrors may be difficult to console upon awakening. A lack of memory for the event
helps to distinguish sleep terrors from nightmares. Somnambulism is characterized by
interruption of sleep by a variety of complex motor activities, including not only
walking, but also dressing, driving, or eating.

REM SLEEP–RELATED PARASOMNIAS

A variety of parasomnias may arise from REM sleep. Nightmares are frightening, vivid
dreams that usually occur during the second half of the night and are remembered well
by patients, unlike sleep terrors. Sleep paralysis is the perception of being unable to
move, usually on awakening. REM behavior disorder is characterized by the loss of the
normal skeletal muscle atonia during REM sleep, with the patient acting out the dreams.
A wide range of behaviors including punching, kicking, jumping, and yelling may occur.
In some cases, these result in injury to the patient or the bed partner. Patients with this
disorder are at increased risk of developing a synucleinopathy such as Parkinson
disease, Lewy body dementia, or multiple system atrophy. Clonazepam administered at
bedtime is the preferred treatment for REM behavior disorder.

SLEEP–WAKE TRANSITION DISORDERS

Nocturnal cramps are experienced as a painful tightness, most often in leg muscles.
Treatment options include gentle exercise before bedtime, potassium and magnesium
supplementation, antihistamines, anticonvulsants, and quinine. Somniloquy is
unintelligible mumbling during sleep, which can be provoked by talking to the patient.

OTHER PARASOMNIAS
Sleep starts or hypnic jerks are commonly experienced myoclonic jerks that occur with
sleep onset. Enuresis is abnormal nocturnal bedwetting, defined as more than three
episodes per week. Boys are more likely to have enuresis than girls. Most cases of
enuresis resolve spontaneously, although conditioning the child or using imipramine
may hasten this resolution. Bruxism is teeth grinding during sleep; treatment of
underlying dental abnormalities or use of a biteplate is often helpful. Sleep-related
dissociative disorders occur in the transition between sleep and wakefulness, usually in
patients with psychiatric disorders. Patients enact complex, bizarre, and nonstereotyped
behaviors, some of which are prolonged.

SLEEP APNEA
Sleep apnea is the cessation of airflow during sleep. It may be divided into obstructive
sleep apnea (OSA), in which a mechanical obstruction of the upper airway prevents
airflow, and central apnea, in which airflow is reduced because of diminished central
nervous system–derived ventilatory effort. Many patients have both obstructive and
central dysfunction. Symptoms of OSA include excessive daytime sleepiness, snoring,
cessation of breathing in the middle of the night, and morning headaches. Untreated OSA
may lead to cognitive complaints including word-finding difficulties, lack of motivation,
and memory loss. In addition, OSA increases the risk for stroke, hypertension, and
cardiopulmonary disease. Risk factors for the development of OSA include obesity
(body mass index >30 kg/m2 or neck circumference greater than 17 inches in men or 16
inches in women), a crowded airway (enlarged tongue, tonsils, and palate), and
advanced age.
PSG confirms OSA: A combination of more than five apneas, hypopneas, or
respiratory event–related arousals per hour is required to establish the diagnosis.
Apneas are defined as respiratory pauses with 90% or greater airflow reduction lasting
10 seconds or more. Hypopneas are defined as reduction of 30% to 90% or more
airflow for more than 10 seconds with at least 4% reduction in baseline oxygen
saturation. Respiratory event–related arousals occur when criteria for apneas and
hypopneas are not met, but there is a decrease in airflow accompanied by an arousal
identified by EEG.
Continuous positive airway pressure (CPAP) is the standard treatment for OSA. This
apparatus delivers air at a predetermined pressure through a tube connected to a
facemask. Patients with a diagnosis of OSA may have a “split-night” PSG in which the
first part of the night is spent in diagnosing and quantifying the severity of the disorder,
whereas the second part of the night is spent titrating the CPAP to best prevent episodes
of interrupted breathing. In addition to CPAP, patients with OSA benefit from weight
loss, alcohol cessation, and sleeping on their sides rather than on their backs. Surgical
intervention may be indicated should CPAP and behavioral modification prove
ineffective or poorly tolerated: Options include uvulopalatopharyngoplasty to relieve
upper airway obstruction and hypoglossal nerve stimulation.

KEY POINTS
● CPAP is the treatment of choice for OSA.

INSOMNIA
Insomnia is defined as difficulty initiating or maintaining sleep. Consequences of
insomnia include excessive daytime sleepiness, poor concentration, and irritability.
Insomnia has a variety of causes including psychological disorders, medical conditions,
toxins and medications, circadian rhythm disorders (see above), and poor sleep
hygiene. In most cases, therefore, a careful medical and sleep history is essential in
establishing its diagnosis. PSG may be needed to make the diagnosis in some cases,
particularly sleep state misperception in which a patient thinks that he or she is sleeping
less than is actually the case. The first step in treating insomnia is to identify and treat
any medical or psychiatric disorders that may be contributing. Behavioral therapy,
including improving sleep hygiene and facilitation of relaxation before bedtime, is also
important in improving insomnia. Agents including melatonin, antihistamines,
benzodiazepines, nonbenzodiazepine medications (e.g., zolpidem, zaleplon, and
eszopiclone), or the selective melatonin receptor agonist ramelteon may be required for
some patients. Many of these agents have addictive properties, however, and should be
used cautiously and for short periods of time.

KEY POINTS
● Insomnia is the most common sleep disorder and is often due to a medical or psychiatric disorder.
● Behavioral modification is the mainstay of treatment, with sedatives reserved for patients with refractory
insomnia.

CLINICAL VIGNETTES

VIGNETTE 1
A 22-year-old woman presents for evaluation of excessive daytime sleepiness. For
the last 2 years, she has felt tired throughout the day and needs to take several short
naps. She cannot fight the need to nap—which seems to develop rather suddenly.
She goes to bed at 11 PM each night and wakes up at 7 AM. She has no difficulty
initiating sleep and does not snore. She does not drink caffeine. She has fallen
asleep while driving three times, on one occasion having a serious accident.
1. Based on this information, what is the most likely diagnosis?
a. Sleep-related dissociative disorder
b. Delayed sleep-phase disorder
c. Insomnia
d. Narcolepsy
e. OSA
 2. What is the next step in the evaluation of this patient?
a. Brain magnetic resonance imaging (MRI)
b. 24-hour video EEG with sphenoidal electrodes
c. MSLT
d. Polysomnogram
e. Sleep log
3. Which of the following would be the most appropriate treatment for this patient?
a. Behavioral modification
b. Caffeine
c. Carbamazepine
d. Modafinil
e. Zolpidem

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer D:
Narcolepsy presents with the clinical tetrad of excessive daytime sleepiness,
cataplexy, hypnagogic hallucinations, and sleep paralysis. By history, this patient
has excessive daytime sleepiness with narcolepsy (including sleep attacks). In
sleep-related dissociative disorder, patients enact complex, bizarre, and non-
stereotyped behaviors. Delayed sleep-phase disorder is characterized by a delay of
sleep onset to the early morning with awakening not taking place until the later
morning or early afternoon. Excessive daytime sleepiness may be a feature of
delayed sleep-phase disorder, but sleep attacks are not. Insomnia is a difficulty
initiating or maintaining sleep, but sleep attacks are not a feature of idiopathic
insomnia. OSA is uncommon at this patient’s age, and her history is not consistent
with this diagnosis.

VIGNETTE 1 QUESTION 2
2. Answer C:
MSLT showing a rapid onset of REM sleep is diagnostic for narcolepsy/cataplexy.
Brain MRI and EEG do not have a role in the evaluation of this patient. Standard
PSG is useful for many sleep disorders, but the MSLT is most appropriate for this
patient. Sleep logs are the diagnostic test of choice for circadian rhythm disorders.

VIGNETTE 1 QUESTION 3
3. Answer D:
Modafinil and amphetamines are the most appropriate treatments for patients with
narcolepsy/cataplexy. Behavioral modification is successful for many patients with
insomnia. Caffeine may help with excessive daytime sleepiness, but is less effective
than modafinil or amphetamines for patients with narcolepsy/cataplexy.
Carbamazepine is prescribed most commonly for patients with epilepsy rather than
for those with sleep disorders. Zolpidem is useful for insomnia, but is not
appropriate for this patient.
 14 Vascular Disease

A stroke is a neurologic injury caused by an abnormality of the blood vessels supplying

the central nervous system. Although strokes may occur in the spinal cord, they are
uncommon and this chapter will focus on strokes that involve the brain. In the United
States each year, about 800,000 individuals have a stroke and 130,000 die from a
stroke, that is, a stroke every 40 seconds and death from stroke every 4 minutes. Stroke
is the fifth leading cause of death in the United States and a very important cause of
prolonged disability. Although strides have been made in the prevention and treatment
of stroke in the last 25 years, the economic, social, and psychological costs of stroke
remain huge.
Many medical conditions and behaviors predispose to stroke. These include
hypertension, diabetes, obesity, hyperlipidemia, sedentary life style, smoking, cardiac
disease, and heavy alcohol use. Prevention of stroke is very important and can be
accomplished by physicians attending to these stroke risk factors, advising patients
about their lifestyles and habits, and prescribing appropriate medications. Primary
prevention is prevention of a first stroke, whereas secondary prevention is prevention of
stroke recurrence. Second and third strokes are most often due to the same stroke
subtype as the initial stroke. Identification of stroke etiology, therefore, is the most
important step in avoiding recurrence.

VASCULAR ANATOMY
The nature of neurologic symptoms and signs helps to localize dysfunction to a
particular area of the brain and a particular vascular supply. Intimate knowledge of the
vascular anatomy of the brain, therefore, is necessary. The cerebral vasculature is
divided into the anterior and posterior circulations, with the anterior (carotid)
circulation supplying the cerebral hemispheres except for the medial temporal lobes and
a portion of the occipital lobes, and the posterior (vertebrobasilar) circulation
supplying the brainstem, thalami, cerebellum, and the posterior portions of the cerebral
hemispheres (Fig. 14-1).

ANTERIOR CIRCULATION
The right common carotid artery (CCA) branches from the innominate artery. The left
CCA arises directly from the aorta. The CCA divides in the neck into the internal
carotid artery (ICA) and the external carotid artery. The ICA travels behind the pharynx,
entering the skull where it forms an S-shaped curve—the carotid siphon. This portion of
the ICA gives rise to the ophthalmic artery. The ICA then penetrates the dura and gives
off the anterior choroidal and posterior communicating arteries before bifurcating into
the anterior cerebral (ACA) and middle cerebral arteries (MCA).
The ACA supplies the anterior medial cerebral hemispheres, the caudate nuclei, and
the basal frontal lobes. The anterior communicating artery connects the two ACAs. The
MCA courses laterally, giving off lenticulostriate artery branches to the basal ganglia
and internal capsule. The MCA trifurcates into small anterior temporal branches and
large superior and inferior divisions. The superior division supplies the lateral cerebral
hemispheres superior to the sylvian fissure, whereas the inferior division supplies the
temporal and inferior parietal lobes.
The anterior choroidal artery arises from the ICA after the ophthalmic and posterior
communicating arteries. It courses along the optic tract giving off branches to the globus
pallidus and posterior limb of the internal capsule and then supplies the medial
temporal lobe and the lateral geniculate body.

FIGURE 14-1. Schematic diagram of the vascular territories of the brain. [coronal section. ACA, anterior
cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral arteries.]

POSTERIOR CIRCULATION
The first branch of each subclavian artery is the vertebral artery (VA). The VA enters
the spinal column via the transverse foramina of C5 or C6 and runs within the
intravertebral foramina, exiting to course behind the atlas before piercing the dura mater
to enter the foramen magnum. The intracranial VAs join to form the basilar artery at the
ponto-medullary junction.
The intracranial VA gives off posterior and anterior spinal artery branches,
penetrating arteries to the medulla, and the posterior inferior cerebellar artery (PICA).
The basilar artery then runs in the midline along the clivus giving off bilateral anterior
inferior cerebellar artery and superior cerebellar artery (SCA) branches before
dividing at the pontomesencephalic junction into the posterior cerebral arteries (PCA).
Small penetrating arteries arise at the basilar artery bifurcation to supply the medial
portions of the midbrain and thalami.
The vascular supply of the brainstem includes large paramedian arteries and smaller,
short circumferential arteries that penetrate the basal portions of the brainstem into the
tegmentum. Long circumferential arteries course around the brainstem and give off
branches to the lateral tegmentum. The PCA gives off penetrating arteries to the
midbrain and thalamus, courses around the cerebral peduncles, and then supplies the
occipital lobe and inferior surface of the temporal lobe.
The circle of Willis connects the anterior circulations of each side through the
anterior communicating artery, and the posterior and anterior circulations of each side
through the posterior communicating artery (Fig. 14-2).

KEY POINTS
● Each carotid artery supplies two-fifths of the brain; the vertebrobasilar circulation, one-fifth.
● The anterior circulation supplies mainly the cerebrum, whereas the posterior circulation supplies the
brainstem, cerebellum, thalami, and the visual cerebral cortex.

BRAIN ISCHEMIA
About 80% of strokes are ischemic whereas 10% each are due to subarachnoid and
intracerebral hemorrhages. Ischemic strokes are divided into thrombotic, embolic, and
systemic hypoperfusion mechanisms.

THROMBOSIS
Thrombosis refers to obstructed blood flow due to a localized occlusive process within
one or more vessels. The most common vascular pathology is atherosclerosis, in which
fibrous tissue and lipid materials form plaques that encroach on the lumen.
Atherosclerosis affects mostly the large cervical and intracranial arteries. Less
commonly, a clot forms within the lumen due to a primary hematologic problem, for
example, polycythemia, thrombocytosis, or hypercoagulability. Vessel wall pathologies
leading to thrombosis include vasoconstriction, fibromuscular dysplasia, and arterial
dissection. Thrombosis of penetrating intracranial arteries is most often the consequence
of hypertension, with hypertrophy of the media and deposition of fibrinoid material.
Microatheromas can obstruct the penetrating artery origins.

FIGURE 14-2. Arteries of the circle of Willis. [ACA, anterior cerebral artery; AICA, anterior inferior cerebellar
artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral arteries; PICA, posterior
inferior cerebellar artery; SCA, superior cerebellar artery.]

EMBOLISM
An embolus occurs when clot material formed elsewhere within the vascular system
lodges in a vessel and blocks blood flow. The material arises proximally, mostly from
the heart; from major arteries such as the aorta, ICAs, and VAs; and from systemic
veins. Cardiac sources of embolism include the heart valves, endocardium, and clots or
tumors within the atrial or ventricular cavities. Artery-to-artery emboli are composed of
clot, platelet clumps, or fragments of plaques. They may begin in large arteries and
occur in the context of arterial dissection. Thrombi originating in systemic veins travel
to the brain through cardiac defects such as an atrial septal defect or a patent foramen
ovale, a process termed paradoxical embolism. Occasionally, air, fat, cholesterol
crystals, bacteria, and foreign bodies enter the vascular system and embolize to brain
vessels.

SYSTEMIC HYPOPERFUSION
Decreased blood flow to brain tissue may be caused by low systemic perfusion
pressure. The most common causes are cardiac pump failure (most often due to
myocardial infarction or arrhythmia) and systemic hypotension (due to blood loss or
hypovolemia). The lack of perfusion is more generalized than in localized thrombosis or
embolism and affects the brain diffusely and bilaterally. Poor perfusion is most critical
in border zone or so-called watershed regions at the periphery of the major vascular
supply territories, for example, between the ACA and MCA or between the MCA and
PCA.

KEY POINTS
● Ischemia can be due to a localized process within an artery (thrombosis), blockage of an artery by emboli
arising proximally, or a general decrease in blood flow (systemic hypoperfusion).
● Emboli most often come from the heart, aorta, and proximal portions of the neck or intracranial arteries.
● Atherosclerosis most often affects the large cervical and intracranial arteries.

COMMON ISCHEMIC STROKE SYNDROMES

Clinical localization often involves matching patterns of clinical deficits with
corresponding vascular localizations.

ANTERIOR CIRCULATION
1. Left cerebral hemisphere strokes lead to
a. Right hemiparesis: often arm, hand, and face > leg
b. Right hemisensory loss
c. Aphasia
d. In large lesions, conjugate deviation of the eyes to the left; right hemianopia or
 hemi-inattention
e. When caused by ICA occlusive disease, transient left monocular visual loss may
also occur.
2. Right cerebral hemisphere strokes cause
a. Left hemiparesis: often arm, hand, and face > leg
b. Left hemisensory loss
c. Poor drawing and copying
d. Neglect of the left visual field
e. In large lesions, conjugate deviation of the eyes to the right, left hemianopia
f. When the signs are due to ICA occlusive disease, transient right monocular visual
loss may accompany the brain signs.
These cerebral hemispheric lesions are most often caused by carotid artery
occlusion, embolism to the MCA or its branches, or basal ganglionic intracerebral
hemorrhages.

POSTERIOR CIRCULATION
1. Lateral medullary stroke (Wallenberg syndrome, usually due to intracranial VA
occlusion) causes
a. Ipsilateral facial pain, or reduced pain and temperature sensation on the ipsilateral
face, or both
b. Loss of pain and temperature in the contralateral limbs and body
c. Ipsilateral Horner syndrome
d. Nystagmus
e. Incoordination of the ipsilateral arm
f. Leaning and veering while sitting or walking, with gait ataxia
g. In deep lesions, dysphagia and hoarseness
2. Bilateral pontine base and often medial tegmentum stroke (usually due to basilar
artery occlusion, or pontine hemorrhage) causes
a. Quadriparesis
b. Unilateral or bilateral conjugate gaze paresis; sometimes internuclear
ophthalmoplegia or sixth nerve palsy
c. When the medial tegmentum is involved bilaterally, coma
3. Cerebellar infarction (usually due to embolism to the PICA or SCA, or cerebellar
hemorrhage) causes
a. Gait ataxia; often inability to walk
b. Dysarthria
c. Ipsilateral arm dysmetria
4. Left PCA territory stroke causes
a. Right homonymous hemianopia
 b. At times, amnesia
c. Alexia without agraphia when the splenium of the corpus callosum is involved
5. Right PCA territory stroke causes
a. Left homonymous hemianopia
b. At times, left-sided visual neglect
PCA territory infarcts are most often caused by embolism arising from the heart,
aorta, or VAs.

LACUNAR SYNDROMES
Lacunar strokes are most often due to occlusion of a penetrating artery. Similar to large-
vessel strokes, they produce a fairly limited range of presentations. Lacunar strokes may
occur in either the anterior or the posterior circulations. Classic lacunar stroke
syndromes include the following:
Pure motor lacune: weakness of the contralateral arm, face, and leg without sensory,
visual, or cognitive or behavioral signs. Common locations of lacunes producing
pure motor stroke include the corona radiata, posterior limb of the internal capsule,
and pons.
Pure sensory lacune: paresthesiae of the contralateral body, limbs, and face without
motor, visual, or cognitive abnormalities. The most common location of a lacune
producing pure sensory symptoms is the ventral posterior thalamus.
Sensorimotor lacune: combination of motor and sensory lacunes. This syndrome is due
to infarction in the ventral posterior thalamus and adjacent posterior limb of the
internal capsule.
Dysarthria—clumsy hand syndrome: slurred speech and clumsiness of the
contralateral hand. The most common location of a lacune producing this syndrome
is in the base of the pons.
Ataxic hemiparesis: weakness and ataxia of the contralateral limbs, often greater in the
leg and foot than in the arm and hand. The most common locations for lacunes
producing ataxic hemiparesis are the base of the pons, the posterior limb of the
internal capsule, and the corona radiata.

ARTERIAL DISSECTION
Dissection of the carotid or vertebral arteries may lead to ischemic stroke. Carotid
dissection typically presents with severe retro-orbital headache ipsilateral to the lesion.
Strokes involve the anterior circulation and occur either by thrombosis of the ICA or
more commonly by an embolus arising from the dissection. On physical examination,
patients with carotid artery dissection may have an ipsilateral Horner’s syndrome due to
the involvement of the ascending oculosympathetic tract. Perspiration is preserved
because those fibers ascend with the external carotid artery. VA dissection may be
produced by neck manipulation or trauma and is commonly associated with ipsilateral
neck pain and stroke in the posterior circulation.

DIAGNOSTIC EVALUATION
After taking a thorough history, performing a general examination emphasizing the heart
and blood vessels, and performing a neurologic examination, the next step in evaluation
of a patient with a suspected stroke is usually a brain image. Computed tomography
(CT) and magnetic resonance imaging (MRI) scans are used to separate brain infarction
from hemorrhage. Figure 14-3 shows a deep brain hemorrhage. Figure 14-4 shows a
brain infarction on CT scan. MRI with diffusion-weighted imaging is more sensitive to
acute brain infarction than is CT (Fig. 14-5).

FIGURE 14-3. Intracerebral hemorrhage. A computed tomographic scan showing a right basal ganglionic
hemorrhage due to hypertension. The hemorrhage has extended into the right frontal horn of the lateral ventricle.
FIGURE 14-4. Computed tomographic scan of the head demonstrates a wedge-shaped hypodensity in the
distribution of a branch of the left middle cerebral artery.

The symptoms and signs, when combined with brain imaging, should allow
localization to the left or right anterior circulation, the posterior circulation, or to a
lacunar syndrome. In patients with cerebral infarction, the heart, aorta, and neck and
intracranial arteries and their branches should be imaged. This can be performed using
echocardiography, extracranial and transcranial ultrasound, CT angiography (CTA), or
MR angiography (MRA). In patients in whom the signs localize to the anterior
circulation, vascular imaging of the ICAs should be emphasized, whereas in posterior
circulation cases, the VAs and their intracranial branches should be emphasized. In
cases of suspected arterial dissection, CTA, or MRA with fat-suppressed imaging (“fat
sats”), to evaluate the cervical carotid and vertebral arteries should be obtained. The
blood should be checked for abnormalities of erythrocytes, leukocytes, and coagulation
by ordering a complete blood count, platelet count, and prothrombin time reported as an
international normalized ratio. Intensive investigation for coagulopathy may be required
for some patients.
FIGURE 14-5. Bright signal is seen on an MRI with diffusion-weighted imaging (DWI), indicating a recent
infarction.

KEY POINTS
● The course of symptom development and results of brain imaging should allow separation of ischemia from
hemorrhage, and in case of ischemia, identification of the most likely stroke mechanism: thrombosis,
embolism, or systemic hypoperfusion.
● Cardiac, brain, and vascular imaging should help to identify stroke etiology.

TREATMENT
In patients seen soon after the onset of neurologic symptoms, an attempt should be made
to reperfuse the ischemic brain if a large artery is occluded and if a large portion of the
brain area supplied by that artery is not already infarcted. Cerebral and vascular
imaging (usually CTA) can show the location and extent of brain infarction and vascular
occlusion. Reperfusion can be attempted using intravenous thrombolysis, intra-arterial
thrombolysis, or mechanical means. The intravenous thrombolytic agent tissue
plasminogen activator (tPA) improves stroke outcome if given to patients with disabling
stroke within 4.5 hours of stroke onset. Intravenous thrombolysis can be associated with
cerebral hemorrhage, and patients must undergo careful evaluation for factors that
would increase this risk even further, such as thrombocytopenia, bleeding diatheses, and
recent surgery. Hyper- and hypoglycemia must also be excluded before initiating tPA
because abnormally high or low blood glucose levels may mimic the symptoms and
signs of acute stroke. Intra-arterial tPA is used for patients who have had symptoms for
longer than the 4.5-hour window for IV tPA and a well-defined occlusion visualized by
CTA or conventional angiography. Mechanical thrombectomy using clot-retrieving stent
devices is helpful for patients with internal carotid or proximal MCA occlusions who
are not tPA candidates.
Prevention of further brain ischemia starts with maximizing cerebral blood flow:
Lowering the blood pressure should be avoided unless there is other evidence of end-
organ damage (e.g., cardiac ischemia or pulmonary edema). Almost all patients will
require an antithrombotic agent as secondary prophylaxis. For most patients, antiplatelet
drugs such as aspirin, clopidogrel, or a combination of aspirin and modified-release
dipyridamole are the agents of choice. In patients with stroke due to intracranial
atherosclerosis, dual antiplatelet therapy with aspirin and clopidogrel is favored.
Anticoagulation with warfarin is useful in specific instances, mostly in patients with
atrial fibrillation, cerebral venous sinus thrombosis, and inherited hypercoagulable
states. The newer oral anticoagulants apixaban, dabigatran, and rivaroxaban may be
more effective and have better safety profiles than warfarin, and are used as secondary
prophylaxis for patients with atrial fibrillation and sometimes for other indications that
would require anticoagulation. Control of stroke risk factors (hypertension, diabetes,
obesity, hyperlipidemia, and smoking) is accomplished by attention to lifestyle,
behavior, nutrition, and exercise, and by prescribing appropriate medications.

KEY POINTS
● Acute and preventive treatments should be tailored to the individual patient.
● Maximizing cerebral blood flow to ischemic regions can be facilitated by opening blocked arteries chemically
or mechanically and by increasing blood flow in collateral vessels.

TRANSIENT ISCHEMIC ATTACK

A transient ischemic attack (TIA) is defined as a focal neurologic syndrome produced
by brain ischemia that lasts for 24 hours or less. The mechanisms of TIA are identical to
those of ischemic stroke. Patients who have had a TIA have a 10% risk of stroke in the
90 days following the event, and the greatest risk of stroke is within the first 24 hours
following a TIA. Therefore, the evaluation should be identical to that for a completed
stroke and should be conducted just as quickly. This evaluation includes brain MRI with
diffusion-weighted imaging (which is abnormal in 50% of patients with TIA), lipid
profile, echocardiography, cardiac telemetry, and carotid artery imaging as appropriate.
Preventive treatment strategies are identical to those described above for ischemic
stroke.

INTRACRANIAL HEMORRHAGE
Bleeding inside the skull can be divided into subarachnoid, intracerebral, epidural, and
subdural hemorrhages. The latter two types of hemorrhages are almost always traumatic
and are discussed in Chapter 17. Intracerebral hemorrhage (ICH) and subarachnoid
hemorrhage (SAH) have different causes, clinical findings, and management.

SUBARACHNOID HEMORRHAGE
SAH is often due to traumatic injury. More serious, though, is SAH caused by bleeding
from an aneurysm located along the circle of Willis. The most common sites of cerebral
aneurysms are shown in Figure 14-6. When blood under arterial pressure is suddenly
released into the space around the brain, patients develop sudden-onset, severe
headache. Often, they vomit and cease what they are doing at the time of the hemorrhage.
When intracranial pressure increases rapidly or the insulae are affected, coma or death
may ensue. An example of SAH is shown in Figure 14-7.

FIGURE 14-6. Common sites of aneurysm in the circle of Willis. (From Ginsberg L. Lecture Notes: Neurology.
8th ed. Oxford: Blackwell Publishing; 2005:87. Copyright © 2005 L Ginsberg. Reprinted by permission of John Wiley
& Sons, Inc.)

Treatment is aimed at preventing the rebleeding and vasoconstriction that often

follow SAH. Aneurysms can be clipped surgically or “coiled” by interventional
techniques. The calcium-channel blocker nimodipine is used to minimize
vasoconstriction and delayed brain ischemia.

FIGURE 14-7. Subarachnoid hemorrhage. A computed tomographic scan showing extensive subarachnoid blood
within the sulci of the brain. The largest area of bleeding is seen in the left frontal region.

INTRACEREBRAL HEMORRHAGE
ICH is bleeding directly into brain parenchyma. The earliest symptoms are headache
and neurologic signs referable to the region in which the bleeding occurs. Hypertension
is the most common cause of ICH. The most common locations for hypertensive ICH are
the basal ganglia-internal capsule, caudate nucleus, thalamus, pons, and cerebellum.
Cerebral amyloid angiopathy is a cause of ICH that is more frequent in the elderly and
preferentially affects the parietal and occipital lobes. Trauma, vascular malformations,
and bleeding diatheses (especially with patients who are taking anticoagulants) are
other common causes. ICH is often a devastating condition, and large hemorrhages are
associated with high mortality rates. Treatment involves correcting any coagulopathy. In
certain situations (particularly cerebellar hemorrhages), surgical decompression is
necessary. Management of risk factors for hemorrhage, specifically hypertension, is
necessary to prevent recurrence.

VASCULAR MALFORMATIONS
There is a variety of congenital and acquired vascular anomalies that have the potential
to bleed, either within the brain (ICH) or around it. Arteriovenous malformations
(AVMs) contain arteries that empty into arterialized veins. These lesions contain no
recognizable normal capillary bed, but abnormal gliotic parenchyma can be found
between the component vessels. In addition to causing ICH, AVMs may result in
seizures. AVMs may be treated with embolization or surgical resection. Cavernous
angiomas consist of a relatively compact mass of sinusoidal vessels close together,
without intervening brain parenchyma. The lesions are well encapsulated. Cavernous
angiomas bleed or lead to seizures occasionally but are not as threatening as AVMs are.
In general, cavernous angiomas may be followed with serial neuroimaging studies.
Surgery is required rarely. They may require antiseizure drug treatment if recurrent
seizures develop. Developmental venous anomalies (DVAs) are composed of
anomalous veins usually separated by morphologically normal brain parenchyma and
are the most common vascular malformations of the brain. They seldom hemorrhage and
are generally not treated surgically or followed with serial neuroimaging studies.
Telangiectasias are dilated capillaries with intervening brain parenchyma. They are
incidental findings and do not require treatment.

KEY POINTS
● AVMs, DVAs, cavernous angiomas, and telangiectasis are different types of malformations, each with
differing clinical findings and management.
● Medical therapy, surgery, interventional obliteration, and radiotherapy are all used in treating brain vascular
malformations.

CLINICAL VIGNETTES

VIGNETTE 1
A 78-year-old man with a history of hypertension and hypercholesterolemia lost the
ability to speak and move the right side of his body an hour ago. On examination, he
has a blood pressure of 168/92 mm Hg and a heart rate of 88 beats/minute. He is
globally aphasic and has a moderate right hemiparesis. Visual fields are full and his
sensation is preserved. He has never had a similar event and otherwise has no
recent medical or surgical history.
1. The most likely localization of this patient’s deficits is:
a. Left cerebellar hemisphere
b. Left frontal lobe
c. Left internal capsule
 d. Left parietal lobe
e. Left thalamus
2. The most appropriate imaging study for this patient at this time is:
a. MRI of the brain with diffusion-weighted imaging
b. Noncontrast head CT
c. MRA of the brain
d. Carotid ultrasound
e. MRI of the brain with susceptibility weighting
3. The patient’s initial head CT was normal. What is the most appropriate step at
this point?
a. Administer tPA
b. MRI of the brain with diffusion-weighted imaging
c. Administer labetalol to lower his blood pressure
d. Check complete blood count, glucose level, and coagulation profile
e. Anticoagulate with heparin

VIGNETTE 2
A 29-year-old woman presents with vertigo, neck pain, right-sided facial pain, and
clumsiness that developed 1 day ago, after a session of neck manipulation.
1. Which of the following might be expected on examination?
a. Left limb ataxia
b. Left hemibody sensory loss
c. Left-sided Horner syndrome
d. Left hemiparesis
e. Rightward deviation of the tongue
2. The patient underwent an MRI of the brain that showed infarction of the right
lateral medulla. What other imaging modality would be most appropriate?
a. Carotid ultrasound
b. Echocardiogram
c. Hypercoagulable profile
d. Magnetic resonance angiogram of the cervical arteries
e. Susceptibility-weighted MRI of the brain
3. What would be the best treatment option for this patient?
a. Aspirin
b. Carotid endarterectomy
c. Intravenous tPA
d. Intra-arterial tPA
e. VA stenting
ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
This patient presents with signs and symptoms that are most consistent with a left
cerebral hemisphere infarction, specifically in the left frontal lobe, causing global
aphasia and contralateral hemiparesis. A left cerebellar hemisphere infarction
would produce ipsilateral limb ataxia, but not hemiparesis or aphasia. Left internal
capsule infarction could produce contralateral hemiparesis, but should not result in
any language disturbance. Left parietal lobe infarction would produce more sensory
deficits and possibly a visual field cut. Left thalamic infarction would lead to a
hemisensory deficit, among other problems, but would not cause hemiparesis.

VIGNETTE 1 QUESTION 2
2. Answer B:
In a patient with suspected acute stroke, CT scan without contrast is the most
appropriate study. Although it may be less sensitive to acute ischemic stroke than
MRI of the brain with diffusion-weighted imaging, it is sufficient to exclude an
intracerebral hemorrhage and allow consideration of thrombolysis. MRA of the
brain produces images of the cerebral vasculature but is not necessary in the acute
setting. Carotid ultrasound is useful for diagnosing carotid artery stenosis and
planning carotid endarterectomy but would not be useful when making initial
treatment decisions. Susceptibility-weighted MRI is used to detect intracranial
hemorrhage and has sensitivity for blood that is equal to or greater than CT scan. CT
scan, however, is more quickly obtained and, for that reason, it is the preferred
imaging study in this setting.

VIGNETTE 1 QUESTION 3
3. Answer D:
This patient is a candidate for intravenous thrombolysis and should undergo
laboratory testing to make sure that he is not at an increased risk for hemorrhage and
that he does not have an abnormal glucose level that could mimic an ischemic
stroke. This testing should include a complete blood count, glucose level, and
coagulation profile. These must be checked before administering tPA. MRI of the
brain with diffusion-weighted imaging may establish the diagnosis of ischemic
stroke with greater certainty but will delay his care. Unless there are signs of end-
organ damage, high blood pressure should not be treated aggressively in patients
with acute ischemic stroke. Heparin may be appropriate for patients with stroke due
to arterial dissection, venous sinus thrombosis, or a hypercoagulable state, but none
of these diagnoses has been established for this patient.

VIGNETTE 2 QUESTION 1
1. Answer B:
This patient has a history most consistent with right lateral medullary infarction. She
would be expected to have left hemibody sensory loss. Her limb ataxia and Horner
syndrome would be ipsilateral to the lesion on the right side. Lateral medullary
syndrome is not associated with hemiparesis. The hypoglossal nucleus is in the
midline of the medulla and would not be affected in a lateral medullary syndrome.

VIGNETTE 2 QUESTION 2
2. Answer D:
The most likely mechanism of injury is right VA dissection. This diagnosis is best
established with MRA or CTA of the neck. Carotid ultrasound would be
inappropriate for a patient with a posterior circulation stroke. Echocardiogram
could be used to define a cardiogenic source of stroke. Although hypercoagulability
is a common cause of stroke in younger people, the history is more suggestive of VA
dissection. Susceptibility-weighted MRI of the brain would be useful to diagnosis
intracranial hemorrhage.

VIGNETTE 2 QUESTION 3
3. Answer A:
Antiplatelet agents are the best treatment for most patients with stroke and are
equivalent in effectiveness to anticoagulation for patients with cervical arterial
dissections. Carotid endarterectomy would not address the affected vessel.
Thrombolysis with tPA is not appropriate for this patient, as she presents well
outside of the “tPA window” of 4.5 hours. VA stenting is a treatment option for
patients with refractory vertebrobasilar stenosis but should not be employed for
dissection.
 15 Seizures

Seizures are among the most common problems in neurology. Up to 10% of the
population will have a seizure at some point in their lives. In addition, seizures can be
among the most dramatic forms of nervous system dysfunction. Although seizures have
many different causes and manifestations, by definition a seizure is an abnormal
hypersynchronous electrical discharge of neurons in the brain, producing a clinical
dysfunction. Epilepsy is defined as a condition in which there is a tendency to have
recurrent unprovoked seizures. Practically, the diagnosis of epilepsy is often applied
after a patient has had two unprovoked seizures.

CLASSIFICATION
Seizures can arise from one specific focus within the brain (focal) or involve both
cerebral hemispheres at the onset (generalized). The diagnosis and categorization of
the seizure is based primarily on the semiology (i.e., signs or symptoms) characterizing
the event. Those that arise from one portion of the brain can evolve and spread to
involve the whole brain (secondarily generalized). Among focal seizures, those in
which awareness is impaired are termed “with impaired awareness” (previously
“complex”), whereas those in which awareness is preserved are termed “aware”
(previously “simple”) (Table 15-1).

FOCAL SEIZURES
By definition, focal seizures (previously termed “partial”) begin in a focal area of the
brain and do not impair awareness, at least at the onset (Fig. 15-1A). In general, such
seizures lead to positive rather than negative neurologic symptoms (e.g., tingling rather
than numbness; hallucinations rather than blindness). The manifestations of focal
seizures depend on their site of origin in the brain. These are designated as motor or
nonmotor. Focal motor seizures, in which one part of the body may stiffen or jerk
rhythmically, involve the motor cortex in the frontal lobe. The classic Jacksonian march
occurs when the electrical discharge spreads along the motor strip, leading to rhythmic
jerking that spreads along body parts following the organization of the motor
homunculus. Focal nonmotor seizures from other regions of the brain can cause sensory
phenomena (sometimes parietal), visual phenomena (usually occipital), or gustatory,
olfactory, and psychic phenomena (frequently temporal). The latter may include déjà vu,
jamais vu, or sensations of depersonalization (“out of body”) or derealization.

TABLE 15-1. Types of Seizures

Focal-onset:
Motor Myoclonic (jerking)
Epilepsia partialis continua (sustained rhythmic jerking)
Clonic (rhythmic movements)
Tonic (stiffening)
Hypermotor (e.g., running)
Focal-onset with secondary generalization (generalized convulsion)
Non-motor Focal-onset with impaired awareness (old “complex partial’)
Sensory, e.g., olfactory, somatosensory, or hemianopic
Focal-onset with altered cognition, e.g., aphasic, amnestic, ‘psychic’ / ‘emotional’

(e.g., altered mood, rage)

Autonomic
Generalized–onset:
Motor Generalized, tonic (then) clonic, convulsion (‘grand mal’)
Myoclonic
Tonic
Atonic (lack of tone, with falls)
Non-motor: Absence
Other primary absence-like seizures, eyelid myoclonia
Myoclonic–absence
Generalized nonconvulsive seizures in comatose or ICU patients
Autonomic
FIGURE 15-1. Characteristics of seizure types. (A) Focal-onset seizures. (B) Generalized seizures. (Reprinted
with permission from Ford SM. Roach’s Introductory Clinical Pharmacology. 11th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2017. Figure 29.1.)

FOCAL SEIZURE WITH IMPAIRED AWARENESS

Focal seizures with impaired awareness (previously termed complex partial seizures)
have a focal onset and involve an impairment of awareness. Many arise in the temporal
lobe, but a frontal lobe focus is also common. Focal seizures with impaired awareness
may include automatisms (stereotyped motor actions without clear purpose) such as lip-
smacking, chewing movements, or picking at clothing. The patient may have speech
arrest or may speak in a nonsensical manner. By definition, the patient does not respond
normally to the environment or to questions or commands. Occasionally, patients may
continue the activities they were participating in at the onset of the seizure, sometimes to
remarkable lengths: Patients may continue folding laundry during a seizure or even
finish driving home. Focal seizures with impaired awareness of frontal lobe origin
may involve strange bilateral movements, such as bicycling or kicking, or behavior such
as running in circles. If the patient’s awareness is not known, the seizure is termed a
focal seizure with unknown awareness.
The last classification of focal seizure is termed focal to bilateral tonic–clonic. This
term refers to the pattern of seizure propagation from one type of focal seizure to
bilateral symptoms. Focal to bilateral tonic–clonic was previously termed partial onset
with secondary generalization.

GENERALIZED SEIZURES
Generalized seizures include two categories: motor seizures and absence seizures
(Fig. 15-1B).

GENERALIZED MOTOR SEIZURES

Generalized motor seizures were previously referred to as generalized tonic–clonic
(GTC) seizures or grand mal seizures. This is the seizure type with which the lay public
is most familiar. They typically begin with a tonic phase, lasting several seconds, in
which the entire body becomes stiff (including the chest and pharyngeal muscles,
sometimes leading to a vocalization known as the epileptic cry). This is followed by the
clonic phase, in which the limbs jerk rhythmically, more or less symmetrically, typically
for less than 1 to 2 minutes. Toward the end of the clonic phase, the frequency of the
jerking may decrease and stop as the body becomes flaccid. The patient may bite the
tongue and become incontinent of urine during a generalized motor seizure. There is
typically a postictal state after the seizure, lasting minutes to hours, during which the
patient may be tired or confused, before returning to normal activity slowly.
FIGURE 15-2. Characteristic EEG findings in absence seizures. (A) Normal EEG recording in an awake adult.
The top four channels are derived from electrodes over the left side of the head, from front to back; the bottom four
are derived from the right side of the head. A normal sinusoidal alpha rhythm is seen most prominently over the
posterior head regions bilaterally (fourth and eighth channels). (B) Midway through the recording, rhythmic 3-Hz
generalized spike-and-slow-wave discharges appear. This is the typical EEG pattern of an absence seizure. During
these discharges, the patient may stare and be unresponsive. (From Ginsberg L. Lecture Notes: Neurology. 8th ed.
Oxford: Blackwell Publishing; 2005:75. Copyright © 2005 L Ginsberg. Reprinted by permission of John Wiley & Sons,
Inc.)

ABSENCE SEIZURES
An absence seizure is a generalized seizure that most commonly occurs in children or
adolescents and is characterized primarily by an unresponsive period, often with
staring, that lasts for several seconds, with immediate recovery thereafter. Absence
seizures can occur tens or even hundreds of times a day and may be noticed first by
schoolteachers and assumed to be daydreaming or difficulty concentrating. A classic 3-
per-second generalized spike-and-wave electroencephalogram (EEG) pattern
accompanies absence seizures (Fig. 15-2). Hyperventilation is a common trigger.

OTHER GENERALIZED SEIZURE TYPES

Less common seizure types include myoclonic–atonic, clonic–tonic–clonic, myoclonic
absence, and absence with eyelid myoclonia, all of which are generalized in onset
(Table 15-1). Seizures that are myoclonic (without other features) may be generalized
or focal.

UNKNOWN ONSET
Unknown onset is the last seizure classification and is used when the semiology and
onset of the seizure are unknown. This term should be used when the onset of the seizure
was not witnessed or the description is unclear. Any information about the seizure
semiology that is known should be added to the diagnosis, such as motor or nonmotor
as well as the description of awareness during the seizure.

UNCLASSIFIED
If no information is known about the seizure semiology, the seizure is labeled as
unclassified. This is a term that should be reserved for patients for whom no additional
information is available. This term should be revised when additional clinical
information about the seizure semiology becomes available.

KEY POINTS
● A seizure is an abnormal hypersynchronous electrical discharge involving neurons in the brain, with a clinical
correlate.
● Epilepsy is a tendency to have recurrent unprovoked seizures.
● Focal seizures may manifest with motor, sensory, or psychic phenomena and are usually characterized by
positive rather than negative neurologic symptoms.
● Focal seizures originate in a focal area of the brain but may become bilateral tonic–clonic seizures;
awareness is preserved during the focal seizures but becomes impaired during secondary generalization.
● Generalized seizures originate in the entire brain at once; tonic–clonic and absence seizures are examples.

EPIDEMIOLOGY AND ETIOLOGIES

Seizures have a U-shaped distribution in age of onset—they are more common in the
very young and the very old. Etiologies vary depending on the age of onset. In infants, a
variety of neonatal infections, hypoxic-ischemic insults, genetic syndromes, and
congenital brain malformations are common causes of seizures.
Febrile seizures are a special case. They are the most common cause of seizures in
children, affecting up to 3% to 9% of this age group. They occur between 6 months and
5 years of age in the setting of a febrile illness without evidence of intracranial infection
and are usually generalized in onset. Most children with febrile seizures do not have
neurologic deficits. For the event to be considered a febrile seizure, the fever may be
present before the seizure or must develop in the immediate postictal period. The risk of
subsequent epilepsy is relatively small unless the seizures are prolonged or focal in
onset or if other neurologic abnormalities or a family history of epilepsy is present.
Older children may also develop seizures related to head injury, meningitis,
encephalitis, or vascular diseases, and genetic syndromes continue to be a significant
etiology in this age group. Among young adults, head injury, substance use, and
excessive alcohol use are common causes of new-onset seizures, but brain tumors and
strokes become more common etiologies by middle age. In the elderly, strokes become
the most common etiology, but substance abuse and alcohol are not uncommon causes.
Metabolic disturbances from systemic problems such as severe hypo- or hyperglycemia,
hepatic failure, or renal failure are also frequent causes.

KEY POINTS
● The incidence of new-onset seizures has a U-shaped distribution, highest among the very young and the very
old.
● Common etiologies of new-onset seizures differ depending on the age of onset.
● Febrile seizures in children are common and generally carry a benign prognosis.
● Seizures may occur as part of specific epilepsy syndromes characterized by distinctive seizure types, EEG
patterns, or associated neurologic abnormalities.

Frequently, seizures occur in children (and sometimes adults) as part of a syndrome

that may include specific seizure types, EEG patterns, and associated neurologic
abnormalities. Many of these are called “idiopathic generalized epilepsies”—usually
considered to be genetic conditions in almost all cases. The diagnosis of a specific
syndrome may have implications both for genetic testing and for the proper choice of
pharmacologic treatments. Examples of epilepsy syndromes are outlined in Table 15-2.

TABLE 15-2. Epilepsy Syndromes: Features and Treatment

Selected Epilepsy Syndromes
 Age of Onset Seizure Types Associated EEG Findings Commonly
Findings Used
Treatments
Lennox–Gastaut Childhood Tonic, atonic, Major cognitive Slow (1- to 2-per- Valproic acid,
syndrome myoclonic, impairment and second) spike- lamotrigine,
generalized tonic– disability and-wave felbamate,
clonic, absence discharges rufinamide,
clobazam
Focal motor Childhood Simple partial Nocturnal Centrotemporal Carbamazepine;
seizure, e.g., seizure involving preponderance of spikes sometimes no
benign rolandic the mouth and seizures treatment
epilepsy face, infrequent necessary
generalized tonic–
clonic
Absence epilepsy Childhood and Absence; Hyperventilation 3-per-second Ethosuximide,
adolescence sometimes, as trigger generalized spike- valproic acid,
generalized tonic– and-wave lamotrigine
clonic seizures
Juvenile Adolescence and Myoclonic, Early morning 4- to 6-per- Valproic acid,
myoclonic young adulthood absence, preponderance of second polyspike- lamotrigine,
epilepsy generalized tonic– seizures and-wave levetiracetam
clonic
EEG, electroencephalogram.

CLINICAL MANIFESTATIONS
HISTORY
The diagnosis of seizures is a clinical one. Most commonly the patient is seen after an
event has occurred, and the diagnosis must be made on the history alone. In these cases,
the patient (and more importantly, witnesses, if the seizure was generalized in onset)
must be questioned for an exact description of the event itself (and especially the onset),
any premonitory symptoms, and the character of the recovery period in order for the
clinician to decide whether the event was a seizure, and, if so, what type of seizure it
was. The clinical details should allow for the differentiation of seizures from other
paroxysmal neurologic events (Table 15-3).

PHYSICAL EXAMINATION
The neurologic examination is most helpful diagnostically in the (relatively uncommon)
instances in which the patient is observed during the event or shortly thereafter. In the
latter case, a postictal hemiparesis, or Todd’s paralysis, may be detected after a
bilateral tonic, then clonic seizure; this suggests that the seizure was of focal onset, even
if not apparent to observers at the time. Other abnormalities on neurologic exam may
also suggest the presence of a focal brain lesion. Of course, the general physical exam
may yield findings suggestive of infection or other systemic disease that might explain a
new-onset seizure. In particular, signs of meningitis should be sought in any patient who
has had a seizure.

TABLE 15-3. Characteristics of Focal Seizures and Other Paroxysmal Neurologic

Events
Focal Seizures Transient Ischemic Attacks Migraine
Onset Progression of symptoms over Sudden onset of symptoms Progression of symptoms
seconds over 15–20 min
Neurologic Positive motor or sensory Negative motor, sensory, or visual Positive sensory and,
symptoms symptoms; “psychic” symptoms symptoms (loss of function) especially, visual symptoms
such as déjà vu such as scintillating
scotomata
Duration Usually less than a few minutes Usually less than 30 min, always Symptoms for 15–20 min,
less than 24 h typically followed by
headache for hours
Consciousness Preserved or impaired Preserved Preserved
Headache Occasionally postictal Infrequent Throbbing pain, often
unilateral, following the
progression of initial
symptoms
Recovery Postictal confusion, sleepiness Rapid Fatigue common
Risk factors Structural brain lesion, family Hypertension, hyperlipidemia, Family history of migraines
history of seizures smoking, diabetes, atrial
fibrillation, stenotic intracranial or
extracranial vessels,
hypercoagulability

DIAGNOSTIC EVALUATION
LABORATORY STUDIES
Laboratory testing may show an underlying metabolic abnormality, such as
hyponatremia or hypocalcemia, that explains a new-onset seizure. After a generalized
seizure, there is commonly a lactic acidosis, resulting in decreased serum bicarbonate.
A toxicology screen for common substances of abuse, as well as an alcohol level,
should be done in all patients. Female patients of reproductive age should also have a
pregnancy test. In cases where infection is suspected, a lumbar puncture should be
performed.

BRAIN IMAGING
An uncomplicated seizure in a patient with known epilepsy does not generally warrant
brain imaging. With rare exceptions, however, neuroimaging should be performed in
patients with new-onset seizures. For seizures of probable focal onset, a magnetic
resonance imaging (MRI) is a necessary part of the diagnostic workup, to look for a
structural abnormality that is a focus for that seizure. A head computed tomography may
suffice in the urgent setting.

KEY POINTS
● Most neurologists begin drug therapy after two unprovoked seizures.
● Each drug has its own set of indications and adverse effects.
● Monotherapy is a desired goal of antiseizure therapy; most patients’ seizures are well controlled on one
medication.

ELECTROENCEPHALOGRAPHY
An EEG may be useful for several reasons: It may identify a potential focus of seizure
onset; it may show abnormalities characteristic of a specific epilepsy syndrome (e.g.,
with rapid, narrow, generalized spike and polyspike discharges in a patient with a
“primary generalized epilepsy”); and it may establish whether a patient who has had a
seizure and is not regaining alertness promptly is postictal or is having ongoing
continuous nonconvulsive seizures. The diagnosis of whether a particular paroxysmal
event was a seizure or not, however, rests primarily on clinical grounds; in patients
with known epilepsy, up to 50% of routine EEGs are normal.

TREATMENT
DRUGS
The mainstay of epilepsy treatment is pharmacologic. The number of available
antiseizure drugs (ASDs) has more than doubled in recent years, and there is now a
large selection of agents from which to choose, each with its own set of indications and
possible adverse effects (Table 15-4).

TABLE 15-4. Selected Antiseizure Drugs

Site of Action Seizure Types Treateda Characteristic Side
Effects
Phenytoin (Dilantin) Na+ channel Focala Gingival hyperplasia,
coarsening of facial
 features, ataxia
Carbamazepine (Tegretol) Na+ channel Focal Hyponatremia, diplopia
Valproic acid (Depakote) Na+ channel, GABA Focal, generalized GI symptoms, tremor,
receptor weight gain, hair loss,
hepatotoxicity,
thrombocytopenia,
teratogenicity
Phenobarbital GABA receptor Focal, generalized Sedation
Ethosuximide (Zarontin) T-type Ca2+ channel Absence GI symptoms
Gabapentin (Neurontin) Unknown, possibly voltage- Focal Sedation, weight gain
gated Ca2+ channel (occasional)
Lamotrigine (Lamictal) Na+ channel, glutamate Focal, generalized Diplopia, rash (rare
receptor Stevens–Johnson
syndrome; more with rapid
introduction)
Topiramate (Topamax) Na+ channel, GABA Focal, generalized Word-finding difficulty,
activity renal stones, weight loss
Tiagabine (Gabitril) GABA reuptake Focal Sedation
Levetiracetam (Keppra) Poorly understood (synaptic Focal, generalized Insomnia, anxiety, irritability
vesicle modulation of
neurotransmitter effects)
Oxcarbazepine (Trileptal) Na+ channel Focal Sedation, diplopia,
hyponatremia
Zonisamide (Zonegran) Unknown; probably multiple Focal, generalized Sedation, renal stones,
mechanisms weight loss
Lacosamide (Vimpat) Na+ channel Focal Sedation, headache,
syncope
Pregabalin (Lyrica) Voltage-gated Ca2+ Focal Sedation, peripheral edema,
channel weight gain
Clobazam (Onfi) Benzodiazepine receptor Generalized Sedation, mood symptoms,
fever
aDrugs
effective for focal seizures are also used for secondarily generalized seizures.
GABA, gamma-aminobutyric acid; GI, gastrointestinal.

An ASD is typically not started after a single seizure unless there is reason to believe
that a second seizure is likely. This applies especially to symptomatic seizures, i.e.,
those due to a treatable or reversible condition, such as meningitis, alcohol withdrawal,
or hyponatremia. Most neurologists would also not start an ASD after a single seizure
for which no underlying cause is found.
ASD treatment is usually begun after two seizures that are not provoked. The primary
goals of ASD treatment are to eliminate seizures and avoid side effects, ideally with
monotherapy—i.e., using a single drug. Most neurologists increase the dose of a single
drug until either seizure control is achieved or adverse effects become intolerable. If the
latter occurs, the dose is lowered and a second drug may be added. If seizure control is
achieved, an attempt is often made to taper the first drug, leaving the second as
monotherapy. For about 70% of epilepsy patients, seizures will be well controlled on
ASDs, often with one of the first drugs tried. For the remainder, two or more ASDs may
be required, or the seizures may remain refractory to medical therapy.

KETOGENIC DIET
The ketogenic diet is a high-fat, high-protein, low-carbohydrate diet often considered
for treatment of patients with epilepsy. It produces urine and plasma ketones, which are
used for monitoring therapy. It can be effective in reducing the seizure frequency in both
adult and pediatric patients. There are several epilepsy syndromes, mostly pediatric, for
which there is good evidence of efficacy of the ketogenic diet. It can be difficult for
patients to tolerate and is not known to be safe for other medical comorbidities,
including lipid disorders.

VAGUS NERVE STIMULATION

The vagus nerve stimulator is a device shown to be effective in the treatment of partial
and generalized seizures. It is implanted subcutaneously below the clavicle and
stimulates the left vagus nerve through programmed electrical impulses delivered
through leads placed in the neck. Various devices for direct brain stimulation including
transcutaneous magnetic stimulation and deep brain stimulation also have promise for
epilepsy treatment in the future, but they are still under development.

SURGERY
Patients refractory to medical management may be candidates for epilepsy surgery.
Exactly what constitutes being medically refractory will depend on an individual
patient’s circumstances; contributing factors typically include seizure type and
frequency, tolerance of ASD therapy, number of ASDs tried, and the effect on the
patient’s quality of life. The most common surgical procedure is resection of the
epileptogenic area, typically following a presurgical evaluation in which continuous
video-EEG monitoring combined with neuroimaging and other tests is used to identify
the focus of seizure onset. For seizures of medial temporal lobe origin (the most
common target of epilepsy surgery), the rate of complete seizure freedom following
resective surgery can be over 60%. Other less commonly used surgical procedures
include corpus callosotomy, hemispherectomy, or multiple subpial transection.

STATUS EPILEPTICUS
Status epilepticus (SE) is an abnormal state in which either seizure activity is
continuous for a prolonged period or seizures are so frequent that there is no recovery
of consciousness between them. There are several types of SE, including the
generalized convulsive form (ongoing clonic movements of the limbs) and more subtle
forms in which the patient may be unresponsive and might have subtle motor signs such
as eyelid twitching or nystagmus. Potential causes of SE include acute metabolic
disturbances, toxic or infectious insults, hypoxic-ischemic damage to the brain, and
underlying epilepsy. Morbidity from SE can be high; outcome depends largely on
etiology and duration. SE is a medical emergency, the management of which centers on
stopping the seizure activity and preventing the occurrence of systemic complications
(Table 15-5). It is particularly important to consider the possibility of ongoing
nonconvulsive seizures in patients whose convulsions have ceased but whose mental
status has not improved, or in whom the mental status is disproportionately impaired
compared to what is expected from other comorbidities. It is also important to note that
a cluster of frequent seizures may warrant similarly aggressive management,
particularly because this condition may evolve to SE quickly. There are evidence-based
guidelines on how to approach adults and children in SE. These guidelines are updated
on a regular basis as new ASDs and procedures become available.

SPECIAL TOPICS
FIRST AID FOR SEIZURES
All physicians should be familiar with first aid measures for patients having a seizure.
In general, the goal is to prevent the patient from becoming injured (and to prevent well-
meaning bystanders from intervening unwisely). The patient with complex partial
seizures may wander or make semipurposeful movements; if necessary, he or she should
be gently guided out of harm’s way. More aggressive attempts at restraint may provoke
a violent reaction. The patient with GTCs should be laid on his or her side, if possible,
so that vomiting does not lead to aspiration. Tight clothing should be loosened. Nothing
should be placed in the mouth. Most GTCs stop within 1 to 2 minutes; immediate
medical attention should be sought if a seizure becomes more prolonged.

TABLE 15-5. Management of Status Epilepticus

Phases Timing Steps Monitoring
Stabilization 0–5 min • Airway • ECG
• Breathing • IV access
• Circulation • Labs studies: CBC, chemistry,
• Oxygen toxicology screen, antiseizure drug
Blood glucose (finger stick) level, if known to be on treatment
• Thiamine and D5W if glucose <60
 mg/dL
If seizures continue:
Initial treatment 5–20 min Administer benzodiazepines.
One of the following:
• IM midazolam
• IV lorazepam
• IV diazepam
If seizures continue:
Second 20–40 min Administer antiseizure drug.
treatment One of the following:
• IV fosphenytoin
• IV valproic acid
• IV levetiracetam
• IV lacosamide
• IV phenobarbital
If seizures continue:
Third treatment 40–60 min Repeat treatments in second phase or • Initiate continuous EEG monitoring
sufficient continuous IV infusion of • Admit to ICU
seizure-suppressing (“anesthetic”) • If continuous IV infusion of sedating
medications: midazolam, propofol, or drugs is administered, patient
pentobarbital (or thiopental) requires intubation
These steps to stabilize a patient in status epilepticus are a suggested guideline; clinicians may and should adapt
these steps appropriately to the individual patient’s presentation.
CBC, complete blood count; ECG, electrocardiogram; EEG, electroencephalogram; ICU, intensive care unit; IM,
intramuscular; IV, intravenous.

SUDDEN UNEXPECTED DEATH IN EPILEPSY

Sudden unexpected death in epilepsy (SUDEP) is a rare and devastating outcome
from epilepsy. It is defined as a “sudden, unexpected death of a person with epilepsy
who is otherwise healthy” (AAN Guideline). SUDEP in children is rare, occurring in 1
of every 4,500 children with epilepsy. In adults, SUDEP is more common, resulting in
the death of 1 in 1,000 adults with epilepsy per year. The causes and mechanisms of
SUDEP are unknown. Risk factors include the following:
• GTCs, especially with a high frequency of GTCs. (Effectively treating and reducing the
frequency of seizures results in a decreased risk of SUDEP.)
• Longer duration of the diagnosis of epilepsy
• Age: 18 to 40 years
• Alcohol use
• Missing ASD doses
Although this can be anxiety provoking to discuss, patients and families should be
counseled about the risk of SUDEP and that adherence to effective ASD treatment
probably decreases the risk.
SEIZURES AND DRIVING
Each state has its own licensing requirements for people with epilepsy. Physicians who
care for seizure patients should be aware of them. Most states require a specific
seizure-free interval before a patient may drive; exceptions can sometimes be made for
purely nocturnal seizures or those with a prolonged focal onset that provides the patient
with a warning without impaired awareness. A few states require physicians to report
patients with seizures to the department of motor vehicles. All patients should be
counseled about driving restrictions.

ANTISEIZURE DRUGS AND PREGNANCY

Women taking ASDs have a somewhat higher risk of fetal malformations than does the
general population, but the absolute risk is still low. Valproic acid has been specifically
associated with a higher rate of neural tube defects. All women with epilepsy who are
considering becoming pregnant should take folic acid (at least 1 mg per day). It is
reasonable to consider modifying the ASD regimen prior to conception, depending on
the severity of a woman’s epilepsy, but the risk of ASD-related teratogenicity must be
balanced with the risk of seizures during pregnancy.

PSYCHOGENIC NONEPILEPTIC SEIZURES

A reported 10% to 30% of patients evaluated at tertiary referral centers for medically
refractory epilepsy actually have events resembling seizures that have no EEG correlate
and are psychogenic in nature. These are referred to as psychogenic nonepileptic
seizures. Some of these patients may have “true” epileptic seizures at other times. Many
patients with psychogenic events have comorbid psychiatric illnesses or a history of
abuse. Continuous video-EEG monitoring to record the typical events is usually the
most reliable method of differentiating psychogenic events from epileptic seizures.

CLINICAL VIGNETTES

VIGNETTE 1
A 23-year-old man has recurrent episodes in which he stares blankly, makes
smacking movements with his lips, and rubs his hands together. He has no memory
of the events afterward, but typically he realizes there has been a lapse in time. His
EEG is normal.
1. Which of the following is a potential cause of his symptoms?
a. Subdural hematoma
b. Mesial temporal sclerosis
 c. Prior head injury
d. Benign brain tumor
e. All of the above
2. The patient sees a neurologist, who diagnoses him with epilepsy and prescribes
oxcarbazepine. MRI of the brain shows left mesial temporal lobe sclerosis.
Unfortunately, the seizures continue despite the use of oxcarbazepine and further
trials of three other antiseizure medications. Which of the following would be
an appropriate treatment to consider for this patient at this point?
a. Electroconvulsive therapy
b. Resective brain surgery
c. Ethosuximide
d. Neuromuscular blocking agents
e. Trigeminal nerve stimulation

VIGNETTE 2
Outside the hospital, you witness a young woman lying on the street unconscious,
with symmetric convulsive movements of all limbs.
1. Which of the following is an appropriate immediate measure to take in the field?
a. Restrain the patient’s arms to prevent self-injury
b. Restrain the patient’s legs to prevent self-injury
c. Insert a tongue depressor into patient’s mouth to prevent tongue biting
d. Turn patient onto her side to prevent aspiration
e. Elevate the head to lower cerebral blood flow
2. The convulsions stop, and the patient is brought directly into the hospital’s
emergency department. Five minutes later, she remains unarousable but has no
focal abnormalities on neurologic examination. She has evidence of a tongue
laceration and urinary incontinence. Before further evaluation can be performed
and before she awakens, two more generalized convulsive seizures occur in
rapid succession. Which of the following would be the first pharmacologic
agent used in this situation?
a. Lorazepam
b. Carbamazepine
c. Phenytoin
d. Phenobarbital
e. Propofol

ANSWERS
VIGNETTE 1 QUESTION 1
1. Answer E:
The patient’s symptoms and behavior are consistent with focal-onset epileptic
seizures with impaired awareness (previously termed complex partial seizures). A
normal EEG does not rule out the clinical diagnosis of seizures. The lip-smacking
and hand-rubbing movements are consistent with automatisms, which are
nonpurposeful, stereotyped movements frequently seen in association with focal
seizures, often in those of temporal lobe origin. Many different acute and remote
brain insults can lead to focal-onset seizures, including subdural hematoma,
sclerosis of the mesial temporal lobe, prior traumatic brain injury, CNS infections,
and benign tumors such as meningiomas and pilocytic astrocytomas. Although
epilepsy can arise at any stage of life, the most common underlying causes differ
according to the age of onset.

VIGNETTE 1 QUESTION 2
2. Answer B:
Most patients with epilepsy attain good seizure control with antiseizure medications
alone, usually with just a single drug, and often with the first drug tried. This
patient’s seizures are refractory to multiple medications, so it is appropriate to
consider nonpharmacologic options at this point. Of the choices listed, resective
brain surgery is the only standard therapy for those with focal-onset seizures and is
particularly likely to be effective in patients with mesial temporal sclerosis.
Electroconvulsive therapy is not a standard treatment for epilepsy. Ethosuximide is
used for absence seizures only, not for those with focal onset. Neuromuscular
blocking agents stop the motor signs of seizures but not the actual brain electrical
activity itself. Vagus nerve stimulation, not trigeminal nerve stimulation, is an
approved therapy for seizures.

VIGNETTE 2 QUESTION 1
1. Answer D:
Appropriate measures to take for a patient having a presumed GTCS include
loosening of tight clothing and repositioning the patient into a lateral decubitus
position to prevent aspiration in the event of vomiting. Attempts at restraint will
generally be ineffective and could increase the risk of injury. Nothing should be
inserted in the mouth, as this increases the chance of dental injury or foreign object
ingestion. Lowering cerebral blood flow is not an appropriate intervention for acute
seizures.

VIGNETTE 2 QUESTION 2
2. Answer A:
At this point, the patient appears to be in generalized convulsive SE, defined as ≥5
minutes of either continuous seizure activity or the recurrence of one seizure after
another, without return to a normal condition between seizures. (In this case, she is
having repeated convulsive seizures without intervening recovery.) SE is a medical
emergency, and pharmacologic treatment usually begins with administration of an
intravenous benzodiazepine, such as lorazepam. Phenytoin, phenobarbital, and
propofol can be used in later steps of SE treatment, if needed. Carbamazepine is not
available in parenteral form and is not generally used for SE. Airway, Breathing and
Circulation ( ABCs) are always addressed concomitantly in patients with SE.
 16 Movement Disorders

PARKINSON DISEASE
Idiopathic Parkinson disease (PD) is the most common neurodegenerative movement
disorder and is the most important form of parkinsonism, the clinical syndrome
characterized principally by bradykinesia and rigidity. Features of other parkinsonian
syndromes are reviewed in Table 16-1.

EPIDEMIOLOGY
PD is most common in middle-aged and older patients, affecting approximately 1% of
people over 60 years. It is typically a sporadic disorder, but hereditary forms of PD due
to mutations in genes such as PRKN, PINK1, LRRK2 , and GBA may affect younger
patients.

PATHOLOGY
The precise source of PD is not known, but the essential motor manifestations of the
disease are due to degeneration of dopaminergic neurons in the substantia nigra pars
compacta. The key histopathologic finding of PD is the Lewy body, which is an alpha-
synuclein containing eosinophilic cytoplasmic inclusion that accumulates in neurons of
the brainstem, cerebral cortex, and sympathetic autonomic ganglia.

CLINICAL MANIFESTATIONS
The four cardinal motor manifestations of PD are tremor, rigidity, bradykinesia, and
postural instability. Approximately 80% of patients with PD have a resting tremor,
which is characteristically asymmetric, involves the hands, recurs about 4 times per
second (4 Hz), and is worse with distraction. A “pill-rolling” tremor involving the
thumb and forefinger is classic. Bradykinesia or slowness of movement is often the
most disabling feature of PD and involves both axial and appendicular muscles. Speech
and swallowing difficulties in PD are manifestations of bradykinesia. Rigidity is an
increase in muscle tone, which is equal in both flexion and extension of a body part. In
patients with PD, rigidity tends to be greater in the limbs than in the trunk. Postural
instability is the final cardinal motor manifestation of PD: Patients with advanced PD
have difficulty with postural control and tend to fall backward when pulled from
behind.

TABLE 16-1. Parkinsonian Syndromes

Parkinsonian Syndrome
Progressive supranuclear palsy
Corticobasal ganglionic degeneration
Diffuse Lewy body disease
Vascular parkinsonism
Multiple system atrophy
Distinguishing Clinical Features
Supranuclear ophthalmoplegia, with greatest limitation of downward
gaze; axial rigidity; early falls due to rigidity, impaired postural
reflexes, neck hyperextension, and inability to look down
Limb apraxia; cortical sensory impairment; alien-limb phenomenon;
asymmetric rigidity; dementia
Early dementia; prominent visual hallucinations; cognitive fluctuations;
extreme sensitivity to extrapyramidal side effects of antidopaminergic
neuroleptic drugs
“Lower-half” parkinsonism in which rigidity in the legs is greater than
in the arms, resulting in slow, shuffling gait
Early and prominent features of autonomic dysfunction (MSA-A);
cerebellar dysfunction (MSA-C); parkinsonism refractory to levodopa
(MSA-P); high-pitched, quivering dysarthria

PD also has important “nonmotor” features. Rapid eye movement (REM) sleep
behavior disorder is characterized by violent enacting of dreams: The patient’s bed
partner will describe them as fighting, kicking, or running while asleep. This
phenomenon is due to the failure to induce muscle atonia in REM sleep and often
predates overt PD by many years. Autonomic dysfunction, especially orthostatic
hypotension, is common in patients with PD. Constipation due to gastrointestinal
hypomotility is another nonmotor feature of PD. Dementia, often accompanied by
psychotic features, occurs in 25% to 30% of PD patients and is more common with
advanced disease.

TREATMENT
The most effective medical treatment for PD is replacement of deficient endogenous
dopamine with levodopa. (Indeed, if this does not help, one should consider the
possibility of illnesses other than idiopathic PD.) Levodopa is combined with
carbidopa, an inhibitor of peripheral dopamine decarboxylase, which allows the
levodopa to cross the blood–brain barrier and reach its target, while also reducing
peripheral dopaminergic side effects including nausea, vomiting, and hypotension.
Initially, levodopa is quite effective for most patients with PD, but over time it loses its
effectiveness, and disabling dyskinesias develop. The long-term treatment of PD is
complicated (Table 16-2).
The monoamine oxidase B inhibitors rasagiline and selegiline may provide slight
benefit to patients with PD and are often used in early stages of the disease as
monotherapy or as a supplement to levodopa.
The dopamine agonists pramipexole and ropinirole are also options for the treatment
of mild or early PD. These medications may improve symptoms and reduce levodopa
requirement, thereby minimizing the long-term probability of dopamine-related
dyskinesias. Rotigotine is a dopamine agonist available in patch form and is designed to
prevent excessive fluctuation in drug levels.
Other medications are used for specific applications in PD. Anticholinergics
including benztropine and trihexyphenidyl are used to treat tremor but generally have
little effect on other PD symptoms. Amantadine is helpful in the management of
dyskinesias and dystonia associated with PD. The catechol-O-methyl transferase
inhibitor entacapone inhibits levodopa metabolism, thereby extending the duration of
levodopa action in patients who experience “wearing off.” Drug treatments are
summarized in Table 16-3.

TABLE 16-2. Therapeutic Strategies in Parkinson Disease

Scenario/Problem
Initial treatment
Poor or no response to initial treatment
Tremor-predominant disease
Overnight or early morning bradykinesia
Levodopa-induced hallucinations
“Wearing off”
Dyskinesia
COMT, catechol O-methyl transferase; MAO, monoamine oxidase.
Therapeutic Approach
Levodopa, dopamine agonist, or MAO inhibitor
Increase levodopa dose and consider alternative diagnoses
Anticholinergic or amantadine
Consider overnight controlled-release preparation of levodopa
Discontinue concurrent therapy with anticholinergics, amantadine,
selegiline, or dopamine agonists
Decrease dose of levodopa
Low-dose atypical antipsychotic (with quetiapine, clozapine, or
pimavanserin)
More frequent dosing
Extended release formulation of levodopa
Add COMT inhibitor
Reduce dose of levodopa
Add or increase dose of dopamine agonist
Change dopamine agonist
Add amantadine
Consider deep brain stimulation

Deep brain stimulation of the subthalamic nucleus (STN) and globus pallidus internus
may be helpful for patients with advanced disease.

KEY POINTS
 ● Idiopathic P D is the most common form of parkinsonism and results from loss of dopaminergic neurons in
the substantia nigra.
● Tremor, rigidity, bradykinesia, and postural instability are the four cardinal motor features of PD.
● There are many nonmotor features of PD, including REM behavior disorder and autonomic dysfunction.
● A wide variety of medical and surgical treatment options are available for PD.

DRUG-INDUCED MOVEMENT DISORDERS

Medications which block dopamine receptors including antipsychotic medications (both
traditional dopamine blockers and newer, atypical agents) and the promotility agent
metoclopramide may produce a variety of movement disorders:
Acute dystonic reactions occur when patients are introduced to dopamine-blocking
medications or given high doses of dopamine blockers to which they are not
accustomed. Intermittent or sustained contraction in any of the muscles in the face,
limbs, or trunk may occur. Forced contraction of the extraocular muscles and tonic
deviation of the eyes may occur. Acute dystonic reactions are best treated with
anticholinergic agents and benzodiazepines. The reaction is short-lived and does not
produce any long-term consequences.
Parkinsonism may occur as the result of long-term use of any neuroleptic agent. The
symptoms are similar to those seen in PD, but tremor is less common and patients tend
to be less responsive to levodopa.

TABLE 16-3. Pharmacologic Treatment of Parkinson Disease

Drug Mechanism of Action Dosing
Levodopa/carbidopa Dopamine precursor/dopa Start with a half of a 25/100
decarboxylase inhibitor tablet bid; increase dose as
needed; typically dosed 3–5
times a day
Trihexyphenidyl Anticholinergic Start with 1 mg bid–tid;
increase to 4 mg tid as
needed
Benztropine Anticholinergic Start with 0.5–1 mg at
bedtime; increase to 2 mg
qid as needed
Amantadine NMDA antagonist 100 mg bid
Pramipexole Dopamine agonist Start with 0.125 mg tid;
titrate gradually to 1.5 mg
tid as needed
Ropinirole Dopamine agonist Start with 0. 25 mg tid;
Side Effects
Anorexia, nausea,
psychosis, hallucinations,
orthostatic hypotension,
dyskinesia
Dry mouth, constipation,
urinary retention, confusion,
hallucinations, narrow-angle
glaucoma
As above
Hallucinations, leg edema,
livedo reticularis
Lightheadedness, sleep
attacks, pathologic
gambling, and other impulse
control disorders
As above
 titrate gradually to 1 mg tid
Rotigotine patch Dopamine agonist as
2 mgneeded
qd; titrate to 6 mg qd As above, patch site
reactions
Entacapone COMT inhibitor 200 mg with each L-dopa Nausea, diaphoresis,
dose lightheadedness
Rasagiline MAO-B inhibitor 1 mg qd Dizziness, flulike syndrome
Selegiline MAO-B inhibitor 5 mg bid Confusion, orthostatic
hypotension, nausea
COMT, catechol O-methyl transferase; MAO-B, monoamine oxidase B; NMDA, N-methyl d-aspartate.

Neuroleptic malignant syndrome occurs when patients are exposed to high doses of
dopamine-blocking medications or when levodopa or dopamine agonists are withdrawn
abruptly. The syndrome includes fever, autonomic instability, encephalopathy, and
muscular rigidity. The offending agent must be stopped, but a combination of
bromocriptine, dantrolene, and benzodiazepines is usually required to control the
muscle rigidity.
Tardive dyskinesia (TD) is a disorder that occurs after chronic exposure to
dopamine-blocking agents. Commonly observed movements include chewing,
grimacing, lip smacking, and tongue thrusting. The limbs, trunk, and even diaphragm
may be affected. Treatment of TD is challenging: Withdrawal of the offending agent
often makes the movements worse. The dopamine-depleting agent tetrabenazine may be
helpful.

KEY POINTS
● Dopamine-blocking agents are the most common cause of drug-induced movement disorders.
● Treatment of TD is challenging, and it may be refractory to any treatment strategy.

TREMOR
Tremor is an involuntary oscillatory movement of a body part (arm, leg, head, jaw, lips,
palate). It can be divided into resting (occurring when the body part is at rest), postural
(occurring when maintaining a fixed posture), or action (occurring with movement).
Postural and action tremors usually accompany each other. The term intention tremor is
applied when an action tremor worsens as the body part approaches its target. Common
types and causes of tremors are summarized in Box 16-1.
Essential tremor (ET) is the most common tremor and overall, the most common
movement disorder. It can begin at any age and tends to get worse over time. Because
there is often a family history, the term “familial tremor” is sometimes applied. The
tremor is a postural and action tremor, which involves the hands, head, and voice. It
often improves with small quantities of alcohol, though this is not recommended as a
treatment strategy. The most effective treatment options are propranolol and primidone.
Deep brain stimulation of the ventral intermediate nucleus of the thalamus may help
patients with disabling ET refractory to medications.

KEY POINTS
● Tremor is an involuntary rhythmic oscillation of a body part.
● PD causes a resting tremor.
● ET is the most common cause of postural and action tremors.
● Intention tremor suggests disease of the cerebellum or its connections.

HUNTINGTON DISEASE AND OTHER CAUSES OF

CHOREA
Chorea is an irregular, twisting or jerky movement of a group of muscles. In most cases,
chorea flows from one muscle group to an adjacent group in a random-appearing
pattern. Chorea is usually accompanied by athetosis, a writhing movement of the limbs.
Motor impersistence often occurs with chorea; two examples are the darting tongue and
milkmaid handgrip, which are seen in patients with Huntington disease (HD). Chorea
has many causes, as highlighted in Box 16-2.

CLINICAL MANIFESTATIONS
HD, an autosomal dominant neurodegenerative disorder is the most important and
serious cause of chorea. HD is characterized by chorea, cognitive impairment, dystonia,
and psychiatric illness. Symptoms usually appear between the ages of 35 and 45 years
and include the triad of chorea, behavioral changes or personality disorder (frequently
obsessive-compulsive disorder), and dementia. The three may occur together at onset,
or one may precede the others by years.

BOX 16-1. Tremor

Resting
Idiopathic Parkinson disease
Other parkinsonian syndromes
Postural/Action
 Essential tremor
Physiologic tremor
Drugs (e.g., theophylline, β-agonists)
Alcohol
Orthostatic tremor
Intention
Cerebellum and cerebellar outflow tract dysfunction (e.g., infarction, multiple sclerosis, tumor, Wilson
disease, drugs)

BOX 16-2. Chorea

Hereditary
Huntington disease (HD)
HD-like syndromes
Neuroacanthocytosis
Dentatorubral pallidoluysian atrophy
Wilson disease
Drugs
Neuroleptics
Antiparkinsonian medications
Toxins
Alcohol
Anoxia
Carbon monoxide
Metabolic
Hyperthyroidism
Nonketotic hyperglycemia
Hepatocerebral degeneration
Pregnancy
Chorea gravidarum
Immunologic
Systemic lupus erythematosus
Antiphospholipid antibody syndrome
Poststreptococcal (Sydenham chorea)
Vascular
Caudate infarction or hemorrhage

DIAGNOSTIC EVALUATION
Diagnosis is by personal and family history, clinical signs, imaging, and genetic testing.
Caudate atrophy, sometimes severe, is the characteristic finding on magnetic
resonance imaging (MRI). Definitive diagnosis is made by finding an expansion of more
than 40 cytosine–adenine–guanine trinucleotide repeats in the HTT gene on chromosome
4.
PATHOLOGY
Pathologic examination shows severe destruction of the caudate and putamen (striatal
and nigral GABA-ergic neurons) and loss of neurons in the cerebral cortex (layer 3).
The molecular mechanisms of HD are unclear but involve accumulation of abnormal
intracellular proteins which triggers cell death.

TREATMENT
Pharmacologic management of dementia and chorea often involves dopaminergic
antagonists, including neuroleptic drugs, but it is far from adequate. Neuroleptics can
ameliorate the chorea, but the other neuropsychiatric symptoms ultimately prove
disabling. Unfortunately, HD is a progressive and ultimately fatal disorder; death occurs
10 to 20 years after onset. Suicide is not rare in at-risk and early-onset HD patients.
Genetic counseling is crucial.

KEY POINTS
● Chorea is characterized by involuntary, abrupt, and irregular movements that flow randomly between muscle
groups. It is usually accompanied by athetosis, a twisting or writhing movement.
● Important causes of chorea include HD, neuroacanthocytosis, poststreptococcal infection, systemic lupus
erythematosus, thyrotoxicosis, and pregnancy.
● HD is characterized by chorea, dementia, and personality and behavioral changes.

BALLISM
Ballism is a brief flinging movement of a limb, most often unilateral (hemiballismus).
The classic lesion responsible for hemiballismus is an ischemic stroke in the
contralateral STN, though lesions in other components of the basal ganglia may be
causative. In many cases, ballism resolves on its own, but dopamine-blocking agents
may be helpful if this spontaneous improvement does not occur.

DYSTONIA
Dystonia is a sustained contraction of agonist and antagonist muscles producing twisting
movements or abnormal postures. Dystonia may be focal (affecting one body part),
segmental (affecting one region), or generalized (affecting multiple body parts). The
abnormal movements are worsened by movement and relieved by sensory tricks such as
touching or stroking the affected body part.
Focal dystonia is more common in adults, and various body parts have characteristic
dystonias. Torticollis is excessive contraction of the neck muscles resulting in a fixed
head position; it is often quite painful. Blepharospasm involves sustained contraction of
the orbicularis oculi and forced closure of the eyelids. Spasmodic dysphonia involves
the laryngeal muscles and may result in choppy or strangled speech (adductor
spasmodic dysphonia) or a breathy voice quality (abductor spasmodic dysphonia).
Writer’s cramp is a focal dystonia of the hand and arm muscles that prevents a patient
from using a writing implement properly. In general, botulinum toxin injections are the
best treatment option for the focal dystonias.
Generalized dystonias are more common in children than in adults. The most common
of these is DYT-TOR1A dystonia, an autosomal dominant disorder caused by a
mutation in the gene that encodes the protein torsinA. DYT-TOR1A dystonia starts in
childhood or adolescence and often begins in the foot and leg muscles. Treatment
options include anticholinergic agents such as trihexyphenidyl, or baclofen,
benzodiazepines, and deep brain stimulation of the globus pallidus interna. The dopa-
responsive dystonias are an important group of childhood-onset dystonias and are
caused most often by a mutation in the gene encoding the enzyme GTP cyclohydrase 1.
Parkinsonism may accompany the dystonia. As the name suggests, this group of
conditions is responsive to dopamine; for this reason, a trial of levodopa is warranted
in all children who develop dystonia.
Dystonia may also occur as a manifestation of other central nervous system disorders
including Wilson disease (WD), PD, HD, anoxic brain injury, stroke, multiple sclerosis,
and medication-induced movement disorders.

KEY POINTS
● Dystonia is a sustained muscle contraction leading to twisting movements or abnormal postures.
● Dystonia may be focal, segmental, or generalized.
● Dopa-responsive dystonia is an important cause of childhood-onset dystonia.

MYOCLONUS
Myoclonus is a sudden jerking movement of a muscle that is sufficient to move a joint.
Asterixis is a negative form of myoclonus in which a patient is suddenly, but briefly,
unable to hold the arms and hands up against gravity, resulting in an erratic and
repetitive downward jerking movement. Both are signs of central nervous system
dysfunction.
The etiologic categories of myoclonus are physiologic, essential, epileptic, and
symptomatic (Box 16-3). Physiologic myoclonus includes common movements such as
jerks that occur just at sleep onset (“sleep starts” or “hypnic jerks”) and hiccups.
Essential myoclonus occurs in isolation without other neurologic symptoms or signs. It
may occur in familial and sporadic forms and may be responsive to alcohol; some
patients may note a striking improvement with small quantities of alcohol. Epileptic
myoclonus occurs as a manifestation of juvenile myoclonic epilepsy and other “benign”
epilepsy syndromes, and with some of the more malignant progressive myoclonic
epilepsies. Symptomatic myoclonus accompanies a wide variety of metabolic
disturbances and neurodegenerative diseases.
Clonazepam and valproate are often effective in controlling myoclonus, but an
underlying source should be identified and treated if possible.

KEY POINTS
● Myoclonus is a sudden, brief jerking movement of a muscle or group of muscles.
● Myoclonus has a wide variety of causes and may respond to medications such as clonazepam or valproate.

TICS
Tics are abnormal, brief muscle contractions that may involve the face, extremities, or
speech. They tend to vary in intensity and are irregular in frequency, sometimes
occurring in runs of multiple tics and often suppressible for short periods of time.
Patients with tics describe an internal sensation of an urge to move or perform the tic,
with a sense of relief after the tic has occurred. Stress tends to exacerbate tics.
Tics can be divided into motor and vocal tics. These, in turn can be divided into
simple and complex tics. Simple motor tics include eye blinks, facial grimaces, and
shoulder shrugs. Complex motor tics include spitting and finger cracking. Examples of
simple vocal tics include grunting, throat clearing, and coughing. Complex vocal tics are
more extensive vocal utterances of several words blurted out, including foul language
(coprolalia). Tics are most often idiopathic, but head trauma, encephalitis, and
cerebrovascular disease may produce tics.

BOX 16-3. Myoclonus

Physiologic
Hypnic jerks (sleep starts)
 Anxiety and exercise induced
Hiccups
Essential
Epileptic
Primary generalized epilepsies (e.g., juvenile myoclonic epilepsy)
Myoclonic epilepsies (often associated with progressive encephalopathy, e.g., Lafora body disease,
Unverricht–Lundborg disease, sialidosis)
Symptomatic
Metabolic encephalopathy (uremia, liver failure, hypercapnia)
Wilson disease
Creutzfeldt–Jakob disease and other advanced dementias
Hypoxia (post-anoxic brain injury or Lance-Adams syndrome)

Gilles de la Tourette syndrome is a pediatric-onset disorder in which patients

develop motor and vocal tics. It has a presumed genetic origin, but a single responsible
gene mutation has not been identified. Boys tend to be affected more often than girls.
Multiple motor and vocal tics are present; they may change over time and even go into
periods of remission. There is a tendency for the tics to improve in adulthood.
Obsessive-compulsive disorder, attention-deficit hyperactivity disorder, and depression
often accompany Tourette syndrome.
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal
infections (PANDAS) are a combination of tics, obsessive-compulsive disorder, and
anxiety following group A β-hemolytic streptococcal infection. The etiology of
PANDAS is controversial, but presumably the streptococcal infection triggers an
autoimmune reaction against the basal ganglia. The symptoms are temporary and
respond to treatment with antibiotics and immunomodulatory therapy.
Tic treatment options include dopamine antagonists (haloperidol, risperidone, and
pimozide are used most commonly), guanfacine, clonazepam, and clonidine. In many
cases, tics improve during youth and disappear by the teenage years or early adulthood.

KEY POINTS
● Tics are abnormal, repetitive, stereotypical movements or vocalizations.
● Gilles de la Tourette syndrome is a pediatric-onset disorder, which produces both motor and vocal tics.
● Dopamine antagonists, guanfacine, clonidine, and clonazepam are treatment options for tic disorders.

WILSON DISEASE
WD is an autosomal recessive disorder that produces neuropsychiatric and hepatic
dysfunction. It is caused by a mutation in the hepatic protein ATP7B, which normally
incorporates copper into apoceruloplasmin to form ceruloplasmin. This results in the
accumulation of copper in the liver, cornea, and central nervous system.
There are multiple neurologic manifestations of WD including tremor, dysarthria,
parkinsonism, ataxia, dystonia, and cognitive decline. The classic but not universally
present tremor is described as a coarse tremor that can resemble a bird flapping its
wings (“wing-beating tremor”). Dystonia of the facial muscles may produce a grimace
known as risus sardonicus. Kayser–Fleischer rings are golden brown or greenish rings
within the Descemet membrane of the cornea. They are usually present in patients with
neurologic manifestations of WD, but slit lamp examination may be required to detect
them.
Laboratory findings in WD include increased serum copper, decreased serum
ceruloplasmin, and increased 24-hour urinary copper excretion. Liver biopsy may be
required to confirm the diagnosis.
Treatment options for WD include the copper-chelating agents trientine and
penicillamine, zinc supplementation, and restriction of copper-containing foods such as
liver, shellfish, and mushrooms. Earlier treatment results in better long-term
neuropsychiatric and hepatic outcome. Liver transplantation may be necessary for
patients with fulminant symptoms including hepatic failure.

KEY POINTS
● WD is an autosomal recessive disorder of copper metabolism, which produces a variety of hyperkinetic and
hypokinetic movement disorders as well as cognitive and hepatic dysfunction.
● Kayser–Fleischer rings represent copper deposition in the cornea and are highly suggestive of the diagnosis
of WD.
● Elevated serum copper levels, low ceruloplasmin levels, and elevated 24-hour urinary copper are useful
screening tests for WD. Liver biopsy is the definitive diagnostic test.
● Copper chelation therapy with trientine or penicillamine is the mainstay of WD treatment.

STIFF-PERSON SYNDROME
Stiff-person syndrome is an autoimmune or paraneoplastic condition characterized by
disabling muscle rigidity and spasms. Symptoms typically start with axial and trunk
muscles and spread throughout the body over time. In addition to progressive muscle
stiffness, patients have episodic worsening of their muscle stiffness often provoked by
physical or psychological stress.
Other autoimmune diseases including diabetes and thyroiditis are often present.
Finding antibodies to glutamic acid decarboxylase-65 (GAD-65) supports the
diagnosis. Antispasmodic medications including benzodiazepines and baclofen are the
standard treatments for stiff-person syndrome. For patients with refractory disease,
immunosuppressive therapy including corticosteroids and intravenous immunoglobulin
may be helpful.

KEY POINTS
● Stiff-person syndrome is characterized by chronic muscle rigidity with a predilection for axial muscles.
● Stiff-person syndrome is an autoimmune or paraneoplastic condition that may be associated with anti-GAD-
65 antibodies.

PAROXYSMAL DYSKINESIAS
Paroxysmal dyskinesias are rare, episodic movement disorders, which typically take the
form of chorea, athetosis, or dystonia. Consciousness is preserved during episodes, and
there are no other neurologic symptoms. In paroxysmal kinesigenic dyskinesia, the
dyskinetic movements are triggered by sudden movements and are brief, lasting for
seconds or minutes. Paroxysmal nonkinesigenic dyskinesias occur independent of
movement and tend to last for minutes to hours. They are often triggered by alcohol,
fatigue, and stress. Carbamazepine is often a helpful treatment for paroxysmal
dyskinesias.

CLINICAL VIGNETTES

VIGNETTE 1
A 48-year-old man presents to the emergency room (ER) with a 2-day history of
involuntary “jerking” movements of the right arm. Symptoms were mild initially but
became more severe over the 48 hours prior to presentation. He is also aware of
similar, but milder symptoms in the right leg. His wife reports some improvement in
symptoms when her husband is asleep. Apart from mild hypertension and
hypercholesterolemia, he is otherwise healthy. On neurologic examination, he is
awake, alert, and oriented. Speech is fluent, and language function is normal.
Intermittent and irregular “flinging” movements of large amplitude are noted in the
right arm. Muscle bulk, strength, and reflexes are all normal.
1. Which of the following terms most accurately describes the observed movement
disorder?
 a. Chorea
b. Athetosis
c. Ballismus
d. Tremor
e. Dystonia
2. Which of the following diagnostic tests would be most likely to help to determine
the origin of hemiballismus?
a. Electroencephalogram (EEG)
b. Electromyography (EMG)
c. MRI of the brain
d. MRI of the cervical spine
e. Serum glucose measurement

VIGNETTE 2
A 27-year-old woman presents to the ER with a 2-day history of diarrhea, nausea,
and vomiting. She is diagnosed with gastroenteritis and receives prochlorperazine
for nausea along with intravenous fluids for rehydration. Within an hour, she is
observed to have some abnormal movements, and the attending ER physician
requests a neurology consultation. When you examine her, you find that she is awake
but having difficulty communicating due to persistent facial grimacing and forced
movements of the jaw. Her eyes and neck turn periodically to one side. The
movements seem erratic and unpredictable rather than stereotypic.
1. Which of the following is the most likely diagnosis?
a. Cerebral sinus thrombosis due to dehydration
b. Seizures induced by the prochlorperazine
c. Hysteria
d. Acute dystonic reaction caused by the prochlorperazine
e. Viral meningoencephalitis caused by the same organism responsible for her
gastroenteritis
2. You diagnose this young woman as having an acute dystonic reaction due to D2
antagonism caused by the administration of prochlorperazine. The most
appropriate course of action is:
a. Reassurance that the effects of the drug are transient and should wear off
quickly
b. Administration of the anticholinergic agent diphenhydramine
c. Administration of a D2 agonist such as pergolide, pramipexole, or ropinirole
to reverse the D2 antagonism caused by the prochlorperazine
d. Intubation because dystonia of the airway may compromise respiratory
function
 e. Order physical restraints to prevent self-injury

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer C:
Ballism is the term used to describe large-amplitude, poorly patterned flinging or
flailing movements of a limb. Movements are often unilateral, in which case the
te r m hemiballismus is used. Chorea, by contrast, describes abrupt, irregular
movements that flow as if randomly from one body part to another. Patients are often
unaware of chorea, even when severe. Athetosis refers to a slow, writhing,
involuntary movement of muscle groups. Tremor is an involuntary rhythmic
oscillation of a body part. Dystonia is a sustained muscle contraction, often leading
to repetitive twisting movements or abnormal postures.

VIGNETTE 1 QUESTION 2
2. Answer C:
Hemiballismus is most often due to a structural lesion (e.g., infarction) in the
contralateral caudate, putamen, or STN. Metabolic disturbances, notably nonketotic
hyperosmolar hyperglycemia, are far less common causes of such movements. EEG
can be helpful in the diagnosis of seizures and encephalopathy, but these are not
consistent with the patient’s presentation. EMG would be used to evaluate lesions of
the peripheral nervous system. MRI of the cervical spine would be helpful in
identifying a compressive lesion of the cervical spinal cord or nerve roots, but these
would not be useful for the evaluation of hemiballismus.

VIGNETTE 2 QUESTION 1
1. Answer D:
The most likely diagnosis is a drug-induced acute dystonic reaction.
Prochlorperazine (Compazine) is a member of the phenothiazine class of drugs. Its
mechanism of action includes blockade of dopamine (D2) receptors. It is well
known to cause an acute dystonic reaction. Whereas dehydration is a risk factor for
cerebral sinus thrombosis, this typically manifests with headache, seizures, and
visual disturbances. Seizures should be more stereotyped. A meningoencephalitis
should cause a fever, headache, altered level of arousal, and stiff neck and should
not cause dystonic movements of this sort.
VIGNETTE 2 QUESTION 2
2. Answer B:
The most appropriate course of action is administration of an anticholinergic
medication such as diphenhydramine or benztropine. The symptoms should resolve
quickly following administration of one of these drugs. Of course, the offending drug
should not be administered again. Although an acute dystonic reaction may
potentially compromise bulbar and respiratory function, preemptive intubation is
seldom necessary.
 17 Head Trauma

EPIDEMIOLOGY
Estimates of the annual number of head injuries in the United States range from 500,000
to 1.5 million, with the large majority being mild in severity. In young adults, motor
vehicle accidents are the most common cause of head trauma, whereas in the elderly,
falls are the most common. Men are more often the victims of head trauma than are
women, by a ratio of at least 2:1.

TYPES OF HEAD TRAUMA

EPIDURAL HEMATOMA
An epidural hematoma is an accumulation of blood between the skull and dura mater. It
is usually the result of a severe head injury with a temporal bone fracture and resulting
laceration of the middle meningeal artery. Less frequently, laceration of the middle
meningeal vein or a dural venous sinus may produce an epidural hematoma. The classic
presentation of epidural hematoma is a “lucid interval” in which the patient has
preserved consciousness immediately after the precipitating event, followed by a
decline in the level of consciousness, often with rapid progression to coma as the
hematoma enlarges. Brain herniation, especially uncal herniation (see later discussion),
may develop as a result of the hematoma expansion. The characteristic computed
tomography (CT) scan appearance of an epidural hematoma is a lens-shaped hyperdense
lesion between the skull and dura (Fig. 17-1). Surgical evacuation is required and, if
performed in a timely fashion, can be life-saving.
FIGURE 17-1. Computed tomographic scan of the head demonstrating the typical hyperdense lens-shaped
appearance of an epidural hematoma (arrows). Note the compression of the ipsilateral ventricles and modest midline
shift. (Reproduced with permission from Daffner RH. Clinical Radiology: The Essentials. 3rd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2007.)

SUBDURAL HEMATOMA
A subdural hematoma is an accumulation of blood between the dura mater and the brain.
It results from tearing of bridging veins that connect the surface of the brain and the
dural sinuses. Subdural hematoma may have an acute or chronic presentation. Acute
subdural hematoma develops shortly after head trauma and can be life-threatening.
Headache is the most common symptom, but the hematoma may also lead to
contralateral hemiparesis, seizures, and a wide variety of cortical dysfunction. If
sufficiently large, a subdural hematoma can increase intracranial pressure (ICP), with a
resulting diminution in the level of consciousness. The CT scan in Figure 17-2 shows a
subdural hematoma as a crescent-shaped hyperdensity overlying the brain surface and
underlying the skull. Subdural hematoma can be distinguished radiologically from an
epidural hematoma by its ability to cross suture lines. Acute subdural hematoma may
require treatment with surgical drainage depending on its size, severity, and clinical
progression.
FIGURE 17-2. Computed tomographic scans of the head showing subdural hematomas overlying the right
cerebral hemisphere: a smaller hematoma with classic crescent shape in A and major mass effect with compression of
the right lateral ventricle and marked shift of the midline in B. (Modified with permission from Haines DE.
Neuroanatomy in Clinical Context. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014. Figure 4-5.)

Chronic subdural hematoma typically develops after mild head trauma and is more
common in the elderly, particularly those who are anticoagulated. Like the acute variety,
chronic subdural hematoma may produce one of several neurologic symptoms, including
headache, hemiparesis, seizures, and behavioral changes. A chronic subdural hematoma
may resolve on its own; indications for operation include rapidly expanding lesions and
progressive clinical deficits. Anticoagulation should be discontinued to allow the best
chance for recovery.

CONCUSSION
A concussion is an alteration of brain function produced by head trauma. The symptoms
of a concussion are the result of a functional rather than structural change, and brain
imaging studies are typically normal. Patients may have loss of consciousness (though
this is not required for the diagnosis of concussion), short periods of amnesia for events
that occurred before the injury (retrograde amnesia), and difficulty learning new
material after the incident (anterograde amnesia). The severity of a concussion is
correlated with the duration of loss of consciousness and consequent amnesia. Other
consequences of concussion include headache, disorientation, dizziness and vertigo,
nausea, and cortical blindness. Concussions are frequent in sporting events, particularly
in children. Athletes who are suspected of having had a concussion should be removed
from play. There is no clear consensus for when return to play should be allowed, but
gradual reintroduction of activity is recommended until an athlete is asymptomatic,
because a history of concussions increases the risk for future concussions.

POSTCONCUSSION SYNDROME
Postconcussion syndrome is usually the consequence of mild traumatic brain injury. The
cause of the syndrome is unclear, but structural, biochemical, and psychological
components have been implicated. Features of the syndrome include headache,
dizziness, sleep disturbance, cognitive impairment, and behavioral abnormalities such
as irritability. Neuroimaging studies are almost always normal. Pending litigation or
workers’ compensation issues and depression are associated with prolonged
postconcussion syndrome. Management should focus on the individual components of
the syndrome, with treatment of headache, sleep disturbance, and psychological
problems, including mood problems.

FIGURE 17-3. Diffuse axonal injury shown on magnetic resonance imaging with fluid-attenuated inversion
recovery sequences.

DIFFUSE AXONAL INJURY

Diffuse axonal injury is associated with severe head trauma and may be seen on CT as
multiple areas of punctate hemorrhage in the deep white matter and corpus callosum
(Fig. 17-3). In many cases, though, it is not well visualized with standard neuroimaging
studies. The presence of diffuse axonal injury is usually associated with poor prognosis.

KEY POINTS
● Epidural hematoma is usually caused by laceration of the middle meningeal artery; it is often clinically
associated with a “lucid interval.”
● Subdural hematoma is usually caused by tearing of bridging veins and can produce a variety of neurologic
deficits including headache, hemiparesis, and seizures.
● Concussion is a loss or alteration of consciousness produced by head injury and is usually accompanied by
normal neuroimaging.
● Components of the postconcussion syndrome include headache, dizziness, cognitive impairment, sleep
disturbance, and behavioral abnormalities.

POSTTRAUMATIC SEIZURES AND EPILEPSY

Seizures after head trauma can be divided into early (within 1 week of head trauma) and
late (beginning at least 1 week later). Approximately 25% of patients with acute severe
head injury (characterized by intracranial hematoma or depressed skull fracture, without
regard to the duration of loss of consciousness or posttraumatic amnesia) have early
posttraumatic seizures, most often generalized tonic–clonic convulsions. Of these, 25%
go on to develop epilepsy (recurrent unprovoked seizures). Antiseizure drugs (ASDs)
reduce the incidence of early seizures but do not change the overall risk for the later
development of epilepsy.
Overall, posttraumatic epilepsy occurs in about 2% of patients with head trauma,
with a higher frequency in patients with severe head injuries. About 50% of patients
who develop posttraumatic epilepsy do so within 1 year of the trauma. Patients who
have a single late seizure usually require treatment with ASDs, as they are at high risk
for posttraumatic epilepsy, that is, recurrent seizures.

KEY POINTS
● Treatment of early posttraumatic seizures does not alter the long-term likelihood of developing epilepsy.
● Late posttraumatic seizures (those occurring more than a week after head injury) increase the risk of epilepsy
and usually necessitate prophylactic ASD treatment.
HERNIATION SYNDROMES
Brain herniation is a life-threatening condition that occurs when increased ICP causes a
shift of brain contents, resulting in compression of brain parenchyma, obstruction of the
ventricles, and occlusion of cerebral blood vessels.

CENTRAL (TRANSTENTORIAL) HERNIATION

Diffuse cerebral edema or a large supratentorial mass may cause downward herniation
of the diencephalon through the tentorial notch. The central herniation syndrome is
heralded by a decrease in the level of alertness, shortly followed by small, reactive
pupils due to disruption of sympathetic pathways from the hypothalamus. As central
herniation proceeds, the patient may assume a decorticate posture upon stimulation.
Progressive herniation leads to midbrain compression, with fixed, midposition pupils
and decerebrate posturing. In the final stages, the patient becomes motionless and
unresponsive to stimulation, and eventually progresses to death.

UNCAL HERNIATION
Uncal herniation is most often produced by the expansion of a mass located laterally
within the brain, resulting in a medial shift of the uncus of the temporal lobe. Uncal
herniation may be preceded by neurologic deficits, particularly hemiparesis related to
the mass itself. As the brain begins to shift away from the mass, the first clinical deficit
is often an ipsilateral third nerve palsy, accompanied or shortly followed by an
impairment of consciousness. Continued uncal herniation produces compression of the
contralateral cerebral peduncle against the free edge of the tentorium with a resulting
hemiplegia ipsilateral to the herniating uncus, the “Kernohan notch” phenomenon.
Compression of the posterior cerebral artery may produce medial temporal lobe or
occipital lobe ischemia or infarction. As signs of uncal herniation appear, neurologic
deterioration may be rapid and often irreversible.

SUBFALCINE HERNIATION
Expanding frontal lobe masses may produce herniation of the cingulate gyrus beneath the
falx cerebri. Most often, the patient has been symptomatic from the frontal lobe mass,
and subfalcine herniation may not alter the clinical picture appreciably, although
compression of the anterior cerebral arteries may lead to a stroke and leg weakness.

KEY POINTS
● The herniation syndromes are life-threatening conditions that must be addressed immediately.
 ● A dilated pupil ipsilateral to the side of a mass lesion is an early sign of uncal herniation.
● Uncal herniation is also associated with ipsilateral hemiplegia due to compression of the contralateral cerebral
peduncle against the free edge of the tentorium.

INITIAL ASSESSMENT OF HEAD TRAUMA

Head trauma may be life-threatening, and careful attention to the patient’s airway,
breathing, and circulation is essential to its initial management. Once life support is
assured, the neurologic aspects of head trauma can be addressed by clinical examination
and CT scan. One tool for grading the severity of traumatic brain injury is the Glasgow
Coma Scale (GCS) (Table 17-1). Scores of 13 to 15 are classified as mild head injury,
8 to 12 moderate, and 3 to 7 severe. Limitations of the GCS include inaccurate
assessment of patients who are already intubated and sedated and a lack of utility in
tracking serial changes. Although the GCS assesses the severity of coma, it does not
assist with the diagnosis of its cause.

TABLE 17-1. Glasgow Coma Scale

Points Best Eye Opening Best Verbal Best Motor
6 — — Obeys commands
5 — Oriented Localizes pain
4 Spontaneous Confused Withdraws to pain
3 To speech Inappropriate Decorticate posturing
2 To pain Incomprehensible Decerebrate posturing
1 None None None

MANAGEMENT OF INCREASED INTRACRANIAL

PRESSURE
In adults, normal ICP is <15 mm Hg. Because the skull is a rigid container, the total
volume of its three components (brain, blood vessels, and cerebrospinal fluid [CSF]) is
fixed and there is no room for expansion. Change in the volume of one of these
compartments can compromise the status of the other two. In patients with head trauma,
intracranial masses, or other causes of cerebral edema, ICP monitoring may be
necessary to determine whether cerebral perfusion pressure (CPP) is adequate. CPP is
defined as the difference between the mean arterial pressure and ICP. A goal CPP is
between 60 and 75 mm Hg; excessively high CPP can cause hypertensive
encephalopathy and cerebral edema, whereas lower pressures may result in diffuse
cerebral ischemia. ICP monitoring, usually in the form of an intraventricular pressure
monitor, should be considered in any head injury patient with a Glasgow Coma Score of
<9 and an abnormal head CT scan.
Correction of the proximate cause of increased ICP, whether by resection of a tumor
or drainage of a hematoma, is the most effective therapy. There are situations, however,
in which this is not possible, and other treatments for increased ICP must be employed.
The first and easiest step to reduce ICP is to elevate the head of the bed, usually to 30
degrees, in order to improve venous drainage. Hyperventilation to a PCO2 between 25
and 30 mm Hg can be useful in the short term. Low PCO2 results in vasoconstriction,
reducing cerebral blood volume and ICP, but prolonged hyperventilation may lead to
excessive vasoconstriction and increase the risk for cerebral infarction. Mannitol, an
osmotic diuretic, or hypertonic saline may help to lower ICP. Intravenous barbiturates,
especially pentobarbital, can reduce cerebral metabolism but should not be used for
extended periods because they are associated with several complications. CSF drainage
with a ventricular drain may be employed to reduce ICP. As stated earlier, correction of
the cause of increased ICP is the definitive therapy, and in some cases, this may require
hemicraniectomy to allow the intracranial contents to expand.

CLINICAL VIGNETTES

VIGNETTE 1
A 52-year-old woman hit the left side of her head while skiing. Initially, she was
responsive, but within half an hour, she developed slurred speech and appeared
confused. Half an hour later, she lost consciousness and was brought to the hospital.
A CT of her head without contrast was performed.
1. Which of the following is the most likely finding?
a. Blood in the subarachnoid space
b. Crescent-shaped hyperdensity overlying the brain
c. Large ischemic infarct of the left frontal lobe
d. Lens-shaped hyperdensity between the dura and the skull
e. Normal image; magnetic resonance imaging (MRI) would be more sensitive
to pathology at this stage
2. When you examine the patient, you find that she is comatose with an unreactive
left pupil. She is intubated immediately. Her blood pressure is 124/62 and her
pulse is 72. What is the next appropriate step in her management?
a. Epinephrine infusion to increase her mean arterial pressure and maintain CPP
b. Induce coma with pentobarbital
c. Ophthalmologic consultation to evaluate anisocoria
 d. Surgical clipping of a left posterior communicating artery aneurysm
e. Surgical decompression of epidural hematoma
3. After urgent surgical drainage of the epidural hematoma, the patient was
transferred to the intensive care unit. On her third hospital day, she had a
generalized convulsion. Which of the following is true concerning seizures and
epilepsy in this patient?
a. Anti-seizure drugs (ASDs) will prevent the development of posttraumatic
epilepsy
b. Intracranial hematoma and depressed skull fracture increase the risk of early
posttraumatic seizures
c. Complex partial seizures are the most common type of posttraumatic seizures
d. Electroencephalogram (EEG) will show a 3-Hz spike-and-wave pattern
e. This seizure would be defined as a late posttraumatic seizure because it
happened more than 24 hours after head trauma

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer D:
The history is most consistent with an epidural hematoma: She had a lucid interval
after head trauma, followed by confusion and then coma. Epidural hematoma is
characterized radiologically by a lens-shaped hyperdensity overlying the dura.
Subarachnoid hemorrhage presents with a sudden-onset, severe headache, but not
with a lucid interval. A crescent-shaped hyperdensity overlying the brain would be
characteristic of a subdural hematoma. An ischemic infarct of the left frontal lobe
would be less likely in a patient who had just sustained a head injury. Although head
MRI is more useful than CT in many contexts, CT is preferred acutely for most
patients with head trauma. A normal head CT with an abnormal MRI occurs in a
number of scenarios (e.g., acute ischemic stroke), but not in epidural hematoma.

VIGNETTE 1 QUESTION 2
2. Answer E:
The patient is comatose with an unreactive pupil, suggesting uncal herniation.
Surgical decompression of the responsible epidural hematoma is the most
appropriate treatment and should be performed urgently. Epinephrine infusion is not
indicated for this patient. Coma induction with pentobarbital may reduce the
cerebral metabolic rate but should not take precedence over addressing the cause of
her coma. The best explanation for her anisocoria is uncal herniation;
ophthalmologic consultation is not needed and will delay definitive treatment.
Although a left posterior communicating artery aneurysm can cause an unreactive
left pupil, her history is not consistent with aneurysmal rupture.

VIGNETTE 1 QUESTION 3
3. Answer B:
Risk factors for early posttraumatic seizures include intracranial hematoma and
depressed skull fracture. ASDs may be used to reduce the incidence of early
posttraumatic seizures, but they do not decrease the chance of developing epilepsy,
that is, later unprovoked seizures. Generalized convulsions, not complex partial
seizures, are the most common type of posttraumatic seizures. The 3-Hz spike-and-
wave EEG pattern is seen in absence seizures, not posttraumatic seizures.
Posttraumatic seizures are divided into early (<1 week after head trauma) and late
(>1 week after head trauma). This patient’s seizure occurred on hospital day 3 and
would thus be classified as an early posttraumatic seizure.
 18 Systemic Conditions with Neurologic
Manifestations

Central and peripheral neurologic dysfunction can arise in the setting of conditions with
primary endocrine, electrolyte, hematologic, or metabolic causes. Nutritional and toxic
factors also contribute to a host of neurologic conditions. Paraneoplastic processes link
malignancy and neurologic syndromes through an immune-mediated process. Similarly,
rheumatologic diseases with inflammatory (or auto-inflammatory) underpinnings can
have neurologic complications. In some cases, the neurologic syndrome is the
presenting feature of a systemic condition—and can even predate the “primary”
diagnosis by years. It is therefore helpful to understand neurologic disorders in the
context of personal and family histories, a comprehensive review of systems, and
results of basic investigatory tests. This chapter highlights systemic conditions with
neurologic manifestations.
Because the nervous system can reflect injury in a limited number of ways, very
different disease processes can cause similar symptoms and signs. The related
neurologic dysfunction can be life-threatening—or minor enough that related signs are
incidentally noted on a meticulous neurologic exam. Perhaps one of the most important
take-home points of this chapter, then, is that non-neurologic causes of neurologic
symptoms are important to consider when evaluating patients in any clinical setting.

ENDOCRINE DYSFUNCTION
Diabetes mellitus can have several neurologic manifestations, including the
neuropathies detailed in Box 18-1. One of the most easily recognized complications of
diabetes is a diabetic polyneuropathy, a distal, symmetric neuropathy affecting sensory
and motor nerves. Autonomic fibers can be involved, as well. Diabetes is also a risk
factor for stroke. Diabetic lumbosacral radiculoplexus neuropathy (a.k.a. diabetic
amyotrophy) and compression neuropathies (e.g., carpal tunnel syndrome) are more
common in patients with diabetes. Rarely, muscle infarction can occur in the setting of
diabetes. Pain, often in the thigh or calf, associated with warmth, redness, and swelling,
in the absence of trauma should raise this possibility—especially when conditions such
as infection and deep vein thrombosis have been excluded. Thus, diabetes is associated
with deficits at all levels of the neuraxis.

BOX 18-1. Diabetic Neuropathies

Hyperglycemic neuropathy
Generalized neuropathies
Distal symmetric predominantly sensory polyneuropathy
Autonomic neuropathy
Chronic inflammatory demyelinating polyradiculoneuropathy
Focal neuropathies
Cranial neuropathies (especially III, IV, and VI)
Thoracolumbar radiculopathy
Focal compression and entrapment neuropathies
Diabetic lumbosacral radiculoplexus neuropathy (diabetic amyotrophy)

In general, the treatment is to optimize control of blood sugar. Of note, lowering

glycosylated hemoglobin (HbA1c) too quickly (e.g., a decrease of > 4% HbA1c over 3
months), however, can cause a painful polyneuropathy referred to as treatment-
induced diabetic neuropathy or “insulin neuritis.” This is a reminder that both chronic
and acute shifts in blood sugar to a range that is too high or too low can have neurologic
complications. Similarly, excess or deficient levels of endocrine hormones can be
associated with conditions such as myopathy or seizures (Box 18-2) . Box 18-2 also
gives examples of the neurologic symptoms and signs of hematologic diseases and
electrolyte disturbances.

BOX 18-2. Examples of Systemic Conditions with Neurologic Manifestations

Category of Syndromes of Excess Syndromes of Deficiency

Systemic
Dysfunction
Hematologic
Anemia Stroke, seizure
Polycythemia Stroke, vasculitic neuropathy
vera
Amyloidosis Polyneuropathy (small fiber,
autonomic), compression neuropathies
Endocrine
Glucose Stroke, radiculoplexus neuropathy, Tremor, dysarthria, confusion, seizure,
polyneuropathy, muscle infarction coma/extensor posturing (glc < 30)
Thyroid Seizures, myopathy, tremor, brisk reflexes Cognitive slowing, myopathy, “hung up”
reflexes
 Cortisol Lethargy, tremor, seizure, aphasia, ataxia,
long tract signs
Hepatic failure Confusion, asterixis
Renal failure Uremic encephalopathy: decreased arousal,
confusion, asterixis, myoclonus, seizure
Electrolyte/mineral
Calcium Confusion, weakness Confusion, papilledema
Magnesium Tetany, tremor, fasciculations
Potassium Flaccid paralysis Weakness, muscle twitching
Sodium Confusion Confusion, seizure
Copper Myelopathy
Vitamin
Vitamin A Pseudotumor cerebri Optic atrophy
Vitamin B1 Wernicke–Korsakoff, encephalopathy,
sensorimotor polyneuropathy (Beri beri)
Vitamin B3 Dementia, encephalopathy, seizure, ataxia,
polyneuropathy
Vitamin B6 Polyneuropathy Seizure
Vitamin B12 Polyneuropathy, subacute combined
degeneration
Vitamin E Polyneuropathy, nystagmus, myelopathy,
ophthalmoplegia, ataxia

Although hyperthyroidism and hyperparathyroidism may have neurologic

manifestations, it is particularly important for neurologists to be aware of how
hypothyroidism can manifest (Box 18-3). From a central nervous system (CNS)
perspective, cognitive slowing can occur. Neuromuscular complications such as carpal
tunnel syndrome and a distal symmetric polyneuropathy may also result. Myopathy,
characterized by stiffness, myalgias, and elevated creatine kinase (CK) levels, can
develop in the context of hypothyroidism—and can improve with return to a euthyroid
state.

BOX 18-3. Neurologic Manifestations of Hypothyroidism

Mental state: poor concentration and memory; dementia, psychosis, coma
Sleep: obstructive and central apnea
Seizures
Headaches: intracranial hypertension
Cerebellum: truncal and gait ataxia more than limb ataxia; dysarthria; nystagmus
Cranial nerves: papilledema, ptosis, tonic pupil, trigeminal neuralgia, facial palsy, tinnitus, hearing loss
Nerves: entrapment neuropathy (e.g., carpal tunnel); axonal polyneuropathy; delayed relaxation of deep tendon
reflexes
Neuromuscular junction: worsening of myasthenia gravis.
 Muscles: cramps, pain and stiffness; proximal more than distal; creatine kinase level may be markedly
increased

KEY POINTS
● Diabetes is associated with increased risk of stroke, lumbosacral radiculoplexus neuropathy, polyneuropathy,
individual entrapment neuropathies such as carpal tunnel syndrome, and even muscle infarction.
● A decrease in glycosylated hemoglobin at an accelerated rate can lead to the development of a painful
treatment-induced diabetic polyneuropathy.
● Hypothyroidism can be associated with cognitive dysfunction, carpal tunnel syndrome, polyneuropathy, and
myopathy—all of which can improve with thyroid hormone replacement.

ELECTROLYTE, MINERAL, AND NUTRITIONAL

FACTORS
Shifts in electrolyte levels can alter mental status, strength, or movement. Disturbances
in sodium and calcium balance can cause confusion and seizures, whereas potassium
abnormalities can cause weakness (Box 18-2). Abnormal movements, including
twitching and tremor, can occur with disturbances of calcium and other electrolytes.
Neuro-ophthalmologic dysfunction (including nystagmus, ophthalmoplegia, or optic
atrophy), polyneuropathy, or both can be caused by vitamin deficiency or excess,
stemming from dietary choices, supplements, medications, renal or hepatic dysfunction,
or hematologic conditions (Box 18-2).
Subacute combined degeneration (SCD). Interestingly, anemia need not be present
for B12 deficiency to cause neurologic sequelae, including SCD. As outlined in Chapter
22, vitamin B12 deficiency can cause spasticity and paraparesis because of the
involvement of dorsolateral white matter tracts in the spinal cord. Patients can also
develop concurrent polyneuropathies. Thus, patients may present with a combination of
paresthesias, ataxia, and weakness. Correction of the vitamin B12 deficiency can be
therapeutic.
When hyponatremia has been present for at least 2 days, it is important that its
correction be carried out gradually (e.g., less than 6–8 mEq/L over 24 hours, with
serum sodium checks every 2–3 hours at the outset). If hyponatremia is corrected too
quickly, central pontine myelinolysis (CPM), also known as osmotic demyelination
syndrome, can result. Affected patients may have abnormal speech and swallowing,
limb weakness, movement abnormalities (including tremor, myoclonus, dystonia, and
choreoathetosis), seizures, and mental status changes. In addition to adventitious
movements, pathologically brisk and primitive reflexes may become evident on exam.
The time course is important: Symptoms tend to develop 2 to 6 days following sodium
correction, and magnetic resonance imaging (MRI) may appear normal for as long as a
month before showing the demyelination. Prevention is key, because some of the
resultant deficits can be permanent.

KEY POINTS
● Electrolyte abnormalities can cause alterations in mental status, strength, and movement.
● B12 deficiency can cause spasticity, weakness, paresthesias, and ataxia through central and peripheral
nervous system damage in SCD.
● While correcting electrolyte imbalances is generally therapeutic, it is important to correct subacute-chronic
hyponatremia carefully to avoid CPM.

METABOLIC DISORDERS
In addition to acquired forms of kidney and liver disease, the term “metabolic
disorders” can include inherited illnesses such as “inborn errors of metabolism” (IEM)
in which a genetic abnormality causes important changes in the levels or function of
enzymes or their cofactors. Although IEMs have broad systemic effects, neurologic
deficits are common. Symptoms and signs may include developmental delay, ataxia,
abnormal tone, dystonia, lethargy, seizure, polyneuropathy, and weakness.
Such multifaceted neurologic deficits are also evident in mitochondrial disorders, a
subset of metabolic diseases. Stroke-like episodes of mitochondrial
encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) can
result in cortical blindness, hemiparesis, and other neurologic deficits. Findings on MRI
are atypical for classic ischemic infarcts because they do not correspond to vascular
territories. The clinical characteristics and family history can provide important hints
that MELAS is on the differential. It is maternally inherited and can be diagnosed by
genetic testing.

KEY POINTS
● IEMs are genetic abnormalities that change the levels or function of enzymes or their cofactors.
● IEMs commonly affect the nervous system and present with a variety of developmental, mental status,
movement, coordination, and neuromuscular features.
● MELAS is a maternally inherited mitochondrial disorder in which MRI findings often do not correspond to
typical vascular territories.
TOXINS
Exposure to heavy metals, environmental toxins, recreational drugs, and even
prescribed medications, including chemotherapy, can cause neurologic injury.
Combined use of tobacco and alcohol can cause a toxic optic neuropathy called
tobacco–alcohol amblyopia in which painless, progressive, bilateral vision loss is
characteristic.

TABLE 18-1. Effects of Alcohol on the Nervous System

Condition Manifestations
Peripheral neuropathy Distal sensorimotor axonal neuropathy; recovery with
abstinence is slow and incomplete
Cerebellar degeneration Gait ataxia greater than limb ataxia, dysarthria, typically
no nystagmus
Tobacco-alcohol amblyopia Insidious and painless loss of vision; centrocecal scotoma
Marchiafava–Bignami syndrome Frontal-type dementia, seizures, and pyramidal signs;
focal demyelination and necrosis of corpus callosum
Acute intoxication Impaired cognition, ataxia, dysarthria, nystagmus, diplopia
Acute withdrawal Agitation, insomnia, tremulousness, hallucinations,
seizures
Wernicke encephalopathy Confusion, ataxia, ophthalmoplegia
Korsakoff syndrome Isolated memory disturbance with confabulation

Excessive alcohol use can have wide-ranging effects on the nervous system (Table
18-1) and can predispose to Wernicke encephalopathy and Korsakoff syndrome, due to
thiamine deficiency. Frequently, confusion is the first symptom of Wernicke
encephalopathy. Inattention, apathy, and disorientation may be particularly apparent
during cognitive assessments. An ataxic gait characterized by a wide base and shortened
stride length, along with ocular abnormalities (e.g., bilateral gaze-evoked nystagmus or
lateral rectus palsies) may also develop as part of the traditional triad. Mammillary
body atrophy can be detected on MRI in about 80% of cases. MRI may also show T2
and fluid-attenuated inversion recovery hyperintensities around the aqueduct and third
and fourth ventricles. If Wernicke encephalopathy is suspected, it is important to
provide parenteral thiamine before glucose is administered; glucose can precipitate or
worsen the condition. Although recovery is often incomplete, eye movement
abnormalities can start to resolve within hours to days. Mental status may improve
within days to weeks, and ambulation thereafter. Typically occurring after an acute
episode of Wernicke encephalopathy, Korsakoff syndrome includes retrograde and
anterograde amnesia. Although confabulation may also develop and there is typically a
lack of insight into the patient’s own illness, there is relative sparing of other cognitive
function. Excessive alcohol use and nutritional deficiency can also be linked with
subcortical white matter lesions and necrosis of the corpus callosum in Marchiafava–
Bignami disease.

KEY POINTS
● Excessive alcohol use and thiamine deficiency are associated with Wernicke encephalopathy and Korsakoff
syndrome; treatment requires the administration of thiamine before glucose to prevent symptom
exacerbation.
● In addition to changes in mental status, Wernicke encephalopathy can be associated with oculomotor and gait
abnormalities on exam and mammillary body atrophy on imaging.
● The hallmark of Korsakoff syndrome is antero- and retrograde amnesia with preservation of other cognitive
functions.

PARANEOPLASTIC PHENOMENA
As reviewed in Chapter 19, tumors can cause neurologic dysfunction from compression
or invasion of neurologic tissue. Less commonly, a remote tumor can cause a neurologic
syndrome, even years before the cancer is found, through an immune-mediated process.
This is thought to occur because a common antigen is expressed by both the tumor and
elements of the nervous system. Whereas antibodies to synaptic and neuronal surface
proteins (e.g., N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-menthl-4-
isoxazolepropionic acid (AMPA) may be identified independent of a malignancy,
antibodies to the intracellular neuronal proteins shown in Table 18-2 are usually linked
to an underlying tumor. Antibodies can be detected in serum and cerebrospinal fluid
(CSF). When the paraneoplastic syndrome is well described, discovery of the specific
antibodies can inform the next steps in investigation. Treatment may include
immunosuppression as well as directed therapy for any identified tumor.

KEY POINTS
● Through an immune-mediated process, occult and identified malignancies can be associated with dysfunction
involving any element of the central or peripheral nervous system.
● Antibodies can be detected in serum and CSF.
● Cancer-specific treatment and immunosuppression are the mainstays of therapy.
 TABLE 18-2. Examples of Paraneoplastic Antibodies, with Associated Cancers and
Neurologic Syndromes
Antibody
Anti-Hu (ANNA-1)
Anti-Yo (PCA-1)
Anti-Ri (ANNA-2)
Anti-Ma proteins (Ma1, Ma2)
Anti-CV2/CRMP5
Caspr2
Anti-amphiphysin
NMDA
LGI1
NMDA, N-methyl-D-aspartate.
Associated Cancers
Small cell lung (SCLC)
Gynecologic, breast
Breast, gynecologic, SCLC
Testicular germ cell tumors, lung
cancer, other solid tumors
SCLC, thymoma, other
Thymoma, variable solid tumors
Breast, lung cancer
Ovarian teratoma; rarely, other
tumors in older patients or men
Thymoma
Clinical Syndromes
Encephalomyelitis, cerebellar
degeneration, sensory ganglionopathy
Cerebellar degeneration
Cerebellar degeneration, brainstem
encephalitis, opsoclonus-myoclonus
Limbic, hypothalamic, brainstem
encephalomyelitis
Encephalomyelitis, cerebellar
degeneration, chorea, peripheral
neuropathy
Morvan syndrome, limbic encephalitis,
neuropathic pain, peripheral
neuropathy, autonomic dysfunction,
cerebellar ataxia, isolated
neuromyotonia
Stiff-person syndrome,
encephalomyelitis
Multistage syndrome with psychosis,
insomnia, memory and behavioral
disturbances, seizures, dyskinesias,
and autonomic dysfunction
Limbic encephalitis, seizures, facio-
brachial dystonic seizures

RHEUMATOLOGIC DISEASES
Neurology and rheumatology often overlap; subspecialists in both disciplines evaluate
patients with diseases such as systemic lupus erythematosus (SLE), a chronic
inflammatory disorder with variable involvement of the skin, musculoskeletal,
hematologic, and nervous systems. SLE patients may have polyneuropathy, seizures,
cognitive dysfunction, and strokes; strokes are more likely to occur when the patient has
antiphospholipid antibodies.
Although the antiphospholipid antibody syndrome (APS) can occur in isolation or
with other rheumatologic conditions, it is more common in the setting of SLE. APS is
diagnosed when an individual has a stroke, peripheral thrombosis, or a pregnancy
complication (often a spontaneous abortion) and has at least one of three antibodies
(anti-cardiolipin, anti-beta2-glycoprotein1, or lupus anticoagulant). Given the
propensity for thrombotic events, it makes sense that strokes are more common in
patients with APS. APS should be considered particularly when young people without
clear risk factors present with stroke. Vasculopathy-related white matter changes may
also be evident on brain MRIs in this population, in whom migraine, epilepsy, and
movement disorders (e.g., hemiballism and chorea) can be seen.
Just as APS is more frequent in SLE, so isreversible posterior
leukoencephalopathy syndrome (RPLS), also referred to as posterior reversible
encephalopathy syndrome (PRES). Immunosuppressive medications, hypertension,
and renal failure are risk factors for RPLS. Most commonly, patients present with a
generalized tonic–clonic or other form of seizure. Other potential manifestations are
visual symptoms, such as auras or hallucinations, or visual signs, including hemianopia
or neglect. In addition to changes in mental status, including agitation or sleepiness,
patients may report a headache unresponsive to treatment. An MRI may show symmetric
white matter abnormalities posteriorly in the cerebral hemispheres—as suggested by the
name of the syndrome.
Similar to SLE in that it affects multiple organ systems, sarcoidosis is a
granulomatous disease typically associated with bilateral hilar adenopathy. Extra-
pulmonary involvement is not uncommon, and up to 10% of patients develop neurologic
comorbidities. Although any element of the nervous system may ultimately become
involved, CNS sequelae usually precede peripheral manifestations. Granulomatous
disease may cause myopathy, mono- (including cranial) and polyneuropathies,
radiculopathies, myelopathy, and neuroendocrine dysfunction. Skin changes, including
painful red nodules (i.e. erythema nodosum), may be a manifestation of sarcoidosis.
There is no single definitive diagnostic test for sarcoidosis. Rather, diagnosis depends
on characteristic symptoms and signs, the exclusion of other diagnostic explanations,
and finding noncaseating granulomas on a biopsied lesion.

KEY POINTS
● SLE can be associated with polyneuropathy, seizures, cognitive dysfunction, and stroke.
● AP S is diagnosed when a vascular event, such as ischemic stroke, occurs in the setting of at least one of
three associated antibodies.
● Neurologic sarcoidosis can involve any aspect of the CNS or peripheral nervous system.

TOXIC METABOLIC ENCEPHALOPATHY

Perturbations in the balance of immune, neurotransmitter, fluid, electrolyte, and
hormonal factors, alone or in combination, can lead to a common clinical syndrome of
toxic metabolic encephalopathy (TME). This umbrella term refers to global cerebral
dysfunction in the absence of a structural cause. Because the underlying systemic illness
disrupts circuits on which complex cognitive function and arousal depend, patients with
TME often have impaired alertness or attention or both, disorientation, and sleep–wake
dysregulation. Fluctuating levels of arousal or alertness are characteristic. Seizures are
not uncommon. Generalized tonic–clonic seizures are identified easily, but
nonconvulsive seizures may be identified on electroencephalogram (EEG) even when
unaccompanied by motor manifestations. Other abnormal movements such as asterixis,
myoclonus, and tremor can develop. Primitive or pathologically increased reflexes and
extensor plantar responses may be noted on exam. Signs of dysautonomia, including
tachycardia and hypertension, may accompany TME. The three primary categories of
conditions causing TME are the metabolic disturbances discussed above, drugs, and
infections (including systemic infections, not necessarily direct CNS infections).
TME is a common neurologic diagnosis for intensive care unit patients but also
appropriate to consider with less dramatic changes in mental status, mood, or behavior.
Structural causes must be ruled out by imaging of the brain and cerebral vessels. In the
absence of a structural explanation, blood work (e.g., a complete blood count,
coagulation studies, a chemistry panel, liver and thyroid function assays, ammonia level,
osmolality, cortisol and vitamin levels, and alcohol and toxicology screens) can help
identify specific causes. Urinalysis, blood cultures, and a chest X-ray can identify
contributing infections. A lumbar puncture is important if there is concern for a CNS
infection. EEG plays a key role in the assessment of TME, confirming the presence of
global dysfunction (with a slow background rhythm, and sometimes with “triphasic
waves”) or in some cases, seizures. Importantly, these EEG abnormalities support a
diagnosis of TME, but they do not specify the exact cause in an individual case.

KEY POINTS
● TME is a global cerebral dysfunction in the absence of a structural cause.
● Clinical signs of TME include decreased arousal, impaired attention, seizures, abnormal movements, increased
reflexes, and dysautonomia.
● TME is most often caused by a metabolic derangement, drug, or infection.
● EEG often shows a slow background rhythm and, sometimes, triphasic waves, findings which support the
diagnosis of TME but do not identify the underlying etiology. It may occasionally show evidence of seizures.
● Blood work, and in some cases lumbar puncture results, can provide a more definitive diagnosis.

CLINICAL VIGNETTES

VIGNETTE 1
A 47-year-old man with hypertension and high cholesterol is seen in the Neurology
clinic for new onset pain, atrophy, and weakness of the right leg. He reports that
symptoms began several weeks earlier, with the onset of sharp pain in the right hip
and thigh. He has since developed a foot drop on the same side, along with
weakness of the right quadriceps. He has lost about 15 lb in weight despite a healthy
appetite. He denies back pain. Examination shows atrophy of the right quadriceps
muscle, with weakness of hip flexion, knee extension, and ankle dorsiflexion on the
right. The patellar reflex on the right is absent, but the ankle reflex is present. Motor
examination in the left leg, and in both arms, is normal. There is very mild distal
stocking-pattern sensory loss in the toes of both feet.
1. Which of the following is the most likely diagnosis?
a. Femoral neuropathy
b. Sciatic neuropathy
c. Lumbosacral radiculoplexus neuropathy
d. Polyneuropathy
e. Lumbosacral polyradiculopathy
2. You correctly make a diagnosis of lumbosacral radiculoplexus neuropathy. What
is the most likely cause?
a. Hypertension
b. Hypercholesterolemia
c. Undiagnosed type 2 diabetes mellitus
d. Undiagnosed hypothyroidism
e. Undiagnosed neurosarcoidosis

VIGNETTE 2
A 54-year-old woman presents to the emergency room with a 2-day history of left
facial droop. She also reports a mild headache and rash on both shins. Examination
shows weakness of both the upper and lower parts of the face on the left, but no
other neurologic deficits. You also notice erythematous nodules over the shins that
are tender to palpation.
1. The most likely neurologic diagnosis is:
a. Bell’s palsy
b. Sarcoidosis
c. Stroke
d. Trigeminal neuralgia
e. Lyme disease
2. You suspect that she may have sarcoidosis, but need to confirm the diagnosis.
Which of the following tests is likely to be least helpful?
a. Serum angiotensin-converting enzyme (ACE)
 b. Chest CT scan
c. Deep punch biopsy of one of the skin lesions
d. MRI of the head
e. EEG
3. Chest CT shows enlarged lymph nodes, and you arrange for a CT-guided biopsy.
Which of the following most accurately describes the expected pathologic
findings?
a. Caseating granulomata
b. Noncaseating granulomata
c. Vasculitis
d. Granulomatous inflammation
e. Histiocytosis

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer: C
The history of asymmetric pain followed by weakness and atrophy in one leg is very
characteristic of lumbosacral radiculoplexus neuropathy. The distribution of
weakness (that includes foot dorsiflexion) is not compatible with a femoral
neuropathy (which could cause weakness of hip flexion and knee extension).
Similarly, the pattern of weakness is not consistent with a sciatic neuropathy (which
would spare both hip flexion and knee extension, but could cause foot drop).
Polyneuropathy is typically length dependent and symmetric. Although the bilateral
distal sensory loss may reflect an underlying polyneuropathy, this is not the cause of
the asymmetric pain, weakness, and atrophy. Lumbosacral polyradiculopathy is
possible, but the absence of back pain or pain that radiates from the back into the
buttock and leg makes this less likely.

VIGNETTE 1 QUESTION 2
2. Answer: C
Undiagnosed type 2 diabetes is the most common cause of lumbosacral
radiculoplexus neuropathy (also known as diabetic amyotrophy), although it also
occurs in type 1 diabetes. There is also a nondiabetic form of lumbosacral
radiculoplexus neuropathy, but there is no association with hypertension or high
serum cholesterol. Hypothyroidism may certainly affect the peripheral nervous
system but typically causes entrapment neuropathies (e.g., carpal tunnel syndrome)
or an axonal polyneuropathy. Sarcoidosis may also affect the nervous system but
more often causes cranial neuropathies, a meningoencephalitis, or hypothalamic
dysfunction.

VIGNETTE 2 QUESTION 1
1. Answer: B
The distribution of weakness, involving both the upper and lower face, indicates
that dysfunction of the lower motor neuron (rather than the corticobulbar upper
motor neuron) is responsible for the facial weakness. As such, her presentation is
not due to a stroke. Instead, she has a lower motor neuron seventh cranial (facial)
neuropathy. Both Lyme disease and sarcoidosis are important causes of a facial
neuropathy. The term Bell’s palsy is used to describe a facial neuropathy when the
cause is unknown. The associated rash in this patient is a clue to the underlying
cause. Both Lyme disease and sarcoid may produce a rash. The rash of sarcoid is
known as erythema nodosum and typically manifests as painful red nodules over
both shins, as in this patient. Lyme disease typically produces a “bull’s-eye” rash,
usually over the trunk. This is not a case of trigeminal neuralgia, which presents
with facial pain rather than facial weakness.

VIGNETTE 2 QUESTION 2
2. Answer: E
An elevated serum ACE level may be a clue to the diagnosis. It is worth checking
but lacks sensitivity. Definitive diagnosis of sarcoid requires histology consistent
with a noncaseating granuloma from affected tissue. Hilar and paratracheal lymph
nodes are often enlarged in sarcoidosis, reflecting pulmonary involvement by the
disease. They are evident on chest CT and often amenable to biopsy. The skin
lesions may also be biopsied and typically show panniculitis with inflammation in
the fat and around blood vessels. An MRI of the head could help ensure that there is
no contributory structural lesion, such as a tumor in the left cerebellopontine angle.
EEG is not helpful in establishing the diagnosis of sarcoidosis.

VIGNETTE 2 QUESTION 3
3. Answer: B
The typical pathology of sarcoidosis is the nonnecrotizing or noncaseating
granuloma. A granuloma is an organized collection of macrophages. The pathology
of tuberculosis, by contrast, is that of the necrotizing or caseating granuloma.
Sarcoidosis may be associated with a systemic vasculitis, but this is not the
hallmark pathology. Granulomatous inflammation is a nonspecific term that may be
used to describe the pathology of not only sarcoid but also several other disorders.
Histiocytosis is a general term that describes a group of conditions characterized by
an increase in the number of immune cells called histiocytes; biopsy may show the
presence of Langerhans cells.
 19 Central Nervous System Tumors

The most common tumors in the central nervous system (CNS) are metastases from
distant neoplasms, with lung cancer accounting for nearly half of such tumors. Primary
brain tumors (PBTs) are a heterogeneous group of neoplasms originating from CNS
tissue and meninges. These tumors range from benign to aggressive. Although primary
CNS tumors have historically been named according to their cellular origin and
histologic appearance, advances in molecular genetics have led to further
characterization and classification based on phenotypic and genotypic parameters. The
official classification of brain tumors by the World Health Organization includes key
genetic information in the grading of tumors, leading to “integrated diagnoses” and
allowing for improved tumor grading. As for location, PBT can occur anywhere in the
intracranial or spinal space. In adults, 70% of PBTs are supratentorial, and of those,
80% to 90% are gliomas and meningiomas. The remaining 30% of PBTs in adults are
infratentorial, including schwannoma, hemangioblastoma, and meningioma in adults. In
children, approximately 70% of PBTs are infratentorial, most commonly
medulloblastoma, cerebellar astrocytoma, brainstem glioma, and ependymoma.

EPIDEMIOLOGY
Approximately 79,000 new cases of CNS tumors are diagnosed in the United States
each year. These include primary malignant and nonmalignant tumors. At present, there
are more than 100 histologically distinct types of primary CNS tumors. Approximately
one-third of these tumors are malignant. Overall survival after diagnosis with a PBT
varies significantly by age, histology, and molecular markers. The median age at
diagnosis of all PBTs is 59, with PBTs being the 10th leading cause of death in adults in
the United States. PBTs are also the most common cancers of childhood and have
surpassed leukemia as the leading cause of cancer-related death in children under age
14. In general, CNS tumors are more common in men (male to female ratio of 1.5:1)
with the exception of meningiomas, which are more common in women (1:1.8).

TABLE 19-1. Hereditary Syndromes Associated with Primary Brain Tumors

Syndrome Chromosome Tumors
Neurofibromatosis 1 17 Glioma (optic nerve) and
 ependymoma
Neurofibromatosis 2 22q12 Meningioma and glioma
von Hippel–Lindau 3p25 Hemangioblastoma
Li–Fraumeni cancer family syndrome 17p13.1 (inherited p53 mutation) Glioma and medulloblastoma

CAUSES AND GENETICS

PBTs generally originate from genetic disruptions in cells, causing them to bypass
normal growth regulatory mechanisms, with simultaneous evasion of the immune system.
Some brain tumors have a strong hereditary component (Table 19-1). Ionizing radiation
used in therapeutic dosages has been associated with an increased risk of meningiomas,
astrocytomas, and sarcomas. The use of mobile phones, low-frequency electromagnetic
fields, specific infections (various viruses, Toxoplasma gondii, etc.), diet (nitrates,
aspartame), tobacco, alcohol, and history of head trauma have not been validated in
epidemiologic studies as risk factors for CNS tumors.

CLINICAL FEATURES
There are no specific clinical symptoms or signs of brain tumors. The clinical
presentation depends on the location of the tumor, the rate of growth, and the degree of
invasion of surrounding structures. Tumors can mimic many other CNS disorders and
should be considered part of the differential diagnosis of almost any neurologic
dysfunction. In general, tumor symptoms tend to present as progressive, nonremitting
neurologic symptoms. Nonetheless, a tumor can present as an acute, subacute, or chronic
neurologic problem. The most common symptoms include headaches as the result of
traction of pain-sensitive structures (arteries, veins, and meninges) or from increased
intracranial pressure; focal or generalized seizures, particularly when tumors infiltrate
the cortex; and altered mental status such as memory loss, lack of concentration, changes
in personality, and apathy. In children, the predilection of tumors for the posterior fossa
may lead to presentation with a decreased appetite and weight loss, reduced school
performance, dizziness, ataxia (especially of gait), neck pain, bulbar weakness, eye
movement abnormalities, or opisthotonos. The clinical findings depend on the location
of the tumor and can include cognitive, motor, sensory, visual, and coordination
abnormalities.

DIAGNOSTIC EVALUATION
Imaging studies (magnetic resonance imaging [MRI] and computed tomography [CT])
play a central role in the diagnosis of brain tumors. Blood work, electroencephalogram,
and plain X-rays are of limited use. MRI with contrast may show a ring-enhancing mass
because of the disruption of the blood–brain barrier by the infiltrating neoplasm, but a
ring-enhancing lesion can also be seen with an abscess, subacute infarction, resolving
hematoma, multiple sclerosis plaques, thrombosed aneurysms, arteriovenous
malformations, and radiation necrosis. Depending on the size and location of the tumor,
MRI features can include hydrocephalus, midline shift, hemorrhages, large areas of
edema surrounding the lesion, meningeal enhancement, and so on. MR spectroscopy can
detect changes in brain tissue that are associated with the type and grade of the tumor
(including a decreased peak of N-acetyl aspartate associated with neuronal loss). The
definitive diagnosis of brain tumors requires histologic examination of samples
obtained either by brain biopsy or open surgery.

KEY POINTS
● The two most important prognostic factors for brain tumors are histologic type and patient age.
● Brain tumors tend to present as progressive nonremitting neurologic symptoms.
● The most common type of brain tumor is metastatic tumor from a systemic malignancy. The most common
PBTs are gliomas and meningiomas.
● Headache and seizures are among the most common presenting symptoms of intracranial tumors.

PRIMARY BRAIN TUMORS

GLIOMAS
Gliomas are a group of tumors that originate from glial cells, the supportive
nonneuronal cells of the CNS. Glioma is a generic histologic term used for four
different CNS tumors: astrocytoma, oligodendroglioma, ependymoma, and choroid
plexus papilloma.

GLIOBLASTOMA MULTIFORME
• Origin: Arises from astrocytes.
• Epidemiology: 15% of all intracranial tumors, and the most common PBT (50%–60%)
in adults. Peak onset age 40 to 60 years; more common in men.
• Pathology: Highly malignant tumors with anaplasia, high cellularity, round and
pleomorphic cells, nuclear atypia, vascular proliferation, and necrosis. Necrosis and
neovascular proliferation help to differentiate between anaplastic astrocytoma
(grade III) and glioblastoma (grade IV). Occasionally, glioblastomas are multifocal
 or infiltrate the brain widely (“gliomatosis cerebri”). Mitotic activity is very high.
Certain genetic mutations, namely isocitrate dehydrogenase 1 (IDH1) and O-6-
methyl-guanine-DNA methyltransferase (O6-MGMT) have clear associations with
prognosis.
• Presentation: Headaches 30% to 50%, seizures 30% to 60%, focal neurologic deficits
40% to 60%, mental status changes 20% to 40%, at the time of diagnosis. Symptoms
may start when the tumor has grown substantially.
• Imaging: CT or MRI demonstrates a solitary brain lesion (commonly in the deep white
matter, basal ganglia, or thalamus; rarely infratentorial) with contrast enhancement
and surrounding edema. About 4% to 10% of glioblastoma multiforme (GBM) do not
enhance. Commonly, the tumor infiltrates white matter tracts involving the corpus
callosum, producing the typical “butterfly” pattern (Fig. 19-1).
• Treatment: Current standard treatment options include maximal-safe surgical resection
followed by radiation with concurrent temozolomide (TMZ; a cytotoxic alkylating
agent), followed by adjuvant TMZ for 6 months. Treatment with TMZ is maximally
beneficial for patients with a methylated form of O6-MGMT. Stereotactic
radiosurgery and antiangiogenesis therapies such as the humanized monoclonal
antibody bevacizumab (which sequesters vascular endothelial growth factor that is
highly expressed in gliomas) can be used for local recurrences. More antiangiogenic
agents are being evaluated. GBMs contain nests of “cancer stem cells” that are
resistant to chemotherapy and radiation and can repopulate the entire tumor. These
stem cells represent a new target for future therapies.
• Prognosis: Poor outcome, with median life expectancy of 15 to 17 months; fewer than
16% survive more than 3 years.
FIGURE 19-1. Contrast-enhanced computed tomographic scan of the brain showing glioblastoma multiforme
(arrow). Note the irregular enhancement pattern with a central area of necrosis. The tumor has also crossed the
corpus callosum. (Reproduced with permission from Patel P. Lecture Notes: Radiology. Oxford, UK: Blackwell
Publishing; 2005:268.)

LOW-GRADE GLIOMAS (GRADE I AND II)

• Origin: Astrocytes (glial cells) or ependymal cells.
• Epidemiology: Up to 10% of PBTs; can occur throughout the brain; in children, more
common in the cerebellar hemispheres.
• More common in the fourth decade of life.
• Pathology: Genotype–phenotype correlation defines the tumor grade. Examples of
grade I tumors include pilocytic astrocytoma and subependymal giant cell
astrocytoma. Examples of grade II include diffuse astrocytoma with IDH-mutant and
pleomorphic xanthoastrocytoma.
• Presentation: Seizure is a typical presentation of slow-growing tumors.
• Imaging: MRI with contrast is the study of choice. Most lesions are bright on T2 and
fluid-attenuated inversion recovery, usually without enhancement (Fig. 19-2).
• Treatment: Close observation with serial neuroimaging may be the first approach,
depending on prognostic factors. Surgical removal can be curative for grade I
astrocytomas; it can be considered for grade II tumors if a “gross total” resection is
possible, but it is often not curative. Radiation or chemotherapy can be used
depending on other prognostic factors.
• Prognosis: Median survival around 7 years.
FIGURE 19-2. T2-weighted magnetic resonance imaging scan of the brain showing a large glioma characterized
by high-intensity signal in the right hemisphere. The tumor is displacing and compressing the ventricular system.
(Reproduced with permission from Armstrong P, Wastie M, Rockall A. Diagnostic Imaging. 5th ed. Oxford, UK:
Blackwell Publishing; 2004:401.)

OLIGODENDROGLIOMA
• Origin: Arises from oligodendrocytes. High frequency of co-deletion of chromosomal
arms 1p and 19q is considered a “genetic signature” of oligodendroglioma.
• Epidemiology: 10% of all gliomas; 2% to 4% of PBTs; peak incidence at age 35 to 45.
Common in the frontal lobes, but can appear in the basal ganglia and thalamus.
Typically very slow growth.
• Pathology: Calcifications are common. Most distinctive microscopic feature is the
“fried egg” appearance (perinuclear halos with swollen cytoplasm).
• Presentation: Seizures in up to 70%.
• Imaging: MRI shows low intensity on T1, high intensity on T2; vasogenic edema
uncommon. Contrast enhancement is a negative prognostic factor, usually seen with
anaplastic oligodendroglioma. CT scan better to visualize intratumoral
calcifications.
• Treatment: Total resection if possible, local radiation and PCV (procarbazine,
lomustine, and vincristine) chemotherapy. TMZ is used increasingly and is less
 marrow-toxic. Patients with 1p/19q co-deletion seem to have a better response to
therapy.
• Prognosis: Better survival with surgery plus radiation; can be decades. Tends to recur
locally and progress into a malignant form.

EPENDYMOMA
• Origin: Arises from ependymal lining of the ventricles.
• Epidemiology: 6% to 9% of PBTs; 30% of PBTs in children under age 3. In children,
90% are intracranial (often in the fourth ventricle) with a tendency toward
subarachnoid spread. In adults, 75% arise within the spinal canal as intramedullary
tumors.
• Pathology: Perivascular pseudorosettes (a halo of cells surrounding a central vascular
lumen) are the histologic hallmark.
• Presentation: Intraventricular location can produce obstructive hydrocephalus with
raised intracranial pressure (papilledema, cranial nerve palsies, cerebellar
dysfunction, etc.). Myxopapillary ependymomas of the conus and cauda equina can
produce conus medullaris or cauda equina syndromes.
• Imaging: MRI enhancement is variable.
• Treatment: Surgery to decrease tumor burden, followed by radiation and chemotherapy.
Recurrence rates are high; close MRI follow-up is necessary.
• Prognosis: Overall 10-year survival 45% to 55%, depending on tumor grade.

MENINGIOMA
• Origin: Arises from meningothelial (mesodermal) cells of the dura mater. Almost
always benign. Can occur intracranially (with predilection for cerebral convexities,
falx cerebri, and the sphenoid wing) or within the spinal canal.
• Epidemiology: Second most common PBT after GBM; 15% to 20% of all PBTs. More
common in women between the ages of 40 and 60. Incidence increases with age.
Some genetic conditions are associated with an increased susceptibility to develop
meningiomas, as with NF-2 (Table 19-1), associated with abnormalities on
chromosome 22.
• Pathology: Histology shows sheets of plump, uniform meningothelial cells with the
tendency to form whorls. Progesterone receptors are found frequently.
• Presentation: Slow growth; symptoms produced by local impingement on brain
(seizures) and nerves (weakness) or compression of nearby structures (weakness,
headache, apathy).
• Imaging: MRI usually shows a rounded extra-axial mass adjacent to dura. In general,
isointense on T1 and T2, with intense contrast enhancement and associated “dural
tail” of enhancement (Fig. 19-3).
• Calcification is seen on CT. Angiography can show rich vascularization. Also noted
on CT or plain X-rays is “hyperostosis” (osteoblastic reaction) that may represent
tumor invasion of the bone.
• Treatment: Surgical removal, often preceded by endovascular embolization of the
feeding vessels, but many lesions <4 cm are treated with radiosurgery, with good
control rates. Stereotactic radiosurgery such as gamma knife radiosurgery is an
option when resection or other radiation is difficult or dangerous. Recurrent
meningiomas are difficult to treat.
• Prognosis: 5-year survival is 70% to 95%; malignant transformation is very rare.
FIGURE 19-3. Axial (A) and sagittal (B) magnetic resonance imaging scans of the brain showing a brightly
enhancing meningioma (arrows). On the sagittal view, the arrow tip points to the dural tail at the margin of the tumor.
(Reproduced with permission from Patel P. Lecture Notes: Radiology. Oxford, UK: Blackwell Publishing; 2005:269.)

MEDULLOBLASTOMA
• Origin: Primarily at the medullary velum of the fourth ventricle (Fig. 19-4); up to 30%
 from the cerebellar hemispheres. It is among the primitive neuroectodermal tumors.
• Epidemiology: Rare in adults, accounting for less than 2% of PBTs, but common in
children, making up 18% of all pediatric brain tumors. More than 70% are diagnosed
in children under age 10.
• Pathology: Small round cells with a high mitotic index.
• Presentation: Rapidly growing tumor that infiltrates surrounding tissue and extends
toward the fourth ventricle, producing hydrocephalus (with morning headache,
unsteadiness, nausea, and vomiting); may spread via the cerebrospinal fluid (CSF)
intracranially, and to the spinal cord (“drop metastases”). Can also spread
extracranially to bone and bone marrow.
• Imaging: MRI of the brain usually shows a heterogenous contrast enhancing midline
tumor compressing the fourth ventricle. MRI of the brain and spinal cord helps to
evaluate subarachnoid metastasis. CSF studies are often done to look for malignancy
(if no contraindication). Bone scan and bone marrow aspiration are indicated due to
the possible extracranial extension of the tumor.

FIGURE 19-4. Medulloblastoma (arrow) in a child, as shown by sagittal magnetic resonance imaging scan with
contrast enhancement. Note that the fourth ventricle and middle portion of the cerebral aqueduct are obliterated,
resulting in hydrocephalus, including dilatation of the third and lateral ventricles. (Reproduced with permission from
Patel P. Lecture Notes: Radiology. Oxford, UK: Blackwell Publishing; 2005:271.)

• Treatment: Surgery plus radiation and chemotherapy. Corticosteroids for vasogenic

edema. Children <3 years are more susceptible to adverse effect of radiation on
 brain development. In those cases, chemotherapy may allow the delay of radiation
treatment. High recurrence rate.
• Prognosis: 20% to 30% relapse after initial treatment. Poor prognosis in children with
metastatic disease or subtotal resection. Good prognostic factors include radical
resection and radiation dose above 50 Gy to the entire neuroaxis. Under these
conditions, recurrence-free survival is >50% at 5 years.

SCHWANNOMA
• Origin: Arises from Schwann cells.
• Epidemiology: ~7% of all intracranial tumors and the most common tumor of
peripheral nerves. More common in middle-aged women. More common in the
vestibular (VIII) cranial nerve (acoustic neuromas) where they can occupy the
cerebellopontine angle, involving trigeminal and facial nerves. Bilateral acoustic
schwannomas can be associated with NF-2 (neurofibromatosis).
• Pathology: Tumor is made up of sheets of uniform spindle cells, forming palisades
called “Verocay bodies.”
• Presentation: Can be asymptomatic, or present with loss of function of the affected
nerve (hearing loss, vestibular symptoms, facial paresthesias, or pain, etc.).
• Imaging: MRI with contrast tends to show circumscribed lesions which displace but do
not invade adjacent structures. Larger tumors show cystic degeneration.
• Treatment: If symptomatic, stereotactic radiosurgery (i.e., gamma knife) is the first
choice, particularly when the lesion does not compress the brainstem and is smaller
than 3 cm. Surgery (microsurgical approach) is an alternative but can be complicated
by focal nerve deficits.
• Prognosis: Good.

LESS COMMON PRIMARY BRAIN TUMORS

GANGLIOGLIOMA
These infrequent PBTs are commonly seen in children and young adults and include a
mixture of neurons and glial cells. They are usually located in the cerebral hemisphere
and characterized by slow growth, with long duration of symptoms (e.g., seizures). MRI
shows increased T2 signal with characteristic swollen gyri. Surgical removal usually
produces an excellent outcome. Radiation is reserved for those with frankly malignant
features, or inoperable or recurrent tumors.

HEMANGIOBLASTOMA
These uncommon cystic lesions account for nearly 2% of intracranial tumors, with a
predilection for the posterior fossa. Approximately 10% of patients with
hemangioblastoma are affected with von Hippel–Lindau disease (hereditary retinal
angiomas, pancreatic cysts, and kidney tumors). Hemangioblastomas can occur at any
age but are most common in patients in the fourth decade.

PRIMARY CNS LYMPHOMA

Lymphoma involving the CNS can be primary or metastatic from systemic non-Hodgkin
lymphoma. Primary CNS lymphoma (PCNSL) accounts for less than 2% of PBTs,
affecting men more than women (2:1) and with a higher incidence in acquired
immunodeficiency syndrome patients. PCNSLs are almost exclusively intermediate to
high-grade non-Hodgkin lymphomas of B cell origin. The clinical presentation is
usually insidious, with progressive neurologic dysfunction (change in mental status,
seizures, focal deficits, etc.). Ocular lymphoma may occur in up to 20% of patients
prior to CNS manifestations. A systemic work up is appropriate to rule out
disseminated disease, as CSF analysis shows tumor dissemination in up to 40% of
cases. MRI appearance varies significantly, with single or multiple lesions, a butterfly
appearance, enhancing or non-enhancing lesions, etc.
The role of surgery in CNS lymphoma is limited to biopsy. Prognosis is poor, with
survival approximately 1.5 months if untreated, 10 to 18 months after radiation therapy,
and 44 months after chemotherapy plus radiation. High-dose systemic methotrexate-
based chemotherapies (along with cytarabine, TMZ, rituximab) with or without
radiation are the treatment of choice. PCNSL are radiosensitive, but radiation is used as
palliation. A dementia incidence of up to 50%, however, can be observed in patients
who survive more than 18 months on these regimens (often ascribed to the radiation
therapy). PCNSL can show a dramatic response to steroids, but the tumor invariably
recurs within months. Even with best treatment, recurrence is very common (median
time to recurrence: 4 to 5 years).

SELLAR AND SUPRASELLAR TUMORS

Pituitary tumors originate in the pituitary gland in the sellar region (Fig. 19-5). They can
be classified as microadenomas (<1 mm) and macroadenomas (>1 mm). Their
histologic cell of origin is responsible for the initial symptoms, usually related to the
production of pituitary hormone. When tumors become large enough, they can compress
neighboring structures (optic chiasm, cavernous sinus, etc.), producing focal symptoms.
In general, diagnosis is by imaging studies and laboratory evaluation of hormonal status.
Surgical removal may be through a trans-sphenoidal approach.
FIGURE 19-5. Sagittal (A) and coronal (B) post-contrast magnetic resonance imaging scans of the brain
demonstrating a pituitary adenoma (arrows). Note that the tumor is anterior to the brainstem and extends upward,
compressing the optic chiasm. (Reproduced with permission from Armstrong P, Wastie M, Rockall A. Diagnostic
Imaging. 5th ed. Oxford, UK: Blackwell Publishing; 2004:406.)

Suprasellar craniopharyngioma is a slow-growing tumor characterized by the benign

nature of its cells but malignant behavior of its growth. It accounts for 1% to 3% of
intracranial tumors and 13% of suprasellar tumors in adults and 50% in children. It
tends to invade neighboring structures, complicating treatment. Tumors present with
headache, visual disturbance, and endocrine dysfunction. The radiologic hallmark is the
appearance of a suprasellar calcified cyst. Treatment can entail full surgical resection,
or minimal resection with radiation or radiosurgery.
SECONDARY (METASTATIC) BRAIN TUMORS
Metastases are the most common brain tumors and originate from malignant neoplasms
outside the CNS. Metastatic lesions occur in 100,000 to 200,000 cases per year in the
U.S. and account for 20% of cancer deaths annually. The most frequent metastatic brain
tumors originate in the lung, skin (melanoma), kidney (renal cell carcinoma), breast, and
colon. Malignant cells reach the brain via the bloodstream (crossing the blood–brain
barrier) or through Batson’s plexus (pelvic and gastrointestinal tumors). In general,
metastatic lesions are located at the junction of white and gray matter and tend to be
solitary, but multiple metastases are not unusual. MRI with contrast is the preferred
diagnostic study (Fig. 19-6). Treatment depends on the number of metastases, the
immediate mass effect of the lesion(s), and the general status of the patient. Single
lesions can be resected, followed by whole brain radiation or radiosurgery.
Radiosurgery is used more often for three or fewer lesions, especially if the systemic
disease is under good control—to prevent the long-term side effects of whole brain
radiation, chemotherapy, or both. The prognosis is poor because metastases usually
represent a more advanced stage and extension of the primary cancer.

FIGURE 19-6. Contrast-enhanced computed tomographic scan of the brain showing several metastatic lesions
characterized by rounded areas of hyperdensity. (Reproduced with permission from Armstrong P, Wastie M, Rockall
A. Diagnostic Imaging. 5th ed. Oxford, UK: Blackwell Publishing; 2004:402.)
 KEY POINTS
● General medical treatment of brain tumors includes glucocorticoids (to reduce vasogenic edema due to the
tumor and following radiation) and anticonvulsant medication. Anticoagulation is not contraindicated in
patients with brain tumor.
● “Drop metastases” are intradural extramedullary spinal metastases that arise from intracranial lesions. They
are most frequently seen with ependymomas or medulloblastomas but can also occur with other PBT.
● Medulloblastoma and other posterior fossa tumors: Avoid lumbar puncture unless CT shows no obstructive
lesion—to prevent cerebellar tonsillar herniation due to increased intracranial pressure.
● NF2 (neurofibromatosis)-associated tumors: bilateral vestibular schwannomas, meningiomas, and
intramedullary ependymomas.
● In P CNSL, remember to evaluate the patient’s immune status and look for ocular involvement by careful
ophthalmologic exam.
● Brain metastases that bleed easily include melanoma, renal cell carcinoma, and choriocarcinoma.

CLINICAL VIGNETTES

VIGNETTE 1
A 46-year-old woman with no significant medical history presents with the new
onset of a witnessed 2-minute generalized tonic–clonic seizure. She has no history
of recent infection, other illness, or head trauma. She denies pain anywhere. On
examination, she has normal vital signs and is afebrile, and her neck is supple. Her
mental status, cranial nerves, strength, coordination, and sensation are all normal.
Blood work and toxicology screen are also normal.
1. Which of the following is the most likely explanation for her seizure?
a. Large stroke
b. Tumor
c. Meningitis or encephalitis
d. Intracranial hemorrhage
e. Nonepileptic seizure (“pseudoseizure”)
2. The most common cause of tumors at this age is:
a. Meningioma
b. GBM
c. Metastatic disease
d. Oligodendroglioma
e. PCNSL
3. The initial head CT with contrast shows a solitary left frontal lesion with
evidence of a smaller, intralesional hemorrhage. If this is a metastatic lesion,
 the most likely primary tumor is:
a. Colon carcinoma
b. Prostate cancer
c. Melanoma
d. Breast cancer
e. Lung cancer

VIGNETTE 2
A 62-year-old woman is brought to the neurologist for evaluation of a few months of
progressive short-term memory problems, difficulty “finding words,” and headache.
She has a history of depression and hypertension. Her mental status examination
shows some paraphasic errors and an inability to recall three objects after 5
minutes; she has a mild right pronator drift. She is not depressed.
1. Which of the following is the best next step to assess the cause of her symptoms
and signs?
a. Lumbar puncture
b. Magnetic resonance angiogram (MRA) of the brain
c. Head CT without contrast
d. MRI of the brain without contrast
e. MRI of the brain with and without contrast
2. The MRI shows a large intracranial mass with contrast enhancement and an area
of surrounding edema. Based on the clinical findings, where would you expect
the lesion is located?
a. Right parietal lobe
b. Right temporal lobe
c. Left occipital lobe
d. Left temporal lobe
e. Right occipital lobe
3. The patient undergoes a tumor biopsy. The pathology report concludes that the
tumor is a glioblastoma multiforme. The best available treatment is:
a. Surgery without radiation
b. Surgery followed by radiation
c. Surgery followed by radiation and concurrent TMZ
d. Surgery followed by TMZ without radiation
e. No treatment is available for this kind of tumor

ANSWERS
VIGNETTE 1 QUESTION 1
1. Answer B:
This patient presents with a new-onset generalized convulsion, is only 46 years old,
and has no cardiovascular risk factors to suggest stroke—and she has a normal
neurologic examination. She has no history to suggest infection, is afebrile, and has
a supple neck, making meningitis or encephalitis unlikely. The normal exam and lack
of severe headache make an acute intracranial hemorrhage or large stroke unlikely.
With this presentation and examination, tumor is most likely.

VIGNETTE 1 QUESTION 2
2. Answer C:
The most common tumors in the CNS are metastases from a primary neoplasm
elsewhere. Each of these tumors can present with seizures as the first clinical
manifestation.

VIGNETTE 1 QUESTION 3
3. Answer C:
The most common primary neoplasms to cause brain metastases with hemorrhagic
components are melanoma, renal cell carcinoma, and choriocarcinoma. The other
primary cancers mentioned above can produce metastases to the brain, but they far
less often undergo hemorrhagic transformation.

VIGNETTE 2 QUESTION 1
1. Answer E:
This patient presents with progressive neurologic dysfunction characterized by
headaches, memory problems, and dysphasia, and with no earlier headaches. The
dysfunction is progressive, not acute. The onset of a new and progressive headache
at this age raises concern for an intracranial tumor. MRI of the brain, with and
without contrast, is the best imaging technique to look for a tumor (or other mass
lesion) and is far superior to head CT. Lumbar puncture should be preceded by
brain imaging when there is a question of increased intracranial pressure. MRA
provides an assessment of intracranial vasculature; it is often used in patients with
strokes.

VIGNETTE 2 QUESTION 2
2. Answer D:
A left temporal lobe mass would explain memory and language problems and might
often be associated with a right pronator drift (likely because of the vasogenic
edema or direct infiltration of the tumor affecting some descending motor fibers).
The other locations do not match the clinical presentation. Left frontal lobe lesions
could also present with a similar constellation of symptoms.

VIGNETTE 2 QUESTION 3
3. Answer C:
Current accepted best treatment for GBM requires maximal-safe surgical resection
followed by radiation with concurrent TMZ (a cytotoxic alkylating agent), followed
by adjuvant TMZ for 6 months. All the other combinations are inferior to option c.
 20 Demyelinating Diseases of the Central
Nervous System

MULTIPLE SCLEROSIS
Demyelinating diseases of the central nervous system (CNS) are characterized
pathologically by an acquired loss of myelin with a relative preservation of axons. The
most common and best known of the CNS demyelinating diseases is multiple sclerosis
(MS). For many reasons, MS is also one of the most feared diagnoses in Neurology: it
strikes young, healthy people in the prime of their lives; its course is marked by
unpredictable relapses; almost any aspect of neurologic function may be affected; and
some patients develop lifelong motor disability requiring a wheelchair.
MS has a wide range of presentations and an equally wide range of prognoses.
Effective treatments aimed both at the underlying disease process and at some specific
complications are available. For the student, the study of demyelinating diseases
provides an excellent opportunity to learn about the dysfunction of different parts of the
CNS and to master the wide variety of neurologic exam abnormalities that accompany
these disorders.

EPIDEMIOLOGY
MS is a chronic neurologic disease that begins most commonly in young adulthood. The
peak incidence of MS is between 20 and 30 years of age. Women are affected twice as
often as men. MS prevalence in the United States is about 90 cases per 100,000 people.
There are epidemiologic findings to suggest both genetic and environmental influences,
as discussed below.
Geographically, MS is more common in northern latitudes. The incidence in
Scandinavian countries is higher than that in southern Europe, and the incidence in the
northern United States is higher than that in the South. There are racial differences as
well, with a higher prevalence in white populations. Interestingly, those who move from
a low-risk to a high-risk geographic region or vice versa before the age of 15 adopt the
risk of MS associated with their new home, whereas those who migrate after age 15
retain the risk associated with their childhood home. The implications of this finding are
unclear, but one theory is that a latent viral infection acquired in childhood may play a
role in the pathogenesis of the disease.
There is strong evidence supporting a genetic predisposition to MS as well. For
example, there is a greater incidence of MS in monozygotic, when compared with
dizygotic, twins of patients with MS, as well as an increased incidence in association
with particular human leukocyte antigen alleles.

KEY POINTS
● The peak incidence of MS occurs in young adulthood, between 20 and 30 years of age.
● MS is more common in women and more common in whites.
● The epidemiology of MS supports both environmental and genetic influences.

CLINICAL MANIFESTATIONS
Classically, MS is diagnosed by finding multiple white matter lesions separated in
space and time. This means that multiple distinct areas of the CNS must be involved
(rather than one area recurrently, for example), and that the disease must not be simply a
monophasic illness (with multiple areas affected simultaneously but not recurring).
The clinical features are defined, as might be expected, by the location of the lesions.
Thus, a right occipital lesion could result in a left homonymous hemianopia, whereas a
right cervical spinal cord lesion may lead to an ipsilateral hemiparesis and loss of joint
position sense, with contralateral loss of pain and temperature sensation. Almost any
neurologic symptom, in fact, can be produced by an MS lesion.
Common clinical features (Table 20-1) include corticospinal tract signs such as
weakness and spasticity, cerebellar problems such as intention tremor and ataxia,
sensory abnormalities such as paresthesias and loss of vibration and proprioception
sensation, and bladder dysfunction. Fatigue is a common complaint. In later stages,
cognitive and behavioral abnormalities may occur. A few syndromes characteristic of
MS warrant further description:

TABLE 20-1. Common Clinical Features of Multiple Sclerosis

Neurologic System Clinical Sign or Symptom
Cranial nerves Optic nerve dysfunction
Visual acuity loss
Red desaturation
Papilledema or optic disc pallor
RAPD
Eye movement disorders
Internuclear ophthalmoplegia
Nystagmus
Motor system Weakness
 Spasticity
Reflex abnormalities
Increased muscle stretch reflexes
Babinski signs
Clonus
Sensory system Paresthesias
Vibratory loss
Joint position sense loss
Lhermitte’s sign
Cerebellar function Ataxia
Intention tremor
Dysarthria
Autonomic system Bladder dysfunction
Other Fatigue
Depression
Uhthoff’s phenomenon
RAPD, relative afferent pupillary defect.

Optic neuritis (ON) is a common initial presenting symptom of MS. (This fact
reminds us that the optic nerve is actually an extension of the CNS rather than a
peripheral nerve.) ON is characterized by a mildly painful loss of visual acuity in one
eye. The visual loss may range from mild blurriness with a loss of color discrimination
to a severe episode with complete blindness. Pulling or tugging pain is most prominent
when the eye moves. On examination, there is loss of acuity and color vision. Most
patients have retrobulbar ON and the optic disc appears normal in the acute stage. In
severe cases, however, the optic disc may be swollen, with indistinct margins
(papilledema). A past history of ON is suggested by the presence of red desaturation
(subtle loss of color appreciation), optic disc pallor or atrophy, and a relative afferent
pupillary defect (RAPD, see Chapter 4).
Transverse myelitis is inflammatory demyelination in the spinal cord. Most
commonly, this affects particular tracts at the level of the lesion in a patchy way, rather
than producing complete involvement of the spinal cord. There may be unilateral or
bilateral weakness or sensory loss below the lesion. Bowel and bladder function may
be disrupted. Reflexes may be exaggerated below the lesion, and Babinski signs may be
present. Patients may report a band of tingling or pain around the torso at the level of the
lesion.
Internuclear ophthalmoplegia (INO) is a characteristic finding in MS. INO results
from dysfunction of the medial longitudinal fasciculus and leads to an inability to adduct
one eye when looking toward the opposite side, with associated nystagmus of the
abducting eye. The adduction of both eyes when observing a near target (convergence)
is preserved. The presence of INO in a young person suggests few other diagnostic
possibilities. See Fig 4-2 for a more complete discussion of the pathophysiology of an
INO.
The other clinical features characteristic of MS include Lhermitte’s sign, a tingling,
electric sensation down the spine when the patient flexes the neck, and Uhthoff’s
phenomenon, a worsening of symptoms and signs in the heat.

KEY POINTS
● MS is characterized by multiple lesions separated in space and time.
● Almost any neurologic symptom can occur, depending on the location and burden of lesions.
● The features characteristic of MS include ON, transverse myelitis, INO, Lhermitte’s sign, and a worsening of
symptoms in the heat.

CLINICAL COURSE AND PROGNOSIS

Most MS patients begin with a relapsing-remitting course (Fig. 20-1), in which there
are discrete episodes of neurologic dysfunction (relapses or “flares”) that resolve after
several weeks or months. Unfortunately, such a course usually evolves into one in which
recovery from each relapse is incomplete and baseline function deteriorates (secondary
progressive). Rarely, patients may have a relentlessly progressive course from the
onset, either with superimposed relapses (progressive-relapsing) or without (primary
progressive).
FIGURE 20-1. Clinical course of multiple sclerosis: (A) relapsing-remitting, (B) secondary progressive, (C)
primary progressive, (D) progressive-relapsing. (From Ginsberg L. Lecture Notes: Neurology. 8th ed. Oxford:
Blackwell Publishing; 2005:131. Copyright © 2005 L Ginsberg. Reprinted by permission of John Wiley & Sons, Inc.)

To put the prognosis in broad terms, about 60% of MS patients lead lives of minimal
disability and continue to work, about 20% require a walking aid but will remain
ambulatory, and about 20% have severe disability, typically becoming wheelchair-
bound. There has been and will likely continue to be a trend toward better prognoses in
the future because of a greater use of effective disease-modifying agents. Features
predicting a good prognosis include young age at onset, female sex, rapid remission of
initial symptoms, mild relapses that leave little or no residual deficits, and a
presentation with sensory symptoms or ON rather than motor symptoms.

KEY POINTS
● Most MS patients have a relapsing-remitting course, which frequently evolves into a secondary progressive
course.
● Prognosis is quite variable and ranges from minimal to severe disability.

DIAGNOSTIC EVALUATION
The diagnosis of MS begins with a thorough history and examination. Patients often
present with what appears to be a single episode of neurologic dysfunction, but upon
further questioning recall earlier episodes of seemingly unrelated neurologic symptoms
that may in fact represent prior lesions. It is important to inquire specifically about past
neurologic symptoms that suggest ON, transverse myelitis, and other typical MS
features. On examination, evidence of old optic nerve or other neurologic lesions should
be sought.
The two most useful laboratory studies are magnetic resonance imaging (MRI) and
cerebrospinal fluid (CSF) analysis. On MRI, new MS lesions appear as discrete T2-
hyperintense areas in the white matter of the brain or spinal cord (Figs. 20-2 and 20-3).
Fluid-attenuated inversion recovery sequences also show these lesions particularly
well. Acute lesions may not be evident on T1-weighted images but may enhance with
gadolinium. Old, chronic MS lesions may become T1-hypointense, with a “black hole”
appearance. MS lesions are most often ovoid in shape and have a predilection for
particular areas, including the periventricular white matter, juxtacortical regions, corpus
callosum, and cerebellar peduncles. Sagittal images may demonstrate foci of
demyelination spreading perpendicularly from the corpus callosum, termed Dawson’s
fingers.
FIGURE 20-2. T2-weighted MRI demonstrating multiple periventricular hyperdensities in both A and B
(arrows), consistent with a diagnosis of MS. [MRI, magnetic resonance imaging; MS, multiple sclerosis.] (Reproduced
with permission from Daffner RH. Clinical Radiology: The Essentials. 3rd ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2007.)
FIGURE 20-3. T2-weighted MRI demonstrating a demyelinating plaque at the C3 level in the cervical spinal
cord in a patient with MS. [MRI, magnetic resonance imaging; MS, multiple sclerosis.] (Reproduced with permission
from Eisenberg RL. An Atlas of Differential Diagnosis. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2003.)

The characteristic CSF finding in MS is an elevation in the concentration of

oligoclonal bands (OCBs), found in more than 90% of MS patients at some point during
the illness. OCBs reflect intrathecal production of IgG antibodies by plasma cell clones.
Although highly suggestive of MS, they can also be found in other neurologic disorders.
CSF studies during an acute relapse may show a moderate pleocytosis and elevated
protein. Calculation of the IgG index, on the basis of relative levels of IgG and albumin
in the CSF and serum, can also suggest intrathecal antibody production.
Finally, visual evoked potentials can be used in suspected MS to document evidence
of old ON. There is often an increased latency of the P100 wave on the affected side.

KEY POINTS
● The diagnosis of MS begins with a thorough history and examination, particularly directed toward identifying
the past episodes of neurologic dysfunction.
● MRI is the best imaging modality to detect both new and old MS lesions.
● The characteristic CSF abnormality is the presence of OCBs.
● Visual evoked potentials may provide evidence of old ON.

PATHOLOGY
The histologic appearance of an acute MS lesion is a sharply defined area of myelin
loss with relative preservation of axons and associated signs of perivascular
inflammation, including the presence of macrophages, lymphocytes, and plasma cells.
Reactive astrocytes may be present. Chronic MS lesions show axon loss and extensive
glial proliferation.

TREATMENT
Treatment for MS falls into three categories: acute therapies for relapses, chronic
therapies that treat the underlying disease process, and symptomatic therapies that
address the various complications of the disease.
Acute relapses of MS are most commonly treated with corticosteroids. A course of
intravenous methylprednisolone for 3 to 5 days, with or without an oral prednisone
taper, is a common protocol. Although the effect of steroids on the long-term outcome is
unclear, steroids do shorten the duration of acute relapses. The Optic Neuritis Treatment
Trial demonstrated that intravenous steroids for patients with ON delayed but did not
prevent the subsequent development of MS.
Disease-modifying agents (Table 20-2) are important treatments for preventing
relapses and potentially for improving long-term outcomes. These include beta-1a
interferon and beta-1b interferon, which are injectable medications that have been
shown to decrease the rate of relapses, the burden of lesions seen on MRI, and the rate
of accumulated disability. Both are currently used in patients with relapsing-remitting
MS and in some patients with secondary progressive disease. Side effects can include
flu-like symptoms, depression, and injection-site reactions. It is important to check a
complete blood count and liver function test routinely; interferons may cause leukopenia
and reversible transaminitis. Patients who are doing poorly with interferons may have
developed neutralizing antibodies that reduce drug effectiveness.
Glatiramer acetate is a polypeptide formulation injected subcutaneously, which is
also used in relapsing-remitting patients.

TABLE 20-2. Immune-Modulating Agents Used in the Treatment of Multiple

Sclerosis
Drug
Interferon beta-1a (Avonex)
Interferon beta-1b (Betaseron)
Interferon beta-1b (Rebif)
Glatiramer acetate (Copaxone)
Natalizumab (Tysabri)
Fingolimod (Gilenya)
Dimethyl fumarate (Tecfidera)
Teriflunomide (Aubagio)
Alemtuzumab (Lemtrada)
Ocrelizumab (Ocrevus)
Administration
30 µg IM every week
250 µg SC every other day
44 µg SC three times a week
20 mg SC daily
300 mg IV every 4 wk
0.5 mg PO every day
240 mg PO bid
7–14 mg qD
First course: 60 mg IV over 5 d.
Second course, 12 mo later: 36 mg IV disease, increased cancer risk
over 3 d
600 mg IV every 6 mo
Side Effects
Flu-like symptoms, anemia,
depression, development of
neutralizing antibodies
Injection-site reactions, flu-like
symptoms, depression,
hematologic/liver abnormalities,
development of neutralizing antibodies
Flu-like symptoms, anemia,
depression, development of
neutralizing antibodies
Injection-site reactions, injection-
related chest pain and shortness of
breath
Progressive multifocal
leukoencephalopathy, hepatotoxicity,
hypersensitivity reaction
Bradycardia, leukopenia, macular
edema
Flushing, lymphopenia, gastrointestinal
intolerance
Hair loss, transaminitis, and
gastrointestinal symptoms,
teratogenicity
Infusion reactions, autoimmune
Infusion reactions, upper respiratory
tract infection, cannot be administered
 to patients with active hepatitis B
infection
IM, intramuscular; IV, intravenous; PO, by mouth; SC, subcutaneous.

In patients who no longer respond to interferons or glatiramer acetate or who have

progressive disease from onset, other immunosuppressive agents may be used.
Natalizumab is a monoclonal antibody against alpha-4-integrin that prevents
lymphocytes and monocytes from crossing the blood–brain barrier. It is administered as
a series of monthly infusions. Although it is likely more effective than interferons in
preventing relapses and disease progression, natalizumab is associated with a small but
significant risk of developing progressive multifocal leukoencephalopathy (PML), an
untreatable and often fatal disorder. Patients without antibodies to John Cunningham
(JC) virus (the virus that produces PML) are at a lower risk for PML, and these
antibodies should be measured prior to starting treatment with natalizumab. In addition,
natalizumab should not be used in combination with other immunomodulatory agents
used to treat MS.
Fingolimod is a mixed agonist/antagonist of the sphingosine-1P1-receptor. It was the
first oral medication approved for use in MS. Its main activity in MS is thought to be
sequestration of autoreactive T cells in lymph nodes. The most serious potential side
effects of fingolimod are bradycardia and macular edema. Thus, patients must be
monitored with an electrocardiogram during the first administration and undergo ocular
coherence tomography to screen for macular edema.
Dimethyl fumarate is another oral medication used to treat MS. Its exact mechanism is
uncertain. Potential side effects include flushing, lymphopenia, and gastrointestinal
intolerance.
Teriflunomide is an oral antimetabolite that is effective in reducing relapse rate in
MS. The side effects to monitor for include hair loss, transaminitis, and gastrointestinal
symptoms. It is highly teratogenic and should be used cautiously in women of
childbearing age.
Alemtuzumab is a CD52 monoclonal antibody indicated for patients with relapsing
forms of MS who have failed two other MS medications. Potential side effects include
infusion reactions, a precipitation of autoimmune disease, and an increased risk for
malignancy.
Ocrelizumab is a CD20 monoclonal antibody that is indicated for relapsing-remitting
and primary progressive forms of MS. It is administered intravenously at a dose of 600
mg every 6 months. Side effects include infusion reactions and upper respiratory tract
infections. It is contraindicated in patients with active hepatitis B infection.
Several of the symptomatic complications that accompany MS have specific
treatments. Fatigue is often the most disabling and persistent symptom of MS. Good
sleep hygiene and a gentle exercise program may be helpful. Medication treatment
options include amantadine, aspirin, modafinil, and amphetamines. Spasticity can be
managed with baclofen, diazepam, tizanidine, or botulinum toxin injections. Bladder
dysfunction can be managed with anticholinergic agents (for urinary urgency) and with
intermittent self-catheterization. It is particularly important to address urinary problems
in order to prevent recurrent infections, which can trigger MS relapses or lead to
chronic renal disease. Tremor and ataxia are disabling MS symptoms that are often
difficult to treat.

KEY POINTS
● Acute MS relapses are treated with intravenous corticosteroids.
● Disease-modifying agents are used to prevent disease flares and are possibly effective in preventing the
accumulation of disability.
● Symptomatic therapies include those for spasticity and bladder dysfunction.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

Acute disseminated encephalomyelitis (ADEM) is a monophasic illness leading to
areas of demyelination within the CNS, commonly following an antecedent viral
infection or vaccination. ADEM may be difficult to distinguish from the initial
presentation of MS.

CLINICAL AND RADIOLOGIC MANIFESTATIONS

As in MS, almost any neurologic symptom or sign can occur, depending on the location
of the demyelinating lesions. In ADEM, the lesions are multiple and are frequently more
patchy, bilateral, and confluent than in MS, where the lesions may be more discrete.
ADEM lesions have a predilection for the posterior cerebral hemispheric white matter.
Clinically, behavioral and cognitive abnormalities and seizures are often seen in
ADEM, whereas they are uncommon until the late stages of MS. Radiologically, all
areas of demyelination in ADEM appear acute and may enhance with gadolinium.

DIAGNOSTIC EVALUATION
The diagnosis of ADEM may be suspected on the basis of clinical presentation and
radiologic findings. CSF typically will show a lymphocytic pleocytosis (usually with
more white blood cells than seen in MS) and an elevated protein. OCBs are rarely
present. When the illness is indistinguishable clinically or radiologically from the initial
episode of MS, a definitive diagnosis of MS may not be possible until a second episode
of neurologic dysfunction occurs.

PROGNOSIS AND TREATMENT

By definition, ADEM is a monophasic illness with a generally favorable outcome. A
course of intravenous corticosteroids is typically administered to shorten the duration of
the episode and lessen the severity of the symptoms.

KEY POINTS
● ADEM is a monophasic disorder characterized by demyelination of the CNS.
● It is often difficult to distinguish ADEM from MS at presentation, and time is required to establish the
diagnosis.

NEUROMYELITIS OPTICA (DEVIC DISEASE)

Neuromyelitis optica (NMO) is characterized by the development of transverse myelitis
and ON. The two components of the disorder may develop simultaneously or there may
be delay of one or even two years between them. Demyelination of the brain should be
absent or relatively minor. Pain is a more common and severe component of the
transverse myelitis and ON of NMO than is seen in MS, and the deficits tend to be more
severe in NMO than in MS. MRI of the spine in NMO is more likely to show lesions
that extend over several segments of the cord and to involve an individual level of the
cord in a complete rather than a patchy fashion. CSF pleocytosis, sometimes with a
neutrophilic pleocytosis, is also seen with greater frequency in NMO than in MS. The
diagnosis of NMO is confirmed with greatest certainty by finding antibodies to the
aquaporin-4 channel (NMO Ab). For patients who are NMO Ab-negative, myelin
oligodendrocyte glycoprotein antibodies (MOG Ab) may be present. It is important to
investigate thoroughly for NMO, because treatments that are used for MS are often
harmful to patients with NMO. Acute treatment of NMO includes steroids and
sometimes plasmapheresis for patients who do not improve quickly. Chemotherapeutic
agents such as azathioprine, mycophenolate mofetil, and rituximab are used to prevent
recurrence. The prognosis is often poor, with patients developing paralysis and
blindness in the long term.

LEUKOENCEPHALOPATHIES
Progressive multifocal leukoencephalopathy is characterized by dementia, focal
cortical dysfunction, and cerebellar abnormalities. It is seen almost exclusively in
patients with AIDS, leukemia, lymphoma, and other immunocompromised states
(particularly in patients treated for MS with natalizumab). The JC virus is the causative
agent and leads to demyelination by infecting oligodendrocytes. MRI characteristically
shows multiple foci of white matter abnormalities, particularly in the posterior regions
of the brain. CSF analysis is usually normal. So far, treatments for PML have not been
particularly effective.
Posterior reversible encephalopathy syndrome (PRES) is a leukoencephalopathy
that develops in the context of rapidly developing hypertension, eclampsia, or due to
calcineurin-inhibiting immunosuppressants used to prevent organ transplant rejection
(tacrolimus and cyclosporine). Most commonly, this condition is characterized by an
acute confusional state and cortical visual loss (blindness with preserved pupillary
reactivity). MRI shows posterior white matter hyperintensities on T2-weighted images.
PRES can be treated by addressing the underlying cause: correcting hypertension,
treating eclampsia, or lowering the dose of the offending immunosuppressant. Calcium
channel blockers may be effective. Despite its name, PRES is not always a reversible
syndrome and can result in coma or death.

CLINICAL VIGNETTES

VIGNETTE 1
A 24-year-old woman presents with 3 days of retrobulbar pain and a progressive
loss of visual acuity in the right eye. On examination, she has an acuity of 20/70 in
the right eye and 20/20 in the left eye. She has a RAPD and red desaturation on the
right. The remainder of her neurologic examination is normal.
1. What is the most appropriate diagnostic test at this point?
a. Computed tomography (CT) scan of the brain with and without contrast
b. Lumbar puncture with measurement of OCBs
c. Measurement of aquaporin-4 antibodies
d. MRI of the brain with and without contrast
e. Visual evoked potentials
2. The patient’s MRI shows contrast enhancement of the right optic nerve and three
periventricular white matter lesions, one of which enhances with contrast. What
is the most appropriate initial management?
a. Glatiramer acetate
b. Interferon B-1b
c. Intravenous methylprednisolone
 d. High-dose oral prednisone followed by a taper
e. Plasma exchange
3. The patient is treated with intravenous methylprednisolone. On the basis of her
clinical presentation and imaging studies, you make a diagnosis of MS and
choose to start a disease-modifying agent. Which of the following is true about
disease-modifying therapy?
a. Fingolimod is associated with tachycardia.
b. Glatiramer acetate increases the risk of progressive multifocal
leukoencephalopathy.
c. Interferon B-1b decreases the rate of relapses in MS.
d. Dimethyl fumarate is the only oral therapy available for MS.
e. Natalizumab and interferon B-1b combination therapy is used most often for
primary progressive MS.

VIGNETTE 2
A 31-year-old woman develops severe, acute mid-back pain followed by weakness
of both legs over the course of several days. On examination, she has dense
weakness and numbness in both legs, a sensory level for both pinprick and vibratory
perception at T6, and bladder incontinence. MRI of the thoracic spine is performed
and shows a confluent T2 white matter hyperintensity extending from T1 to T5.
1. Which of the following features in this case is atypical for MS?
a. Age of onset
b. Bladder incontinence
c. Extensive spinal cord lesion
d. Female gender
e. Loss of vibratory perception
2. The history of which of the following would be most likely to help establish the
diagnosis:
a. A 3-day episode of cerebellar ataxia 3 years ago
b. A diagnosis of Lyme disease
c. An episode of severe bilateral visual loss a year ago
d. An earlier episode of incontinence of bowel and bladder
e. A family history of MS
3. On further questioning, the patient reports an episode of severe bilateral visual
loss that occurred a year ago and was treated with intravenous steroids with
partial improvement. Which of the following tests would be most helpful in
establishing the diagnosis?
a. Lumbar puncture to evaluate for neutrophilic pleocytosis
 b. Measurement of aquaporin-4 antibodies
c. MRI of the brain, with and without contrast
d. MRI of the cervical spine, with and without contrast
e. Visual evoked potentials

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer D:
This patient presents with ON. The most appropriate diagnostic test is MRI of the
brain with and without contrast to look for other lesions that would suggest MS.
MRI also serves a second purpose: to confirm the diagnosis of ON. CT scan is less
useful than MRI in diagnosing MS or ON. Although OCBs in the CSF would support
the diagnosis of MS, they are not as useful as MRI in the initial evaluation.
Aquaporin-4 antibodies are present in NMO, but the patient’s history is not
suggestive of that diagnosis. Although visual evoked potentials could confirm the
presence of ON, the clinical history and examination are sufficient in this case. The
main clinical utility of visual evoked potentials in MS is to investigate for prior
optic nerve lesions.

VIGNETTE 1 QUESTION 2
2. Answer C:
The Optic Neuritis Treatment Trial demonstrated that intravenous (but not oral)
steroids hastened recovery from an episode of ON and delayed the development of
MS in the short term. Glatiramer acetate and interferon B-1b are disease-modifying
agents that are mostly used for relapsing-remitting MS. They can be started at this
stage of the disorder, but intravenous steroids are the appropriate initial treatment.
Plasma exchange is sometimes used to treat aggressive MS but not for ON.

VIGNETTE 1 QUESTION 3
3. Answer C:
Interferon B-1b decreases the rate of relapses in relapsing-remitting MS and is often
initiated at disease diagnosis. Dimethyl fumarate, fingolimod, and teriflunomide are
oral medications available for the treatment of MS. Fingolimod may lead to
bradycardia, not tachycardia. Natalizumab, rather than glatiramer acetate, increases
the risk of progressive multifocal leukoencephalopathy. Natalizumab should not be
combined with interferon B-1b or other immunosuppressants.
VIGNETTE 2 QUESTION 1
1. Answer C:
Longitudinally extensive spinal cord lesions are more consistent with idiopathic
transverse myelitis or NMO than they are with MS. The other features listed are all
typical of MS.

VIGNETTE 2 QUESTION 2
2. Answer C:
The patient presents with an episode of severe, painful transverse myelitis. Although
this may occur in isolation, the diagnosis of NMO needs to be considered. A prior
episode of severe (especially bilateral) visual loss would support this diagnosis. A
prior episode of cerebellar ataxia or family history of MS would be more consistent
with a diagnosis of MS. Lyme disease, in rare cases, may present with
demyelination of the CNS, but this is uncommon. Incontinence of bowel and bladder
might occur in any severe myelopathy and would not change the clinical impression
of NMO in this case.

VIGNETTE 2 QUESTION 3
3. Answer B:
Finding aquaporin-4 antibodies would support the diagnosis of NMO. Lumbar
puncture may show neutrophilic pleocytosis in NMO, but this is less sensitive than
finding aquaporin-4 antibodies. MRI of the brain, with and without contrast, is
typically normal in NMO, although patients with NMO-spectrum disorders may
have an abnormal brain MRI. MRI of the cervical spine may show other
demyelinating lesions but would not change the diagnosis. Visual evoked potentials
may confirm the clinical history of ON but would not establish the diagnosis of
NMO as clearly as aquaporin-4 antibodies would.
 21 Infections of the Nervous System

It is important for physicians to be familiar with the common types and manifestations of
nervous system infections for several reasons. First, this category of neurologic illness
can be quite acute in presentation. Additionally, some nervous system infections can
have severe and potentially life-threatening consequences. Finally, for many infections,
specific therapies are available, and tailored to the identified etiologic organism.

BACTERIAL INFECTIONS
Three common and important forms of bacterial nervous system infection are acute
bacterial meningitis, brain abscess, and spinal epidural abscess.

ACUTE BACTERIAL MENINGITIS

Clinical Findings
Acute bacterial meningitis is a medical emergency. It is critical for all physicians to
know its presentation, its initial diagnostic evaluation, and the urgency with which a
potential case of bacterial meningitis needs to be addressed. The cardinal findings
include headache, fever, and neck stiffness. Patients can also be confused or have a
depressed level of consciousness, develop seizures, or have other focal neurologic
symptoms or signs, depending on the extent to which the meningeal infection or
inflammatory process also affects the brain parenchyma (thus causing
meningoencephalitis). In immunosuppressed patients, as well as in the very elderly,
there may be no fever, so it is vital to have a high degree of clinical suspicion in these
populations. On exam, patients often have nuchal rigidity, that is, rigidity with flexing
the neck forward. Two classically described physical signs associated with meningitis
(Fig. 21-1), although not specific to the bacterial form, are:
FIGURE 21-1. Kernig sign is elicited by flexion of the hip at 90 degrees. If the patient experiences pain by
extending the knee, the Kernig sign is positive. Brudzinski sign is elicited by flexing the patient’s neck. The sign is
positive if the patient flexes the hips and knees in response. (Reused with permission from Lippincott’s Clinical
Simulations. 1st ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.)

• Kernig sign: The patient lies supine, and the knee is extended passively while the hip
is flexed. If the patient is unable to extend the knee because of pain, the sign is
positive.
• Brudzinski sign: An involuntary flexion at the hips when the neck is flexed.

Etiology
The most common organisms causing bacterial meningitis vary depending on the
patient’s age at presentation (Table 21-1). The introduction of vaccines against
Streptococcus pneumoniae (“pneumococcus”), Neisseria meningitides
(“meningococcus”), and Haemophilus influenzae has substantially reduced the incidence
of acute bacterial meningitis among children in the United States. In most cases, bacteria
reach the subarachnoid space by hematogenous spread from the respiratory tract,
although bacterial meningitis may also be a direct sequela of traumatic or mechanical
invasion of the subarachnoid space, such as after neurosurgical procedures or open head
injury. It is also possible to have direct infiltration of the subarachnoid space from
parameningeal foci, such as the sinuses.

TABLE 21-1. Common Causes of Meningitis by Age, and Empiric Antibiotic

Treatment
Age Bacterial Empiric Treatments
0–3 mo —Group B Streptococcus Ampicillin + cefotaxime
—Streptococcus pneumonia OR ampicillin + an aminoglycoside
—Listeria monocytogenes
—Escherichia coli
3–24 mo —S. pneumonia Vancomycin + a third-generation
—Neisseria meningitides cephalosporin
—Haemophilus influenza type B
 —Group B Streptococcus
2–18 y —N. meningitides Vancomycin + a third-generation
—S. pneumonia cephalosporin
Older adults —S. pneumonia Vancomycin + ampicillin + a third-generation
—N. meningitides cephalosporin
—H influenza, type B
—Group B Streptococcus
—L. monocytogenes

Diagnostic Workup
The critical test in the diagnosis of acute bacterial meningitis is cerebrospinal fluid
(CSF) analysis from a lumbar puncture (LP). Because of the concern that LP may
precipitate brain herniation in the presence of a focal intracranial mass with increased
intracranial pressure, head imaging (usually with computed tomography [CT], because it
is available more readily) should be performed before LP when papilledema is present
on fundoscopic examination or if there is any focal sign on neurologic examination
suggesting the possibility of an intracranial lesion. Many neurologists advocate head
imaging prior to LP under any circumstances with an acute presentation.
The characteristic CSF profile in acute bacterial meningitis includes an elevated
white blood cell (WBC) count, with a predominance of polymorphonuclear leukocytes
(generally never acceptable in a CSF sample), elevated protein, and low glucose (<40
mg/dL or less than two-thirds of a simultaneously measured serum glucose level) (Table
21-2). The differential on the CSF WBC must be interpreted with caution early in the
course of meningitis because patients with bacterial meningitis may present initially
with a lymphocytic predominance. Patients with viral meningitis may also have a
neutrophil predominance early in the course. Severely immunosuppressed patients with
pancytopenia may also not have classic CSF patterns. CSF Gram stain can demonstrate
the bacteria and narrow the differential diagnosis of causative organisms. CSF cultures
in acute bacterial meningitis can often identify the specific organism, which can then be
tested for antibiotic sensitivity.

TABLE 21-2. Common Cerebrospinal Fluid Patterns in Different Forms of

Meningitis
Bacterial Viral Fungal TB
Opening pressure Elevated Normal May be normal or May be normal or
elevated elevated
WBC ≥100 cells/µL <100 cells/µL <500 cells/µL <500 cells/µL
Cell type Polymorphonucleocytes Lymphocytes Lymphocytes Lymphocytes
Glucose Low May be normal Low Low
Protein Elevated Elevated Elevated Elevated
TB, tuberculosis; WBC, white blood cells.
 Because of the potentially life-threatening nature of acute bacterial meningitis, a
prolonged delay in obtaining CSF may necessitate the institution of empiric antibiotic
coverage prior to LP—using antibiotics that are effective against the most likely
organisms, at doses that ensure adequate penetration into the subarachnoid space, or
“meningitis doses.” In this case, CSF cultures may not grow organisms if they were not
obtained until well after antibiotic therapy was begun, and it may be necessary to
complete an entire course of empiric therapy.

Treatment
Appropriate antibiotic therapy needs to be administered promptly upon the diagnosis of
acute bacterial meningitis, with specific drugs initially chosen on the basis of the most
likely organisms, and subsequently modified on the basis of Gram stain or culture
results (Table 21-1). In addition to the antibacterial therapy, some adjunctive therapies
may also be helpful in certain situations. Corticosteroids are often used in children in an
attempt to prevent some long-term complications of acute bacterial meningitis, such as
deafness.

KEY POINTS
● Acute bacterial meningitis is a medical emergency.
● The typical clinical presentation consists of headache, fever, neck pain, or stiffness, and often, altered
consciousness.
● Immunocompromised patients may lack some of the cardinal features of meningitis such as fever.
● The classic CSF profile of bacterial meningitis demonstrates a high WBC count (mostly polymorphonuclear
leukocytes), high protein, and low glucose.
● Antibiotic treatment should be initiated early and is tailored on the basis of the identification of responsible
organisms and penetration into the subarachnoid space.

BRAIN ABSCESS

Clinical Findings
Brain abscesses typically present much like any other focal intracranial lesions, with
headache, focal neurologic signs (that depend on the location of the abscess), seizures,
and potentially, signs of increased intracranial pressure. Fever may be present, but this
is not invariable.

Etiology
Solitary brain abscesses often arise from invasion of the intracranial space from
neighboring sites of infection, such as the sinuses, or from direct open trauma or
mechanical instrumentation. The first stage of brain abscess development is often
cerebritis in which there is an active infection in the brain but not yet walled off. CSF
studies are abnormal, and imaging studies or electroencephalogram (EEG) or both may
also be abnormal. In the second stage, the infection becomes organized and walled off
to form a classic abscess. Multiple brain abscesses are typically the result of
hematogenous dissemination, such as from infective bacterial endocarditis, or with
immunocompromised states. Responsible organisms depend on the etiology: respiratory
pathogens may invade from the sinuses; abscesses from trauma or instrumentation are
often skin flora; multiple abscesses are often caused by organisms that cause infective
bacterial endocarditis. Most abscesses contain multiple organisms, often a mixture of
aerobic and anaerobic pathogens (Table 21-3).

TABLE 21-3. Causes of Brain Abscesses

Source of Infection Bacterial Causes
Traumatic brain injury Staphylococcus aureus
Staphylococcus epidermidis
Pseudomonas aeruginosa
Enterobacter species
Neurosurgery Staphylococcus aureus
Staphylococcus epidermidis
Pseudomonas aeruginosa
Propionibacterium acnes
Streptococcus species
Hematogenous spread Staphylococcus aureus
Streptococcus viridans
Klebsiella pneumoniae
Ear Proteus mirabilis
Streptococcus milleri group organisms
Streptococcus pneumonia
Dental Streptococcus species
Bacteroides fragilisus

Diagnostic Workup
The diagnosis of brain abscess is usually made by neuroimaging. CT or magnetic
resonance imaging (MRI) with intravenous contrast agents will usually demonstrate a
mass lesion, often surrounded by “ring enhancement” and signs of central necrosis
within the brain parenchyma (Fig. 21-2). There may be surrounding edema. At the top of
the radiologic differential diagnosis are malignant neoplastic lesions, which often have
a similar ring-enhancing mass appearance. Sometimes, single photon emission
computed tomography (SPECT) scanning can help differentiate a neoplastic process
from an abscess. Depending on the source of the infection, blood cultures may identify
the responsible organisms, but neurosurgical drainage is often necessary for definitive
pathogen identification.

FIGURE 21-2. Presentation of brain abscess on CT and MRI. On noncontrast CT (A), the abscess appears
hypodense (asterisk). On MRI (B), the edema (arrow) surrounding the abscess appears hyperintense, and contrast
enhancement (C) visualizes the capsule (arrow). On diffusion-weighted imaging (D), the abscess cavity appears
hyperintense (arrow). [CT, computed tomography; MRI, magnetic resonance imaging.] (Reprinted with permission
from Scheld WM, Whitley RJ, Marra CM. Infections of the Central Nervous System. 4th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2014. Figure 31.15.)

Treatment
Prolonged courses of intravenous antibiotics, either chosen empirically for broad-
spectrum coverage of aerobic and anaerobic organisms or tailored specifically on the
basis of culture results, are the mainstay of treatment for brain abscesses. If the lesion
does not respond to antibiotics, surgical drainage may be required. If the lesion causes
mass effect and the patient is at risk of herniation, surgical drainage may also be
necessary.

CENTRAL NERVOUS SYSTEM EMPYEMA

Collections of pus, known as empyemas can occur in the central nervous system (CNS)
as in other tissues. CNS empyemas most commonly occur in the subdural or epidural
spaces. One must have a high degree of clinical suspicion because the empyema may be
difficult to differentiate from a subdural hematoma on a scan. Consequently, these
lesions are missed frequently. Patients may present with fever and headache. The
infection typically arises from direct spread from an adjacent tissue (sinus, bone, or
skin) or hematogenous spread (Fig. 21-3).
FIGURE 21-3. Frontal sinusitis with intracranial empyema. T1-weighted, contrast-enhanced image confirming
likely subcortical infarction. Blue arrow: empyema. Violet arrow: subcortical infarct.(Reprinted with permission from
Mancuso AA. Head and Neck Radiology. 1st ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010. Figure
13.16.)

SPINAL EPIDURAL ABSCESS

Clinical Findings
Spinal epidural abscesses typically present with the combination of neck or back pain
and focal neurologic signs consistent with spinal cord compression or cauda equina
involvement, depending on the spinal level of the abscess. For thoracic or lumbar
abscesses, clinical signs may include leg weakness, sensory loss with a discernible
sensory level on examination, and urinary and sexual dysfunction. Cervical abscesses
may present with the same symptoms as those at lower levels, but the arms may be
involved as well, resulting in arm weakness or sensory symptoms there, or both. Fever
is not necessarily present. Symptoms may come on acutely or more insidiously; an
acute, rapid presentation raises concern for a spinal cord infarction.

Etiology
Spinal epidural abscesses can be sequelae of spinal instrumentation, including epidural
or spinal anesthesia or spine surgery. In these cases, the responsible organisms are often
skin pathogens such as staphylococcal species. Abscesses can also be the result of
spread from more anterior infections, including vertebral body osteomyelitis or diskitis.

Diagnostic Workup
If there is a clinical suspicion on the basis of history and exam, spine imaging should be
obtained urgently because an intraspinal lesion such as an epidural abscess can cause
cord compression with resulting paralysis. In general, the administration of contrast
(with either CT or MRI) can help demonstrate the enhancing nature of spinal epidural
abscesses (Fig. 21-4). LP is contraindicated in most situations before the anatomic
extent of the lesion is defined clearly by imaging, because there is a theoretical
possibility of seeding the subarachnoid space with bacteria using the spinal needle. As
with intracranial abscesses, blood cultures can sometimes demonstrate the responsible
organisms, but in many cases, radiologically guided biopsy or surgical drainage for
microbiologic studies is necessary.

KEY POINTS
● Abscesses affecting the CNS are mass lesions that are often ring-enhancing on imaging studies with contrast.
● They present with focal neurologic signs that are dependent on their intracranial or spinal location.
● Prolonged courses of intravenous antibiotics are the mainstay of treatment, but surgical drainage is necessary
sometimes.
● MRI or CT imaging should be obtained urgently in patients for whom there is a high clinical concern for
epidural abscess, because there is a risk of cord compression from these lesions.
● Patients with evidence of cord compression or a cauda equina syndrome often require surgical
decompression in addition to antibiotic treatment for the abscess.

FIGURE 21-4. Sagittal T2-weighted MRI of the lumbosacral spine demonstrating a large spinal epidural abscess
(orange arrow). [MRI, magnetic resonance imaging.] (Reprinted with permission from Rathmell JP. Atlas of Image-
Guided Intervention in Regional Anesthesia and Pain Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2011. Figure 5.27B.)

Treatment
Prolonged courses of intravenous antibiotics are the mainstay of treatment for spinal
epidural abscesses, although in some cases neurosurgical drainage is necessary. When a
clinical syndrome of acute cord compression or cauda equina involvement is present,
surgical decompression may be required urgently.

TUBERCULOSIS
One-third of the global population is infected with tuberculosis. In the United States, it
is less common (3.0 cases per 100,000 people). Mycobacterium tuberculosis affects the
nervous system in several ways: tuberculous meningitis, intracranial tuberculomas, and
Pott’s disease (tuberculoma of the spine).

Tuberculous Meningitis
Tuberculous meningitis arises from hematogenous dissemination of mycobacteria from a
pulmonary source. A number of features distinguish tuberculous meningitis from acute
pyogenic bacterial meningitis (described previously). First, meningitis caused by M.
tuberculosis has a predilection for affecting the basal meninges (those at the base of the
brain) and can thus present with cranial nerve palsies in addition to the usual features of
acute bacterial meningitis. A basal meningitis can also lead to hydrocephalus or brain
infarctions from inflammation affecting cerebral vessels. Second, tuberculous meningitis
tends to have a more subacute or chronic, insidious presentation than acute bacterial
meningitis, so a prolonged prodrome of malaise and fairly nonspecific constitutional
symptoms may precede the appearance of frank neck pain or stiffness. Finally, the CSF
profile in tuberculous meningitis typically demonstrates a leukocytosis with lymphocytic
predominance, rather than polymorphonuclear predominance (except initially), and the
CSF glucose is often very low (Table 21-2). Acid-fast bacilli staining of the CSF can
identify mycobacterial infection, but culture of this organism takes weeks to grow, and
some never become positive. Fortunately, polymerase chain reaction (PCR) testing of
mycobacterial antigens is available. The treatment of tuberculous meningitis requires a
regimen of multiple antituberculous drugs that penetrate the intrathecal space
effectively, usually with isoniazid, rifampin, pyrazinamide, and streptomycin.

Intracranial Tuberculoma
Tuberculomas are mass lesions caused by M. tuberculosis infection. Although
uncommon in the United States, tuberculomas are one of the most common focal brain
lesions in the developing world. Typically, they present with features that would be
expected for any inflammatory mass lesion within the brain, including headache, focal
neurologic symptoms and signs, and seizures. They can calcify, be variably enhancing
on radiologic studies with contrast, and sometimes be associated with hydrocephalus.
The radiologic differential diagnosis typically includes brain tumor, bacterial abscess,
or cysticercosis (see below). Appropriate treatment includes prolonged courses of
antituberculous therapy and neurosurgical intervention if needed.

KEY POINTS
● Tuberculosis affects the nervous system in several different ways, including meningitis, focal brain lesions, or
focal spine lesions.
● Tuberculous meningitis has a predilection for the basal meninges, is typically insidious, can present with
cranial nerve palsies, and has a different CSF profile from bacterial meningitis.
● Pott’s disease, or tuberculosis of the spine, affects the nervous system when there is direct invasion into the
epidural space.
● Diagnosis is based on history, radiographic findings, and cultures.

Pott’s Disease
Pott’s disease, or tuberculosis of the spine, typically presents with neurologic symptoms
and signs when a vertebral body infection extends into the epidural space, leading to
subacute spinal cord or cauda equina compression, depending on the level of
involvement. Fever and back pain are common. Spread through disk spaces to adjacent
vertebral bodies often suggests Pott’s disease (Fig. 21-5), usually differentiating it from
metastatic cancer. Treatment includes antituberculous drugs and spine stabilization
procedures if necessary.

LYME DISEASE
Lyme disease, caused by the spirochete Borrelia burgdorferi and transmitted by the deer
tick, is a common infection in the northern United States and in Europe. Lyme disease
affects the nervous system in several ways, including Lyme-associated meningitis,
cranial nerve palsies, and a syndrome of polyradiculopathy.
FIGURE 21-5. Tuberculous spondylitis (Pott’s disease). A vertebral body is almost completely replaced by
tuberculous tissue. Note the preservation of the intervertebral disks. (Reprinted with permission from Rubin R, Strayer
DS, Rubin E. Rubin’s Pathology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Figure 26.22.)

Clinical Findings
Although the typical rash of erythema chronicum migrans (Fig. 21-6) can occur within
the first week after a bite from an infected tick, neurologic manifestations typically do
not appear until the more disseminated stage of Lyme disease, several weeks after the
bite. Headache, neck stiffness, and myalgias may develop into more frank signs of
meningismus, along with cranial nerve palsies. Patients commonly present with a
unilateral or bilateral facial nerve (CN VII) weakness (Fig. 21-7). In the persistent stage
of systemic disease, several months after the initial bite, there may be a
polyradiculopathy (often with significant pain), polyneuropathy, encephalopathy (with
signs of white matter signal change on MRI), or combinations of these.
FIGURE 21-6. Erythema migrans, the characteristic rash of Lyme disease. This photograph depicts the “bull’s-
eye” pattern rash at the site of a tick bite on the upper arm of a woman who subsequently contracted Lyme disease.
(Reprinted with permission from Engleberg NC, Dermody T, DiRita V. Schaechter’s Mechanisms of Microbial
Disease. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. Figure 25.2.)
FIGURE 21-7. Facial weakness due to a seventh nerve lesion, as can be seen in Lyme disease. Patients exhibit
a lower motor neuron pattern of facial weakness with the features noted above. (Reprinted with permission from
Bhatnagar SC. Neuroscience for the Study of Communicative Disorders. 4th ed. Philadelphia, PA: Lippincott Williams
& Wilkins; 2012. Figure 1.17.)

Diagnostic Workup
Serologic tests of the blood or CSF can be diagnostic, but sometimes not until late in the
course of the disease. The Centers for Disease Control and Prevention (CDC) has clear
guidelines on the diagnostic approach to Lyme serology (Fig. 21-8). The routine CSF
profile typically demonstrates a lymphocytic pleocytosis with elevated protein and
normal glucose. A PCR assay of the CSF is available for spirochetal antigen. This is
very sensitive but can give a false positive in patients with neurosyphilis. Serology may
also remain positive for years after treatment, which poses a challenge for patients in
establishing a new diagnosis. In cases of encephalopathy, MRI of the brain can
sometimes show patchy foci of signal change in the white matter. These can resemble
findings in patients with multiple sclerosis or migraine and may be nonspecific. In cases
of peripheral nervous system involvement, electromyographic (EMG) and nerve
conduction studies (NCS) may be useful to identify the pattern of the polyradiculopathy
or polyneuropathy.

Treatment
Patients with isolated facial weakness and negative CSF studies can often be treated
with oral antibiotics, whereas signs of more disseminated neurologic infection suggest
the need for intravenous antibiotics at dosages that can penetrate the subarachnoid
space. IV ceftriaxone, cefotaxime, and penicillin are effective treatments for both
peripheral and central Lyme disease.

FIGURE 21-8. Serologic testing for Lyme disease. [EIA enzyme immunoassay; IFA, immunofluorescence
assay; IgG, immunoglobulin G; IgM, immunoglobulin M.] (Based on Centers for Disease Control and Prevention.
Health Care Providers. CDC guidelines, 2017. https://www.cdc.gov/lyme/healthcare/index.html.)

KEY POINTS
● Lyme disease, caused by the spirochete B. burgdorferi, is a common infection in the northern United States
and in Europe.
● The CDC has clear diagnostic criteria on diagnosis.
● Early neurologic manifestations of Lyme disease include an aseptic meningitis, facial nerve weakness, or
both, within weeks after infection.
● Later neurologic manifestations include leukoencephalopathy, cranial neuropathies, and painful
polyradiculopathy or polyneuropathy or both, sometimes months after the initial infection.

VIRAL INFECTIONS
Most viral infections of the nervous system present as one of several clinically
recognized syndromes. The evolving field of neuroinfectious diseases continues to
identify new viruses that can present with CNS manifestations. It is, therefore, important
for clinicians to be aware of the endemic pathogens and screen patients for travel or
other exposures that would put them at risk for exposure to pathogens from other
regions. Viral meningitis and encephalitis are discussed in the following sections.

VIRAL MENINGITIS
Viral meningitis is commonly caused by enteroviruses, such as Coxsackievirus, or
arboviruses, such as West Nile virus. Clinically, the presentation may be very similar to
that of acute bacterial meningitis, and it is mainly the latter that needs to be considered
and ruled out immediately, even if viral meningitis is suspected to be more likely. The
CSF profile differs from that of acute bacterial meningitis, in that viral meningitis
usually features a lymphocytic predominance of WBCs (except initially, when
polymorphonuclear leukocytes can be present) and an elevated protein without a
concomitant significant lowering of CSF glucose (Table 21-2). Gram stain and bacterial
culture of CSF are, of course, unrevealing. Testing the blood and CSF for virus-specific
serologies and PCR assays can help identify the responsible virus. Treatment generally
involves just supportive care, unless herpes simplex virus (HSV) 1 is suspected.

ENCEPHALITIS
Viral encephalitis, which affects the brain parenchyma itself, usually presents with
headache, fever, altered consciousness or behavior, and often seizures, focal neurologic
abnormalities, or both. Although most viruses causing encephalitis have no specific
anti-infective therapy available, encephalitis caused by HSV1 leads to some distinct
clinical features and warrants specific, emergency therapy. HSV1 encephalitis has a
predilection for the base of the brain, specifically including the medial temporal lobes
and orbitofrontal regions of the cortex (Fig. 21-9). Limbic dysfunctions, including
complex partial seizures of mesial temporal lobe origin, olfactory hallucinations, and
memory disturbances (including sometimes profound anterograde amnesia and some
degree of retrograde amnesia), are common parts of the clinical presentation. The CSF
in HSV1 encephalitis often demonstrates an elevated red blood cell count in addition to
leukocytosis (and thus needs to be distinguished from traumatic LP results). A CSF PCR
test is available for HSV1. EEG recording may demonstrate periodic epileptiform
discharges over one or both temporal regions, particularly after several days of
infection. HSV1 encephalitis is treated with a prolonged course of intravenous
acyclovir. This drug can be started empirically if there is initial clinical or laboratory-
based suspicion for HSV1 encephalitis, while awaiting results of the more definitive
CSF PCR test to return, which can take several days. Other cases of viral encephalitis
are managed with supportive care, including analgesics for headache and
anticonvulsants for seizures, as appropriate.
FIGURE 21-9. MRI findings in HSV encephalitis. T2-weighted coronal MRI demonstrating predominantly right
mesial temporal hyperintensity and swelling in presumed HSV1 encephalitis. [HSV, herpes simplex virus; MRI,
magnetic resonance imaging.] (Reprinted with permission from Wyllie E. Wyllie’s Treatment of Epilepsys. 6th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Figure 32-3a.)

ZIKA VIRUS
Zika virus has become recognized recently as another serious cause of viral
encephalitis, transverse myelitis, and Guillain–Barré syndrome (GBS). Clinically
significant neurologic manifestations of Zika occur in about one-quarter to one-fifth of
infected patients. The virus can also be transmitted both during pregnancy and at birth.
Congenital Zika infections often cause serious birth defects, including microcephaly,
dysmorphic faces, hypertonia, sensorineural hearing loss, eye abnormalities, and
arthrogryposis; seizures are common. Zika infections can be diagnosed by virus
serology or by a real-time reverse-transcription PCR for Zika virus RNA. Treatments
include supportive care and treatment of seizures; immune globulin has been used to
treat patients with GBS due to Zika infection.

KEY POINTS
● Viral meningitis may resemble acute bacterial meningitis but has a different CSF profile, and specific anti-
infective therapy is generally not available.
● Viral encephalitis can be caused by a number of different agents, but HSV1 encephalitis is associated with
some distinct clinical features and is treated with intravenous acyclovir.
FUNGAL INFECTIONS
There are numerous mycoses that cause nervous system infection. The most common are
Cryptococcus neoformans, Aspergillus, and various Candida species. Others include
Coccidioides immitis, blastomycosis, zygomycosis, dematiacious (Cladophialophora),
and Histoplasma capsulatum. Mycotic infections are most common in
immunosuppressed patients. The causes of immune suppression are broad, including
chronic steroid use, chemotherapy, organ transplantation, HIV/AIDS, malignancies, and
other chronic diseases. Many fungal infection occur worldwide, but there are several
with geographically endemic regions:
• Coccidioides: Southwest US; Mexico
• Blastomyces: Mississippi valley; Northern-Central and Mid-Atlantic US
• Histoplasma: Central Mississippi and Ohio Valley; Latin America

TABLE 21-4. CNS Signs of Fungal Infections

Aspergillosis Cryptococcosis Histoplasmosis Coccidioidomycosis Candidiasis
Meningitis
Focal mass
Stroke
syndrome
Spinal
syndrome

It is, therefore, important to screen patients for exposures including travel.

Fungal infections present with varied neurologic syndromes. Meningitis and
intracranial mass lesions (abscesses or granulomas) are the most common findings. The
presentation of a mycotic infection is influenced by the type of fungus and method of
spread in the CNS (hematogenous vs. local). Table 21-4 outlines different neurologic
syndromes associated with mycotic infections. The CSF profiles of fungal infections are
listed in Table 21-2. Diagnosis is made by LP and serologies. Treatment with antifungal
therapy is vital because patients with fungal infections have a high mortality. The
initiation of therapy can result in immune reconstitution inflammatory syndrome, so
patients require very close monitoring. Cryptococcus is one of the most common form of
fungal meningitis and is discussed here.

CRYPTOCOCCAL MENINGITIS
Cryptococcal meningitis typically affects immunocompromised subjects but
occasionally immunocompetent people, as well. It is acquired by inhalation of the
fungus (which is present in soil and pigeon droppings) and is then disseminated
hematogenously. Cryptococcal meningitis often presents insidiously with headache,
neck pain, and confusion; fever is variably present. The CSF profile demonstrates a
lymphocytic predominance of WBCs (except initially), elevated protein, and low
glucose, which is a pattern seen across most fungal infections. Although India Ink
staining of CSF was historically a time-honored way of detecting the presence of
Cryptococcus organisms, a rapid latex agglutination assay for cryptococcal antigen is
the standard diagnostic test now. Treatment includes the use of antifungal agents such as
amphotericin.

KEY POINTS
● Mycotic infections occur most commonly in immunocompromised individuals.
● Different fungi are endemic in different geographic regions.
● Meningitis and mass lesions are the most common clinical syndromes and often have an insidious
presentation.
● The CSF profile of fungal infections is distinct from that of most bacterial and viral infections.

PARASITIC INFECTIONS OF THE NERVOUS

SYSTEM
CNS parasitic infections remain prevalent in certain regions of the world and have a
high morbidity and mortality. Neurocysticercosis is the most common parasitic
infection, followed by toxoplasmosis. They are discussed in the following sections.
There are numerous less common parasitic infections, including the following:
American trypanosomiasis (Chagas disease), schistosomiasis, Human African
Trypanosomiasis, malaria, echinococcosis, onchocerciasis, paragonimiasis,
toxocariasis, and angiostrongyliasis. Clinically, patients often present with seizures and
sometimes with focal neurologic deficits. Some parasitic infections also cause
meningitis. LPs in patients with parasitic infections often show eosinophilia.

TOXOPLASMOSIS
Toxoplasma gondii is an intracellular parasite that most commonly affects humans either
as a congenital infection (it is one of the TORCH infections, the others being “other,”
rubella, cytomegalovirus, and herpes simplex) or as an intracranial infection in patients
with AIDS or severe immune incompetence. Humans are exposed through cat feces or
ingestion of undercooked meat. Clinically, toxoplasmosis in the AIDS patient presents
as expected for any intracranial mass lesion, with headache, mental status changes,
seizures, and focal neurologic signs and symptoms that depend on the lesion location.
Fever may be present. Imaging studies typically show multiple ring-enhancing lesions in
the basal ganglia or at the gray matter–white matter junction. Serologies, CSF PCR
assays, and CSF Wright or Giemsa stains can help confirm the diagnosis. Primary CNS
lymphoma is often in the radiologic differential diagnosis in AIDS patients with such
intracranial lesions (Fig. 21-10). In some cases, brain biopsy may be necessary to make
a definitive diagnosis, particularly if empiric antitoxoplasmosis therapy has not led to
any improvement.

FIGURE 21-10. CNS toxoplasmosis. Contrast-enhanced MR shows ring-enhancing lesions, one of which
demonstrates eccentric target-like enhancement (arrowhead), a relatively specific sign for toxoplasmosis. Note the
second ring-enhancing lesion in the left thalamus (arrow). [CNS, central nervous system; MR, magnetic resonance.]
(Reprinted with permission from Scheld WM, Whitley RJ, Marra CM. Infections of the Central Nervous System. 4th
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014. Figure 3.16.)

NEUROCYSTICERCOSIS
Neurocysticercosis, an infection caused by the pork tapeworm Taenia solium, is the
most common parasitic infection of the CNS and one of the most common causes of
new-onset focal seizures in much of the developing world. It is endemic in, among other
places, Central and South America and is thus commonly seen in immigrant populations
in the United States. Clinically, nervous system infection presents with seizures,
headache, and signs of increased intracranial pressure. Imaging studies demonstrate
multiple cystic lesions, which can be ring-enhancing or calcified, and often have
surrounding edema (Fig. 21-11). Anti-infective treatment includes albendazole, and
steroids are often used to control the inflammation and edema that accompany the initial
treatment because this inflammation can lead to increased symptoms. Anticonvulsant
medications are used to control seizures.

KEY POINTS
● Toxoplasmosis, acquired from cat feces or undercooked meat, is a common cause of intracranial mass lesions
in severely immunosuppressed patients, including AIDS patients.
● Congenital toxoplasmosis is one of the TORCH infections.
● Cysticercosis, caused by a pork tapeworm, is the most common parasitic infection of the CNS and one of the
most common causes of new-onset focal seizures in the world.

NERVOUS SYSTEM COMPLICATIONS OF HIV

INFECTION
The retrovirus human immunodeficiency virus (HIV) is associated with a variety of
nervous system syndromes in about half of all infected patients. Some of these appear to
be late complications of direct HIV infection and prolonged immunosuppression (HIV-
associated dementia, vacuolar myelopathy), some of which are due to opportunistic
infections (toxoplasmosis, cryptococcal meningitis, progressive multifocal
leukoencephalopathy), some of which reflect peripheral nervous system involvement
(discussed in Chapter 23), and some of which are neurologic complications of
antiretroviral therapy (ART).

HIV-ASSOCIATED DEMENTIA
HIV-associated dementia is a late complication of HIV infection, generally occurring
after prolonged periods of immunosuppression. Its incidence has declined in recent
years with the widespread use of combination ART. Clinically, this syndrome presents
as a subcortical dementia, with cognitive impairment and psychomotor slowing. MRI
can show patchy T2 hyperintensity in the white matter, as well as cerebral atrophy.
There is no specific treatment other than aggressive ART and supportive therapies.
Prior to ART, the development of HIV-associated dementia was often seen as one of the
final stages of terminal illness due to HIV.
 FIGURE 21-11. Neurocysticercosis: contrast-enhanced CT (A) showing a single, small, ring-enhancing
lesion with a well-defined eccentric scolex, and perilesional edema (arrow). T2-weighted MRI (B) showing a
single cysticercosis lesion with a scolex and bright perilesional edema (arrow). [CT, computed tomography; MRI,
magnetic resonance imaging.] (Reprinted with permission from Shaffner DH, Nichols DG. Rogers’ Textbook of
Pediatric Intensive Care. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Figure 91.11a.)

VACUOLAR MYELOPATHY
Vacuolar myelopathy is also a late complication of HIV infection that occurs with
severe immunosuppression. Clinically, this disorder resembles the subacute combined
degeneration syndrome associated with vitamin B12 deficiency, in that patients develop
posterior column signs and symptoms (loss of vibration and joint position sense, with
sensory ataxia) and signs of corticospinal tract dysfunction (spasticity and
hyperreflexia) bilaterally. Urinary and sexual dysfunction may also occur. Treatment
involves ART and supportive therapy.

PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the
CNS caused by infection of oligodendrocytes by the John Cunningham (JC) virus. JC
virus is a ubiquitous polyomavirus for which most humans are seropositive because
they were exposed early in life. The virus becomes activated and causes PML in the
context of immune suppression such as from HIV or with immunomodulatory treatment
for illnesses such as multiple sclerosis and Crohn disease. The presentation may be
insidious, and patients may present with cognitive dysfunction, encephalopathy, ataxia,
visual symptoms or weakness, depending on the cerebral territories involved. MRI of
the brain shows patchy nonenhancing foci of T2 hyperintensity within the subcortical
white matter (Fig. 21-12). Treatment in HIV patients involves ART and supportive
therapy when appropriate.
Primary CNS lymphoma, which is thought to be mediated by Epstein–Barr virus, is
discussed in Chapter 19.
FIGURE 21-12. Progressive multifocal leukoencephalopathy: (A) axial CT; (B) postcontrast T1-weighted MRI;
(C) T2-weighted MRI. Images show a subcortical focus of abnormality within the high left frontal lobe (arrows),
corresponding to the motor association region. The characteristic features of this demyelinating process include
minimal to no mass effect, even when very large, and essentially no contrast enhancement or hemorrhage. A very low
T-cell count reflecting an immunocompromised status is also key to the diagnosis. In an immunocompetent patient,
differential diagnostic considerations for this type of lesion include posterior reversible encephalopathy syndrome,
which can have a similar appearance. [CT, computed tomography; MRI, magnetic resonance imaging.](Reprinted with
permission from Brant WE, Helms C. Fundamentals of Diagnostic Radiology. 4th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2012. Figure 7.14.)

CLINICAL VIGNETTES
VIGNETTE 1
A 67-year-old woman who recently underwent a lumbar epidural steroid injection
for low back pain now presents with low-grade fever, worsened back pain, and
difficulty walking. She has not urinated in 2 days. Examination shows mild
weakness in both legs, absent knee and ankle reflexes, and sensory loss involving
the perineum, posterior thighs, and posterolateral legs bilaterally.
1. Which of the following is the appropriate initial step in evaluation and
management?
a. Brain imaging
b. Spine imaging
c. Lumbar puncture
d. Electromyography and NCS
e. Physical therapy
2. MRI of the lumbar spine, with and without contrast, is performed. An epidural
mass with contrast enhancement is identified at the level of the L2 vertebral
body. A radiologically guided biopsy is performed, and microbiologic studies
sent. Which of the following organisms is most likely to be responsible for this
infectious lesion?
a. Staphylococcus aureus
b. HSV type 2
c. HIV
d. Streptococcus group A
e. Cytomegalovirus

VIGNETTE 2
A 45-year-old man is brought to the neurologist’s office by his girlfriend because of
recent problems with memory and behavior over the past few days. He has
appeared confused and cannot remember recent conversations or events. He has
been complaining of odd, overpowering smells that are not noticed by others.
Surprisingly, he is relatively unconcerned by these symptoms despite their rapid
onset and progression. The neurologist sends the patient to the emergency room for
evaluation. He is afebrile and appears systemically well. An MRI of the brain
shows bilateral medial temporal and orbitofrontal lesions that are bright on T2-
weighted images and enhance after gadolinium administration. An EEG shows
periodic epileptiform discharges over both temporal lobes.
1. Which of the following might be expected on CSF analysis?
a. Hypoglycorrhachia (low CSF glucose)
b. Gram-positive cocci in clusters
 c. Cytoalbuminologic dissociation
d. Infectious organisms revealed by India Ink staining
e. Elevated red blood cell count
2. The patient is admitted to the inpatient Neurology service, and CSF is sent for
HSV1 PCR on the basis of a clinical suspicion for HSV1 encephalitis. Which of
the following pharmacologic agents would be appropriate to begin
immediately?
a. Prednisone
b. Methylprednisolone
c. Acyclovir
d. Valacyclovir
e. Warfarin

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
The patient is presenting with symptoms concerning for a cauda equina syndrome,
with bladder dysfunction, motor and reflex abnormalities in the legs, and saddle
anesthesia. This requires urgent attention to prevent permanent neurologic deficits.
Although an LP may be necessary as part of the evaluation for cauda equina
syndrome, in this case, urgent spine imaging should be performed first to rule out a
structural lesion. In particular, an LP carries the theoretical risk of seeding the
subarachnoid space in the presence of a spinal epidural abscess, a distinct
possibility here. Spinal epidural hematoma is another structural concern, especially
in patients on anticoagulation. Parasagittal brain lesions can cause bilateral leg
motor and sensory problems, but this is rare, and the constellation of symptoms and
signs, particularly the saddle anesthesia, render this very unlikely. EMG/NCS and
physical therapy are not part of an urgent approach to a cauda equina syndrome.

VIGNETTE 1 QUESTION 2
2. Answer A:
The MRI finding is consistent with a spinal epidural abscess. In this case, the
instrumentation that occurred with the recent epidural steroid injection is likely to
have been related and suggests that skin bacteria, such as staphylococci, are the
most likely pathogens responsible for this abscess. HSV type II, HIV, and CMV are
all potential viral causes of a lumbosacral polyradiculopathy but would be unlikely
to cause an epidural mass lesion.
VIGNETTE 2 QUESTION 1
1. Answer E:
This clinical presentation is most consistent with HSV1 encephalitis. This infection
has a predilection for the base of the brain, including the medial temporal lobes and
orbitofrontal regions, as seen on his MRI. Common clinical features include memory
disturbances, olfactory hallucinations, and complex partial seizures. Periodic
temporal lobe discharges on EEG are a characteristic feature, particularly after
several days of infection. The CSF profile in HSV1 encephalitis, although sharing
features in common with other viral encephalitides (including leukocytosis, high
protein, and normal glucose), is distinctive in that elevated red blood cells can be
seen. Bacterial infection is unlikely here without fever and with the lack of signs of
systemic illness. Cytoalbuminologic dissociation is seen in GBS. India Ink staining
shows Cryptococcus neoformans organisms.

VIGNETTE 2 QUESTION 2
2. Answer C:
Although most viral encephalitides do not have specific treatments, HSV1
encephalitis is an exception and can be treated with a prolonged intravenous course
of acyclovir. In the appropriate clinical setting, acyclovir should be started while
awaiting PCR results because those results can take several days to return and
HSV1 encephalitis can be fatal if left untreated. Supportive care would also be
appropriate, including hydration, analgesics for headaches, and anticonvulsants for
clinical seizures, as appropriate. Corticosteroids are not generally used, nor is
valacyclovir (which is available only in oral form). Warfarin is not appropriate.
 22 Disorders of the Spinal Cord

The central nervous system (CNS) comprises the brain and the spinal cord. The spinal
cord plays a particularly important role in relaying sensorimotor signals between the
brain and the body. An understanding of the anatomic arrangement of cord structures can
help an examiner to localize related lesions.

ANATOMY
The spinal cord extends from the medulla, through the foramen magnum, and down the
spinal canal. The filum terminale, a connective tissue band, anchors the cord to the end
of the canal. Anterior to the cord are 7 cervical, 12 thoracic, 5 lumbar, and 5 sacral
vertebral bodies. These vertebral bodies are related to the motor and sensory nerve
roots that emerge from the ventral and dorsal aspects of the cord along its length. Both
the vertebral bodies and nerve roots are numbered, but those sets of numbers do not
match consistently. Most cervical nerve roots (i.e., C1 to C7) emerge above the
corresponding cervical vertebral bodies (e.g., the C6 nerve root traverses between the
C5 and C6 vertebral bodies), but the C8 nerve roots exit between the seventh cervical
and first thoracic vertebral bodies (i.e., at the C7-T1 level), because there is no C8
vertebral body. Distal to the T1 level, nerve roots are located below the corresponding
vertebral body so the L3 nerve root is located between the L3 and L4 vertebral bodies,
or at the L3-4 level (Fig. 22-1). The spinal cord extends to approximately the level of
the L1 vertebral body. Accordingly, safe lumbar punctures can be performed below this
level because there is no spinal cord in the canal there.
In cross section, the spinal cord contains the “central gray” matter and neuron cell
bodies, distributed in the shape of an H (Fig. 22-2). Each side of this central gray has an
anterior and posterior (dorsal) horn. The anterior horns contain primarily the alpha
motor neurons and motor nerve fibers innervating skeletal muscles. The dorsal horns
represent the gateway for sensory information. The right and left aspects of the central
gray matter are connected by the transverse commissure.
Surrounding the gray matter are white matter tracts traveling to and from the brain.
The most important descending motor tract is the corticospinal tract (CST) (Fig. 22-3).
After descending from the cortex, the CST crosses at the medulla before descending in
the lateral aspect of the cord. Accordingly, fibers from the left motor cortex cross at the
medullary pyramids before descending on the right side of the spinal cord to serve the
right limbs, and vice versa. Thus, spinal cord injuries that involve the right CST cause
right body (ipsilateral) motor deficits.
The lateral aspect of the cord also contains autonomic fibers from the hypothalamus
and brainstem. Sympathetic fibers course from T1 to L2 where they exit the spinal cord.
Injuries to autonomic fibers proximal to S2 can result in a “neurogenic bladder.” This
term describes automatic, involuntary bladder emptying when a certain level of
distention occurs. Parasympathetic nerve fibers leave the spinal cord in the S2 to S4
cord segments. Injuries to peripheral nerve fibers at these distal levels can result in
overflow incontinence from a flaccid bladder.
There are two important ascending sensory tracts: the dorsal column and the
spinothalamic tracts (Fig. 22-2). The dorsal columns refer to the heavily myelinated
tracts in the posterior aspect of the spinal cord that mediate joint position,
discriminative touch, and, to some degree, vibration sense. These tracts are arranged
with fibers ascending from the cervical spinal cord (fasciculus cuneatus) lateral to the
fibers ascending from the lumbosacral segments (fasciculus gracilis) medially. These
ascending fibers remain ipsilateral to their site of origin until they cross at the level of
the medulla, en route to the ventroposterolateral nucleus of the thalamus. Thus, spinal
cord injuries affecting the right dorsal columns may impair proprioception in the right
limbs. The lateral spinothalamic tracts are unmyelinated and carry pain and temperature
sensory information. After these fibers enter the spinal cord and ascend about two
levels, they cross in the ventral white commissure. Thus, a spinal cord lesion involving
the right lateral spinothalamic tracts may impair pain and temperature sensation starting
a few levels below the level of the lesion on the left (because these ascending fibers
have already crossed).
FIGURE 22-1. Posterior view of vertebral bodies in the cervical (A) and lumbar (B) regions showing the
relationship that can exist between a herniated nucleus pulposus (pink) and the spinal nerve roots. (Note that there are
eight cervical nerves and only seven cervical vertebrae.) In the lumbar region, the emerging L4 nerve roots emerge
laterally, close to the pedicles of the fourth lumbar vertebra, and are not closely related to the intervertebral disk
between the fourth and fifth lumbar vertebrae. Pressure on the L5 motor nerve root can prvoduce weakness of
dorsiflexion at the ankle. (From Snell RS. Clinical Neuroanatomy. 7th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2009.)

FIGURE 22-2. Transverse section of the spinal cord showing the sensory pathways. The posterior columns relay
information concerning proprioception and two-point discrimination. The spinothalamic tracts relay pain and
temperature information. (From Ginsberg L. Lecture Notes: Neurology. 8th ed. Oxford: Blackwell Publishing;
2005:122. Copyright © 2005 L Ginsberg. Reprinted by permission of John Wiley & Sons, Inc.)
 The blood supply for the anterior two-thirds of the spinal cord comes primarily from
a single anterior spinal artery (ASA) running along most of the ventral surface of the
cord. The cephalad portion of the ASA arises from branches of the two vertebral
arteries. The caudal portion of the ASA originates as aortic branches that form the
a r te r y of Adamkiewicz. The anterior horns, spinothalamic tracts, and lateral
corticospinal tracts, are perfused by the ASA. There are two posterior arteries that
perfuse the dorsal columns.

FIGURE 22-3. The corticospinal tract from the cortex to the ventral horn. [Copyright © 2012 Dr. Juan Acosta,
MD.]

The spinal cord is protected chemically by the blood–brain (or blood–CNS) barrier
and structurally by the resilient connective tissue of the dura mater and surrounding
vertebrae. Importantly, related spinal structures, such as the intervertebral disks, can
cause neurologic dysfunction when out of place.For example, herniated disks can cause
potentially serious “extradural” compression of the cord. Compressive lesions can also
occur within the dura but outside of the spinal cord itself (“intradural, extramedullary”
lesions); examples include meningiomas and neurofibromas. Finally, lesions within the
cord itself (“intramedullary” lesions), such as gliomas, can cause cord impingement and
dysfunction. Spinal cord compression causes weakness, incoordination, and sphincter
dysfunction below the level of the lesion and often causes a sensory level at or below
the lesion. Spinal cord compression is a neurologic emergency, although related
symptoms and signs can evolve over time.

KEY POINTS
● The corticospinal tract is an important descending motor tract that runs in the lateral aspect of the cord.
● The dorsal columns contain ascending sensory fibers in the posterior aspect of the cord that convey joint
position, discriminative touch, and vibration input.
● The spinothalamic tract is an ascending sensory tract in the lateral aspect of the cord, carrying pain and
temperature sensation.
● The corticospinal and dorsal column fibers cross at the medulla, while the spinothalamic fibers cross a few
levels above their level of entry into the spinal cord.
● A single anterior spinal artery supplies blood to the anterolateral aspects of the spinal cord, whereas two
posterior arteries are primarily responsible for the dorsal column’s blood supply.
● Spinal cord compression is a neurologic emergency.

LOCALIZATION OF SPINAL CORD DYSFUNCTION

The symptoms of spinal cord dysfunction can be protean, but the patient’s history and a
careful neurologic examination can help point to a lesion in this region of the CNS.
Patients may report sensorimotor symptoms. Bowel and bladder dysfunction often
accompanies cord dysfunction. A girdle or band-like sensation around the torso can
reflect cord dysfunction with involvement of the dorsal columns, as can a sensation of
limb swelling in the absence of visible edema. In classic, chronic spinal cord
dysfunction, “long tract signs” such as limb spasticity and hyperreflexia may be present.
Indeed, the combination of increased reflexes and weakness in the same somatic
territory (such as a motor root distribution) are a common finding in the setting of cord
dysfunction. By performing a sensory (e.g., pinprick) examination of the limbs and
posterior trunk bilaterally, a “level” demarcating the boundary between normal and
abnormal sensation can be sought. Such a finding indicates a cord lesion at or above the
identified level. (Because of the laminated organization of fibers in the cord, this level
can rise over time.) It is important to remember that acute cord lesions (e.g., spinal
shock) can be associated with paralysis and a loss of, rather than increase in, reflexes
and tone. In this scenario, the more characteristic signs of cord dysfunction may emerge
only after a period of weeks.

KEY POINTS
 ● Patients with spinal cord lesions may report sensorimotor symptoms, bowel or bladder dysfunction, a tight
“girdle-like” sensation, or a combination of symptoms.
● Classic, subacute to chronic cord lesions are associated with long tract signs, including increased reflexes and
spasticity together with weakness.
● Acute spinal shock can result in flaccid paralysis.
● An identified sensory level signifies a lesion at or above this location.

SPINAL CORD SYNDROMES

Spinal cord dysfunction can be characterized according to the region of the cord
involved and on the basis of the underlying cause of the impairment. Complete cord
transection, hemicord, central cord, posterior cord, conus medullaris/cauda equina, and
ASA syndromes are associated with specific anatomic patterns of neurologic deficit.
Autoinflammatory, infectious, (para)neoplastic, traumatic, treatment-related, toxic-
metabolic, vascular, and degenerative disorders can manifest with spinal cord
dysfunction that may or may not adhere to more clear-cut distributions. Accordingly, a
working familiarity with spinal cord anatomy and etiology of lesions is important.

COMPLETE CORD TRANSECTION

Severe trauma may cause complete transection of the spinal cord. Because this injury
disrupts all descending tracts traveling from above and all ascending tracts coming from
below, sensorimotor function is abolished below the level of the lesion. The level of
transection further dictates specific deficits. If transection occurs above the level of the
C3–C5 nerve roots, which control the diaphragm, respiratory insufficiency may result.
Autonomic regulation and abdominal reflexes may be lost with lesions above T6.
Bowel and bladder dysfunction (e.g., constipation and urinary urgency, retention, or
incontinence) may accompany lesions above the sacral cord level.

HEMICORD LESIONS
When one side of the spinal cord is affected, a “hemicord” or Brown-Sequard syndrome
results. In this disorder, there is weakness and impaired proprioception and vibration
sensation ipsilateral to the lesion, together with loss of pain and temperature sensation
contralateral to the lesion. This makes sense because a lesion, involving one side of the
cord will affect descending CST fibers that have already crossed in the medulla,
ascending dorsal column fibers that have yet to cross in the medulla, and ascending
spinothalamic fibers that have already crossed from the opposite side a few levels
below the lesion. (It can help visualize involved pathways by drawing them out!)
Hemicord lesions may occur, for example, in the setting of transverse myelitis due to
infection.
 Hemicord syndromes can also be caused by structural lesions such as herniated disks.
When structural lesions are associated with cord compression, urgent treatment with
dexamethasone to reduce local pressure prior to decompressive surgery may be
necessary.

FIGURE 22-4. Clinical features of syringomyelia. [LMN, lower motor neuron.] (From Ginsberg L. Lecture
Notes: Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:124. Copyright © 2005 L Ginsberg. Reprinted by
permission of John Wiley & Sons, Inc.)

CENTRAL CORD LESIONS

A structural abnormality in the center of the spinal cord tends to impact spinothalamic
tract fibers because they cross in the ventral white commissure situated just in front of
the middle of the cord. Deficits in pain and temperature sensation are usually bilateral
and span several segments. Thus, with a central lesion in the cervical cord, there can be
a “cape-like” loss of these sensations over the shoulders and arms, with preservation of
the same sensations above and below the lesion. The sensory loss is described as
“dissociated” because pain and temperature sensation is affected but touch and position
sense are not. In addition, a variety of motor and sensory functions can be impaired
below the lesion. Syringomyelia is one cause of a central cord syndrome (Fig. 22-4).

POSTERIOR CORD (DORSAL COLUMN) LESIONS

The posterior aspect of the cord can be affected preferentially. As one would predict in
this case, there is dysfunction of proprioception and vibration sense. Patients can
experience lancinating pain, paresthesias, gait dysfunction, and dysuria. The classic
disorder with this localization is aptly named tabes dorsalis and is historically
associated with late-stage syphilis. Subacute combined degeneration is a condition in
which the dorsal columns are affected in combination with the lateral columns of the
spinal cord—primarily in the cervical segment. As a result, patients can have limb
spasticity, hyperreflexia, sensory ataxia, and bladder dysfunction.

CONUS AND CAUDA EQUINA LESIONS

The spinal cord ends in the conus medullaris, located at approximately the L1 level.
Lesions there can cause leg weakness (including a flaccid paralysis), saddle anesthesia,
bowel and bladder dysfunction, and impotence. Cauda equina lesions are distal to the
cord, and affect the lumbar and sacral spinal nerve roots within the spinal canal.
Patients can have back pain that radiates asymmetrically into the legs, and they may
have bowel or bladder dysfunction, or both. On examination, weakness, fasciculations,
and a loss of reflexes in lower lumbosacral distributions may be detected. These lesions
can evolve in the setting of advanced degenerative disk disease.

ANTERIOR SPINAL ARTERY LESIONS

The spinal cord, like the brain, can incur a stroke when the blood supply is
compromised. The most common form of cord stroke is the ASA syndrome. Patients
may present following the acute onset of back or girdle-like pain, weakness, and loss of
sphincter control. On examination, small fiber (pain and temperature) sensory loss is
prominent, with preservation of position sense because posterior column function is
unaffected in this syndrome—a major neurologic clue to the diagnosis. Because it is a
watershed region, the thoracic cord is most vulnerable, and there is often a spinal
sensory level at about T4. Spinal cord infarction is rare, but can be seen following
surgical procedures, particularly those involving aortic surgery.

KEY POINTS
● In complete spinal cord transection, sensory and motor function is abolished below the level of the lesion.
● A Brown-Sequard (hemicord) syndrome affects one side of the cord and causes ipsilateral weakness and
position sense loss, with contralateral deficits in pain and temperature sensation below the level of the lesion.
● A central cord syndrome includes motor and sensory dysfunction below the lesion and often a “cape-like”
loss of pain and temperature sensation at levels near the lesion.
● Posterior column syndromes cause deficits of proprioception.
● Conus medullaris and cauda equina lesions may present with weakness, alterations in sphincter control, and
 sexual dysfunction.
● The ASA syndrome affects CST and spinothalamic function while sparing dorsal column function.

OTHER CAUSES OF SPINAL CORD DYSFUNCTION

There are many inherited and acquired causes of spinal cord dysfunction that fall into
the categories of autoinflammatory, infectious, (para)neoplastic, traumatic, treatment-
related, toxic-metabolic, vascular, and degenerative disorders. Potential
autoinflammatory causes include demyelinating disorders (e.g., neuromyelitis optica and
multiple sclerosis, as discussed in Chapter 20). Connective tissue diseases such as
systemic lupus erythematosus, sarcoidosis, scleroderma, and rheumatoid arthritis can
also affect the cord. Enterovirus infection has been associated with poliomyelitis. More
recently, West Nile Virus has caused anterior horn cell dysfunction. Infections including
HIV/AIDS and HTLV can be associated with a spastic paraparesis. Particularly in
patients with risk factors (e.g., recent invasive procedures), epidural abscess should be
included on the differential. Spinal cord tumors can cause dysfunction by compression.
Remote tumors can cause cord dysfunction via a paraneoplastic process, as can be seen
in the setting of lymphoma. Trauma (e.g., from motor vehicle collisions and falls) is an
important cause of spinal cord lesions of all sorts and is often readily identifiable. In
contradistinction, treatment-related cord lesions can be elusive. For this reason, it is
worthwhile to ask patients with clinical signs of spinal cord dysfunction if they have
ever had radiation treatment; the emergence of radiation myelopathy can be delayed by
months or years. Vitamin deficiencies (including of B12), or copper deficiency, and
hepatic disease can be associated with spinal cord dysfunction.
In addition to spinal cord infracts due to ASA disease, dural arteriovenous fistulas
(AVFs) and intramedullary spinal arteriovenous malformations (AVMs) can cause cord
dysfunction. AVFs can manifest with progressive paraparesis, with leg pain or
weakness, ambulation difficulty, and sensory symptoms, sphincter dysfunction or
combinations of these deficits—often in a stepwise pattern as venous pressure builds.
Although AVFs are more common in middle-aged men, teenagers and young adults may
develop similar symptoms from bleeding or ischemia in the cord because of
intramedullary spinal AVMs. Although these causes are relatively rare, degenerative
disk disease is quite common. Spondylotic changes or herniated disks in the cervical
region are a frequent cause of a myelopathy manifested by a spastic gait, weakness
(often with hand dysfunction and atrophy), sensory loss, and urinary urgency.
Neighboring symptoms and signs narrow the differential and inform the investigation
and treatment.
Some sporadic and inherited neurodegenerative diseases tend to affect certain spinal
cord elements. For instance, amyotrophic lateral sclerosis (ALS) is a disease of
anterior horn cells with sporadic and familial forms. Patients present with painless,
progressive weakness associated with increased tone and hyperreflexia. Although the
disease involves the anterior horn of the spinal cord, it also affects related motor nerve
roots and the end-organ muscles innervated by these roots. As a result, upper motor
neuron findings are often accompanied by lower motor neuron findings including
atrophy and fasciculations. Importantly, many disorders that affect the spinal cord,
including ALS, occur on an upper to lower motor neuron continuum so that there is a
mixture of localizing signs. Some disorders, like hereditary spastic paraplegia (HSP),
have primarily upper motor neuron findings; others, such as Friedreich ataxia (which
affects the posterior columns and spinocerebellar tracts) have predominantly lower
motor neuron features (e.g., weakness and areflexia).

KEY POINTS
● Acquired causes of spinal cord dysfunction are diverse; accompanying symptoms and signs narrow the
differential and direct diagnostic investigation.
● Many neurodegenerative disorders involving the spinal cord, such as ALS, have both upper and lower motor
neuron features on examination.
● Congenital abnormalities in spinal cord structure include syringomyelia, myelomeningocele, and tethered cord
syndrome.

Many congenital abnormalities affect the spinal cord. In syringomyelia, a fluid-filled

cavity in the center of the spinal cord (most common in the cervical and thoracic
regions), can be associated with a Chiari malformation, a downward protrusion of the
medulla, with or without the cerebellum, through the foramen magnum.
FIGURE 22-5. Arnold Chiari malformation with syrinx. Sagittal T1-weighted MRI of the cervical spine. Note the
downward displacement of the cerebellar tonsils projecting through the foramen magnum caudally to the C1 level
(arrow) and the uniformly low signal intensity (of fluid) in the syrinx cavity that enlarges the entire cervical spinal cord
(arrowhead). Note also the unrelated changes of degenerative spondylosis at C5-C6 (crossed arrow). [MRI, magnetic
resonance imaging.] (From Ginsberg L. Lecture Notes: Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:123.
Copyright © 2005 L Ginsberg. Reprinted by permission of John Wiley & Sons, Inc.)

Improper closure of the neural tube can result in midline structural deficits referred to
as “dysraphisms.” Resultant structural abnormalities range from asymptomatic (as in
spina bifida occulta) to paraplegia, bladder dysfunction, and maldevelopment of the
legs, as can be seen with myelomeningocele, in which there is protrusion of the spinal
cord tissue outside of the spinal canal. Hypertrophy of the filum terminale can produce a
“tethered cord syndrome” with pain and cord dysfunction, especially at lower levels.

SPINAL CORD DIAGNOSTIC TESTS

The overall clinical picture helps inform the choice of diagnostic tests. Magnetic
resonance imaging (MRI) is one of the most informative studies (Fig. 22-5); it can show
the relationship of the spinal cord to surrounding structures (including spinal elements
such as bones and disks) and other extrinsic or intrinsic abnormalities. Vascular lesions
such as strokes and hemorrhages are often demonstrated well, and can indicate a need
for spinal angiography. Cerebrospinal fluid (CSF) from a lumbar puncture can provide
evidence of infection, inflammation, or malignancy. If an epidural abscess is a concern,
blood cultures can be helpful. Additional blood work can be done to assess for other
forms of infection, connective tissue diseases, and toxic-metabolic processes.
Increasingly, genetic assays are used to make definitive diagnoses in the appropriate
clinical context.

KEY POINTS
● MRI is one of the most helpful tests in characterizing spinal cord lesions.
● CSF analysis can provide support for the presence of infection, inflammation, or malignancy.
● Additional blood work, including genetic assays, may provide more specific diagnostic information.

CLINICAL VIGNETTES

VIGNETTE 1
A 72-year-old man presents with lower back pain, numbness and weakness of the
legs, and urinary retention. He has a history of prostate cancer that was treated with
radical prostatectomy 4 years ago. His exam shows a normal mental status, normal
arm strength, and normal coordination in finger–nose–finger. Upper limb reflexes
are normal. He has a sensory level to pinprick at T6, with brisk reflexes at the
knees, ankle clonus, and upgoing toes (Babinski sign) bilaterally. Both legs are
weak, but tone is increased. Vibration and joint position sense are reduced.
1. The most likely localization of the lesion is:
a. Brainstem
b. Thoracic cord
c. Lumbar cord
d. Cauda equina
e. Conus medullaris
2. MRI of the entire spine shows an epidural spinal cord compression at the T6
level from a metastatic lesion in the epidural space. The best immediate step
will be:
a. Take the patient to the operating room for surgical decompression
 b. Admit the patient for observation with neuro checks every 4 hours
c. Place a catheter to deal with urinary incontinence or retention
d. Administer 100 mg IV of dexamethasone
e. Pain management
3. The patient underwent decompression and radiation for a single epidural
metastasis. His symptoms resolved, and his examination returned to normal.
Four weeks later, he presents with a sudden onset of paraplegia, numbness in
the legs, and urinary retention. The exam this time shows a sensory level to
pinprick and temperature at T8, absent knee and ankle jerks, flaccid tone, and
areflexia. Your attending physician performs one bedside test and states that
this is an anterior spinal artery syndrome. The test that most reliably supports
this diagnosis is:
a. MRI of the spine
b. Preserved proprioception when the patient’s toes are moved
c. Diminished tone on rectal exam
d. Absent abdominal reflexes
e. The scenario above is untrue. There is no way one can make a clinical
diagnosis of an ASA syndrome on examination alone.

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
Findings on exam suggest a lesion at the thoracic or cervical levels, as a sensory
level was found at T6. Conus medullaris lesions usually present with prominent
bowel or bladder problems (or both) and sexual dysfunction, with or without
associated leg weakness, but not a thoracic sensory level. A cauda equina syndrome
can produce weakness and numbness with diminished reflexes in the legs, but not a
sensory level at T6. Lumbar cord lesions will produce signs similar to those found
in this patient, except for a sensory level at T6. Remember that a sensory level at T6
indicates that the lesion is at or above that level.

VIGNETTE 1 QUESTION 2
2. Answer D:
In epidural metastatic cord compression, the first step in management is the use of
high-dose steroids (dexamethasone) to reduce edema and relieve some of the
pressure. This can be followed by surgical decompression and external radiation
therapy.
VIGNETTE 1 QUESTION 3
3. Answer B:
The ASA supplies blood to the anterior two-thirds of the spinal cord and therefore
the descending motor corticospinal tract and ascending sensory spinothalamic tracts.
It does not supply the posterior columns, where joint position sense
(proprioception) travels. The ASA syndrome is a “cord infarction” with an acute
onset, bilateral lower extremity weakness, loss of sphincter control, and sensory
loss below the level of the lesion to pinprick and temperature. On examination, only
proprioception is relatively preserved. The ASA syndrome is a bedside diagnosis.
An acute cord syndrome can present with flaccid paralysis and areflexia, and later
manifest more spasticity and hyperreflexia below the level of the lesion.
 23 Radiculopathy, Plexopathy, and
Peripheral Neuropathy

The peripheral nervous system (PNS) consists of spinal nerve roots, the brachial and
lumbosacral plexi, peripheral nerves, autonomic ganglia, the neuromuscular junction,
and muscles. This chapter focuses on the more proximal elements of the PNS, whereas
Chapter 24 discusses the neuromuscular junction and muscle disorders. The symptoms
and signs of PNS dysfunction often form recognizable patterns that can help localize
deficits to one of these parts of the nervous system. Electrodiagnostic studies can also
be particularly helpful in characterizing contributory lesions.

SPINAL NERVE ROOTS AND RADICULOPATHY

ANATOMY
The vertebral bodies form the bony building blocks of the spine. Intervertebral disks are
located between the vertebral bodies. They provide some degree of cushioning and
allow movement. Together with neighboring joints, the elements of the vertebral bodies
above and below each intervertebral disk form a bony canal called an intervertebral
foramen. Spinal nerve roots travel through the intervertebral foramina on their way to
the limbs. Each spinal nerve root is formed by a combination of a ventral and dorsal
nerve root leaving the spinal cord. Ventral nerve roots ultimately facilitate motor
function; the muscles served by a ventral nerve root make up a myotome. Dorsal nerve
roots transmit sensory information; the cutaneous region in the distribution of a dorsal
root is referred to as a dermatome. It is important to note that there is overlap in the
somatic territories from one myotome or dermatome to the next. As a result, strength and
sensation may be relatively preserved on neurologic examination even if there is
demonstrable injury to a given nerve root.

PATHOPHYSIOLOGY
Nerve root dysfunction is referred to as radiculopathy. Radiculopathy can result from
structural or nonstructural causes. Structural causes are most common, and there are two
main sources of nerve root compression: intervertebral disk herniation and degenerative
changes in the spine. Acute disk herniation is common in younger individuals and is
more likely to affect a single spinal nerve root. Degenerative changes include disk
desiccation, arthritic bony growth (spondylosis and osteophyte formation), and changes
in bony alignment (spondylolisthesis). Often these changes cause narrowing of the
intervertebral foramina, with secondary impingement of nerve roots at multiple levels.
Radiculopathies at the C7 and L5/S1 spinal levels are the most frequent ones in the
cervical and lumbosacral regions respectively. Thoracic radiculopathies are relatively
uncommon.
In the absence of a compressive cause, consideration must be given to infectious,
inflammatory, infiltrative, and vascular etiologies. For instance, cytomegalovirus,
herpes simplex, varicella zoster, and human immunodeficiency viruses and Lyme
disease can cause radiculopathy. Sarcoidosis can be associated with an inflammatory
radiculitis. Neoplastic processes can damage the nerve root through infiltration.
Infarction (e.g., from vasculitis or diabetes) is an unusual cause of radiculopathies.

SYMPTOMS AND SIGNS

Pain, sensory changes, or both, radiating in the distribution of a spinal nerve root point
to a radiculopathy. Accordingly, there can be some degree of sensory, strength, or reflex
abnormality that helps specify the nerve root of interest (Table 23-1). When patients
present with upper extremity symptoms, Spurling’s maneuver can be performed by
putting gentle pressure on the head as it is turned toward the side of pain while the neck
is extended; the test is considered positive if symptoms are reproduced. Of note, the
assessment should be avoided in patients who could have spine instability, as in the
setting of rheumatoid arthritis. The straight leg raise test can be helpful in corroborating
a lumbosacral radiculopathy. The test is considered positive when the patient’s
symptoms are reproduced when the leg is passively elevated, typically beyond 30 to 60
degrees, with the knee extended and the foot dorsiflexed.

TABLE 23-1. Root Syndromes Distribution of Abnormalities

Segment Sensory Abnormality Motor Deficit / Weakness Reflex Changes
Cervical
C5 Pain in lateral shoulder; sensory Deltoid, supraspinatus, and biceps Decreased or lost biceps
loss over deltoid reflex
C6 Radial side of the arm to thumb Biceps and brachioradialis Decreased or lost biceps
reflex
C7 Between the 2nd and 4th fingers Triceps, wrist extensors and Decreased or lost triceps
flexors, pectoralis major reflex
Lumbosacral
L3 Often none; sometimes medial Quadriceps; possibly adductors Decreased or lost patellar
thigh and knee reflex
 L4 Medial leg below the knee, to Quadriceps and anterior tibial Decreased or lost patellar
L5 medial
Dorsummalleolus
of the foot to great toe Extensor hallucis longus, extensor reflex
None
digitorum longus, inverters and
everters of the foot
S1 Lateral side of the foot Plantar flexion, toe flexion Decreased or lost Achilles
reflex

DIAGNOSIS
A diagnosis of radiculopathy can usually be made on clinical grounds. Immediate
imaging is warranted if infection or malignancy is a concern, if pain is accompanied by
saddle anesthesia and urinary retention, or if symptoms are acute in onset and associated
with progressive deficits. Magnetic resonance imaging (MRI) is best, when possible to
obtain. Nerve conduction studies (NCSs) and electromyography (EMG) are most
helpful in confirming the presence of a radiculopathy when performed at least 3 weeks
after symptom onset and when there is clinical weakness. A lumbar puncture (LP) may
be indicated when an infiltrative or infectious process is high on the differential. The
results of investigative studies guide treatment approaches.

KEY POINTS
● Muscles and cutaneous regions in the distribution of a spinal nerve root are myotomes and dermatomes,
respectively.
● Structural lesions, including disk herniation and degenerative changes, are the most common causes of
radiculopathy.
● Radiculopathy is often associated with pain or sensory symptoms in the distribution of a given nerve root.
Corresponding strength, sensory, and reflex abnormalities on exam can support clinical hypotheses.
● MRI, EMG, and LP are investigative studies that can help elucidate the cause of a radiculopathy.

PLEXUS AND PLEXOPATHIES

ANATOMY
Multiple spinal nerve roots form an intricate network called a plexus, in the upper and
lower limbs. In the arms, roots C5-T1 form the brachial plexus. The brachial plexus can
be organized into trunks, divisions, cords, and branches before forming the individual
nerves that serve the skin and muscles in the arms (Fig. 23-1). The brachial plexus lies
behind the scalene and pectoralis muscles and clavicle. All of the major nerves in the
legs arise from the lumbosacral plexus, a combination of the L1-S3 nerve roots. The
upper portion of this plexus, the lumbar plexus, is depicted in Figure 23-2. The
lumbosacral plexus lies behind the psoas muscles in the retroperitoneum before
continuing below the pelvic outlet.

FIGURE 23-1. The brachial plexus. (Reprinted with permission from Williams A. Massage Mastery. 1st ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2012. Figure 5.8.)

PATHOPHYSIOLOGY
Trauma, compression, inflammation, metabolic disturbance, malignancy, and radiation
can cause plexus lesions. Trauma is the most common etiology of brachial plexopathies
in adults. Specifically, motorcycle and other motor vehicle accidents can result in
damage from abrupt traction when the head is pulled away from the shoulder.
Inflammatory brachial plexopathies, also referred to as brachial neuritis or Parsonage-
Turner syndrome, are also often acute in onset. Triggers can include antecedent illness,
vaccination, surgical procedures, or exercise; some triggers are difficult to identify. An
apical lung (Pancoast) tumor can lead to a more insidious development of a brachial
plexopathy from local infiltration or direct compression. Similarly, radiation therapy
may be associated with a slowly developing brachial plexopathy, even a year following
the conclusion of treatment to the shoulder or chest region. In neonates, brachial
plexopathies may result from traction injuries at birth, particularly in the setting of
shoulder dystocia.
Type 2 diabetes, in the form of diabetic amyotrophy, is the most common cause of
lumbosacral plexopathy. As with brachial plexopathies, neoplasias can be associated
with lumbosacral plexopathies. Compression (e.g., from a neonate’s skull) in the
peripartum period or from a retroperitoneal hematoma, is also a cause of lumbosacral
plexopathies.

FIGURE 23-2. The lumbosacral plexus (left), and upper (lumbar) plexus alone (right). Reprinted with permission
from Anderson MK. Foundations of Athletic Training. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
Figure 12.4.

SYMPTOMS AND SIGNS

Plexus lesions cause patchy pain and sensory symptoms and signs. It can be helpful to
think about brachial plexus lesions in two main etiologic categories: (1) structural (e.g.,
a brachial plexopathy from a tumor, traction injury during trauma or surgery, or
laceration due to line placement) and (2) inflammatory (e.g., as in brachial neuritis or
Parsonage-Turner syndrome). In a classic Parsonage-Turner syndrome, patients awaken
from sleep in the early hours of the morning with pain in the periscapular and shoulder
girdle regions. Typically, pain is severe and can last up to 4 weeks before abating
spontaneously. The pain is ultimately associated with weakness (sometimes resulting in
scapular winging) and muscle atrophy. If brachial neuritis is on the differential, it is
important to assess for scapular winging but also to look for a Horner’s syndrome; the
latter can be caused by an apical lung tumor.
Typically, patients with lumbosacral plexopathies present with leg pain, sensory
change, atrophy, and asymmetric weakness. Weakness of knee extension, adduction hip
flexion, or combinations of these, points to a lumbar plexus problem. Foot drop is more
consistent with a lumbosacral plexopathy. In diabetic amyotrophy, there is associated
weight loss and autonomic dysfunction.

DIAGNOSIS
EMGs can be very helpful in characterizing plexus lesions. In certain situations, imaging
is important to evaluate for structural compression of the plexus. An analysis of
serology for infectious, autoinflammatory, and metabolic disturbances and, less
commonly, cerebrospinal fluid analysis, may help determine a cause and guide
management. Ultimately, plexopathies due to inflammation often recover spontaneously
over months, whereas compressive lesions may require intervention.

KEY POINTS
● Spinal nerve roots C5-T1 and L1-S3 combine to form complex networks called the “brachial plexus” and
“lumbosacral plexus,” respectively.
● Trauma is the most common cause of brachial plexus lesions, whereas type 2 diabetes is commonly
associated with a form of lumbosacral plexopathy.
● Plexus lesions present with pain and patchy sensorimotor deficits; the pattern of abnormalities can help
localize the parts of the plexus affected.
● EMG, imaging, and laboratory testing can help characterize plexopathies and guide treatment.

PERIPHERAL NERVES AND MONO- AND

POLYNEUROPATHIES
ANATOMY AND TERMINOLOGY
In the limbs, individual peripheral nerves are derived from the brachial and
lumbosacral plexuses. The term “polyneuropathy” refers to the involvement of many
nerves. In classic polyneuropathies, the most distal aspects of the nerves are initially
and preferentially affected. A mononeuropathy is a dysfunction of an individual nerve,
as can occur in the setting of focal compression, such as in the carpal tunnel syndrome.
Cranial nerves (except CN II) are also peripheral; their dysfunction can also be a
mononeuropathy (e.g., in the facial nerve, as can be seen in a Bell’S palsy). In the rare
case that separate individual nerves are affected simultaneously or sequentially, the
condition is characterized as a mononeuropathy multiplex.
Peripheral nerve deficits can be classified according to whether they affect motor,
sensory, autonomic, or combinations of fibers. Further, neuropathies may preferentially
affect large-diameter fibers responsible for proprioception, or small-diameter fibers
that relay pain and temperature information. The pattern of nerve involvement can give
hints to underlying pathophysiology (Box 23-1).

PATHOPHYSIOLOGY
A myriad of acquired and genetic processes can underlie peripheral nerve lesions.
Infectious, inflammatory, toxic, and metabolic conditions may play roles in acquired
conditions; diabetes is a particularly common cause of neuropathies (Table 23-2).
Genetic variations, such as those associated with Charcot–Marie–Tooth (CMT)
disease, can be seen in hereditary disorders. Injured nerves can react only in a limited
number of ways. Accordingly, key information gleaned from the history, exam, and
investigative studies help characterize the type of peripheral nerve lesion.

SYMPTOMS AND SIGNS

Patients may describe positive or negative sensory, motor, and autonomic symptoms.
For example, tingling and “pins and needles” sensations, together with reduced joint
position sense and reflexes suggest large fiber dysfunction. Burning, shooting, and
jabbing pain, combined with deficits in pain and temperature sensation, often indicate a
small fiber neuropathy. Weakness can accompany sensory changes, or, less often, be the
primary symptom. Autonomic symptoms include blood pressure (BP) dysregulation
(particularly orthostatic hypotension), abnormal sweating, urinary retention, and
impotence. The temporal course (e.g., acute, subacute, or insidious) and the pattern of
progression (e.g., gradually progressive, stepwise, or relapsing-remitting) can point to
specific etiologies. It is equally important to gather data about the patient’s medical
history (e.g., the presence of diabetes, thyroid dysfunction, malignancy, or autoimmune
disease), medication use (e.g., chemotherapy), habits (e.g., alcohol intake), and
occupational history (e.g., work that requires lots of typing) that may inform the search
for a cause.

BOX 23-1. Approach to the Classification of Peripheral Neuropathy

 Functional involvement
Motor
Sensory
Small fiber
Large fiber
Small and large fiber
Autonomic
Anatomic distribution
Asymmetric
Symmetric
Upper extremity
Lower extremity
Temporal course
Acute: GBS, porphyria, diphtheria, polio, toxins (thallium, lead, arsenic, adriamycin), paraneoplastic, uremia,
vasculitis
Subacute: deficiency states (vitamins B1 and B12), toxins, uremia, diabetes, sarcoidosis, paraneoplastic,
vasculitis, toxins, drugs
Chronic: CIDP, diabetes, uremia
Relapsing: CIDP
Pathologic mechanism
Axonal
Demyelination
Combined neuropathy

[CIDP, chronic inflammatory demyelinating polyneuropathy; GBS, Guillain–Barré syndrome.]

TABLE 23-2. Diabetic Neuropathies

Type Clinical Features
Chronic progressive distal symmetric diabetic Mixed sensory–autonomic–motor polyneuropathy;
polyneuropathy variants include small fiber (painful, usually spontaneous
burning pain), large fiber (ataxic), and autonomic
Diabetic proximal motor neuropathy (diabetic Severe thigh pain, followed within weeks by mild-to-
amyotrophy) severe hip and thigh muscle weakness with muscle
atrophy; usually affects older type 2 diabetic patients
Acute axonal diabetic polyneuropathy (intensely painful Diabetic neuropathic cachexia often associated with
acute or subacute progressive symmetric sensory axonal weight loss; “insulin neuritis” (with improved control of
peripheral neuropathy) hyperglycemia)
Diabetic mononeuropathy, radiculopathy, and Can present with cranial neuropathy (third, fourth, or
polyradiculopathy sixth nerves), multisegmental truncal radiculopathy, or
limb mononeuropathy
Focal compression neuropathies associated with diabetes Diabetic patients are more susceptible to compression
neuropathies, such as in the median nerve at the wrist,
the ulnar nerve at the elbow, and the peroneal nerve at
the knee
 On exam, distal symmetric sensory or sensorimotor deficits are the most typical
presentation of a polyneuropathy. If the presenting symptoms and signs follow an
atypical pattern, that can narrow the differential, as shown in Table 23-3. Hammertoes
and high-arched feet raise the possibility of a genetic condition such as CMT disease.
More common mononeuropathies, such as carpal tunnel syndrome, ulnar neuropathy at
the elbow, radial neuropathy at the spiral groove (“Saturday night palsy”), lateral
femoral cutaneous neuropathy (“meralgia paresthetica”), peroneal neuropathy at the
fibular neck, and facial neuropathy (e.g., a Bell’s palsy) have sensory, strength, and
reflex abnormalities that correspond to the affected nerves (Table 23-4). Autonomic
dysfunction can be detected at the bedside with orthostatic BP measurements and a pupil
exam.

TABLE 23-3. Atypical Neuropathy Features That Narrow the Differential Diagnosis
Atypical Feature Potential Diagnoses
Begins in proximal rather than distal limbs Sensory: porphyria, occasionally Charcot–Marie–Tooth
and Tangier disease
Motor: GBS, CIDP, diabetes
Sensory symptoms and signs predominate Autoimmune: Miller Fisher syndrome, IgM
paraproteinemia, paraneoplastic, Sjögren syndrome
Toxic: pyridoxine, doxorubicin
Infectious: diphtheria, HIV
Nutritional: vitamin E deficiency
Motor symptoms and signs predominate GBS, porphyria, and multifocal motor neuropathy
Cranial nerves are involved Diphtheria, sarcoidosis, diabetes, GBS, Sjögren syndrome,
polyarteritis nodosa, Lyme disease, porphyria, Refsum
disease, syphilis, arsenic
Individual nerve territories are affected in a Trauma, diabetes, vasculitis, leprosy, HIV, Lyme,
stepwise, non-length-dependent manner (as in sarcoidosis, tumor infiltration, lymphoid granulomatosis,
mononeuritis multiplex) HNPP
Peripheral nerves are palpable CMT and Dejerine–Sottas, amyloidosis, Refsum disease,
leprosy, acromegaly, neurofibromatosis
[CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CMT, Charcot–Marie–Tooth; GBS, Guillain–
Barré syndrome; HIV, human immunodeficiency virus; HNPP, hereditary neuropathy with liability to pressure
palsies; IgM, immunoglobulin M.]

TABLE 23-4. Common Mononeuropathies

Nerve Clinical Features Exam Findings Etiology
Upper extremity
Median nerve: Numbness or tingling involving Weakness and atrophy of Compression of the median nerve
at the wrist is one or more of the first four the thenar muscles, at the wrist within the space
called carpal digits. Symptoms may awaken the particularly APB. Reduced known as the carpal tunnel.
tunnel patient from sleep. sensation in the volar
syndrome aspect of the first three and
 a half digits. Tinel and
Phalen signs may be
present.
Ulnar nerve: at Paresthesias and pain in the fifth Weakness and atrophy in Compression of the ulnar nerve in
the elbow is digit and the medial half of the the FDI and ADM. the cubital tunnel at the elbow.
called cubital fourth. Difficulty spreading the
tunnel fingers.
syndrome
Radial nerve Wrist drop and sensory loss on Weakness includes triceps, Compression of the radial nerve
the dorsal aspect of the hand. brachioradialis, supinator, at the level of the axilla
and wrist and finger (“Saturday night palsy”); in the
extensors. The triceps is spiral groove, or in the forearm
affected by axillary (posterior interosseous
compression but spared by neuropathy).
spiral groove compression.
Weakness of wrist
extensors causes wristdrop.
Lower extremity
Meralgia Burning sensation and variable Area of sensory change Entrapment of the lateral femoral
paresthetica loss of sensation over the over the lateral aspect of cutaneous nerve near the inguinal
anterolateral thigh. the thigh. Tenderness upon ligament.
palpation of the inguinal
ligament. No motor
involvement.
Femoral Leg weakness on attempting to Weakness of the Usually trauma from surgery,
neuropathy stand or walk. Pain in the anterior quadriceps muscles, absent stretch injury (prolonged lithotomy
thigh is common. or diminished patellar position in childbirth), diabetes
reflex, and sensory loss mellitus, and other inflammatory
over the anterior thigh— processes.
and, with saphenous nerve
involvement, the medial leg
or foot of both. Adductors
are intact (differentiates
from an L2-3
radiculopathy).
Peroneal Foot drop, with minimal sensory Weakness of extensor Entrapment of the peroneal nerve
neuropathy complaints. hallucis longus, tibialis between the neck of the fibula
anterior, and the peroneal and the insertion of the peroneus
muscles (eversion of the longus muscle.
foot); sensory loss over the
dorsal part of the foot is
mild.
[ADM, abductor digiti minimi; APB, abductor pollicis brevis; FDI, first dorsal interosseus.]

DIAGNOSIS
In general, an outpatient diagnostic evaluation for polyneuropathy starts with lab testing
for the more common causes; a panel might include HbA1c, B12, TSH, SPEP, UPEP,
IFE, ANA, and ESR. Depending on the clinical context, additional studies designed to
assess for toxic–metabolic abnormalities (e.g., heavy metals), infection (Lyme, HIV,
hepatitis B or C), autoinflammatory processes (e.g., Ro, La, ACE, or RF levels),
paraneoplastic syndromes (e.g., anti-Hu, anti voltage-gated potassium channel (VGKC)
antibodies), and vitamin excess or deficiency (e.g., with vitamins B6 and B1,
respectively) may be performed. One of the most helpful tests for poly- and
mononeuropathies is an EMG, which can help characterize whether multiple or
individual nerves are involved and whether the primary pathophysiology is axonal or
demyelinating; this can help narrow the differential diagnosis and guide the next steps in
investigation and management. Importantly, standard NCSs can test only large-diameter
nerve fibers. Therefore, if a patient is thought to have a small fiber neuropathy, a skin
biopsy may be necessary. In the setting of small fiber neuropathy and significant
autonomic dysfunction, a fat pad biopsy or genetic testing may be warranted to look for
amyloidosis. In the setting of the mononeuritis multiplex, a combined nerve and muscle
biopsy to assess for the evidence of vasculitis may be considered. Genetic testing may
be worthwhile if features of the history, exam, and EMG suggest a hereditary process.
Autonomic testing can assist if dysautonomia is a prominent element of the presentation.

KEY POINTS
● Polyneuropathy refers to a generalized process that involves many nerves, whereas a mononeuropathy
describes injury to an individual nerve, as can be seen in an entrapment neuropathy such as carpal tunnel
syndrome.
● The temporal course, the pattern of progression, medical history, medication use, and habits can provide hints
to the type and cause of neuropathy affecting a patient.
● The neurologic examination can help determine which fibers are involved, and in what distribution, to help
narrow the differential.
● Electrodiagnostic studies can characterize further the polyneuropathy as axonal or demyelinating and detail
the severity.

CONDITIONS OF NOTE
On the inpatient service, acute inflammatory demyelinating polyradiculoneuropathy
(AIDP) or Guillain–Barré syndrome (GBS) is relatively common. Its worldwide
incidence is about 1 to 2 cases/100,000 people per year. Men are more commonly
affected than women. Often, there is an antecedent infection. Symptoms include
weakness and gait unsteadiness. The classic presentation is of ascending paralysis, but
there may be considerable variation in the pattern of weakness. Loss of power may be
accompanied by sensory changes and back or leg pain. Symptoms typically develop
quickly, often progressing over days to weeks. Signs often include relatively symmetric
weakness and decreased reflexes in at least two limbs. Patients may also have facial,
bulbar, and respiratory weakness in addition to autonomic symptoms. The Miller-Fisher
variant is characterized by gait ataxia, areflexia, and external ophthalmoplegia, usually
without limb weakness. An EMG can be particularly helpful in this setting, confirming
the characteristic signs of demyelination. An LP should be done to rule out an infection
or inflammatory process and to assess for an elevated protein with a normal white
blood cell count, a cytoalbuminologic dissociation. Importantly, it may take up to 3
weeks before this finding becomes apparent—and it does not ever occur in about 25%
of patients. Positive assays for campylobacter jejuni and the GQ1b antibody provide
support for the diagnosis. If the patient has a marked functional deficit and presents
within about four weeks, treatment with plasma exchange or intravenous
immunoglobulin (IVIG) is often beneficial.
GBS is a monophasic illness. In some cases, however, individuals have symptoms
that progress beyond the 4-week mark or recur after initial resolution. In this setting,
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) should be
considered as a more likely diagnosis. In contrast to GBS, there is often no readily
identifiable antecedent trigger for CIDP. Weakness affects both proximal and distal
muscles symmetrically. Sensory symptoms may be present, and the exam often shows
more pronounced deficits in vibration and position sensation than in pain and
temperature sensation. Reflexes tend to be diminished throughout the limbs. As in GBS,
EMG plays a key role in confirming the presence of demyelination. An LP can help
exclude inflammation or infection and provide support for the diagnosis in the form of a
cytoalbuminologic dissociation. MRI of the spine may demonstrate enlargement or
enhancement of nerve roots. Although corticosteroids are not helpful in the setting of
GBS, they may be helpful treatment for CIDP in the absence of contraindications (e.g.,
diabetes).
Thus, although there is overlap in the features of GBS and CIDP, there are some
distinguishing features, as outlined in Box 23-2. GBS and CIDP occur on a temporal
continuum; monitoring over time may be necessary to confirm the diagnosis. Although
the classic forms of these conditions are outlined here, it is worth noting that there are
many variants.

BOX 23-2. Characteristics of Acute and Chronic Inflammatory Demyelinating

Polyradiculoneuropathy

Feature AIDP (GBS) CIDP

Classic distribution of Symmetric, Symmetric,
weakness at onset: distal proximal and distal
 CSF findings: Elevated protein, normal white Elevated protein, normal white blood cell
blood cell count count
Classic NCS/EMG findings: Primary demyelination Primary demyelination
Duration of symptom Up to 3–4 wk Beyond 8 wk
progression:
Symptom recurrence/relapse? No Yes
Treatments: IVIG, PLEX Corticosteroids, steroid-sparing agents,
IVIG, PLEX

AIDP, acute inflammatory demyelinating polyradiculoneuropathy; GBS, Guillain–Barré syndrome; CIDP, chronic
inflammatory demyelinating polyradiculoneuropathy; CSF, cerebrospinal fluid; NCS/EMG, nerve conduction study /
electromyography; IVIG, intravenous immunoglobulin; PLEX, plasma exchange.

CMT refers to a group of hereditary polyneuropathies caused by mutations in genes

important for the myelin sheath or for the axons of peripheral nerves, or for both. The
most common presentation is that of a slowly progressive, distal, symmetric,
predominantly motor neuropathy. Patients often have high-arched feet (pes cavus) and
hammertoes. In addition to the atrophy of hand and foot muscles, there may be a loss of
muscle bulk distally in the legs, leading to a “stork leg deformity” or an “inverted
champagne bottle” appearance. Achilles tendon reflexes are almost always absent.
EMG can help characterize the pathophysiology as primarily demyelinating or axonal,
guiding the choice of genetic studies. Treatment is supportive.

KEY POINTS
● GBS is an acute form of polyneuropathy classically associated with ascending paralysis, areflexia, sensory
disturbance, and dysautonomia, responsive to plasma exchange and IVIG.
● CIDP is a chronic form of polyneuropathy classically associated with symmetric proximal and distal
weakness, areflexia, and large-fiber sensory disturbance, responsive to corticosteroids, steroid-sparing
agents, plasma exchange, and IVIG.
● CMT is a hereditary motor sensory neuropathy associated with high arches and hammertoes; genetic testing
can provide a diagnosis; treatment is supportive.

CLINICAL VIGNETTES

VIGNETTE 1
A 52-year-old man presents to your clinic with a few month history of intermittent
paresthesias (tingling and numbness) and mild pain on the bottom of his feet.
Examination shows a normal mental status, brisk reflexes at the knees, but absent
ankle jerks, upgoing toes and hypoesthesia to pinprick in the bottom of his feet.
Vibration sensation is reduced in the toes.
1. You order blood work to evaluate for possible causes of peripheral neuropathy
or polyneuropathy. Which abnormal finding is most likely?
a. Low TSH
b. High TSH
c. Low B12
d. High B6
e. High glucose
2. Your test results confirm your initial diagnostic impression. What is the best
treatment?
a. Thyroid hormone replacement
b. Vitamin B12 replacement
c. Oral hypoglycemic agents
d. Insulin
e. Fish oil
3. If the patient were to remain untreated, what other complication could most likely
occur?
a. Seizures
b. Dementia
c. Hyperglycemia
d. Infection
e. Skin disease

VIGNETTE 2
A 49-year-old, previously healthy woman presents to the emergency department
because of difficulty walking and bilateral foot pain. This was preceded 2 weeks
earlier by a gastrointestinal syndrome with 2 days of diarrhea. She states that she
developed some weakness in her feet 4 days ago, but today she is barely able to
walk. She has also noticed reduced handgrip strength and mild dyspnea. In addition,
she describes burning pain in her feet and lancinating lower back pain. She has no
bowel or bladder symptoms. Your exam shows BP 198/105, pulse 110, respiratory
rate 28/minute. O2 sat is 98% on room air. Her lungs are clear. She has a normal
mental status, cranial nerve examination, and finger–nose–finger testing. She has no
reflexes in any limb. Arm strength is good except for hand intrinsic muscles that are
4/5. Leg muscle strength includes 3/5 weakness of foot dorsiflexion and plantar
flexion and 4/5 hip flexion and knee extension. The sensory exam shows some
reduced vibration sense and some pinprick hyperalgesia in the soles of her feet. She
has difficulty walking and a bilateral steppage gait.
1. Which of the following tests would you do next?
a. MRI of the lumbosacral spine
b. Lumbar puncture
c. Anti-Hu antibodies
d. Lyme serology
e. Vitamin B12 levels
2. You get the results of a patient’s laboratory testing, showing a normal complete
blood count and differential, and a normal comprehensive metabolic panel. An
LP shows no white blood cells (WBCs), with a protein of 115 mg/dL (normal
15 to 40 mg/dL) and a glucose of 62 mg/dL. Your best next step is:
a. Start ceftriaxone 1 g IV q 12 hours
b. Begin a beta-2 agonist for possible obstructive airway disease
c. Obtain NCSs and EMG
d. Determine forced vital capacity (FVC) and negative inspiratory force (NIF)
e. Start hydrocodone for treatment of pain
3. You admit the patient to the intensive care unit (ICU) where her FVC remains 25
mL/kg and NIF −55 cm H2O. What treatment would you start next?
a. High-dose intravenous (IV) steroids
b. Oral prednisone at 1 mg /kg per day
c. IVIG
d. No need for treatment, just observation
e. Intubate

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer C:
This patient has features suggesting a peripheral neuropathy (paresthesias or tingling
and pain in the feet) plus a myelopathy (upgoing toes and brisk knee jerks), raising
the possibility of subacute combined degeneration, a complication of severe vitamin
B12 deficiency. Thyroid disease (hypo or hyperthyroidism), B6 intoxication, and
hyperglycemia can all cause peripheral neuropathies but are unlikely to produce
signs of a myelopathy, such as those described above. Other causes of subacute
combined degeneration include neurosyphilis, tropical myeloneuropathies, Lyme
disease, multiple sclerosis, and HIV-1-associated vacuolar myelopathy.
VIGNETTE 1 QUESTION 2
2. Answer B:
In this case, B12 replacement is the treatment of choice. All the other therapies are
appropriate for different illnesses. Fish oil has no known benefit in the management
of peripheral neuropathy.

VIGNETTE 1 QUESTION 3
3. Answer B:
Vitamin B12 deficiency can also produce psychiatric and cognitive symptoms
(including dementia), gait instability, and hematologic abnormalities, including
anemia with an increased mean corpuscular volume. It has not been associated with
an increased risk of infection or skin disease. Hyperglycemia is a complication of
diabetes. Seizures are not associated with B12 deficiency.

VIGNETTE 2 QUESTION 1
1. Answer B:
The presentation with a painful, symmetric, ascending (motor more than sensory)
polyneuropathy, with no reflexes, is consistent with an AIDP or a GBS. LP is
important to rule out infectious and inflammatory causes of a polyradiculopathy. It
may also show a “cytoalbuminologic dissociation” (high protein, with no or few
WBCs), characteristic of GBS—after the first week or so. MRI of the lumbosacral
spine is worthwhile if an acute lumbosacral polyradiculopathy (cauda equina
syndrome) is the initial diagnosis, but upper extremity involvement and respiratory
problems make this unlikely. Anti-Hu antibodies are associated with paraneoplastic
polyneuropathies (sensory ganglionopathy or sensorimotor polyneuropathy) that are
unlikely to present acutely as in this case. Lyme serology is always worthwhile, but
nothing in this case points to a history of a tick bite or other typical finding in that
disease. B12 deficiency would not explain this clinical picture.

VIGNETTE 2 QUESTION 2
2. Answer D:
This patient has signs of respiratory distress, with a respiratory rate of 28/minute
and symptoms of dyspnea. Weakness may be progressing to involve respiratory
muscles (particularly the diaphragm), and respiratory failure could occur at any
time, requiring intubation. When the FVC is less than 15 mL/kg and the NIF closer to
zero (normal is at least −60 cm H2O) or less (negative) than −25 cm H2O,
prophylactic intubation and ventilation should be considered. Also, a decrease of
more than 30% of FVC or NIF in 24 hours may indicate the need for intubation.
NCSs and EMG can help in the diagnostic evaluation of GBS but are not a task to be
done in the emergency department. Additionally, this patient is already presenting
signs of autonomic instability (with hypertension and tachycardia) that could change
to hypotension or bradycardia at any time. ICU admission is required.

VIGNETTE 2 QUESTION 3
3. Answer C:
The use of IVIG or plasmapheresis is the first line of therapy in patients with GBS
with progressive weakness. IV steroids and oral prednisone are not beneficial and
could be potentially harmful. Intubation is not indicated because the FVC and NIF
remain stable. Observation alone is not appropriate in patients with significant
weakness and respiratory or autonomic compromise.
 24 Disorders of the Neuromuscular
Junction and Skeletal Muscle

Disorders of the neuromuscular junction and muscle are pure motor phenomena. The
underlying pathophysiology can result in distinctive patterns of weakness that narrow
the list of potential causes. In addition to laboratory studies including genetic assays,
nerve conduction studies and electromyography can be particularly helpful in
diagnosing neuromuscular junction and muscle disorders (see Table 24-1).

DESCRIBING THE NEUROMUSCULAR JUNCTION

The neuromuscular junction (NMJ) is an electrical–chemical–electrical link between
nerve and muscle. More specifically, electrical action potentials in the nerve can be
communicated and then transmitted through muscle to cause a contraction via the
neurotransmitter acetylcholine in a well-choreographed cascade. An action potential
propagates down the entire length of a motor nerve axon to the axon button.
Depolarization then triggers voltage-gated calcium channels (VGCCs) to open and, in
turn, the influx of calcium causes a proportional release of acetylcholine from the
presynaptic terminal; when more calcium is present, more acetylcholine is released.
Acetylcholine then travels across the synaptic cleft and binds to receptors on the muscle
membrane, stimulating sodium channels to open (see Fig. 24-1). The resultant
depolarization creates end-plate potentials with amplitudes proportional to the amount
of bound acetylcholine. If the end-plate potentials are great enough, an action potential
is transmitted through the muscle fiber. Acetylcholinesterase metabolizes acetylcholine
in the synaptic cleft.
Neuromuscular dysfunction can arise from abnormalities in key points along this
multistep path. The resultant disorders can be classified pathophysiologically as
presynaptic, synaptic, or postsynaptic. NMJ diseases can be further characterized by
their etiologies. Some are congenital and affect the packaging, metabolism, and
receptors of acetylcholine. Toxic and metabolic causes include snake and black widow
spider venom, organophosphate poisoning, botulism, and hypermagnesemia. The most
commonly encountered disorders, however, are immune-mediated: Lambert–Eaton
myasthenic syndrome (LEMS) is a presynaptic disorder, while myasthenia gravis (MG)
is a postsynaptic disorder of the NMJ.

KEY POINTS
● Acetylcholine plays a key role in transmitting an electrical signal from the presynaptic motor axon terminal to
the postsynaptic muscle membrane, where binding can prompt an action potential and, ultimately, muscle
contraction.
● The amount of acetylcholine released is proportional to the amount of calcium present in the presynaptic axon
terminal; the size of the postsynaptic electrical response is proportional to the amount of acetylcholine that
binds effectively to receptors on the muscle membrane.
● NMJ disorders are pathophysiologically classified as presynaptic, synaptic, and postsynaptic.
● LEMS is a presynaptic disorder. MG is a postsynaptic disorder. Both have immune-mediated underpinnings.

DISORDERS OF THE NEUROMUSCULAR

JUNCTION
MYASTHENIA GRAVIS
Several identified antibodies play a role in the pathogenesis of MG. In the most common
form of antibody-positive MG, there is an IgG-directed attack on postsynaptic nicotinic
acetylcholine receptors (Fig. 24-1). The antibody binding effectively limits the number
of functioning receptors to which acetylcholine can bind. Therefore, even though the
amount of acetylcholine released from the nerve axon button into the cleft is sufficient, it
is not ultimately sensed in adequate quantities by the motor endplate. Patients with MG
may also have elevated MuSK or LRP4 titers, although some patients do not have any
detectable antibodies. Nevertheless, “seronegative” MG presents in a manner
indistinguishable from seropositive MG.

TABLE 24-1. Disorders of the Neuromuscular Junction and Skeletal Muscle

Disease
Myasthenia gravis
Lambert–Eaton myasthenic
syndrome
Hyperkalemic periodic paralysis
Hypokalemic periodic paralysis
Common Clinical Phenotype Commonly Associated
Abnormalities
Fatigable proximal muscle weakness; Antibodies against the muscle
prominent ocular and bulbar nicotinic acetylcholine receptor or
involvement muscle specific kinase
Fatigable proximal muscle weakness; Antibodies against the P/Q-type
ocular and bulbar involvement rare; voltage-gated calcium channel
prominent autonomic symptoms
Episodes of generalized weakness Voltage-gated sodium channel
lasting minutes to hours mutations
Episodes of generalized weakness Voltage-gated calcium channel

Duchenne and Becker muscular
dystrophy
Emery–Dreifuss muscular dystrophy Early onset of joint contractures;
Myotonic dystrophy
Facioscapulohumeral muscular
dystrophy
Limb-girdle muscular dystrophy
lasting hours to days
Childhood onset of proximal muscle
weakness, including neck flexors; no
ocular or bulbar involvement
humeroperoneal pattern of muscle
weakness
Distal muscle weakness and stiffness,
myotonia, systemic features (ptosis,
balding, etc.)
Weakness predominantly affecting
the face, shoulder girdle, and upper
arms
Proximal muscle weakness; no ocular
or bulbar involvement
mutations
Dystrophin gene mutation
Emerin and lamin A/C gene mutations
Intronic tri/tetra-nucleotide repeat
expansion in DMPK (DMI) and
ZNF9 (DMII) genes
DUX4 gene mutation
Genetic mutations in sarcoglycan and
several other structural proteins,
including calpain, caveolin, and
dysferlin

The characteristic symptom is “fatigable weakness,” a loss of power that becomes

more pronounced with the use of the affected muscles, and at the end of the day.
Although some patients have symptoms limited to the ocular region, most develop some
combination of weakness involving ocular, bulbar, respiratory, and limb muscles. On
exam, patients may have asymmetric ptosis or extraocular abnormalities, nasal voice,
limited palate elevation, impaired gag reflex, slurring of speech, head drop, proximal
weakness, or combinations of these.
Several specialized bedside examination maneuvers can be done to assess for
fatigable weakness. To test sustained up-gaze, the examiner asks the patient to look
upward at a fixed target for about 60 seconds. Findings supportive of MG include the
subjective experience of double vision or the objective development of ptosis, eye
misalignment over time, or both. If there is detectable ptosis at baseline, ice can be
applied to the affected eye for at least 2 minutes, as tolerated; a transient decrease in the
degree of ptosis suggests MG. Checking neck muscle strength is also important, because
weakness there may be accompanied by diaphragmatic weakness; nerve roots C3, 4,
and 5 serve both neck and diaphragmatic muscles—the latter through the phrenic nerves.
Asking the patient to count as high as possible during a single exhalation can also
provide a rough idea of respiratory function; an inability to count to 40 should raise
concern, as should shortness of breath that increases in the supine position (when the
mechanical advantage of gravity is lost). Limb strength can be checked before and after
a brief exercise task. For instance, after checking deltoid strength, have the patient
perform 20 “arm pumps” in which the arm is repeatedly abducted to shoulder level and
then adducted to the torso. A subsequent reduction in deltoid strength indicates fatigable
weakness.
FIGURE 24-1. The neuromuscular junction: key components of the NMJ are depicted, including the motor axon
and muscle endplate, the synaptic cleft, and the muscle fiber. When an action potential reaches the terminal, ACh is
released into the synapse and binds to the nicotinic ACh receptors on the sarcolemma, triggering a muscle fiber action
potential and contraction. The antigenic targets in MG and LEMS are indicated, as is the site of action of botulinum
toxin. [NMJ, neuromuscular junction; ACh, acetylcholine; MG, myasthenia gravis; LEMS, Lambert–Eaton myasthenic
syndrome]. Reprinted with permission from Louis ED, Mayer SA, Rowland LP. Merritt’s Neurology. 13th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Figure 89.1.

The diagnosis of MG is made largely on the clinical evaluation. It can be confirmed

by the identification of elevated acetylcholine receptor, MuSK, or LRP4 antibody titers.
Elevated anti-striated muscle antibody titers may also be present and have been linked
with a higher incidence of thymoma. All patients with a new diagnosis of MG should
have chest imaging to assess for thymic tumors.
In the absence of characteristic antibodies, electrodiagnostic tests can be very
helpful. Specifically, a “decremental” (decreasing) response on slow repetitive nerve
stimulation may occur. The most sensitive electrodiagnostic test, however, is single-
fiber electromyography (SF-EMG) when performed on a weak muscle; this test is
abnormal in 95% to 99% of patients with generalized MG. Of note, increased “jitter” on
SF-EMG isnot specific and can be seen in other neuromuscular conditions, including
LEMS.
Treatment with antiacetylcholinesterase agents, such as pyridostigmine (Mestinon),
can provide relief of symptoms, but it is important to remember that pyridostigmine
does not address the underlying cause of MG. Rather, immunomodulatory therapies such
as prednisone and steroid-sparing agents may be necessary. In the setting of myasthenic
crisis, with pronounced respiratory distress potentially requiring intubation, intravenous
immunoglobulin (IVIG) and plasmapheresis are indicated because they act much more
quickly.

KEY POINTS
● MG is a postsynaptic NMJ disorder mediated by abnormal antibodies; acetylcholine receptor antibodies are
the most common.
● The signs of fatigable weakness may be identified on the exam using specialized techniques; transient
improvement in ptosis with the application of ice can support a diagnosis of MG.
● When performed on a weak muscle, SF-EMG is the most sensitive test for MG.
● There is an important association between MG and thymoma.
● Treatment includes pyridostigmine and immunomodulatory therapies.

LAMBERT–EATON MYASTHENIC SYNDROME

In LEMS, IgG antibodies are directed against the P/Q type of VGCC, impeding the
calcium-dependent release of acetylcholine from the presynaptic membrane. The
downstream effect can be neuromuscular transmission failure.
Patients may develop proximal leg weakness associated with aching muscles and
cramps—particularly following exertion. For this reason, the syndrome is sometimes
misinterpreted as neurogenic claudication. Unlike neurogenic claudication, however,
LEMS is typically associated with autonomic symptoms including dry mouth, blurred
vision, and constipation. Examination may show proximal weakness. Reflexes may be
depressed or absent at rest, but rechecking an abnormal reflex after a patient contracts a
related muscle for 10 seconds (e.g., straightening the leg by activating the quadriceps
muscle before rechecking the patellar reflex) can yield a stronger reflex. In LEMS,
strength may also improve mildly after 10 seconds of maximal voluntary contraction.
This phenomenon is referred to as “facilitation.”
LEMS occurs more frequently in patients greater than 40 years of age. It is more
common in men than in women. Smokers are at particular risk; small cell lung cancers
are discovered in about 60% of patients.
Electrodiagnostic studies, including repetitive nerve stimulation, can aid in diagnosis.
Specifically, the combination of a “decrement” upon slow repetitive nerve stimulation
and an “increment” on rapid repetitive nerve stimulation supports the diagnosis. Blood
work can also be done to evaluate for the presence of an elevated VGCC antibody titer.
Given the link with malignancy, cancer screening should be undertaken. Treatments are
aimed at addressing both any detected cancer and the NMJ disorder. Although 3,4
diaminopyridine is the most effective therapy, it is not widely available, so
pyridostigmine, IVIG, and other oral immunosuppressants may be tried.

KEY POINTS
● LEMS is a presynaptic NMJ disorder mediated by P/Q-type VGCC antibodies.
● The signs of “facilitation” may be identified on the strength exam, reflex assessment, and rapid repetitive
nerve stimulation during electrodiagnostic tests.
● There is an important association between LEMS and small cell lung cancer.

DISORDERS OF MUSCLE
Patients may report “weakness,” a term used to describe a variety of symptoms ranging
from fatigue to limited mobility (e.g., due to stiffness). It is, therefore, important to
elucidate if the symptom actually reflects a loss of power. Asking what specific
activities pose a challenge (e.g., standing from low chairs, moving in or out of cars,
maintaining the arms above shoulder level) can be helpful. The exam may help
characterize the distribution of affected muscle groups further. Although there are
exceptions, many primary muscle disorders are symmetric and proximal. Additional
information may be gained through laboratory studies, including a creatine kinase (CK)
level, and electrodiagnostic studies. In certain instances, muscle ultrasound and MRI
may show pattern-specific abnormalities or help guide the choice of a biopsy site,
although biopsies are becoming increasingly rare with advances in genetic testing.
Muscle disorders may be acquired or inherited. Further, they can represent a primary
disease or occur in the setting of systemic illness. Trauma or strenuous exercise can
cause CK elevations in the absence of an underlying disease. Conversely, muscle
disorders can be discovered incidentally (e.g., through CK or liver function test (LFT)
abnormalities) during routine screening. As always, the clinical context is important in
interpreting laboratory findings.

ACQUIRED MUSCLE DISORDERS

Infectious
Infectious myopathies are some of the easiest to diagnose because there is usually an
identifiable antecedent illness. Associated muscle symptoms and signs occur along a
spectrum from myalgias to demonstrable rhabdomyolysis. In the United States,
enteroviruses and influenza A and B are most frequently linked to self-limited viral
myositis. HIV is associated with a more chronic myopathy.
Toxic
Excessive alcohol use can be associated with both acute and chronic myopathies. The
former usually occurs after a binge and results in diffuse muscle tenderness, cramps,
swelling, and weakness that may be most pronounced in the calves. Malnourished
women who suffer from alcohol dependence are most susceptible to the chronic form of
myopathy which is gradual in onset and proximal in distribution. Abstinence can help.
Just as taking an alcohol use history is important, so is reviewing medication lists.
Lipid-lowering and antiretroviral drugs and glucocorticoids can cause myopathies. At
doses above 40 to 60 mg per day, prednisone can lead to detectable weakness within 2
weeks. Proximal limb weakness is most common. Muscle enzyme assays and
electromyographies (EMGs) are usually normal. Although not typically performed in
this setting, a biopsy would be likely to show atrophy of type II fibers. Strength can
improve when the glucocorticoid dose is lowered (e.g., to less than 10 mg/day of
prednisone).
Skeletal muscle is also affected in the drug-related neuroleptic malignant syndrome
(NMS), although mental status changes (for example, agitation and inattention) are often
the initial symptoms. NMS is a consideration when mental status change is accompanied
by a temperature above 38°C, generalized muscular rigidity (with CK elevations >1,000
µ/L), and autonomic instability. Dysautonomia variably manifests as profuse
diaphoresis, tachypnea, hypertension, tachycardia, and cardiac arrhythmias. The
dysautonomia accounts for most fatalities from NMS. NMS can develop because of
withdrawal from dopamine agonists used to treat Parkinson disease but is more
commonly caused by the use of neuroleptic agents; NMS can occur after many years of
neuroleptic treatment or just after a single dose. Discontinuing the culprit medication is
one of the most important steps to take. Sometimes drugs such as dantrolene and
bromocriptine are given. In any case, supportive measures are important during
recovery, which often takes about 2 weeks. Most patients have no chronic deficits
following an episode of NMS. NMS can be distinguished fromserotonin syndrome by
a few key features: shivering, hyperreflexia, ataxia, and myoclonus are more common in
serotonin syndrome than with NMS.

Endocrine
Untreated hypo- and hyperthyroidism can be associated with weakness, muscle aches,
and cramps. An EMG can be normal or show myopathic features in both conditions, but
there are several features that can help distinguish between them. In hypothyroidism,
deep tendon reflexes (DTRs) may have a delayed relaxation phase and CK levels are
often elevated. In hyperthyroidism, DTRs may be increased and CK levels are often
normal. Thyroid function tests can help make the diagnosis; treatment of the thyroid
dysfunction can lead to improvement in muscle symptoms within weeks to months.
Inflammatory
Inflammatory myopathies include disorders such as polymyositis, dermatomyositis, and
inclusion body myositis. Polymyositis and dermatomyositis generally present with
symmetric, proximal limb and neck flexor weakness and sometimes, dysphagia,
myalgias, arthralgias, and interstitial lung disease. Dermatomyositis is associated with a
distinctive purplish (or heliotrope) eyelid color and skin changes in the upper torso and
hip regions. Importantly, there is an increased risk of malignancy with dermatomyositis.
Slowly progressive leg weakness and frequent falls may herald inclusion body
myositis, which can preferentially affect proximal legs and forearm flexors. The signs
of an inflammatory myopathy on EMG, elevated CK, aldolase, aminotransferases,
lactate dehydrogenase, and myositis-specific autoantibody titers (e.g., anti-Jo-1) help
support a diagnosis of inflammatory myopathy. Glucocorticoids are generally the initial
therapy. With a goal of lowering the cumulative dose of prednisone, a steroid-sparing
agent such as azathioprine or methotrexate may also be started. IVIG is indicated in
certain situations, including when the degree of dysphagia poses an aspiration risk or
when weakness is life-threatening.

KEY POINTS
● Enterovirus and influenza can cause a self-limited viral myositis.
● Alcohol and medications including glucocorticoids can cause myopathies.
● NMS is associated with mental status changes, fever, muscle rigidity, and dysautonomia.
● Thyroid dysfunction can lead to weakness and reflex abnormalities.
● Inflammatory myopathies include polymyositis, dermatomyositis, and inclusion body myositis, which can be
distinguished by the pattern of weakness and by the presence of systemic symptoms and signs, such as a
rash.

CONGENITAL MUSCLE DISORDERS

Congenital muscle disorders can be categorized as “nondystrophic” or “dystrophic.” In
the latter, muscle biopsies show “dystrophic” changes such as increased connective
tissue and fiber splitting. Inherited disorders are phenotypically diverse, and the number
of contributory genetic variants is ever-expanding.

NONDYSTROPHIC

Metabolic Myopathies
Metabolic myopathies present as proximal myopathies, one element of a more diffuse
neurologic syndrome with central nervous system dysfunction, or as intermittent
myoglobinuria and cramps. The hallmark of metabolic myopathies is exertion-related
symptoms, including the development of muscle pain and cramps during exercise. These
processes reflect dysfunction in lipid or glycogen metabolism.
An important group of metabolic myopathies is the mitochondrial myopathies, which
are related to abnormalities in the oxidative phosphorylation pathway. They have
several forms. One form is a myopathy associated with short stature and other
multisystem abnormalities. An example of this form is mitochondrial
encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), which is
discussed more fully in Chapter 18. Another mitochondrial myopathy is chronic
progressive external ophthalmoplegia, a syndrome of bilateral ptosis and weakness of
extraocular muscles that worsens over time. A third type is limited to the skeletal
muscle; it presents with muscle aches, fatigue with exercise, elevated CK, and
sometimes, rhabdomyolysis. In each of these cases, symptom exacerbations can occur
because of physiologic stressors such as cold exposure, fasting, and heavy exercise.

Channelopathies
Physiologic stressors can also precipitate symptoms in inherited muscle disorders
because of ion channel dysfunction. These “channelopathies” include hyper- and
hypokalemic periodic paralysis (PP). In both of these rare conditions, patients have
bouts of painless weakness, most pronounced in proximal limbs. Bulbar and respiratory
muscles are generally not affected, and consciousness is preserved. During symptoms, a
chemistry panel may demonstrate a high or a low potassium level. Abortive treatments
include calcium or beta-adrenergic agonists (for hyperkalemic PP) or potassium
chloride without dextrose (for hypokalemic PP). Prophylactic therapies include
acetazolamide, but attacks may also be avoided by limiting exercise and carbohydrate
intake. During asymptomatic periods, when strength is normal, nerve conduction studies
and EMG may demonstrate characteristic changes in motor response amplitudes and
motor unit action potentials. Further, the presence of electrical myotonia on an EMG
points to hyperkalemic, rather than hypokalemic, PP. Genetic testing can be most helpful
in identifying an underlying cause. Although hyperkalemic PP is related to sodium
channel dysfunction, hypokalemic PP results from a calcium channel defect. Whenever
PP is a diagnostic consideration, obtaining an ECG is important because the
channelopathies and associated electrolyte abnormalities can predispose to arrhythmias,
including with a prolonged QTc. Caution with general anesthesia, and avoidance of
depolarizing agents, is recommended to avoid paralysis and complications with
extubation.
 KEY POINTS
● The hallmark of metabolic myopathies is exertion-related symptoms, including the development of muscle pain
and cramps during exercise.
● In hyper- and hypokalemic P P, patients experience episodes of painless weakness most pronounced in
proximal limbs.
● Physiologic stressors can cause symptom exacerbations in these inherited muscle disorders.

DYSTROPHIC

Duchenne and Becker Muscular Dystrophies

Muscular dystrophies, congenital causes of weakness, are a heterogeneous group of
disorders with variable ages of onset and phenotypic expression. Duchenne and Becker
muscular dystrophies are X-linked disorders that lead to progressive weakness in young
boys. Duchenne muscular dystrophy (DMD) is more severe; weakness develops by 2 to
3 years of age. Affected individuals may have trouble navigating stairs, running, and
jumping. Use of the arms to rise from the floor to a standing position (Gower’s sign), a
waddling gait, decreased reflexes, lumbar lordosis, and calf enlargement are
characteristic findings. Cardiac involvement (e.g., conduction abnormalities and a
dilated cardiomyopathy) is common. Becker muscular dystrophy (BMD) has similar
manifestations, but onset is later and life expectancy is longer. Individuals with DMD
tend to die of respiratory insufficiency or cardiac complications in their teens or 20s,
but those with BMD can live beyond 30 years of age. Genetic testing is key in
establishing a diagnosis. If genetic testing is negative, a muscle biopsy can be
diagnostic. Glucocorticoids are generally prescribed after the age of 4 when motor
skills stop progressing or start to decline.

Emery–Dreifus Muscular Dystrophy

Emery–Dreifus muscular dystrophy (EDMD) is genetically heterogeneous and can be
autosomal recessive, autosomal dominant, or X-linked recessive. In general, children
present with weakness in a humeroperoneal distribution (with preferential involvement
of biceps, triceps, and tibialis anterior). Contractures of the Achilles tendons and elbow
flexors are characteristic. Dilated cardiomyopathy and cardiac conduction
abnormalities are common. For this reason, cardiac status should be evaluated when
EDMD is on the differential. Genetic testing can provide a definitive diagnosis.
Treatment is supportive.

Myotonic Dystrophy
Myotonic dystrophy is an autosomal dominant, multisystem disorder associated with
myotonia, or delayed muscle relaxation after activation. Individuals with myotonic
dystrophy types I (DMI) and II (DMII) tend to have a narrow, elongated face, frontal
balding, temporal wasting, ptosis, and a horizontal smile (due to facial weakness). In
both forms of the disorder, sleep and endocrine disturbances, cataracts, and cardiac
conduction abnormalities typically develop. Although similar in many ways, the two
forms of the disorder can be distinguished by the time of symptom onset, the distribution
of weakness, and the presence of pain. Patients with DMI usually present in their late
teens with distal weakness and wasting, whereas DMII usually presents in adults in
their 40s or older with proximal weakness. Pain in the arms, thighs, and back is more
frequent in DMII.

Facioscapulohumeral Muscular Dystrophy

Chronic pain can also be a component of facioscapulohumeral muscular dystrophy
(FSHD). A typical early finding of FSHD is scapular winging. As suggested by its
name, however, patients with this disorder may also have facial and upper arm
weakness; legs and abdominal muscles are variably affected. FSHD is linked with a
mutation in the double homeobox protein 4 (DUX4) gene.

Limb-girdle Muscular Dystrophy

There is no single gene responsible for the limb-girdle muscular dystrophies, which
encompass a growing group of disorders characterized by progressive loss of power
and muscle bulk primarily in the shoulder and pelvic girdle regions. The severity of
symptoms and signs, the age of onset, and the phenotype for these disorders is variable
—even in the setting of a common genetic mutation. CK levels are often at least mildly
elevated. EMG generally shows myopathic changes. Genetic testing is required for
definitive diagnosis. Therapy is supportive, with help from members of a
multidisciplinary team, for example from genetics, orthopedics, cardiac, pulmonary,
nutrition, occupational therapy, and physical therapy.

KEY POINTS
● Duchenne and Becker muscular dystrophies are X-linked disorders that lead to progressive weakness in
young boys.
● EDMD is characterized by humeroperoneal weakness, contractures, and cardiac conduction abnormalities.
● Individuals with DMI and DMII tend to have narrow, elongated faces, frontal balding, temporal wasting,
ptosis, and a horizontal smile, in addition to myotonia.
● FSHD can present with scapular winging and facial weakness.
● Limb-girdle muscular dystrophies are multiple disorders associated with progressive loss of power and muscle
bulk in the shoulder and pelvic girdle regions.
CLINICAL VIGNETTES

VIGNETTE 1
A 63-year-old man with hypertension (on a thiazide diuretic) and high cholesterol
(on an HMG CoA reductase inhibitor) is seen in the Neurology clinic with
symptoms of generalized weakness and difficulty getting up from a low-seated
position. There is no clear diurnal fluctuation in the severity of symptoms. He
reports no ocular or bulbar symptoms and no muscle pain. He has, however, noticed
that he feels a little light-headed if he stands up quickly from the lying or seated
position. He reports a 10-pound weight loss. Examination shows very mild
weakness of hip flexion and hip abduction. He seems weaker initially and then gets
stronger. DTRs are absent.
1. Which of the following diagnoses do you suspect is the most likely?
a. Myasthenia gravis
b. LEMS
c. Polymyositis
d. Statin-induced myositis
e. Hypokalemic PP due to potassium wasting from hydrochlorothiazide (HCTZ)
2. Clinically you suspect LEMS, but your differential diagnosis includes MG.
Which of the following test results would be most helpful in differentiating the
two?
a. Normal acetylcholine receptor antibody titers
b. A decremental response on slow repetitive nerve stimulation (RNS)
c. Elevated jitter on SF-EMG
d. An incremental response on fast RNS
e. A negative ice pack test
3. You confirm the diagnosis of LEMS on the basis of an incremental response
following fast RNS and the presence of anti-P/Q VGCC antibodies. Which of
the following is not relevant to the management of patients with LEMS?
a. Pyridostigmine
b. 3,4-diaminopyridine
c. Prednisone
d. Chest computed tomography (CT) to exclude underling small cell lung cancer
e. Thymectomy

VIGNETTE 2
A 37-year-old African American woman is seen in the Neurology clinic with a 2-
month history of diplopia, ptosis, dysarthria, and shortness of breath. Her symptoms
fluctuate somewhat: worse in the evening than in the morning. Examination shows
fatigable ptosis bilaterally, diffuse ophthalmoplegia, mild bifacial weakness, and
moderate weakness of neck flexion. Her primary care physician thought she likely
had MG despite negative acetylcholine receptor antibody titers but found that her
symptoms responded only minimally to treatment with pyridostigmine.
1. The most likely diagnosis is:
a. botulism
b. LEMS
c. MG
d. polymyositis
e. Guillain–Barré syndrome
2. On further review of medical records, you discover that she has elevated anti-
MuSK antibody titers, supporting a diagnosis of MG. The most appropriate next
step is:
a. obtain a CT scan of the chest
b. check antistriated muscle antibody titers
c. refer for electrophysiologic studies (repetitive nerve stimulation and SF-
EMG)
d. check respiratory muscle function with a forced vital capacity (FVC)
e. perform an ice pack test

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
The history of mild proximal weakness and autonomic symptoms (orthostatic
hypotension) along with the finding of absent DTRs and weakness that facilitates
(i.e., improves over a period of seconds while testing muscle strength), all point
strongly to a diagnosis of LEMS. MG may also produce proximal weakness, but
reflexes are typically preserved and autonomic symptoms are absent. Polymyositis
and statin-induced myositis may both cause proximal weakness, but there is often
some degree of muscle pain (myalgia), and the reflexes should not be absent in the
face of relatively mild weakness. Neither of these disorders is associated with
orthostatic hypotension, and neither should produce weakness that facilitates.
Although HCTZ does cause potassium wasting, the history of static weakness is not
characteristic of hypokalemic PP, which typically causes episodes of severe
weakness with complete recovery between attacks. Also, it would be highly unusual
for an inherited ion channelopathy such as PP to manifest at this late age.

VIGNETTE 1 QUESTION 2
2. Answer D:
LEMS is characterized both by a decremental response following slow RNS and an
incremental response following fast RNS or tetanic muscle contraction. A
decremental response following slow RNS is also seen in myasthenia and so would
not help differentiate the two diagnoses. Increased jitter on SF-EMG may be seen in
both disorders. Although elevated acetylcholine receptor antibodies help confirm
the diagnosis of myasthenia, negative antibody titers do not preclude the diagnosis,
as about 20% of people with generalized myasthenia do not have elevated
acetylcholine receptor antibodies. A negative ice pack test similarly does not
exclude the diagnosis of MG (particularly if there is no ptosis) and so is not helpful
in differentiating myasthenia from LEMS.

VIGNETTE 1 QUESTION 3
3. Answer E:
3,4-diaminopyridine and pyridostigmine are frequently used together for
symptomatic management of muscle weakness in LEMS. Prednisone may also be
helpful. Because about 60% of patients with LEMS have an underlying cancer (most
often a small cell lung cancer), a chest CT should always be performed.
Thymectomy has no role in the management of LEMS except in the rare
circumstance when a thymoma represents the underlying malignancy (rather than a
small cell lung carcinoma).

VIGNETTE 2 QUESTION 1
1. Answer C:
The most likely diagnosis is still MG, but probably with elevated anti-MuSK
(muscle specific kinase) antibodies, rather than acetylcholine receptor antibodies.
MuSK-positive myasthenics are typically young (<40 years old) women, often
African American, who typically present with early respiratory dysfunction and
often do not respond well to treatment with cholinesterase inhibitors such as
pyridostigmine. The clinical presentation could be consistent with botulism, but the
diurnal fluctuation in symptom severity suggests MG, and there is no history of
environmental exposure to food containing botulism and no history of a wound that
might have been contaminated by the Clostridium bacterium. Polymyositis should
not cause ophthalmoplegia and typically is more subacute in onset. The constellation
of symptoms is compatible with Guillain–Barré syndrome, but the temporal course
of her illness (2 months) and the diurnal fluctuation argue against this diagnosis.

VIGNETTE 2 QUESTION 2
2. Answer D:
It is essential to quantify the severity of her respiratory muscle weakness, and a
bedside test such as the FVC or negative inspiratory force is appropriate. The ice
pack test and electrodiagnostic studies are unnecessary because the diagnosis of MG
has already been confirmed. CT scan of the chest is not necessary, because thymoma
and thymic hyperplasia are associated with acetylcholine receptor antibody-positive
myasthenia and not anti-MuSK myasthenia. Antistriated muscle antibodies are
similarly unnecessary, because they have no diagnostic value in this context.
 25 Pediatric Neurology

Neurologic disorders in children are encountered commonly by pediatricians and family

physicians. Although many neurologic illnesses that affect infants and children also
affect adults (such as infection, epilepsy, inflammatory and demyelinating diseases,
peripheral neuropathies, and myopathies), some, including developmental disorders,
malformations, and many genetically determined conditions, are especially
characteristic of the pediatric population.
The history is the most important component of the evaluation of a child with a
neurologic problem. It shares the same principles as described for the adult history but
also requires a complete review of the pregnancy, labor, and delivery (especially in
cases of perinatal injury), congenital infection, and family history.

DEVELOPMENT AND MATURATION

One of the most important elements of the neurologic history is a developmental
assessment of the child. The Denver Developmental Screening Test is an efficient and
reliable method to assess achievement of developmental milestones. It evaluates four
components of development: gross motor skills, fine motor adaptive skills, language,
and personal–social interaction. Table 25-1 summarizes developmental milestones by
age. This is based on averages and therefore can be used only with an understanding of
the variability among children. Table 25-2 gives a brief description of primitive
reflexes and their significance.

CEREBRAL PALSY
Cerebral palsy (CP) is a static (nonprogressive) disorder due to pre- or perinatal
damage to cerebromotor pathways. It is the most common motor disability in childhood,
affecting about 2.7 per 1,000 live births. Risk factors for CP include hypoxic–ischemic
insult to the brain in the perinatal period, prematurity, low birth weight,
chorioamnionitis, prenatal viral infections, and prenatal strokes.

CLASSIFICATION
The most commonly used classification of CP is based on the distribution of the affected
motor dysfunction:
• Hemiparetic: Weakness and spasticity are seen on one side of the body. Signs include
fisting on the affected side, early hand preference, and increased reflexes on the
affected side.
• Diparetic: There is spasticity of all four limbs but affecting the legs much more than
the arms. The children are often of normal intelligence and are less likely to have
seizures than children with other forms of CP.
• Spastic quadriplegic: All four limbs are affected. Seizures often occur within the first
48 hours of life. The infant may show signs of cerebral hypotonia (see later
discussion).

CLINICAL MANIFESTATION
CP may be diagnosed as early as the first week of life: infants may have flaccid
weakness, asymmetric limb movements, or seizures. In older children, spasticity,
dystonia, and developmental delay are common presentations.

DIAGNOSTIC EVALUATION
The diagnosis of CP is based on the clinical symptoms and signs. The time course of
symptoms should be static, rather than progressive. Other entities that may present with
dystonia, ataxia, or spasticity but that progress with time (e.g., metabolic disorders and
leukodystrophies) must be excluded. Magnetic resonance imaging (MRI) is indicated to
exclude the structural causes of the symptoms and signs, such as tumor, stroke, or
vascular malformations.

TABLE 25-1. Developmental Milestones

Age Adaptive/Fine Motor Gross Motor Language Personal/Social
Skills Skills
1 mo Grasp reflex; hand fisted Raises head slightly Facial response to sounds Stares at face
when prone
2 mo Follows objects with eyes Lifts head from prone Coos Smiles in
past midline to 45 degrees response to
others
4 mo Hands open; brings objects Sits, head steady; Laughs and squeals; Smiles
to mouth rolls to supine toward voice spontaneously
6 mo Palmar grasp of objects; Sits independently; Babbles (consonant Reaches for toys;
starts transfer of objects stands with hands sounds); mimics sounds recognizes
held strangers
9 mo Pincer grasp; claps hands Pulls to stand Says “mama,” “dada,” Finger-feeds self;
nonspecifically; waves bye-bye
comprehends “no”;
 associates word and action
(“bye-bye,” “no,” etc.)
1y Helps to turn pages of Stands independently; 2–4 words; follows Points to indicate
book; tower of two blocks walks with one hand command with gesture wants
held
18 mo Turns pages of book; Walks up steps 10–20 words; points to four Feeds self with
imitates vertical lines body parts; obeys simple spoon; uses cup
commands
2y Solves single-piece puzzles Jumps; kicks ball Combines 2–3 words; uses Removes coat;
I and you; 50–300 words verbalizes wants
3y Copies circle; draws Throws ball Gives full name, age, and Toilet trained;
person with three body overhand; walks up sex; names two colors puts on shirt and
parts; imitates horizontal stairs, alternating feet knows front from
lines; towers of six cubes; back
draws circles
4y Counts four objects; Hops on one foot Understands prepositions Dresses with little
identifies some numbers (under, on, behind, in front assistance; shoes
and letters; uses scissors of); asks “how” and “why” on correct feet
5y Prints first name; counts 10 Skips, alternating feet Asks the meaning of Ties shoes
objects; draws triangle; words; understands
draws person with several conjunctions and past
parts tenses; knows colors
DENVER II Technical Manual © 1990 William K Frankenburg and Josiah B Dodds © 2009 Wilhelmine R.
Frankenburg
Adapted from Frankenburg WK, Dodds J, Archer P, et al. The DENVER II Technical Manual. Denver, CO:
Denver Developmental Materials Inc.; 1996.

TREATMENT
In general, a multidisciplinary approach is necessary, with early infant stimulation,
physical and occupational therapy, orthopedic and psychologic evaluation, and speech
therapy.

KEY POINTS
● CP is a static disease. If the disease is progressing, it is not CP.
● It occurs in almost 3 in 1,000 births worldwide.
● The most common neurologic abnormality is spasticity.

TABLE 25-2. Primitive Reflexes

Reflex Significance Appears Disappears
Moro (startle reflex) Elicited by head extension. Term newborns 3 mos
Two phases: extension and
abduction of arms and leg
 extension, followed by
slower abduction of arms.
Asymmetry indicates
central nervous system
dysfunction such as
hemiparesis, spinal cord
lesion, or brachial plexus
injury.
Tonic neck Turning head: arm and leg 1 month 5 mos
extended on the side of the
turn, with flexion on the
other side (fencing posture).
If an infant is unable to
move out of posture, implies
possible brain pathology.
Traction response Lift baby by traction in both Birth to 6 mos Persists throughout life
hands. Head lag after 6 mo
is pathologic and indicates
hypotonia.
Parachute Elicited by plunging 6 mos Persists throughout life
suspended infant
downward. Arms should
thrust forward
symmetrically as if breaking
the fall. Also elicited with
baby in sitting position and
pushed forward. Arms
should try to break the fall.
Asymmetry suggests
hemiparesis, spinal cord
lesion, or brachial plexus
pathology.

INTELLECTUAL DISABILITY AND

DEVELOPMENTAL DELAY
Intellectual disability (ID) is the term used to describe impairment in the ability to
achieve an expected level of cognitive function. The disorder can vary significantly in
severity but manifests prior to adulthood. It can be classified by the results of standard
intelligence tests such as the Stanford–Binet IQ and the Wechsler Preschool and
Primary Scale of Intelligence—Revised. Normal IQ is 100 with a standard deviation of
15. ID is categorized as follows:
• Mild: IQ between 55 and 70
• Moderate: IQ between 40 and 55
• Severe: 25 to 40
• Profound: less than 25
For most children with ID, the cause is not known. There are many known causes of
ID, including prenatal and postnatal trauma (e.g., intracerebral hemorrhage and
hypoxic–anoxic encephalopathy); congenital and postnatal infection (e.g., congenital
rubella, syphilis, cytomegalovirus, toxoplasmosis, and HIV infection); chromosomal
abnormalities (e.g., Down syndrome, fragile X syndrome, Angelman syndrome, Prader–
Willi syndrome); chromosomal translocations (e.g., cri du chat syndrome); inherited
metabolic disorders (e.g., hypothyroidism, galactosemia, Tay–Sachs disease); and
toxic, nutritional, and environmental causes. Table 25-3 summarizes some important
chromosomal abnormalities associated with ID.
Developmental delay is the failure to acquire age-appropriate cognitive, language,
fine or gross motor skills, or social skills. The Denver Developmental Assessment is a
standard test that can help establish the diagnosis. Many of the etiologies of
developmental delay are similar to those responsible for ID and include intrauterine
toxins and infections, genetic abnormalities, neuronal migrational disorders, hypoxic–
ischemic encephalopathy, and inborn errors of metabolism. Most often, though, no cause
for developmental delay is found, in which case it is labeled “idiopathic” (or more
appropriately, cryptogenic).
The treatment for both ID and developmental delay includes referral to early
intervention programs for special education and training.

KEY POINTS
● ID implies a substantially below-average cognitive ability and impaired adaptive behavior.
● Developmental delay implies the inability to achieve developmental milestones at the usual age. It is not
synonymous with ID.

AUTISTIC SPECTRUM DISORDERS

Autism is a developmental disorder of brain function. Usually, the etiology is unknown.
Autism is the most common of the disorders that fall under the rubric of pervasive
developmental disorders.

TABLE 25-3. Intellectual Disability Syndromes Associated with Chromosomal

Abnormalities
Condition Epidemiology Genetic Defect Clinical Characteristics
Down syndrome Most common inherited ID Trisomy 21 ID; upslanting palpebral

Fragile X syndrome
Prader–Willi syndrome
Angelman syndrome
Rett syndrome
ID, intellectual disability.
fissures; protruding tongue;
simian crease; Brushfield
spots
Relatively common form of Defect in the X 20% of boys are normal;
ID; affects boys more than chromosome; mutation in 30% of carrier girls are
girls the 5' end of the gene with mildly affected; moderate
amplification of a CGG ID; behavioral problems;
repeat (200 or more copies) somatic abnormalities: long
face, enlarged ears, and
macroorchidism
Uncommon inherited The absence of segment ID, reduced muscle tone,
disorder 11–13 on the long arm of short stature, emotional
the paternally derived lability, and insatiable
chromosome 15 appetite (obesity)
Uncommon neurogenetic Deletion of segment 11–13 ID; abnormal gait; speech
disorder on the maternally derived impairment; seizures;
chromosome 15 inappropriate happy
behavior that includes
laughing, smiling, and
excitability (“happy puppet”
syndrome)
Progressive Causal gene is MeCP2, Normal development until
neurodevelopmental found on the long arm of 6–18 mo; a first sign is
disorder; generally affects chromosome X (X 28) hypotonia; autistic-like
girls only; incidence of 1 in behavior; stereotyped hand
10,000 births movements (wringing and
waving); lag in brain and
head growth; gait
abnormalities; seizures

CLINICAL MANIFESTATIONS
Autism is characterized by a combination of social, behavioral, and language
abnormalities with onset before age 3. Marked deficiencies in social and
communication skills manifest as a lack of attachment to other members of the family
and poor social interactions. A restricted range of behaviors, interests, and activities is
demonstrated and may include repetitive and stereotyped behaviors such as toe walking,
rocking, flapping, banging, and licking. Abnormal language features include echolalia
and stereotyped speech.

DIAGNOSTIC EVALUATION
The diagnosis of autism is clinical. Differential diagnosis includes other causes of
speech and language problems, such as deafness, ID, and seizures (e.g., in Landau–
Kleffner syndrome). Asperger syndrome can be considered a variant of autism
characterized by social isolation and eccentric behavior with normal intelligence and
language development.

TREATMENT
The treatment of autism includes support and behavior modification. No cures are
available at present.

KEY POINTS
● Autism is characterized by a combination of social, behavioral, and language abnormalities. Asperger
syndrome is an autism variant with normal intelligence and language development.

DEVELOPMENTAL REGRESSION AND INHERITED

NEURODEGENERATIVE DISORDERS
Developmental regression is defined as a loss of previously attained developmental
milestones. It is often related to an inherited neurodegenerative disorder. It is one of the
most distressing complaints confronted by pediatricians and neurologists. An extensive
battery of diagnostic tests is the wrong approach. Rather, a complete history, physical
and neurologic examination, and additional tests based on those findings, are
fundamental in reaching an accurate diagnosis. It is important to differentiate regression
from developmental delay (see previous section). Table 25-4 shows common causes of
progressive encephalopathy at different ages that can produce developmental delay or
regression.
The inherited neurodegenerative diseases are classified according to the involved
intracellular structure: the lysosome, peroxisome, mitochondria, Golgi apparatus, and
cell membrane. Whatever the cellular and molecular mechanism responsible, it is often
more productive to recognize the common patterns of disease expression according to
the age of onset, symptoms, and systems involved. The most common clinical features of
neurometabolic diseases presenting in infancy and childhood are developmental delay
or regression.

TABLE 25-4. Causes of Progressive Encephalopathy

Onset Before Age 2 Onset After Age 2
Mitochondrial disorders AIDS
Hypothyroidism Congenital syphilis
Neurocutaneous syndromes Subacute sclerosing panencephalitis
Tuberous sclerosis complex Enzymatic lysosomal disorders
 Neurofibromatosis Gaucher disease
Gray matter disorders Gangliosidosis
Infantile ceroid lipofuscinosis Late-onset Krabbe disease
Rett syndrome Metachromatic leukodystrophy
White matter disorders Other gray matter disorders
Alexander disease Ceroid lipofuscinosis
Canavan disease Huntington disease
Neonatal adrenoleukodystrophy Mitochondrial disorders
Pelizaeus–Merzbacher disease (peroxisomal Other white matter disorders
disorders)
Disorders of amino acid metabolism Adrenoleukodystrophy
Homocystinuria Alexander disease
Maple syrup urine disease
Phenylketonuria
Enzymatic disorders
Gangliosidosis
Gaucher disease
Krabbe disease
Mucopolysaccharidoses
Metachromatic leukodystrophy

Lysosomal disorders are caused by the genetic defects of lysosomal enzymes and
cofactors that result in the accumulation of undegraded substrates in lysosomes. They
are classified according to the accumulated material: sphingolipidoses,
mucopolysaccharidoses, mucolipidoses, glycogen storage disease type II, sialidoses,
and neuronal ceroid lipofuscinosis. Some of the most important characteristics of these
clinical entities are reviewed in Table 25-5.

TABLE 25-5. Inherited Neurodegenerative Disorders

Disorder Metabolic Defect Chromosome and Notes
Inheritance
Tay–Sachs disease Hexosaminidase A 15, autosomal recessive Cherry-red spot. More
common in Ashkenazi
Jews.
Niemann–Pick disease Sphingomyelinase 11, autosomal recessive Cherry-red spot. More
common in Ashkenazi
Jews.
Gaucher disease Glucocerebrosidase 1, autosomal recessive Cherry-red spot. Gaucher
cells in bone marrow.
Krabbe disease Galactosylceramide P- 14, autosomal recessive Globoid cells with PAS-
galactosidase positive granules.
Hurler syndrome a-L-iduronidase 4, autosomal recessive Clouding of the cornea.
Characteristic facies and
dwarfism.
 Hunter syndrome Iduronate sulfatase X-linked Hurler phenotype without
corneal clouding.
Metachromatic Arylsulfatase A 22, autosomal recessive Cherry-red spot.
leukodystrophy Demyelinating disorder.
Can present as
schizophrenia in adults.
Positive urine sulfatides.
Adrenoleukodystrophy Very long chain fatty acid X-linked White matter hyperintensity
oxidation on MRI. May present as a
neuropathy or myelopathy
in adults.
Alexander disease Glial fibrillary acidic protein 11 or 17, autosomal Rosenthal fibers on biopsy.
recessive Macrocephaly.
Dysmyelination of the
CNS.
Canavan disease Aspartoacylase 17, autosomal recessive Macrocephaly.
Dysmyelination of the
CNS.
Pelizaeus–Merzbacher Proteolipid protein X-linked Pendular nystagmus.
disease Dysmyelination of the
CNS.
Leigh disease Mitochondrial Autosomal recessive or X- Bilateral putaminal
linked hyperintensity on MRI.
Rett syndrome Methyl-CpG-binding X-linked Occurs exclusively in girls.
protein-2 Microcephaly, autism, and
hand-wringing.
Neuronal ceroid Excess lipofuscin storage Variety of mutations, Dementia, myoclonus,
lipofuscinosis autosomal recessive ataxia, retinitis pigmentosa.
Variety of forms with
different ages of onsets and
severities.
[CNS, central nervous system; MRI, magnetic resonance imaging; PAS, periodic acid–Schiff.]

Peroxisomal disorders are a heterogeneous group of syndromes characterized by

abnormalities in lipid metabolism. Multiple enzyme deficiencies have been
characterized. These disorders are rare. The most important of these disorders to
diagnose is X-linked adrenoleukodystrophy as it has potentially life-saving therapies.
Most of the degenerative diseases of infancy and childhood are not treatable (see Table
25-5). Attempts to reach a final diagnosis are still important in order to provide parents
with genetic counseling, prognosis, and further management advice.

KEY POINTS
● Neurodegenerative diseases involving the white matter include metachromatic leukodystrophy, Krabbe
 disease, adrenoleukodystrophy, Pelizaeus–Merzbacher disease, Canavan disease, and Alexander disease.
● Peripheral nerve involvement is found in metachromatic leukodystrophy, Krabbe disease, Canavan disease,
and adrenoleukodystrophy.
● Congenital macular cherry-red spots (red color of the macula compared with a pale retina) are found in Tay–
Sachs disease, Sandhoff disease, Niemann–Pick disease, Gaucher disease, metachromatic leukodystrophy,
and the sialidoses.

NEUROCUTANEOUS DISORDERS
Neurocutaneous disorders (phakomatoses) are characterized by lesions in the central
nervous system (CNS) and peripheral nervous system (PNS), skin, eyes, and other
organs. A summary of neurocutaneous disorders and their clinical features is given in
Table 25-6.

TABLE 25-6. Neurocutaneous Syndromes

Inheritance Neurologic Cutaneous Other Findings
Findings Findings
Neurofibromatosis 1 Autosomal dominant; Optic nerve gliomas Café-au-lait spots, Lisch nodules in the
chromosome 17 neurofibromas, iris
axillary or inguinal
freckles
Neurofibromatosis 2 Autosomal dominant; Bilateral acoustic Neurofibromas and
chromosome 22 neuromas café-au-lait spots are
less common than in
NF-1
Tuberous sclerosis Autosomal dominant; Cortical tubers, Adenoma sebaceum, Angiomyolipomas of
TSC 1–chrom 9; TSC subependymal ash-leaf spots, kidneys, cardiac
2–chrom 16 nodules and shagreen patches rhabdomyoma
astrocytomas, ID,
seizures
Ataxia-telangiectasia Autosomal recessive; Truncal ataxia, Telangiectasias Immunodeficiency
chromosome 11 progressive dementia and susceptibility to
infections, leukemia,
lymphoma
von Hippel–Lindau Autosomal dominant; Cerebellar Café-au-lait spots Renal lesions
chromosome 3 hemangioblastomas, including
ataxia hemangiomas and
carcinomas,
pheochromocytoma
Sturge–Weber Sporadic Venous angioma of Port-wine stain in the
the pia mater, distribution of the
seizures, hemiparesis, ophthalmic nerve
ID

[ID, intellectual disability; NF, neurofibromatosis; TSC, tuberous sclerosis complex.]

THE HYPOTONIC INFANT
Hypotonia is diminished resistance of muscles to passive stretching. Although weak
infants are always hypotonic, hypotonia can present with normal strength. It may be the
manifestation of a CNS or PNS disorder or both.
The most common cause of hypotonia is cerebral hypotonia, a static encephalopathy
from pre- or perinatal brain injury. The most useful diagnostic finding in this group of
disorders is not the hypotonia but the other signs of CNS dysfunction. Seizures,
microcephaly, dysmorphic facies, and ID point to the brain as the source of hypotonia.
The other causes of hypotonia include spinal cord disease (e.g., transection during
breech presentation), anterior horn cell lesions (spinal muscular atrophy),
neuromuscular junction abnormalities (congenital myasthenia), and myopathies
(congenital muscular dystrophies, congenital myopathies). The physical and neurologic
examinations and the presence or absence of “central” signs, such as increased reflexes,
may help localize the site of disease.

KEY POINTS
● Hypotonia can be caused by central or peripheral causes, or by both.
● Severe hypotonia but only marginal weakness is usually not due to a peripheral or lower motor neuron cause.
● Cerebral hypotonia is usually associated with the other signs of CNS dysfunction (seizures, developmental
delay, etc.).

ATTENTION DEFICIT–HYPERACTIVITY
DISORDER
CLINICAL MANIFESTATION
The essential features of attention deficit–hyperactivity disorder (ADHD) are
inappropriate inattention, impulsivity, and hyperactivity for age. Children with the
hyperactive–impulsive subtype are fidgety, leave their seats in the classroom, and have
difficulty playing quietly. Children with the inattentive–distractible subtype do not pay
close attention to details, have difficulty organizing tasks, and are forgetful in daily
activities. Often, there is a family history of ADHD, implying a genetic etiology.

DIAGNOSTIC EVALUATION
A diagnosis is made by clinical history and neuropsychological screening tests.
Children usually have normal IQs but low scores on tests of sustained attention. Imaging
and laboratory tests are generally not helpful.

TREATMENT
The standard medical treatment of ADHD includes the use of stimulant drugs like
methylphenidate and dextroamphetamine. It is important to emphasize parent
participation in the treatment program, which must also incorporate behavioral
modifications like goal setting and incentives.

KEY POINTS
● Children with ADHD often have a positive family history for the disorder.
● Stimulants like methylphenidate and dextroamphetamine are often effective treatments for ADHD.

CLINICAL VIGNETTES

VIGNETTE 1
A 4-year-old boy is evaluated for mild developmental delay. On dermatologic
examination, you find multiple café-au-lait spots, neurofibromas, and a freckle in the
left axilla.
1. What is the most likely diagnosis?
a. Neurofibromatosis type 1
b. Neurofibromatosis type 2
c. Sturge–Weber syndrome
d. Tuberous sclerosis
e. Von Hippel–Lindau disease
2. You learn that there is a family history of a similar but milder disorder in the
patient’s father and older sister. You decide to pursue genetic testing to confirm
the diagnosis. What is the inheritance pattern and location of the gene
responsible for this disorder?
a. Autosomal dominant, chromosome 3
b. Autosomal dominant, chromosome 16
c. Autosomal dominant, chromosome 17
d. Autosomal dominant, chromosome 22
e. Autosomal recessive, chromosome 11
 3. In the course of your evaluation, you obtain an MRI of this patient’s brain.
Which of the following tumors is associated with this condition?
a. Acoustic neuroma
b. Cerebellar hemangioblastoma
c. Hypothalamic hamartoma
d. Optic glioma
e. Subependymal giant cell astrocytoma

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer A:
The finding of multiple café-au-lait spots, neurofibromas, and axillary or inguinal
freckling is diagnostic of neurofibromatosis type 1. Café-au-lait spots and
neurofibromas are also seen in neurofibromatosis type 2, but they are less common
than in neurofibromatosis type 1. Patients with tuberous sclerosis may also have
café-au-lait spots, but other characteristic dermatologic findings including adenoma
sebaceum, ash-leaf spots, and shagreen patches are also present. Von Hippel–
Lindau disease is also associated with café-au-lait spots, but patients do not have
any of the other listed dermatologic features. The expected dermatologic finding in
Sturge–Weber syndrome is a port-wine stain in the distribution of the ophthalmic
nerve.

VIGNETTE 1 QUESTION 2
2. Answer C:
Neurofibromatosis type 1 is an autosomal-dominant disorder associated with a
mutation on chromosome 17. Von Hippel–Lindau disease is an autosomal-dominant
disorder associated with a mutation on chromosome 3. Neurofibromatosis type 2 is
also an autosomal-dominant disorder and is associated with mutations on
chromosome 22. Tuberous sclerosis is inherited in an autosomal-dominant fashion
as well and is produced by mutations on chromosome 9 and chromosome 16.
Ataxia-telangiectasia is an autosomal-recessive neurocutaneous disorder due to a
mutation on chromosome 11.

VIGNETTE 1 QUESTION 3
3. Answer D:
Optic glioma is associated with neurofibromatosis type 1. Acoustic neuroma
(usually bilateral) is associated with neurofibromatosis type 2; cerebellar
hemangioblastoma with von Hippel–Lindau disease; and subependymal giant cell
astrocytoma with tuberous sclerosis. Hypothalamic hamartoma is not associated
with any of the neurocutaneous disorders.
 Questions

1. A 78-year-old woman with dementia and rigidity is hospitalized with

dehydration. During her hospitalization, she becomes agitated and has
prominent visual hallucinations. After a dose of haloperidol, she becomes very
rigid and mute. The most likely type of dementia in this patient is:
a. Alzheimer disease
b. Parkinson disease
c. Dementia with Lewy bodies
d. Pick disease
e. Vascular dementia
2. A 32-year-old woman presents to the emergency room (ER) complaining of
blurred vision and pain in the right eye. Your evaluation shows decreased
visual acuity in the right eye that does not correct with pinhole testing. There is
a relative afferent pupillary defect on the right, and testing of the right visual
field shows a small central scotoma. The most likely localization of the lesion
is the:
a. Optic chiasm
b. Optic nerve
c. Optic tract
d. Occipital cortex
e. Optic radiations
3. In the course of evaluating an infant with developmental regression, a pediatric
neurologist notes a cherry-red spot on funduscopic examination. Which of the
following diagnoses is consistent with that finding?
a. Alexander disease
b. Hurler syndrome
c. Krabbe disease
d. Niemann–Pick disease
e. Canavan disease
4. A 62-year-old woman presents with progressive distal symmetric paresthesias
and dysesthesias, with preserved muscle strength. She smokes cigarettes. Your
electrodiagnostic study indicates that this is likely a sensory neuronopathy.
Which one of the following tests will help find the possible etiology?
 a. Anti-GM1 antibodies
b. Anti-DNA antibodies
c. Anti-Hu antibodies
d. MRI of the spine
e. CT myelogram
5. A 40-year-old woman is evaluated in the ER after a motor vehicle accident
resulting in left facial injuries. Subsequent examination shows that her left
seventh and eighth cranial nerves remain dysfunctional. Which of the following
skull structures may have been affected by her injury?
a. Cribriform plate
b. Optic canal
c. Superior orbital fissure
d. Internal auditory meatus
e. Jugular foramen
6. A 54-year-old woman is seen in the ER complaining of a severe headache. Head
CT was normal. A lumbar puncture (LP) was performed. The opening pressure
was 14 cm H2O, and cerebrospinal fluid (CSF) analysis showed the following:
150 RBC/mm3, xanthochromic fluid, protein 55 mg/dL (slightly increased), 3
WBC/mm3 (90% lymphocytes), and normal glucose. Which of the following is
true?
a. The xanthochromia may have been caused by a traumatic tap.
b. The lymphocytic pleocytosis indicates an active infectious process.
c. Viral meningitis is unlikely because of the normal CSF glucose.
d. This patient should undergo a vascular imaging study of the brain.
e. The opening pressure is elevated and reflects pseudotumor cerebri.
7. A 29-year-old woman is brought into the ER in an unresponsive state. Her
temperature is 37°C (98.6°F), heart rate 84/minute, respiration 10 breaths per
minute, and blood pressure 152/84 mm Hg. On examination, she withdraws to
noxious stimulation only. Her right pupil is 10 mm and does not constrict to
light. Her left pupil is 5 mm and reacts normally. Which of the following is
clinically contraindicated?
a. Raising the head of the bed
b. Intravenous administration of mannitol
c. Hyperventilation
d. Lumbar puncture
e. Neurosurgical consultation
8. A patient presents with gradually worsening weakness of the proximal arm and
leg muscles symmetrically over several months. On examination, weakness is
 identified in neck flexors and extensors, and there is mild diffuse atrophy with
preserved reflexes. There is no muscle pain or tenderness. What is the most
likely site of dysfunction in the nervous system?
a. Peripheral nerve
b. Brachial plexus
c. Spinal nerve root
d. Internal capsule
e. Muscle
9. An 8-year-old boy is brought to a child psychiatrist for evaluation of potential
attention deficit/hyperactivity disorder. His mother states that his teachers have
been concerned about his attention because they frequently have to repeat
instructions to him. At home, his brother has noticed that he will stare for
several seconds at a time, during which he does not respond to questions. An
EEG demonstrates a 3-Hz spike-and-wave pattern. Which of the following is
the most appropriate treatment?
a. Methylphenidate (Ritalin)
b. Ethosuximide (Zarontin)
c. Clonidine (Catapres)
d. Fluoxetine (Prozac)
e. Carbamazepine (Tegretol)
10.A 28-year-old woman comes to the ER with a severe unilateral throbbing
headache accompanied by photophobia and phonophobia. These headaches
started in her teens and she has one every month. Which of the following
medications is effective as abortive treatment?
a. Propranolol
b. Sumatriptan
c. Verapamil
d. Amitriptyline
e. Valproic acid
11.A 42-year-old man is brought to the neurologist for evaluation of a few months’
history of personality changes. His family indicates that, over the previous year,
he has made unusual movements with his hands, and he seems to have some
memory difficulties. His father died in his 50s with a similar clinical syndrome,
including prominent chorea and dementia. The most likely genetic abnormality
will be localized on chromosome:
a. 19
b. 6
c. 4
d. 11
 e. 21
12.A 55-year-old woman with a history of ovarian cancer and moderate alcohol
consumption is seen in the Neurology ambulatory clinic with a 1-month history
of progressive unsteadiness of gait and dysarthria. Examination confirms the
presence of gait and limb ataxia as well as nystagmus. These symptoms were
fairly abrupt in onset, progressed over a period of a few weeks, and now
appear to have stabilized, but there has been no sign of spontaneous
improvement. Which of the following statements is correct?
a. The findings of gait ataxia, dysarthria, and nystagmus indicate diffuse
involvement of the cerebellum and suggest that alcohol consumption is the
likely cause.
b. The constellation of symptoms and their temporal evolution are most
consistent with paraneoplastic cerebellar degeneration, a disorder
associated with underlying gynecologic malignancy.
c. The constellation of symptoms and their temporal evolution are most
consistent with a spinocerebellar ataxia.
d. The symptoms and signs indicate cerebellar hemisphere dysfunction and are
most suggestive of a metastasis from an underlying ovarian cancer.
e. The sudden onset of symptoms and diffuse cerebellar involvement suggest
midline cerebellar hemorrhage as the cause.
13.A 45-year-old man with multiple sclerosis (MS) comes to the Neurology clinic
complaining of urinary incontinence. He indicates that he experiences increased
urgency and frequency of urination. The most likely urodynamic finding in this
patient is:
a. An atonic bladder
b. A spastic bladder
c. Stress incontinence
d. Absence of abnormalities
e. Overflow incontinence
14.A 65-year-old man complains of a 3-month history of intermittent urinary
incontinence. Urodynamic studies show an atonic bladder. Which of the
following is most likely responsible for his problem?
a. Diabetes
b. Old stroke
c. Multiple sclerosis
d. Right parietal tumor
e. Pineal tumor
15.A 35-year-old man is seen in the Neurology outpatient clinic with the complaint
 that his fingers occasionally “get stuck” when he tries to open jars. On
examination, you find subtle weakness of the fingers and toes as well as
percussion myotonia. You suspect the diagnosis of myotonic dystrophy. Which
of the following statements is true?
a. Myotonic dystrophy is a systemic disorder that may also cause cataracts,
diabetes, mental retardation, and cardiac arrhythmias.
b. Myotonic dystrophy is a disorder affecting skeletal muscles alone.
c. Myotonic dystrophy should not be considered in the differential diagnosis
because it is an inherited disorder that typically manifests itself either at
birth or early in life.
d. Myotonic dystrophy is an autosomal recessive disorder caused by a triplet
expansion in the DMPK gene.
e. Electromyography is usually normal in myotonic dystrophy and genetic testing
is essential to confirm the diagnosis.
16.An 18-year-old woman is brought to the Neurology clinic by her mother, who
explains that her daughter has been behaving strangely recently and appears to
have paranoid delusions. She has a slight tremor of both hands and the examiner
notes that there is a brownish discoloration of the cornea in the vicinity of the
limbus. Laboratory studies show a mild transaminitis. Which of the following
test results are most likely?
a. Increased serum free copper, increased ceruloplasmin, and decreased 24-
hour urinary copper excretion
b. Increased serum free copper, decreased serum ceruloplasmin, and increased
24-hour urinary copper excretion
c. Decreased serum free copper, increased serum ceruloplasmin, and increased
24-hour urinary copper excretion
d. Decreased serum free copper, increased ceruloplasmin, and decreased 24-
hour urinary copper excretion
e. Decreased serum free copper, decreased serum ceruloplasmin, and decreased
24-hour urinary copper excretion
17.A 40-year-old woman with systemic lupus erythematosus develops weakness of
her right finger and wrist extensors and pain on the right dorsum of her hand
several months after being diagnosed with left carpal tunnel syndrome and right
sciatic neuropathy. What is the most likely diagnosis?
a. Mononeuropathy multiplex
b. Axonal polyneuropathy
c. Demyelinating polyneuropathy
d. Neuromuscular junction disease
e. Polyradiculopathy
18.A 70-year-old man develops acute onset of an inability to speak. Examination
reveals that he struggles to pronounce a complete word and cannot string words
together. He is unable to repeat a sentence, but can follow simple and multistep
commands. What is the most likely diagnosis?
a. Global aphasia
b. Conduction aphasia
c. Broca’s aphasia
d. Wernicke’s aphasia
e. Transcortical motor aphasia
19.A 28-year-old woman is brought to the ER by her husband. In addition to having
neck stiffness, she has had a fever for several days, has been somewhat
confused, and has not been “acting like herself.” A lumbar puncture shows 9
WBCs with a lymphocytic predominance, 32 RBCs, protein = 63, and glucose =
65. Gram stain is negative. What is the most likely diagnosis?
a. Bacterial meningitis
b. Viral meningitis
c. Fungal meningitis
d. Meningitis from tuberculosis
e. Subarachnoid hemorrhage
20.A healthy 32-year-old man is brought to the ER after he stopped speaking
suddenly, fell to the ground, lost consciousness, and shook for 2 minutes. After
the event, he was noted to have a tongue laceration and urinary incontinence. He
has no history of similar events. His physical examination shows a mild right
hemiparesis. Routine laboratory studies and a head CT are normal. An EEG
performed the next day is normal. The normal EEG suggests that this man:
a. Had a pseudoseizure and does not require anticonvulsants
b. Needs admission for long-term video-EEG monitoring
c. Probably had a seizure, and the normal EEG result is not surprising
d. Requires hyperventilation to elicit an absence seizure on EEG
e. Has actually had an ischemic stroke rather than a seizure
21.Two days after coronary artery bypass surgery, a 62-year-old man with
hypertension complains that “there is another man’s arm in bed” with him.
When asked to hold up his arms, the patient raises his right arm only. When
asked about his left arm, he claims it is the examiner’s or another patient’s.
What is the most likely diagnosis?
a. Right hemisphere stroke with neglect
b. Left hemisphere stroke with neglect
c. Conversion disorder
d. Adjustment disorder
 e. Alien-limb phenomenon
22.A 35-year-old man with no known history of seizures is brought in by
paramedics in status epilepticus. Which of the following medications or
medication classes is used as initial therapy for this condition?
a. Benzodiazepines
b. Barbiturates
c. Propofol
d. Carbamazepine
e. Lamotrigine
23.Subfalcine herniation most often results in which of the following?
a. Ipsilateral third nerve palsy
b. Contralateral third nerve palsy
c. Contralateral hemiparesis
d. Small, reactive pupils
e. Bilateral leg weakness
24.A 23-year-old woman presents with loss of vision in the right eye accompanied
by slight pain in that eye over a period of 3 days. She has 20/200 acuity, red
desaturation, and an afferent pupillary defect in the right eye. The remainder of
her examination and MRI are normal. A diagnosis of optic neuritis is made.
Which of the following is true about treatment?
a. Interferon β-1b will hasten recovery from this episode.
b. Natalizumab is the most effective treatment.
c. Medical treatment is not likely to help optic neuritis.
d. Oral corticosteroids are preferred for the treatment of optic neuritis.
e. Corticosteroids may delay the development of MS.
25.A 22-year-old right-handed woman develops horizontal diplopia acutely. Your
evaluation shows normal right lateral gaze but difficulty with adduction of the
right eye while looking to the left and nystagmus in the abducting left eye. What
is the most likely anatomic localization?
a. Left paramedian pontine reticular formation (PPRF) producing a right
internuclear ophthalmoplegia (INO)
b. Right PPRF producing a right one-and-a-half syndrome
c. Right medial longitudinal fascicle (MLF) producing a right INO
d. Left MLF producing a right INO
e. Lateral geniculate nuclei
26.A 55-year-old man with a history of tick bite and erythema chronicum migrans
is diagnosed with Lyme disease. He asks his primary care physician about
neurologic symptoms he should watch for. Which of the following is an early
 neurologic manifestation of Lyme disease?
a. Facial nerve palsy
b. Painful polyradiculopathy
c. Spinal cord compression
d. Leukoencephalopathy
e. Generalized epilepsy
27.A 34-year-old man is seen in the Neurology outpatient clinic with symptoms of
headache and bilateral lower motor neuron (LMN) facial weakness. There is no
history of a skin rash. Neurologic examination shows a relative afferent
papillary defect in the right eye and the bilateral facial weakness.
a. Guillain–Barré syndrome is the most likely diagnosis, and he should have an
LP to help confirm the diagnosis.
b. Lyme disease is the most likely diagnosis, and Borrelia serology should be
sent to confirm the diagnosis.
c. Sarcoidosis is likely the correct diagnosis, and appropriate investigations
include MRI of the brain, LP, and chest X-ray.
d. Multiple sclerosis is most likely the correct diagnosis, because bilateral
facial weakness and optic neuropathy are both common manifestations of
this disease.
e. Mononeuritis multiplex secondary to vasculitis is the most likely diagnosis,
so the patient should be referred for rheumatologic evaluation.
28.A 64-year-old man with a history of hypertension presents to the ER with the
sudden onset of numbness of his left leg, arm, and face. His motor examination
is normal. What is the most likely site of his lesion?
a. Right thalamus
b. Right internal capsule
c. Right precentral gyrus
d. Right occipital lobe
e. Right corona radiata
29.While playing baseball, a 15-year-old boy was hit on the side of the head with
a ball. He was knocked unconscious briefly, but recovered fully. Two hours
later he became increasingly lethargic, so his parents brought him to the ER.
When you evaluate the patient, he is barely rousable to voice. He has mild
weakness on the left side of his body, and his right pupil is slightly larger than
the left pupil; the right pupil does not appear to react to light. What is the most
likely cause of the patient’s symptoms and signs?
a. Concussion
b. Epidural hematoma
c. Diffuse axonal injury
 d. Ischemic infarct
e. Drug intoxication
30.Which of the following syndromes or diseases could cause bilateral weakness
and loss of pain and temperature sensation with preservation of joint position
sense in both legs?
a. Amyotrophic lateral sclerosis
b. Vitamin B12 deficiency
c. Brown-Séquard syndrome
d. Anterior spinal artery syndrome
e. Tabes dorsalis
31.A 2-year-old child presents with new seizures. Her mother tells you that the
child is not walking yet. SHe has a 5-year-old brother with a seizure disorder
and mental retardation. On examination, using the Wood’s lamp, you find
hypomelanotic lesions. The most appropriate next test is:
a. Skeletal surveillance
b. Skin biopsy
c. Head CT or MRI
d. No need for further tests
e. Lumbar puncture
32.A 3-year-old boy is brought to his pediatrician for evaluation of repetitive
behaviors, delay of language development, and social isolation. He has normal
motor development otherwise. Which of the following is a feature of autism, but
not of Asperger syndrome?
a. Abnormal language development
b. Social isolation
c. Restricted, repetitive patterns of behavior
d. Failure to meet milestones for gross motor development
e. Failure to meet milestones for fine motor development
33.A 62-year-old woman with a history of small cell lung carcinoma presents to
the Neurology clinic complaining of bilateral paresthesias of the legs. She has
no history of diabetes or family history of polyneuropathy. She describes severe
pain in the soles of her feet when standing and has difficulty walking. On
examination, there is severe pain to light touch over both soles. On your sensory
examination description, you will state that this patient has:
a. Hyperesthesia
b. Paresthesia
c. Allodynia
d. Sensory loss
 e. Hypesthesia
34.A 38-year-old man presents to the ER complaining of a mild headache. He had
neck trauma a week earlier. The examination shows anisocoria, with the right
pupil being 3 mm and the left 5 mm, both reactive to light. What other findings
will help localize the lesion?
a. Look at the pupils in the dark and check tongue deviation.
b. Look for evidence of ptosis in the left eye and anhidrosis on the left face.
c. Look for evidence of ptosis in the right eye and anhidrosis in the right face.
d. Look for evidence of horizontal diplopia and a cut in the right visual field.
e. Look for evidence of dysarthria and hemiparesis.
35.A 35-year-old woman presents to the ER reporting 10 days of progressive
ascending muscle weakness. She had a viral infection a few weeks earlier. On
examination, you find diffuse weakness and areflexia. The most likely finding in
the CSF is:
a. High protein–high cell count
b. High protein–low cell count
c. Low protein–high cell count
d. Low protein–low cell count
e. Normal CSF
36.A 33-year-old man is seen in the ER for difficulty walking. He has paresthesias
in his feet and a left foot drop. Initial physical examination shows mild distal
weakness in both legs, with absent ankle jerks and reduced reflexes throughout.
While the patient is waiting in the ER, his weakness worsens, involving the
arms, but he has no difficulty breathing. You want to admit the patient to the
intensive care unit. What will be your best argument to convince your ER
attending to do so?
a. Absence of reflexes in the arms
b. Decreased gag reflex
c. A forced vital capacity below 25 mL/kg
d. The patient’s weakness is worsening very quickly, and you fear that he may
need mechanical ventilation.
e. The presence of a left foot drop
37.A 35-year-old man who is HIV-positive presents with radicular pain in the legs
and associated bladder distension. The most likely agent responsible for these
symptoms is:
a. Cytomegalovirus
b. Clostridium
c. Toxoplasma
 d. Cryptococcus
e. Pneumocystis carinii
38.A 45-year-old woman presents to the ER with “dizziness,” by which she means
that she feels a spinning sensation. The sensation is intermittent and seems to be
exacerbated by head movement. She has some nausea with the episodes, but
otherwise has no other symptoms such as double vision, weakness, hearing
loss, tinnitus, or difficulty swallowing. What diagnosis is most likely?
a. Vestibular neuronitis
b. Ménière disease
c. Brainstem infarction
d. Benign positional paroxysmal vertigo
e. Cerebellar infarction
39.A 32-year-old woman is seen in the neurology outpatient clinic with symptoms
of diplopia and ptosis that fluctuate during the course of the day. Examination
shows fatigable proximal weakness. You suspect that she has myasthenia gravis
(MG). Which of the following statements concerning MG is true?
a. It is an autoimmune disorder caused by antibodies that are directed against
presynaptic nicotinic acetylcholine receptors.
b. It is an autoimmune disorder caused by antibodies directed against
postsynaptic muscarinic acetylcholine receptors.
c. It is an autoimmune disorder caused by antibodies directed against
presynaptic voltage-gated calcium channels.
d. It is an autoimmune disorder caused by antibodies directed against
postsynaptic nicotinic acetylcholine receptors.
e. It is an autoimmune disorder caused by antibodies directed against the
synaptic enzyme acetylcholinesterase.
40.A patient complains of difficulty chewing. On examination, he is found to have
decreased strength of his muscles of mastication. Which of the following cranial
nerves is responsible for this motor function?
a. Trigeminal
b. Facial
c. Oculomotor
d. Glossopharyngeal
e. Hypoglossal
41.The following patients are being evaluated in a neurologic intensive care unit.
For which patient would the Glasgow Coma Scale be used most commonly to
follow his or her clinical status?
a. A 75-year-old man in coma after cardiac arrest
 b. A 29-year-old woman with delirium after medication overdose
c. A 69-year-old woman with a thromboembolic stroke and Broca aphasia
d. A 20-year-old man who is unresponsive after head trauma
e. A 59-year-old man with subarachnoid hemorrhage after aneurysm rupture
42.A 68-year-old man taking dabigatran falls while in the hospital, is found on the
floor, and is difficult to rouse. He has a new right hemiparesis. You order a CT
of the head without contrast. Which of the following possible etiologies for his
presentation will be assessed with the CT?
a. Subdural hematoma
b. Epidural hematoma
c. Intraparenchymal hemorrhage
d. Large territory cerebral infarction
e. All of these
f. None of these
43.A 75-year-old man presents to your office with a 1-month history of
progressive pain in the left temporal area and pain in his jaw while eating. On
laboratory testing, the patient is found to have an elevated erythrocyte
sedimentation rate of 94. What is the treatment of choice?
a. Sumatriptan
b. Carbamazepine
c. Verapamil
d. Surgical resection of brain tumor
e. Prednisone
44.A 35-year-old man presents to your office for difficulty concentrating. He has
fallen asleep while driving and also in the middle of important business
meetings, despite sleeping at least 8 hours each night. He denies hallucinations
or a history of his knees buckling while laughing. His wife reports that he
snores loudly during sleep. His examination is normal except for moderate
obesity. Which of the following tests would be most helpful in diagnosing this
patient’s disorder?
a. Multiple sleep latency test
b. EEG
c. MRI of the brain
d. Lumbar puncture
e. Polysomnography
45.A previously healthy 21-year-old man presents to the ER after being involved
in a high-speed motor vehicle accident. You note that he is unresponsive, makes
no spontaneous movement, and has a dilated pupil on the right that is
 nonreactive to light. What is the best explanation for these signs?
a. Infarction of the left occipital lobe
b. Concussion from the motor vehicle accident
c. Uncal herniation
d. Cervical spine fracture
e. Diffuse axonal injury
46.An 84-year-old man is transferred from another hospital with a reported
hypertensive hemorrhage. The films from that hospital are not available, and no
further details are available. Which of the following is the most likely location
of his hemorrhage?
a. Basal ganglia
b. Midbrain
c. Internal capsule
d. Frontal lobe
e. Corpus callosum
47.A 28-year-old man has been diagnosed with obstructive sleep apnea. Of the
following choices, which is the most appropriate treatment?
a. Sodium oxybate
b. Methylphenidate
c. Continuous positive airway pressure
d. Clonazepam
e. Clomipramine
48.A 45-year-old man with a prior history of migraine headaches with aura
presents to the ER complaining of a progressively worsening headache for the
past month that is different from his usual migraine. There is no associated
nausea or vomiting. His neurologic examination is completely normal. Your
next step in management should be:
a. Brain imaging study
b. Abortive migraine treatment
c. Preventive migraine treatment
d. Reassurance and discharge home
e. Administration of pure oxygen
49.Which of the following features is most commonly associated with a pituitary
adenoma?
a. Homonymous hemianopia
b. Bitemporal hemianopia
c. Ring enhancement on brain imaging with contrast
d. Seizures
 e. Hemiparesis
50.A 24-year-old construction worker falls from a ladder and fractures his
cervical spine with resulting signs of upper motor neuron (UMN) dysfunction.
Which of the following signs is characteristic of a UMN lesion?
a. Hypotonia
b. Decreased reflexes
c. Flexor plantar response
d. Spasticity
e. Absent reflexes
51.A 67-year-old woman presents to the ER with a new onset of headache, nausea,
vomiting, and unsteadiness of gait. Her history is significant for atrial
fibrillation, for which she is chronically anticoagulated with rivaroxaban. She
also has a pacemaker in place. You are concerned about the possibility of a
cerebellar hemorrhage. The imaging modality of choice is:
a. A CT scan without contrast, because this is the imaging test most sensitive to
the presence of acute intracranial blood and can be obtained rapidly
b. An MRI, because blood in the posterior fossa will not be visualized on CT
c. An MRI, because CT is contraindicated by the presence of a pacemaker
d. A CT scan with contrast, because it provides the best images of the contents
of the posterior fossa
e. A single-photon emission computed tomography scan to show metabolic
activity in the cerebellum
52.A 22-year-old woman presents with acute bilateral facial nerve palsy and
intermittent peripheral nerve symptoms for over 3 weeks. You find elevated
Lyme titers in serum and CSF. What treatment would you choose first?
a. Oral doxycycline
b. Intravenous ceftriaxone
c. Oral amoxicillin
d. Oral amoxicillin and doxycycline
e. Fluconazole
53.A 58-year-old man is seen in the Neurology ambulatory clinic with a 3-month
history of right-sided resting tremor. On examination, he is noted to have mild
masking of facial expression and there is diminished swing of the right arm
when he walks. You suspect that he may have early idiopathic Parkinson
disease. Which of the following statements concerning this disorder is true?
a. Most cases are familial with mutations in the α-synuclein or parkin genes.
b. It is characterized by the death of dopaminergic neurons in the substantia nigra
pars reticulata.
 c. The four cardinal features of this disorder are tremor, rigidity, bradykinesia,
and postural instability.
d. Impairment of vertical gaze is a common manifestation of this disorder.
e. Early falls are a common problem in this disorder.
54.A 5-year-old boy is seen in the Pediatric Neurology clinic. His motor
milestones have been delayed, and examination shows proximal muscle
weakness with difficulty arising from the floor. There is pseudohypertrophy of
his calf muscles. He has an older brother with Duchenne muscular dystrophy
(DMD) who is confined to a wheelchair. Which of the following statements
concerning DMD is true?
a. It is an autosomal recessive disorder caused by mutation in the dystrophin
gene.
b. It is an autosomal dominant disorder caused by mutation in the dystrophin
gene.
c. DMD and limb-girdle muscular dystrophy are allelic disorders, both being
due to mutations in the dystrophin gene.
d. It is a disorder caused by mutation in the dystrophin gene, which is located on
the X chromosome.
e. DMD and Becker muscular dystrophy are allelic disorders, due to mutations
in the dystrophin gene on chromosome 4.
55.A 9-year-old boy presents with difficulty walking. Neurologic examination
demonstrates, among other things, that he performs rapid alternating movements
poorly, with a lack of proper rhythm and coordination. This finding, called
dysdiadochokinesis, is most typically associated with dysfunction of which of
the following brain structures?
a. Basal ganglia
b. Medulla
c. Cerebellum
d. Parietal lobe
e. Thalamus
56.An ischemic stroke involving the right side of the pons could lead to which of
the following patterns of weakness?
a. Left facial weakness and right body weakness
b. Right facial weakness and left body weakness
c. Right facial weakness and right body weakness
d. Left arm weakness and right leg weakness
e. Right arm weakness and left leg weakness
57.A 27-year-old woman with complex partial seizures is well controlled on
 carbamazepine. Which of the following is a characteristic side effect of this
medication?
a. Thrombocytopenia
b. Agitation
c. Diabetes insipidus
d. Nephrolithiasis
e. Hyponatremia
58.A 53-year-old construction worker is brought to the ER with a severe, sudden-
onset headache accompanied by vomiting. A CT scan of his head demonstrates
a subarachnoid hemorrhage. Which of the following is the most common cause
of subarachnoid hemorrhage?
a. Tearing of bridging veins
b. Laceration of the middle meningeal artery
c. Aneurysmal rupture
d. Amyloid angiopathy
e. Arteriovenous malformation rupture
59.A 45-year-old woman has an MRI scan of the brain for evaluation of
progressive headaches. The scan shows a lesion that enhances in a
homogeneous manner with contrast administration. Which of the following
lesions is most likely to account for the appearance of the MRI scan?
a. Glioblastoma multiforme
b. Meningioma
c. Brain abscess
d. Toxoplasmosis
e. Granuloma
60.A 75-year-old man is brought to the ER after having lost consciousness briefly
in his bathroom. By the time he arrives he is feeling fine and is able to give a
clear account of what happened. He recalls walking to the bathroom to urinate.
Shortly thereafter he became light-headed and felt as if his vision were graying
out. These symptoms lasted for about 30 seconds. The next thing he recalls is
awakening on his bathroom floor. His wife notes that he was unconscious only
briefly. Which of the following descriptions pertinent to this clinical scenario is
correct?
a. The symptoms of light-headedness and graying out of vision are atypical
symptoms described by patients with syncope.
b. He has micturition syncope.
c. Orthostatic hypotension is the likely explanation for his syncopal episode.
d. Vasovagal syncope is the likely explanation for his syncopal episode.
e. Vestibular neuronitis is the likely explanation for his symptoms.
61.A 36-year-old man comes to the ER with a 4-day history of fever and a
generalized convulsion 2 hours earlier. He has been on long-standing immune
suppression for treatment of ulcerative colitis and is mildly pancytopenic at
baseline. His CT scan of the head shows no focal lesions, and a nontraumatic
LP shows 5,000 RBCs and 25 WBCs. Which of the following is the most
appropriate clinical management?
a. MRI of the brain
b. Treatment with an anti-seizure drug
c. Empiric treatment with broad spectrum antibiotics
d. Empiric treatment with acyclovir
e. All of the above
62.A 55-year-old woman comes to the Neurology clinic complaining of numbness
in the fourth and fifth fingers of her right hand; it tends to worsen at night. On
examination, you find a positive Tinel sign at the right elbow (percussion of the
ulnar nerve at the right elbow produces a tingling sensation in the fourth and
fifth fingers). You are convinced that this is an ulnar neuropathy at the right
elbow and perform electrodiagnostic studies. Why do you think that this is a
peripheral nerve problem?
a. The acuteness of presentation
b. The physical examination findings
c. The symptoms described by the patient
d. You do not think this is a peripheral nerve problem.
e. There is no central nervous system complaint.
63.A 25-year-old man is now comatose after suffering blunt force trauma to the
head. On the basis of the clinical history, neurologic examination, and head CT
scan, he is diagnosed with an epidural hematoma. Of the following choices,
which is the best treatment option?
a. Neurosurgical decompression
b. Hyperventilation
c. Administration of mannitol
d. Conservative management with close monitoring of vital signs and neurologic
status
e. Administration of tissue plasminogen activator
64.A 19-year-old man is admitted to a Neurology service with an episode of
transverse myelitis. Workup includes an MRI of his head and LP. Which of the
following distinguishes acute disseminated encephalomyelitis (ADEM) from
MS?
a. Presence of oligoclonal bands in the CSF
b. Pleocytosis with neutrophilic predominance
 c. Monophasic course
d. Multiple lesions on MRI
e. A positive family history of ADEM
65.A 55-year-old man with type 2 diabetes presents with a 5-week history of pain
in his right knee, followed by weakness and atrophy of his right quadriceps.
Examination shows weakness of the right quadriceps and iliopsoas muscles and
an absent right knee jerk. This presentation is most characteristic of which of
the following conditions?
a. Diabetic distal symmetric polyneuropathy
b. Diabetic amyotrophy
c. Mononeuropathy multiplex
d. Stroke
e. Herniated intervertebral disk at L5-S1
66.A 19-year-old man is accidentally hit on the left side of the head with a
baseball bat. He loses consciousness and is taken to an ER. A head CT scan
showed a lenticular-shaped hyperdensity over the left temporal region that is
exerting some mild mass effect on the brain. Which of the following
mechanisms best explains the patient’s head CT scan results?
a. Tearing of bridging veins
b. Laceration of the middle meningeal artery
c. Contact of the frontal poles of the brain with the skull
d. Rotational acceleration and deceleration of the head
e. Rupture of a cerebral aneurysm
67.A 56-year-old woman is referred to the Neurology clinic by her optometrist,
who noted that she had limited movement of her eyes. The patient herself notes
only that she has fallen a few times in recent months. Examination confirms that
there is marked limitation of vertical eye movements (both up and down gaze).
There is mild rigidity in both arms and legs but no tremor. Her postural reflexes
are poor. Which of the following is the most likely diagnosis?
a. Parkinson disease
b. Progressive supranuclear palsy
c. Corticobasal ganglionic degeneration
d. Miller–Fisher syndrome
e. Chronic progressive external ophthalmoplegia
68.A 65-year-old obese woman is referred to the Neurology clinic with complaints
of burning pain in both feet, which has been present for several months. You
suspect that she may have a small fiber peripheral neuropathy. The most likely
findings on examination are:
 a. Symmetric weakness and atrophy of intrinsic muscles of the feet with loss of
ankle reflexes
b. Symmetric stocking pattern diminution of pinprick and temperature sensation
c. Symmetric stocking pattern diminution of vibration and joint position sense
with absent ankle reflexes
d. Symmetric stocking pattern diminution of all sensory modalities with absent
deep tendon reflexes in the arms and legs
e. Symmetric stocking pattern diminution of vibration and joint position sense
with retained ankle reflexes
69.A 45-year-old man presents with a several-month history of weakness in his
arms and legs. On examination, in addition to weakness in multiple muscle
groups, he has atrophy, hyperreflexia, spasticity of the legs, and bilateral
Babinski signs. Fasciculations in multiple muscles are also noted. His sensation
of pain, temperature, and joint position are intact. What is his most likely
diagnosis?
a. Amyotrophic lateral sclerosis
b. Vitamin B12 deficiency
c. Anterior spinal artery syndrome
d. Central cord syndrome
e. Brown-Séquard syndrome
70.A 60-year-old woman presents with a primary complaint of insomnia. She feels
fatigued during the day and needs to take a nap each afternoon. She goes to
sleep at 7:00 PM and awakens at 3:00 AM each day. What is the most
appropriate treatment for this patient?
a. Continuous positive airway pressure
b. Behavioral modification therapy
c. Modafinil in the morning
d. Zolpidem at bedtime
e. Bright light therapy
71.A 54-year-old man is seen in the Neurology clinic with complaints of resting
tremor of the left hand and a general feeling of slowing down. As an example,
he explains that it takes him at least 20 minutes to get dressed in the morning.
You suspect that he has idiopathic Parkinson disease. If you are correct,
examination would be most likely to show which of the following combinations
of physical signs?
a. Asymmetric rest tremor, asymmetric rigidity, and poor postural reflexes
b. Symmetric rest tremor, asymmetric rigidity, and poor postural reflexes
c. Asymmetric rest tremor, symmetric rigidity, and poor postural reflexes
d. Symmetric rest tremor and rigidity and poor postural reflexes
 e. Asymmetric rest tremor, symmetric rigidity, and impairment of vertical gaze
72.A 55-year-old man with a history of hypertension is seen in the ER with
complaints of clumsiness and incoordination; they began 2 days earlier and
have increased in severity. He also reports double vision on lateral gaze, which
resolves when one eye is covered. He is awake, alert, and oriented.
Examination shows restricted eye movements in all directions, with eye
abduction in both directions most limited. Deep tendon reflexes are absent, and
there is impaired joint position sense. The most likely diagnosis is:
a. Brainstem stroke
b. Cerebellar infarction with compression of the brainstem
c. Miller–Fisher syndrome
d. Mysathenia gravis
e. Alcoholic cerebellar degeneration
73.A 44-year-old woman presents to the ER complaining of urinary incontinence
and lower back pain. What will be the most useful diagnostic procedure to try
in the effort to find the etiology of her problem?
a. Urodynamic studies
b. Blood testing including glucose level
c. MRI of the spine
d. Post-void residual
e. Lumbar puncture
74.A 48-year-old woman reports recurrent episodes of stabbing unilateral head
pain associated with tearing and conjunctival injection. Which of the following
is characteristic of chronic paroxysmal hemicranias, and not of cluster
headache?
a. Unilateral pain
b. Conjunctival injection
c. Male predominance
d. Indomethacin responsivity
e. Headache duration of hours
75.A 75-year-old right-handed man with hypertension, diabetes, and
hypercholesterolemia is seen in the ER. His family explains that he has had
difficulty doing things around the house for the past few days. The patient
himself admits that he has found it difficult to get dressed and to prepare his
breakfast, but he feels healthy otherwise. On examination, his speech is fluent,
and he is able to name objects and repeat short phrases without difficulty. He is,
however, unable to mimic certain activities described by the examiner, although
he seems to have no difficulty understanding what it is that he is supposed to do.
 a. He likely has a form of Wernicke aphasia due to a lesion in the left superior
temporal lobe.
b. He likely has a form of apraxia due to a lesion in the right frontal lobe.
c. He likely has a form of Wernicke aphasia due to a lesion in the left inferior
frontal lobe.
d. He likely has a form of apraxia due to a lesion in the right parietal lobe.
e. He likely has a form of apraxia due to a lesion in the left parietal lobe.
76.The most reliable method for distinguishing between a subarachnoid
hemorrhage and a “traumatic” spinal tap (LP) is the presence of:
a. Increased opening pressure
b. Increased red cell count
c. Increased white cell count
d. Xanthochromia
e. Pain upon needle insertion
77.The MRI sequence that is most sensitive for the presence of blood breakdown
products (e.g., after a hemorrhage) is:
a. T1
b. T2
c. Contrast-enhanced T1
d. Fluid-attenuated inversion recovery (FLAIR)
e. Susceptibility
78.Which of the following disorders is most closely associated with rapid eye
movement sleep behavior disorder?
a. Alzheimer disease
b. Multiple sclerosis
c. Multiple system atrophy
d. Myasthenia gravis
e. Primary lateral sclerosis
79.Which of the following vascular malformations is the most likely to result in an
intracranial hemorrhage?
a. Arteriovenous malformation
b. Capillary telangiectasia
c. Cavernous hemangioma
d. Developmental venous anomaly
e. Vein of Galen
80.An 81-year-old right-handed man with hypertension and hypercholesterolemia
presents with sudden onset of a dense right hemiplegia. His language is normal,
and he has normal eye movements and pupillary reactions. He has no sensory
 deficits. What is the most likely localization of his stroke?
a. Left motor cortex
b. Left internal capsule
c. Left thalamus
d. Left lateral medulla
e. Left cerebellar hemisphere
81.In which of the following disorders would the highest elevation of creatine
kinase be expected?
a. Becker muscular dystrophy (BMD)
b. Duchenne muscular dystrophy (DMD)
c. Lambert–Eaton myasthenic syndrome
d. Limb-girdle muscular dystrophy
e. Myotonic dystrophy
82.A 68-year-old man with no major medical problems has his annual visit with
his primary care physician. The doctor wishes to perform a brief screening
neurologic examination. Which of the following parts of the neurologic
examination would be the most sensitive for the detection of potential
abnormalities in multiple different parts of the nervous system?
a. Deep tendon (muscle stretch) reflexes
b. Gait evaluation
c. Visual field examination
d. Joint position sense testing
e. Total weight-lifting capacity
83.A 78-year-old woman with a history of coronary artery disease and
hypercholesterolemia develops sudden onset of paralysis of all four limbs. On
examination, her eyes are open, she appears alert, and she can consistently
respond to complex questions and commands by blinking her eyes, but
otherwise has minimal facial movement and no movement of the limbs. This
condition is best described as:
a. Locked-in syndrome
b. Persistent vegetative state
c. Brain death
d. Coma
e. Stupor
84.A 30-year-old man is found to have increased intracranial pressure after a head
injury. Which of the following treatments can serve to lower intracranial
pressure?
a. Lowering the head of the bed
 b. Intravenous fluid load
c. Depression of respiratory rate
d. Mannitol
e. Basilar artery stent
85.An 80-year-old man has developed gradually worsening memory over the past
several years. His wife also reports that he appears to have vivid visual
hallucinations at times, and his alertness has been fluctuating on a day-to-day
basis. Examination shows bradykinesia and rigidity in the limbs, without any
dyskinesias. What is the most likely diagnosis?
a. Alzheimer disease
b. Dementia with Lewy bodies
c. Vascular dementia
d. Huntington disease
e. Progressive supranuclear palsy
86.A 71-year-old with a clinical diagnosis of Alzheimer disease comes to autopsy
after a fatal motor vehicle accident. Which of the following is a
neuropathologic hallmark of Alzheimer disease?
a. Lewy bodies in the substantia nigra
b. Lewy bodies in cortical neurons
c. Prominent atrophy of caudate
d. Spongiform changes in cortex
e. Neurofibrillary tangles
87.A 34-year-old man comes in for neurologic consultation because of paroxysmal
episodes of speech difficulty that have occurred recently. The best way to
distinguish whether these are seizures or other types of events is:
a. History
b. Neurologic examination
c. Brain MRI
d. Routine EEG
e. Empiric anticonvulsant trial
88.An 18-year-old college student is seen in the ER because of fever, confusion,
and headache. LP is performed. Which of the following CSF profiles is most
consistent with acute bacterial meningitis?
a. Normal WBC count, high protein, low glucose
b. Normal WBC count, high protein, high glucose
c. Elevated WBC count, high protein, low glucose
d. Elevated WBC count, high protein, high glucose
e. Decreased WBC count, high protein, high glucose
89.A 55-year-old man presents with headache and right hand weakness. On
examination, you find bilateral papilledema and UMN weakness in the right arm
and leg. MRI with contrast shows an enhancing mass in the left frontal region,
crossing the corpus callosum in a “butterfly” pattern with surrounding edema.
Before requesting a biopsy, you discuss with your resident that this is most
likely a:
a. Meningioma
b. Astrocytoma
c. Glioblastoma
d. Ependymoma
e. Schwannoma
90.You evaluate a 22-year-old woman complaining of visual problems. Your
examination shows bitemporal visual field defects. Where is the lesion?
a. Right optic nerve
b. Right occipital lobe
c. Left optic radiation
d. Optic chiasm
e. This visual field defect is nonphysiologic, suggesting a psychiatric
explanation.
91.You are asked to evaluate a 33-year-old construction worker who is
complaining of paresthesias in the first and second digits of his right hand. Your
physical examination shows no weakness, but he has a mild decrease in light
touch over the thumb. You request a nerve conduction study to rule out carpal
tunnel syndrome, and it turns out to be normal. On repeated history, the patient
indicates that on occasion, he gets a sharp, “electric” pain travelling from his
neck to the right hand. What are you missing?
a. A median neuropathy at the wrist
b. A neuromuscular junction disorder affecting distal hand muscles
c. A C8-T1 radiculopathy
d. A lower trunk brachial plexopathy
e. A C6–C7 radiculopathy
92.A 75-year-old man underwent surgery to correct a large abdominal aortic
aneurysm. The procedure appeared to go well, but you are called in a few hours
later to evaluate the patient who states that he cannot move or feel his legs. On
the way to the ICU, you consider the possible causes of his symptoms and plan
your physical examination. Which of the following neurologic examination
signs do you expect to be normal?
a. Pinprick sensation in the legs
b. Leg strength
 c. Cold sensation in the legs
d. Pinprick sensation over the posterior trunk
e. Toe position sense
93.A 19-year-old man presents to the emergency department with 2 days of
ascending weakness. He denies associated pain, sensory changes, and bowel or
bladder dysfunction. He had diarrhea 3 weeks earlier. He looks comfortable.
On examination, you find moderate weakness in all limbs, and mild weakness
of neck muscles. Facial strength is full. There is no sensory level. You suspect
Guillain Barré syndrome and recommend admission to the neurology unit. What
should be done first?
a. Do an LP to look for albumin-cytologic dissociation.
b. Call for an emergency EMG to verify diagnosis.
c. Send the patient for a whole spine MRI to rule out cord compression.
d. Obtain pulmonary function tests, including forced vital capacity.
e. Start high-dose steroids and then move to the floor.
94.A 55-year-old woman is seen in the ER with the complaint that when she rolled
over in bed in the morning she felt acutely vertiginous for about 30 seconds,
with associated nausea and vomiting. Over the course of the day, the vertigo has
recurred, each time precipitated by turning her head. She has no other symptoms
and feels well in between the episodes of vertigo. She has poorly controlled
diabetes and hypertension. When examined in the ER, she has rotatory and
down-beating nystagmus during the Dix–Hallpike maneuver with the head tilted
one way but not the other. The neurologic examination is otherwise entirely
normal. Which of the following is the most likely diagnosis?
a. Ménière disease
b. Cerebellar stroke
c. Benign positional paroxysmal vertigo
d. Perilymph fistula
e. Vestibular neuronitis
95.A 77-year-old woman with a history of migraine in her 20s and 30s is seen by
her primary care physician with the complaint that she has headaches again for
the first time in many years. Upon further enquiry she reports a sense of
generalized fatigue and notes that there is discomfort over her right temple when
she brushes her hair. The neurologic examination is normal. Which of the
following would be the most appropriate clinical course?
a. Reassurance that her headaches are probably a recurrence of her old
migraine. No further investigations are needed.
b. MRI of the brain to rule out an intracranial mass lesion, because new-onset
headaches in the elderly are commonly caused by raised intracranial
 pressure.
c. LP to rule out high or low pressure headaches
d. Erythrocyte sedimentation rate, C-reactive protein, and temporal artery
biopsy, because giant cell arteritis is the most likely diagnosis.
e. Explanation that she likely has trigeminal neuralgia, given the distribution of
her symptoms over the right temporal region
96.A 63-year-old man with poorly controlled hypertension is brought to the ER
after being found by his wife, struggling to speak. When you examine him you
find that his naming is impaired and his verbal fluency is reduced, but other
language functions, including comprehension and repetition, are intact. Which of
the following conclusions is most accurate?
a. The reduced verbal fluency, together with an anomia, is most suggestive of a
posterior (Wernicke) aphasia.
b. The pattern of language impairment suggests a transcortical motor aphasia.
c. He does not have aphasia given that his language functions other than verbal
fluency and naming are intact.
d. The impaired ability to name objects (anomia) is most suggestive of a
conduction aphasia.
e. This is likely a confusional state rather than an aphasia.
97.A 27-year-old African-American woman with diabetes presents to the
outpatient Neurology clinic with subacute onset of bilateral facial weakness.
She explains that the symptoms have developed over the course of the past few
days. She also reports having a slightly raised and tender rash over the anterior
aspects of both shins. On examination, you find bilateral LMN facial weakness
as well as tender erythematous nodules over both shins. Which of the following
is the most likely diagnosis?
a. Guillain Barré syndrome
b. Lyme disease
c. Neurosarcoidosis
d. Diabetes
e. Tuberculosis
98.Ataxia may be a manifestation of which vitamin deficiency?
a. Vitamin A
b. Vitamin B12
c. Vitamin C
d. Vitamin D
e. Vitamin E
99.Which of the following are features most consistent with essential tremor?
 a. Asymmetry from left to right
b. Worse with rest than with action
c. Sporadic (i.e., nonfamilial) pattern of onset
d. Worsening with alcohol
e. Otherwise normal neurologic examination
100.Which of the following statements regarding higher cortical function is true?
a. Aphasia is characterized by a problem with articulation of words.
b. Apraxia is defined by the inability to carry out an automatic or unlearned
motor task.
c. Agnosia is an inability to recognize objects through a sensory modality even
when the primary sensory modality is unimpaired.
d. Neglect is a form of apraxia in which there is insufficient attention paid to one
hemispace.
e. Agraphia is a disorder in which affected individuals are unable to draw
pictures.
 Answers

1. c (Chapter 12)
The presence of visual hallucinations is an early symptom of dementia with Lewy
bodies (DLB). Other characteristics include cognitive decline, fluctuations of
alertness, extrapyramidal symptoms, and an extraordinary sensitivity to
neuroleptics. Visual hallucinations and sensitivity to neuroleptics are not early signs
of Alzheimer disease, Parkinson disease (PD), Pick disease, or vascular dementia.

2. b (Chapter 4)
Decreased visual acuity that does not correct with pinhole testing, a relative afferent
pupillary defect, and a central scotoma are characteristic of optic nerve disease. A
lesion affecting the optic chiasm will produce a bitemporal heteronymous
hemianopia. If a lesion affects the optic tract, the optic radiations (in both temporal
and parietal areas) or the occipital cortex (unilaterally), it will produce a
homonymous hemianopia that in the occipital cortex may be “macular sparing.”

3. d (Chapter 25)
Niemann–Pick disease, Gaucher disease, and Tay–Sachs disease are all associated
with cherry-red spots in the macula. Niemann–Pick disease is an autosomal
recessive disorder caused by sphingomyelinase deficiency. Alexander disease and
Canavan disease are dysmyelinating disorders with prominent macrocephaly, but
not cherry-red spots. The classic ophthalmologic finding of Hurler syndrome is
clouding of the cornea rather than a cherry-red spot in the macula. Krabbe disease is
an autosomal recessive disorder caused by galactosylceramide β-galactosidase
deficiency. It does not produce a cherry-red spot in the macula.

4. c (Chapter 23)
One possible etiology of sensory neuronopathies is a paraneoplastic disorder, in
particular one caused by small cell lung cancer. This is generally associated with
positive anti-Hu antibodies (antineuronal antibodies) and can also be associated
with paraneoplastic encephalomyelitis, ataxia, and autonomic neuropathy. Anti-
GM1 has been associated with multifocal motor neuropathy with conduction block.
MRI of the spine would not help at this stage. Other causes of sensory neuronopathy
include Sjögren syndrome, pyridoxine intoxication, and chemotherapy (cisplatin).
Chest CT to search for occult malignancy is also recommended.

5. d (Chapter 1)
Each cranial nerve courses through a particular foramen, or opening, in the skull.
Skull base fractures and other such injuries can result in damage to these structures
and injury to the associated cranial nerves. The seventh (facial) and eighth
(vestibulocochlear) nerves both course through the internal auditory meatus, which
may have been damaged in this woman’s case.

6. d (Chapter 2)
Despite the normal head CT, this woman has had a subarachnoid hemorrhage. She
should undergo a vascular imaging study of the brain such as a conventional
angiogram, CT angiogram, or MR angiogram to investigate for a cerebral aneurysm.
Xanthochromia is the result of breakdown of blood within the subarachnoid space.
Its presence in a bloody cerebrospinal fluid (CSF) sample helps distinguish
intrathecal hemorrhage from a traumatic tap. This patient’s CSF contains relatively
few WBCs, and thus does not suggest an active infection. The CSF glucose is
typically normal in both subarachnoid hemorrhage and viral meningitis; it is
frequently low in bacterial, mycobacterial, and carcinomatous meningitis. An
opening pressure of 14 cm H2O is within the normal range of 6 to 15 cm H2O.

7. d (Chapter 3)
This patient’s clinical presentation suggests increased intracranial pressure (ICP)
from a right hemisphere lesion. The “blown” right pupil suggests that herniation of
the right hemisphere has compressed the right oculomotor nerve. Choices A through
C are all measures that acutely decrease ICP, whereas neurosurgery may be needed
as a more definitive intervention. Performing a lumbar puncture in this situation
could be dangerous and could cause worsening herniation.

8. e (Chapter 5)
Symmetric proximal weakness usually suggests a primary muscle problem, as does
weakness of neck flexors and extensors. The absence of muscle pain and tenderness
does not argue against primary muscle pathology. The other listed choices would not
usually result in this pattern of weakness.

9. b (Chapter 15)
This child likely has absence seizures, which are frequently diagnosed after a
teacher or parent notices inattention, “daydreaming,” or staring episodes. Absence
seizures often last a few seconds each, can occur many times a day, and have a
classic EEG appearance. Ethosuximide and valproic acid are typical drugs of
choice.

10. b (Chapter 10)

This woman is suffering from a migraine headache. Sumatriptan is effective as
abortive treatment. The other medications are effective in decreasing the severity
and frequency of attacks and are used as preventive therapy.

11. c (Chapter 12)

This case represents an early onset of dementia with associated personality changes
and movement disorder (chorea)—the classic triad of Huntington disease (HD). HD
is linked to chromosome 4p16.3, also known as the HD gene, encoding for a protein
called huntingtin. This gene normally contains a CAG repeat sequence that, when
expanded beyond 40 repeats, causes an abnormally long and neurotoxic version of
the huntingtin protein. HD is not linked to the other chromosomes listed.

12. b (Chapter 8)
Paraneoplastic cerebellar degeneration is typically a pancerebellar syndrome with
clinical manifestations including ataxia, dysarthria, and nystagmus. The underlying
malignancy is typically a gynecologic one or breast cancer. The temporal evolution
is typically that of acute or subacute onset with fairly rapid progression over weeks
to months, followed by stabilization. Spinocerebellar ataxia would be present
earlier in life and progress more slowly. Metastatic cerebellar disease would more
likely affect a cerebellar hemisphere and produce lateralized cerebellar dysfunction.
Alcoholic cerebellar degeneration typically affects the vermis, and the
characteristic manifestation is that of a gait ataxia. Stroke (ischemic or
hemorrhagic), although abrupt in onset, would not be expected to progress over a
period of weeks to months.

13. b (Chapter 9)
Multiple sclerosis (MS) characteristically produces an upper motor neuron (UMN)
bladder or spastic bladder with increased frequency and urgency. Stress
incontinence is an involuntary loss of urine during coughing, sneezing, laughing, or
other physical activities that increase intra-abdominal pressure. An atonic bladder
is characterized by overflow incontinence and increased capacity and compliance.

14. a (Chapter 9)
Atonic bladder implies a lower motor neuron (LMN) lesion at the level of the conus
medullaris, cauda equina, sacral plexus, or peripheral nerves. It is characterized by
overflow incontinence and increased capacity and compliance. Diabetes is the only
one in the group likely to produce that type of deficit.
15. a (Chapter 24)
Myotonic dystrophy is a multisystem disorder that may also cause frontal balding,
diabetes, and gastrointestinal symptoms. It is the most common adult-onset muscular
dystrophy. It is inherited in an autosomal dominant manner and is caused by a triplet
repeat expansion in the DMPK gene. EMG typically shows myotonic discharges.

16. b (Chapter 16)

She likely has Wilson disease, an autosomal dominant disorder of copper
metabolism that presents with neuropsychiatric symptoms as well as a movement
disorder. The pigment changes in the cornea are Kayser–Fleischer rings and are
characteristic of Wilson disease. The most common pattern of laboratory
abnormalities is increased serum free copper, decreased serum ceruloplasmin, and
increased 24-hour urinary copper excretion.

17. a (Chapter 5)
The patient’s current symptoms are suggestive of a right radial neuropathy. Multiple
sequential mononeuropathies, each affecting a single peripheral nerve, are known as
mononeuropathy multiplex. Pain is a typical feature. Patients with rheumatologic
conditions are susceptible; vasculitis may be involved.

18. c (Chapter 11)

Broca’s aphasia is characterized by effortful nonfluent speech and an inability to
repeat, with relatively preserved comprehension. Transcortical motor aphasia is
similar but has preserved repetition.

19. b (Chapter 21)

Along with the clinical picture, a CSF profile of lymphocytic pleocytosis, elevated
protein, normal glucose, and a negative Gram stain point to viral or aseptic
meningitis. The clinical presentations of illnesses (a) through (d) could appear very
similar, but the CSF analysis is crucial in identifying the responsible organism. This
patient’s CSF should still be screened for herpes simplex virus (HSV), and empiric
acyclovir should be considered because the morbidity and mortality from untreated
HSV meningitis is high. Bacterial meningitis tends to produce a granulocytic
pleocytosis. Fungal meningitis is usually associated with hypoglycorrhachia
(defined as a CSF-serum glucose ratio below 0.4). Subarachnoid hemorrhage
characteristically produces a large number (thousands) of RBCs.

20. c (Chapter 2)
About 50% of patients with epilepsy have normal routine EEGs. A seizure is a
clinical diagnosis, and this patient’s convincing history supersedes the normal EEG.
Long-term video-EEG monitoring is not required to prove the diagnosis of seizure.
Although hyperventilation can help elicit absence seizure activity on EEG, his
history and age make an absence seizure unlikely. Although an ischemic stroke can
precipitate a seizure, this man’s history is most suggestive of seizure. The mild right
hemiparesis is more likely a Todd’s paralysis rather than due to an ischemic stroke.

21. a (Chapter 11)

This patient exhibits a form of neglect, in which he does not recognize his left arm
as his. Right frontal or parietal lesions are the most common causes. In the alien-
limb phenomenon, patients retain awareness of the limb but feel that it is not under
their control.

22. a (Chapter 15)

Benzodiazepines are the first agents used in the treatment of status epilepticus.
Typically, phenytoin and then phenobarbital are used subsequently. Propofol is used
if status epilepticus becomes refractory, while carbamazepine and lamotrigine are
anti-seizure drugs not often used in the early treatment of status epilepticus, as they
have no intravenous preparation.

23. e (Chapter 17)

Subfalcine herniation may result in compression of the anterior cerebral arteries,
and therefore bilateral leg weakness. Ipsilateral third nerve palsy is the first sign of
uncal (not subfalcine) herniation. Continued uncal herniation may result in
compression of the contralateral cerebral peduncle against the free edge of the
tentorium, leading to ipsilateral hemiparesis (the “Kernohan’s notch” phenomenon).
Small, reactive pupils are seen in early transtentorial (central) herniation.

24. e (Chapter 20)

Intravenous corticosteroids may delay, but not prevent, the development of MS in a
patient with optic neuritis. They are preferred to oral corticosteroids. Interferon β-
1b and natalizumab are used for the longer term treatment of MS, but not in the
treatment of isolated optic neuritis.

25. c (Chapter 4)
Lesions of the medial longitudinal fascicle (MLF) produce an internuclear
ophthalmoplegia (INO). The clinical characteristics of a right INO include inability
to adduct the right eye in left lateral gaze plus nystagmus of the abducting left eye.
(Adduction during convergence is maintained because this action does not depend
on the MLF.) “One-and-a-half syndrome” occurs as a consequence of a lesion
involving the PPRF or sixth-nerve nucleus and the adjacent ipsilateral MLF. This
produces an ipsilateral gaze palsy and INO on the contralateral side; the only eye
movement present in the lateral plane is abduction of the contralateral eye.

26. a (Chapter 21)

Aseptic meningitis and cranial nerve palsies (such as facial nerve palsy) are among
the early manifestations when the nervous system becomes involved in Lyme
disease. Painful polyradiculopathy or leukoencephalopathy are two (typically later)
neurologic complications of Lyme disease. Spinal cord compression and
generalized epilepsy are unlikely to occur due to Lyme disease.

27. c (Chapter 18)

Sarcoidosis is one of the most common causes of bilateral LMN facial weakness. It
is also an important cause of a lymphocytic meningitis (hence the headache) and may
cause a variety of other cranial neuropathies, including optic neuropathy (hence the
relative afferent papillary defect). MS is another important cause of optic neuritis,
but bilateral facial weakness would be unusual. Guillain–Barré syndrome (GBS)
may cause bilateral facial weakness, but typically in the context of areflexia and
generalized weakness; a relative afferent papillary defect is not likely to occur in
GBS. Lyme disease may cause bilateral facial weakness similarly (although
unilateral facial weakness is more common); the afferent papillary defect would not
be expected. Vasculitis is an extremely unusual cause of bilateral facial weakness.

28. a (Chapter 14)

The sudden onset of symptoms in the context of the patient’s stroke risk factors
makes a pure sensory stroke in the contralateral thalamus the most likely diagnosis.
Lesions of the internal capsule, precentral gyrus, or corona radiata would be more
likely to produce predominantly motor deficits. A lesion in the right occipital lobe
would usually produce a visual field deficit, but not somatosensory numbness.

29. b (Chapter 17)

The middle meningeal artery travels between the skull and the dura. When it is
damaged (typically due to trauma resulting in a skull fracture that lacerates that
artery), blood accumulates in the epidural space, resulting in an epidural hematoma.
Patients often have a brief episode of loss of consciousness at the time of trauma,
followed by a “lucid interval,” and then clinical deterioration as the bleeding
continues. If untreated, the blood will continue to collect and may cause brain
herniation, as in this case. An ischemic infarct would be expected to have a sudden
onset, without a progressive decline in function. Likewise, a concussion should not
cause progressive neurologic decline and, similar to drug intoxication, would not
result in the physical signs seen in this patient. Diffuse axonal injury should not
produce lateralized deficits.

30. d (Chapter 22)

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with involvement of
the LMNs and corticospinal tracts. Weakness, muscle atrophy, and muscle
fasciculations are prominent features. Sensory findings almost never occur in ALS.
Vitamin B12 deficiency classically results in degeneration of the dorsal columns and
corticospinal tracts. Therefore, joint position sense loss and weakness are typical
features, but pain and temperature sensation are spared. Brown-Séquard syndrome
results from hemisection of the spinal cord. The classic features are ipsilateral
weakness and loss of joint position sense, with contralateral loss of pain and
temperature sensation below the lesion. Tabes dorsalis is a late complication of
neurosyphilis and is characterized by isolated dorsal column dysfunction resulting in
loss of joint position sense. Anterior spinal artery syndrome usually results from
infarction of the anterior spinal artery, causing ischemia to the anterior two-thirds of
the spinal cord. Therefore, dorsal columns are spared, but weakness and loss of
pain and temperature sensation result because of involvement of the ventral horns
and spinothalamic tracts.

31. c (Chapter 25)

This patient has features suggestive of tuberous sclerosis complex (TSC). A head
CT or MRI may identify cortical tubers, subependymal giant cell astrocytomas, or
other lesions. The other tests do not help in the evaluation of TSC.

32. a (Chapter 25)

A diagnosis of autism requires a combination of social, behavioral, and language
abnormalities. Asperger syndrome shares social isolation and eccentric behavior
with autism, but language is normal. Gross and fine motor delays are not required
features of either condition.

33. c (Chapter 6)
Allodynia is pain provoked by normally innocuous stimuli; hyperesthesia is
increased sensitivity to sensory stimuli, and paresthesias are abnormal spontaneous
sensations. “Hypesthesia” refers to decreased sensation.

34. c (Chapter 4)
This patient appears to have a Horner’s syndrome on the right, likely produced by a
carotid dissection as a consequence of neck trauma. Horner’s syndrome is
characterized by unilateral miosis, ptosis, and (sometimes) ipsilateral facial
anhidrosis as a result of impaired sympathetic innervation. Examine the pupils in the
dark (turn the lights off and look at the pupils during the first 5 to 10 seconds). A
dilation lag in the small pupil and anisocoria greater in darkness means a
sympathetic defect in the smaller pupil and will help with the diagnosis.

35. b (Chapter 23)

This patient appears to have a Guillain Barré syndrome. Albuminocytologic
dissociation means high protein with almost no cells in the CSF, which is
characteristic of this syndrome. Immediately after the onset of weakness, however
(the first 3 to 4 days), the CSF could be completely normal. Additional studies to
corroborate the diagnosis include nerve conduction studies and EMG to demonstrate
slowing of conduction velocities, prolongation of F-wave latency, and possible
conduction block.

36. d (Chapter 23)

This patient appears to have acute ascending weakness with loss of reflexes
characteristic of Guillain Barré syndrome or acute inflammatory demyelinating
polyradiculoneuropathy. His examination worsens while in the emergency room,
and that should be an indication that he is deteriorating quickly and needs to be
admitted to the ICU for close observation. A forced vital capacity (FVC) below 15
mL/kg is an indication for intubation and mechanical ventilation. The presence of a
foot drop should not factor into decisions about ICU admission.

37. a (Chapter 23)

Cytomegalovirus (CMV) infection is the most common cause of polyradiculitis or
cauda equina syndrome in an immunocompromised individual. The other agents do
not affect the nerve roots or cauda equina primarily. CMV polyradiculitis occurs in
about 2% of AIDS cases and is characterized by the subacute onset of a flaccid
paraparesis, sacral pain, paresthesias, and sphincter dysfunction. Polymerase chain
reaction evaluation of the CSF for CMV can provide a definitive diagnosis.
Treatment is with ganciclovir or foscarnet or, in severe cases, both drugs.

38. d (Chapter 7)
Her symptoms consist of a feeling of movement—which is vertigo. The intermittent
nature of her vertigo, the exacerbation with head movement, and the absence of
brainstem signs are consistent with benign positional paroxysmal vertigo (BPPV).
To confirm the diagnosis, one can perform the Dix–Hallpike maneuver at the
bedside. Brainstem and cerebellar infarctions rarely present with isolated vertigo,
and Ménière disease is characterized by hearing loss and tinnitus along with
episodic vertigo.
39. d (Chapter 24)
The primary antigenic target in autoimmune myasthenia gravis (MG) is the
postsynaptic nicotinic acetylcholine receptor. Presynaptic voltage-gated calcium
channels are the target of the Lambert–Eaton myasthenic syndrome.

40. a (Chapter 1)
The trigeminal nerve is responsible for the muscles of mastication. The facial nerve
innervates the muscles of facial expression, the oculomotor nerve subserves eye
movements, the glossopharyngeal nerve innervates some pharyngeal muscles, and
the hypoglossal nerve moves the tongue.

41. d (Chapter 3)
The Glasgow Coma Scale (GCS)—which provides a composite assessment of
unresponsive patients depending on their eye movements, motor function, and
language ability—is typically used for patients after head trauma. It has prognostic
value for patients with head injuries and is easy for nonphysicians to use.

42. e (Chapter 3)
A noncontrast head CT is the imaging study of choice in suspected intracranial
hemorrhage. This allows for the easiest delineation of acute blood, which should
appear hyperdense (bright) on this study—whether subdural, epidural, or
intraparenchymal hemorrhage. A CT scan might not show a small cerebral
infarction, but it would probably show a large infarction compatible with the
patient’s poor responsiveness.

43. e (Chapter 10)

The patient’s clinical presentation is typical of temporal arteritis: age over 50, pain
over the temporal arteries, jaw claudication, and an elevated erythrocyte
sedimentation rate (ESR). Definitive diagnosis is made by temporal artery biopsy.
Treatment with prednisone for several months must be initiated early, because
involvement of the ophthalmic artery can lead to blindness if diagnosis and
treatment are delayed.

44. e (Chapter 13)

The history and examination suggest a diagnosis of obstructive sleep apnea.
Polysomnography is the best test to confirm the diagnosis. Although narcolepsy is
also associated with excessive daytime sleepiness, patients often have associated
hypnagogic hallucinations or cataplexy, which are absent in this patient. The
multiple sleep latency test (MSLT) is useful for diagnosing narcolepsy, whereas
MRI of the brain, LP, and EEG are unlikely to be of diagnostic value in this patient.
45. c (Chapter 17)
Uncal herniation results from mass lesions of the middle cranial fossa. This patient
most likely has a hemorrhage in the middle cranial fossa from head trauma. If large
enough, the mass lesion causes displacement of the medial portion of the temporal
lobe (uncus) downward over the tentorium cerebelli, typically resulting in
entrapment of the ipsilateral third cranial nerve and compression of the brainstem.
This compression can cause coma due to disruption of the ascending arousal system
in the brainstem. It causes an ipsilateral dilated pupil due to compression of the
parasympathetic nerve fibers (traveling with the third cranial nerve) that normally
cause pupillary constriction. Diffuse axonal injury can result in coma, but would not
be expected to cause the dilated, unreactive pupil. Infarction of the occipital lobe
should produce a homonymous hemianopia, not a loss of consciousness. Cervical
spine fracture may lead to weakness below the level of the lesion but should not
impair consciousness.

46. a (Chapter 14)

Intracerebral hemorrhages caused by hypertension are most often found in the basal
ganglia, thalamus, pons, and cerebellum, in order of decreasing frequency.

47. c (Chapter 13)

Continuous positive airway pressure is the treatment of choice for patients with
obstructive sleep apnea. Sodium oxybate, methylphenidate, and clomipramine are
used for patients with narcolepsy and cataplexy. Sedating drugs such as clonazepam
and other benzodiazepines can decrease upper airway tone, leading to worsened
symptoms of obstructive sleep apnea.

48. a (Chapter 19)

A headache that is either different from the normal pattern or progressive deserves
to be investigated further with a brain imaging study. Slowly progressive brain
tumors can be associated with a normal neurologic examination or minor
abnormalities. Nausea and vomiting need not be present, especially in the early
stages of a tumor. Administration of pure oxygen is an effective treatment for cluster
headaches, but the patient’s description is not consistent with that diagnosis.

49. b (Chapter 19)

Seizures or hemiparesis are not usual features of pituitary adenoma. Varying degrees
of bitemporal hemianopia (a visual field deficit in the temporal visual fields
bilaterally) may be caused by compression of the optic chiasm. A homonymous
hemianopia results from dysfunction of the optic radiations or visual cortex
posterior to the chiasm. On brain imaging with contrast, pituitary adenomas usually
enhance in a homogeneous manner and do not typically exhibit ring enhancement.

50. d (Chapter 22)

Signs of UMN or corticospinal tract dysfunction include hypertonia, spasticity,
increased reflexes, and an extensor plantar response (Babinski sign). Signs of LMN
dysfunction include hypotonia, decreased or absent reflexes, and a flexor plantar
response (downgoing toe). Weakness may be present with either UMN or LMN
dysfunction. Hypotonia is not characteristic of a UMN lesion, but it is fair to note
that a flaccid paralysis may follow an acute, severe insult, such as in “spinal shock.”

51. a (Chapter 2)
C T without contrast is the imaging modality of choice for demonstrating acute
intracranial bleeding. Although it is true that MRI provides better visualization of
the contents of the posterior fossa, a cerebellar hemorrhage usually will be visible
on CT. Patients with pacemakers and most other implanted metal objects cannot
undergo MRI. Although MRI with diffusion-weighted imaging is the most sensitive
test for ischemic stroke, a susceptibility-weighted MRI sequence is preferred for
detecting intracranial blood. A single-photon emission computed tomography
(SPECT) scan may help in the evaluation of dementia or epilepsy, but will not be
useful in this scenario.

52. b (Chapter 21)

In the presence of severe Lyme disease with central nervous system (CNS)
involvement, as in this case, intravenous antibiotics followed by oral therapy are the
first choice. Intravenous ceftriaxone is the first choice here. The combination of oral
amoxicillin and doxycycline is the most common treatment for uncomplicated Lyme
disease. Fluconazole is an antifungal agent and has no value in the treatment of
Borrelia burgdorferi infection.

53. c (Chapter 12)

Pathologically, PD is characterized by progressive death of dopaminergic neurons
of the substantia nigra pars compacta. Most cases of PD are sporadic, but there are
reports of familial cases in which mutations in the parkin and α-synuclein genes
have been described. Impairment of vertical gaze is a common feature of
progressive supranuclear palsy (PSP), a neurodegenerative disorder that also has
parkinsonian features. Despite the gait manifestations of PD, early falls are actually
uncommon (but are common in PSP).

54. d (Chapter 24)

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are
allelic disorders due to mutations in the dystrophin gene, located on the X
chromosome. The inheritance pattern is X-linked. The limb-girdle muscular
dystrophies are a heterogeneous group of disorders, some with autosomal dominant
and some with autosomal recessive inheritance. Mutations in a wide variety of
genes have been reported in patients with limb-girdle muscular dystrophy, including
the sarcoglycan genes.

55. c (Chapter 1)
The cerebellum is the primary brain structure involved in coordination, although
other components of the motor pathways are involved as well. Testing for rapid
alternating movements is part of the coordination examination. The other choices
listed have less, or no, primary role in coordination.

56. b (Chapter 5)
“Crossed signs” can occur with unilateral lesions in the pons if descending motor
fibers heading for the ipsilateral facial nucleus are affected, with the descending
fibers heading for the contralateral spinal cord. With right pontine lesions, the right
face and left body could be weak.

57. e (Chapter 15)

Characteristic side effects of carbamazepine include hyponatremia, agranulocytosis,
and a risk for Stevens–Johnson syndrome. Except for the hyponatremia, these side
effects are rare, and the hyponatremia may not cause symptoms.

58. c (Chapters 14 and 17)

Aneurysmal rupture is the most common cause of (nontraumatic) subarachnoid
hemorrhage. Tearing of bridging veins produces a subdural hematoma. Laceration of
the middle meningeal artery causes an epidural hematoma. Amyloid angiopathy is a
cause of lobar hemorrhage in the elderly. Although rupture of an arteriovenous
malformation may lead to a subarachnoid hemorrhage, aneurysmal rupture is a more
common cause.

59. b (Chapter 19)

Meningiomas enhance in a bright and mainly homogeneous manner. Certain tumors
(particularly glioblastoma multiforme and metastatic lesions), brain abscesses,
toxoplasmosis, granulomas, and active demyelinating lesions typically show ring
enhancement after contrast administration. Although lymphomas can enhance in a
homogeneous manner, they can also be ring enhancing.

60. b (Chapter 7)
Micturition syncope is a form of reflex or neurogenic syncope that involves the
triggering of cardioinhibitory or vasodepressor responses or both. The symptoms of
light-headedness and graying of vision are typically reported by patients with
syncope. Other symptoms might include a heavy feeling at the base of the neck,
buckling at the knees, and tinnitus. Although orthostatic hypotension is a common
cause of syncope, the occurrence of syncope after micturition, rather than upon
standing, suggests that this is not the cause in this case. Vasovagal syncope is
another common cause of syncope but typically occurs in the setting of acute pain or
with a strong emotional response. Vestibular neuronitis is characterized by vertigo,
and there is no associated loss of consciousness. (Older patients with syncope
should be screened carefully for cardiogenic causes as well.)

61. e (Chapter 21)

HSV infection is the leading diagnostic consideration. In HSV, the magnetic
resonance imaging often shows contrast enhancement and edema of the temporal
lobes, helping to establish the diagnosis and ruling out some other concerns.
Treatment for viral meningitis is mainly supportive, because there are no specific
treatments for most viral infections. If HSV infection is suspected, however,
treatment should begin promptly with intravenous acyclovir even while tests are
pending, because mortality is close to 70% in untreated cases. In immune
suppressed patients, it is appropriate to cover for bacterial infections as well until
the preliminary cultures return.

62. b (Chapter 23)

Physical examination is the most important information to define symptoms as
belonging to the peripheral nervous system (PNS). Sensory symptoms can have a
central or peripheral origin. The acuteness of the presentation does not help
localization in this case. Paresthesias may be seen in both PNS and CNS
dysfunction.

63. a (Chapter 17)

Neurosurgical decompression is the proper treatment for an epidural hematoma
causing coma. This is a neurosurgical emergency, so conservative management
would only result in further neurologic decline. Although hyperventilation and
administration of mannitol may help to decrease ICP, these are temporizing
measures; neurosurgical decompression is necessary to remove the accumulating
blood. Because the patient has a hemorrhage, tissue plasminogen activator, which is
used in acute ischemic strokes, would be contraindicated.

64. c (Chapter 20)

Acute disseminated encephalomyelitis (ADEM) is a monophasic demyelinating
illness. MS is characterized by multiple white matter lesions separated in space and
time; it is not monophasic (although, of course, the monophasic nature of the course
will not be clear at the onset of this illness). Oligoclonal bands in the CSF are more
common in MS than in ADEM. The pleocytosis of ADEM is usually lymphocytic. It
may be neutrophilic in neuromyelitis optica. Both MS and ADEM can produce
multiple lesions on MRI. ADEM is acquired and commonly occurs after viral
infections or vaccinations. A positive family history is more likely to be relevant for
a patient with MS.

65. b (Chapter 23)

This presentation is most consistent with diabetic amyotrophy, a condition that
affects the lumbosacral plexus and tends to resolve spontaneously over months to
years. Diabetes predisposes to both diabetic amyotrophy and peripheral neuropathy.
Peripheral neuropathy, or polyneuropathy, is a more common manifestation of
diabetes and often causes painful sensory symptoms distally in both legs. Patients
with mononeuritis multiplex, a vasculitic neuropathy, often report the stepwise
development of painful sensorimotor deficits in several individual nerve territories;
nerves in watershed regions (e.g., peroneal in the leg, ulnar in the arm) are more
vulnerable given the lack of overlapping blood supply. Strokes are unlikely to
produce pain. An intervertebral disk herniation at L5–S1 would not cause weakness
of iliopsoas or quadriceps.

66. b (Chapter 17)

The patient’s symptoms and head CT findings are consistent with an epidural
hematoma, which results from laceration of the middle meningeal artery. The classic
head CT finding of an epidural hematoma is a hyperdense region with a biconvex or
lenticular shape. Tearing of bridging veins leads to subdural hematoma. Contact of
the brain’s frontal poles with the skull leads to cerebral contusions. On head CT,
these areas appear as hyperdensities within the brain parenchyma and not in the
epidural or subdural spaces. Diffuse axonal injury results from rotational
acceleration and deceleration of the brain can be associated with either a normal
head CT scan or hemorrhages within the deep white matter of the brain. Rupture of a
cerebral aneurysm results in subarachnoid hemorrhage, not an epidural hematoma.

67. b (Chapter 16)

Progressive supranuclear palsy is a disorder characterized by parkinsonism,
supranuclear impairment of eye movements (vertical gaze typically affected more
prominently than horizontal gaze), and impaired postural reflexes. Corticobasal
ganglionic degeneration and Parkinson disease may also cause rigidity and poor
postural reflexes, but are not typically associated with eye movement abnormalities.
Miller–Fisher syndrome and chronic progressive external ophthalmoplegia are both
associated with eye movement abnormalities, but these disorders affect the external
ocular muscles rather than the supranuclear gaze centers and are not associated with
extrapyramidal features.

68. b (Chapter 18)

Small-fiber neuropathy typically produces symptoms of neuropathic pain, and
examination shows impaired temperature and pinprick sensation. Other sensory
modalities are mediated by large fibers. Weakness and atrophy reflect involvement
of motor fibers rather than small-fiber sensory function.

69. a (Chapter 22)

The patient exhibits both UMN signs (hyperreflexia, spasticity, and Babinski signs)
and LMN signs (atrophy and fasciculations), which are the hallmark of ALS.
Weakness can occur with either LMN or UMNdysfunction. None of the other
options listed would cause widespread UMN and LMN signs. Vitamin B12
deficiency classically results in degeneration of the dorsal columns (loss of joint
position sense) and corticospinal tracts (UMN signs). Anterior spinal artery
syndrome usually results from infarction of the anterior spinal artery, causing
ischemia to the anterior two-thirds of the spinal cord; therefore, dorsal columns are
spared, but weakness and loss of pain and temperature sensation result because of
involvement of the ventral horns and spinothalamic tracts. Central cord syndrome is
most common in the cervical cord and typically results in loss of pain and
temperature sensation in a capelike distribution. Brown-Séquard syndrome results
from hemisection of the spinal cord. The classic features are ipsilateral weakness
and loss of joint position sense with contralateral loss of pain and temperature
sensation below the lesion.

70. e (Chapter 13)

This patient has a history consistent with advanced sleep phase disorder. It is most
appropriately treated with bright light therapy in the evening and melatonin to help
reset her circadian rhythms. Continuous positive airway pressure is used to treat
obstructive sleep apnea. Behavioral modification is useful for many forms of
insomnia, but bright light therapy is more effective for advanced sleep phase
disorder. Modafinil is more appropriate for narcolepsy. The patient sleeps 8 hours
each night, and zolpidem is not likely to help her.

71. a (Chapter 16)

The extrapyramidal features of idiopathic PD are typically asymmetric. Postural
reflexes may be impaired in a number of extrapyramidal disorders including
idiopathic PD. Impaired vertical gaze is more typical of PSP than of idiopathic PD.

72. c (Chapter 8)
Miller–Fisher syndrome (MFS) is a disorder characterized by ataxia,
ophthalmoplegia, and areflexia. It is considered a variant of the Guillain Barré
syndrome and is associated with the finding of anti-GQ1b antibodies in the serum.
Stroke (involving either the brainstem or cerebellum) should be sudden in onset, not
typically progressing over several days. Ophthalmoplegia may be seen in both
myasthenia gravis (MG) and MFS, but areflexia is not a feature of MG. Alcoholic
cerebellar degeneration may be associated with a peripheral neuropathy and loss of
joint position sense and deep tendon reflexes, but should not produce
ophthalmoplegia (unless associated with Wernicke’s encephalopathy, in which case
confusion should also be present).

73. c (Chapter 9)
Acute urinary incontinence is an emergency. MRI of the spine will help determine
whether an acute lesion is responsible for the incontinence (cauda equina or conus
medullaris syndrome, spinal cord compression, etc.). Determination of the post-void
residual would not help in this situation, and urodynamic studies are not indicated in
the acute setting. LP is not indicated in this situation.

74. d (Chapter 10)

Both chronic paroxysmal hemicrania and cluster headache are unilateral and can
produce conjunctival injection. Chronic paroxysmal headache is more common in
women, whereas cluster headache is more common in men. Response to
indomethacin is seen in chronic paroxysmal hemicrania, but not in cluster headache.
Episodes of chronic paroxysmal hemicrania typically last for 20 minutes rather than
hours.

75. e (Chapter 11)

Although the patient’s symptoms are somewhat nonspecific, examination shows that
he has normal language function but with inability to perform certain actions
described by the examiner. “Apraxia” refers to the inability to perform a learned
motor task and it is typically caused by lesions in either the frontal or parietal lobe
of the (language) dominant hemisphere.

76. d (Chapter 2)
Xanthochromia is a yellow discoloration of the supernatant in a spun sample of
CSF. It signifies the presence of blood due to a subarachnoid hemorrhage (if blood
has been present for a few hours). In a traumatic tap, the red cells precipitate, and
the supernatant is colorless. Increased opening pressure, increased white cell count,
and pain upon needle insertion may or may not be present in either condition.
Increased red cell count is seen both in a subarachnoid hemorrhage and in a
traumatic tap.

77. e (Chapter 2)
Although T1 and T2 images may detect blood breakdown products, susceptibility
imaging or gradient-echo imaging is the most sensitive technique for determining the
presence of intracranial hemorrhage. Contrast-enhanced T1 is more useful for
detecting the presence of a brain tumor. Fluid-attenuated inversion recovery
(FLAIR) imaging is the single best MRI technique for screening for most types of
intracranial lesions, particularly demyelinating ones.

78. c (Chapter 13)

Rapid eye movement (REM) sleep behavior disorder often predates the
development of synucleinopathies by years or even decades. Examples of
synucleinopathies include Parkinson disease, Lewy body dementia, and multiple
system atrophy. Alzheimer disease, multiple sclerosis, myasthenia gravis, and
primary lateral sclerosis are not synucleinopathies and are not associated with REM
sleep behavior disorder.

79. a (Chapter 14)

Of the vascular malformations, arteriovenous malformations are at the greatest risk
for bleeding, with a rate of bleeding of approximately 2% to 3% per year. Capillary
telangiectasias, cavernous hemangiomas, and developmental venous anomalies are
vascular malformations that rupture much less frequently. The vein of Galen is a
normal anatomic structure.

80. b (Chapter 14)

The patient has a pure motor stroke involving the right hemibody. Possible
localizations for this syndrome include the left corona radiata, left internal capsule,
and the left side of the base of the pons. Infarction of the motor cortex capable of
producing a right hemiplegia would also likely cause aphasia. Thalamic strokes
produce more prominent sensory deficits. The lateral medullary (Wallenberg)
syndrome is associated with ipsilateral ataxia, ipsilateral Horner’s syndrome, and
ipsilateral facial sensory loss, with contralateral impairment of pain and
temperature in the arm and leg, nystagmus, and vertigo; weakness is absent in a
Wallenberg syndrome because motor fibers travel more anteriorly within the
medulla. Cerebellar hemisphere infarctions produce limb ataxia but not a dense
hemiplegia.
81. b (Chapter 24)
DMD is associated with a marked elevation of the serum creatine kinase (CK)
level. BMD and limb-girdle muscular dystrophy are associated with less markedly
elevated CK levels. Myotonic dystrophy may be associated with a normal CK or
only mild elevation. Lambert–Eaton myasthenic syndrome is a neuromuscular
junction disorder, not typically associated with elevations in CK levels.

82. b (Chapter 1)
The ability to walk in a steady, coordinated manner requires the concerted
functioning of multiple parts of the nervous system, including motor pathways,
sensory tracts, and the cerebellum, among other systems. Testing for gait
abnormalities is thus a sensitive way to detect abnormalities in many different
nervous system functions.

83. a (Chapter 3)
Locked-in syndrome (or a “de-efferented” state) that generally occurs with large
lesions in the base of the pons, such as infarcts from cardiac embolism or basilar
artery stenosis, is characterized by loss of all significant motor function except eye
blinking or perhaps vertical eye movements, with preservation of awareness and
cognitive function. A large pontine lesion will typically affect corticobulbar and
corticospinal fibers bilaterally, but blinking and vertical eye movements are
preserved because of intact midbrain function.

84. d (Chapter 3)
Mannitol is an osmotic diuretic that can be used to lower increased ICP, although
the benefit may be transient. Lowering the head of the bed, loading intravenous
fluids, or decreasing the respiratory rate would raise ICP. Basilar artery stenting is
not an appropriate intervention for increased ICP.

85. b (Chapter 12)

Dementia with Lewy bodies may be the second most common type of dementing
illness after Alzheimer disease. It is characterized by a parkinsonian motor
syndrome, visual hallucinations, and marked fluctuations in alertness, as well as an
exquisite sensitivity to neuroleptic medications.

86. e (Chapter 12)

The two neuropathologic hallmarks of Alzheimer disease are amyloid plaques and
neurofibrillary tangles. The presence of Lewy bodies in the substantia nigra suggests
Parkinson disease and in cortical neurons suggests dementia with Lewy bodies.
Prominent atrophy of the caudate is seen in Huntington disease. Spongiform changes
in cortex suggest the possibility of Creutzfeldt–Jakob disease.

87. a (Chapter 15)

The diagnosis of seizures is a clinical one. Except on the rare occasion when a
paroxysmal event is directly observed by the physician, the best way to distinguish a
seizure from other episodes of neurologic dysfunction such as syncope, migraine, or
transient ischemic attack is by detailed characteristics obtained from the history.
The other listed choices may contribute to the diagnostic workup, but none is as
important as the history in making the diagnosis.

88. c (Chapter 21)

A CSF leukocytosis, elevated protein, and depressed glucose level form the
characteristic profile in acute bacterial meningitis. Viral meningitides typically do
not depress the CSF glucose. Fungal and tuberculous meningitides can share a
common profile with bacterial meningitis except that the leukocytosis predominantly
involves lymphocytes rather than neutrophils (except initially).

89. c (Chapter 19)

The typical “butterfly” pattern is characteristic of glioblastoma multiforme. There
are other tumors that can cross white matter tracts, such as lymphoma. The other
options are very unlikely to produce this radiologic pattern. Moreover, the usual
location of meningiomas, ependymomas, and schwannomas is not those found on this
MRI.

90. d (Chapter 4)
Bitemporal visual field defects are seen in conditions affecting the optic chiasm,
such as suprasellar tumors. Lesions in the left optic radiation produce a right
homonymous hemianopia, and lesions of the right occipital lobe a left homonymous
hemianopia. Optic nerve lesions produce unilateral visual field defects.

91. e (Chapter 6)
Sensory symptoms in the thumb can be related to median neuropathies (as in a
carpal tunnel syndrome) but also to higher lesions such as those seen in a C6
radiculopathy. Lower trunk brachial plexopathy or C8 or T1 radiculopathies would
involve the fourth and fifth digits and intrinsic muscles of the hand (including those
innervated by the median nerve). The fact that the EMG did not show median
neuropathy at the wrist, plus the history of radicular pain, makes a C6 or C7
radiculopathy the most likely cause. Neuromuscular junction disorders do not
present with pain or sensory symptoms.

92. e (Chapter 22)

The patient appears to have an anterior spinal artery syndrome (ASAS), a well-
recognized complication of abdominal aortic surgery. The anterior two-thirds of the
spinal cord is perfused by the ASA, while the posterior third (posterior columns) is
perfused by posterior spinal arteries. Therefore, the corticospinal and spinothalamic
tracts are affected in ASAS, but the posterior columns remain intact. Leg strength,
pinprick appreciation, and cold sensation should be impaired, whereas joint
position sense should be preserved (a dissociated sensory loss). A sensory level
should be present over the torso, reflecting a spinal cord injury.

93. d (Chapter 23)

The patient has ascending weakness, and the preceding gastrointestinal syndrome
makes GBS likely. Other tests need to be considered to confirm the diagnosis, but it
is important to know the current respiratory status before any other test, particularly
because neck weakness may be accompanied by diaphragm weakness. If the FVC is
less than 15 mL/kg, the patient should be transferred to the ICU and intubated. If the
FVC is normal, the patient should have frequent FVC checks early during the
hospitalization, because a rapid deterioration can occur. Steroids are not a treatment
option for Guillain–Barré, which is treated with intravenous immunoglobulin or
plasmapheresis.

94. c (Chapter 8)
This is a very characteristic history of BPPV. Typically, episodes of vertigo are
brief, lasting 10 to 30 seconds, with no symptoms in between attacks. The absence
of any other associated symptoms, the normal neurologic examination, and the
characteristic nystagmus when the affected ear is closer to the ground during the
Dix–Hallpike maneuver, are distinguishing features. Ménière disease is associated
with tinnitus and hearing loss. A cerebellar stroke would not produce recurrent
positional symptoms and would likely be associated with other neurologic deficits.

95. d (Chapter 10)

This history is very characteristic of giant cell (temporal) arteritis (GCA). Other
symptoms might include jaw claudication. Testing the ESR and C-reactive protein
and proceeding to temporal artery biopsy are critical if the feared complication of
blindness from an anterior ischemic optic neuropathy is to be avoided. Migraine is
very unlikely; it would be a mistake to assume that a new headache in a 77-year-old
woman represents recurrence of an old problem. MRI and LP are of no value in
suspected GCA (although they may be helpful if the diagnosis of GCA is ruled out).

96. b (Chapter 11)

The anomia (impaired naming) and reduced verbal fluency indicate the presence of
an aphasia (language disorder). The preservation of repetition and comprehension
points to a transcortical motor aphasia. Wernicke’s aphasia should be associated
with normal or increased fluency. All aphasias impair naming to some degree. This
patient’s history is not consistent with a confusional state.

97. c (Chapter 18)

The rash on her shins likely represents erythema nodosum. Sarcoidosis is one of the
most common causes of bilateral LMN facial weakness, especially in the African-
American population.

98. e (Chapter 18)

Vitamin E deficiency may cause ataxia, myelopathy, and polyneuropathy. Vitamin
B12 deficiency may cause subacute combined degeneration of the spinal cord and
dementia.

99. e (Chapter 16)

Essential tremor is usually symmetric, present with posture and action, may have a
familial component, and improves with alcohol consumption. Besides the tremor,
the neurologic examination is otherwise normal.

100. c (Chapter 11)

Aphasia is a language (not a speech) disorder. Apraxia is the inability to carry out a
learned motor task. Neglect is not a form of apraxia. Agraphia is an inability to
write.
 Appendix
Evidence-Based Resources

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Vertinsky AT, Schwartz NE, Fischbein NJ, et al. Comparison of multidetector CT angiography and MRI imaging
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CHAPTER 3
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Malik K, Hess DC. Evaluating the comatose patient. Rapid neurologic assessment is key to appropriate
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Häring M, Zeisel A, Hochgerner H, et al. Neuronal atlas of the dorsal horn defines its architecture and links
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CHAPTER 7
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Furman JM, Cass SP. Benign paroxysmal positional vertigo. N Engl J Med. 1999;341:1590–1596.
Grubb BP. Neurocardiogenic syncope. N Engl J Med. 2005;352:1004–1010.
Hilton M, Pinder D. The Epley (canalith repositioning) manoeuvre for benign paroxysmal positional vertigo.
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Wipperman J. Dizziness and vertigo. Prim Care. 2014;41:115–131.

CHAPTER 8
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Rubino FA. Gait disorders. Neurologist. 2002;8:254–262.
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antibodies: analysis of 50 patients. Brain. 2003;126:1409–1418.

CHAPTER 9
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Hay-Smith J, Ellis G, Herbison GP. Which anticholinergic drug for overactive bladder symptoms in adults.
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Khandelwal C, Kistler C. Diagnosis of urinary incontinence. Am Fam Physician. 2013;87(8):543–550.
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of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629–808.
International Headache Society. The International Classification of Headache Disorders 3rd edition.
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Lipton RB, Bigal ME, Goadsby PJ. Double-blind clinical trials of oral triptans vs. other classes of acute migraine
medication—a review. Cephalalgia. 2004;24:321–332.
Purdy RA, Kirby S. Headaches and brain tumors. Neurol Clin. 2004;22:39–53.
Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based
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2000;55(6):754–762. [Erratum in: Neurology. 2000;56(1):142.]
Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic
migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of
Neurology and the American Headache Society. Neurology. 2012;78:1337–1345.

CHAPTER 11
Buxbuam LJ, Shapiro AD, Coslet HB. Critical brain regions for tool-related and imitative actions: a componential
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Gernsbacher MA, Kaschak MP. Neuroimaging studies of language production and comprehension. Ann Rev
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Hillis AE. Aphasia: progress in the last quarter of a century. Neurology. 2007;69:200–213.
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CHAPTER 12
Bhogal P, Mahoney C, Graeme-Baker S, et al. The common dementias: a pictorial review. Eur Radiol.
2013;23(12):3405–3417.
Knopman DS, Boeve BF, Petersen RC. Essentials of the proper diagnoses of mild cognitive impairment,
dementia, and major subtypes of dementia. Mayo Clin Proc. 2003;78:1290–1308.
Sosa-Ortiz AL, Acosta-Castillo I, Prince MJ. Epidemiology of dementias and Alzheimer’s disease. Arch Med
Res. 2012;43(8):600–608.

CHAPTER 13
Kapur VK, Auckley DH, Chowdhuri S, et al. Clinical practice guideline for diagnostic testing for adult obstructive
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Scammell TE. Narcolepsy. N Engl J Med. 2015;373:2654–2662.
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Mayo Clin Proc. 2017;92:1723–1736.

CHAPTER 14
Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent
ischemic stroke. N Engl J Med. 2001;345:1444–1451.
Moresoli P, Habib B, Reynier P, et al. Carotid stenting versus endarterectomy for asymptomatic carotid artery
stenosis: a systematic review and meta-analysis. Stroke. 2017;48:2150–2157.
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ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American
Stroke Association. Stroke. 2018;49:e46–e99.

CHAPTER 15
American Epilepsy Society. Guidelines. https://www.aesnet.org/clinical_resources/guidelines
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Harden C, Tomson T, Gloss D, et al. Practice guideline summary: Sudden unexpected death in epilepsy incidence
rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee
of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2017;88(17):1674–
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Nguyen DK, Spencer SS. Recent advances in the treatment of epilepsy. Arch Neurol. 2003;60:929–935.
Schachter SC. Seizure disorders. Primary Care. 2004;31:85–94.

CHAPTER 16
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Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options
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Stamelou M, Hoeglinger GU. Atypical parkinsonism: an update. Curr Opin Neurol. 2013;26:401–405.

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158.
West TA, Marion DW. Current recommendations for the diagnosis and treatment of concussion in sport: a
comparison of three guidelines. J Neurotrauma. 2014;31:159–168.

CHAPTER 18
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Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol
Neurosurg Psychiatry. 2005;75(suppl 3):22–28.
McIntosh C, Chick J. Alcohol and the nervous system. J Neurol Neurosurg Psychiatry. 2004;75:(suppl 3):16–21.
Rosenfeld MR, Dalmau J. Diagnosis and management of paraneoplastic neurologic disorders. Curr Treat Options
Oncol. 2013;14:528–538.
Watkins PJ, Thomas PK. Diabetes mellitus and the nervous system. J Neurol Neurosurg Psychiatry.
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CHAPTER 19
Keogh BP, Henson JW. Clinical manifestations and diagnostic imaging of brain tumors. Hematol Oncol Clin
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Lu-Emerson C, Eichler AF. Brain metastases. Continuum (Minneap Minn). 2012;18(2):295–311.
Ohka F, Natsume A, Wakabayashi T. Current trends in targeted therapies for glioblastoma multiforme. Neurol
Res Int. 2012;2012:878425.

CHAPTER 20
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optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326:584–588.
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Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN Guideline on the pharmacological treatment of
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Wingerchuk DM, Banwell B, Bennett JL. International consensus diagnostic criteria for neuromyelitis optica
spectrum disorders. Neurology. 2015;85:177–189.

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Hussein AS, Shafran SD. Acute bacterial meningitis in adults. A 12-year review. Medicine. 2000;79:360–368.
Schmutzhard E. Viral infections of the CNS with special emphasis on herpes simplex infections. J Neurol.
2001;248:469–477.
Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin
Infect Dis. 2004;39(9):1267–1284.
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Li XY, Xiao HB, Pai P. Myelitis in systemic lupus erythematosus. J Clin Neurosci. 2017;44:18–22.

CHAPTER 23
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distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of
the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic
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2009;72:177–184.
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CHAPTER 24
Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;372:1734–1747.
Emery AE. The muscular dystrophies. Lancet. 2002;359:687–695.
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CHAPTER 25
Colver A, Fairhurst C, Pharoah PO. Cerebral palsy. Lancet. 2014;383(9924):1240–1249.
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 Index

Note: Page numbers followed by f and t indicates figures and tables respectively.

A
Abducens nerve root, 30f
Abducens nucleus, 30f
Abnormal gaits, 69t
Absence seizures, 124–125, 124f
ACA (anterior cerebral), 112
Acoustic neuroma, 59–60
Acquired muscle disorders
endocrine, 212
infectious, 211
inflammatory, 212
toxic, 211–212
Acute bacterial meningitis
clinical findings, 174
diagnostic workup, 175–176
etiology, 174–175
treatment, 176
Acute confusional state, 25
definition, 25
diagnostic evaluation, 25–26
differential diagnosis of, 25
treatment and prognosis, 26
Acute disseminated encephalomyelitis (ADEM)
clinical and radiologic manifestations, 170–171
diagnostic evaluation, 171
prognosis and treatment, 171
Acute dystonic reactions, 135
Acute onset, 67–68
AD. See Alzheimer disease
ADEM. See Acute disseminated encephalomyelitis
Agnosia, 94
AION (anterior ischemic optic neuropathy), 35
Airway, breathing, and circulation (ABC), 18
Akinetic-rigid gait, 69
Alcoholic cerebellar degeneration, 68
Alemtuzumab (Lemtrada), 169t
Alexia without agraphia, 94
Allodynia, 51
Alzheimer disease (AD), 99–101, 101t
Ambulation, 8
Amyloid PET imaging, 15
Aneurysm in circle of Willis, 118f
Anomia, 91
Anterior cerebral (ACA), 112
Anterior circulation, 115
Anterior ischemic optic neuropathy (AION), 35
Anterolateral system, 49, 50f
Antiphospholipid antibody syndrome (APS), 153
Antiseizure drugs, 128t
and pregnancy, 131
Aphasia
Broca aphasia, 91–93
conduction aphasia, 94
diagnosis, 91
disorders of written communication, 94
examination of language function, 93t
global aphasia, 94
mixed transcortical aphasia, 94
subcortical aphasias, 94
transcortical motor aphasia, 94
transcortical sensory aphasia, 94
Wernicke aphasia, 93
Aphemia, 94
Apperceptive agnosia, 95
Apraxia, 3, 94–95
APS (antiphospholipid antibody syndrome), 153
Argyll Robertson pupil, 34
Arnold Chiari malformation with syrinx, 194f, 195
Arousal disorders, 109
Arterial dissection, 116
Arteries of circle of Willis, 114f
Arteriovenous malformations (AVMs), 119
Asperger syndrome, 220
Associative agnosia, 94
Ataxia
acute onset, 67–68
alcoholic cerebellar degeneration, 68
autosomal dominant spinocerebellar ataxia, 68
diagnostic approach, 66
differential diagnosis of, 67, 67t
disorders, 66
episodic ataxia, 68
Friedreich ataxia, 68
of gait, 8
Ataxic hemiparesis, 116
Attention, 2
Atypical neuropathy, 202t
Aubagio. See Teriflunomide
Autism, 220
Autistic spectrum disorders, 219
clinical manifestations, 220
diagnostic evaluation, 220
treatment, 220
Autonomic dysfunction, 134
Autosomal dominant spinocerebellar ataxia, 68
AVMs (arteriovenous malformations), 119
Axonal neuropathies, 17t

B
Babinski sign, 7, 21
Bacterial infections
acute bacterial meningitis. See Acute bacterial meningitis
brain abscess. See Brain abscess
Ballism, 137
Bladder continence
anatomy and physiology, 72
classification, 74
control of bladder function, 73f
diagnostic evaluation, 72–73
neurogenic bladder, 74t
Bladder function, control of, 73f
Blepharospasm, 138
Blood testing, 22
Brachial plexus, 198, 199f
Brachial plexus anatomy, 44, 45f
Brain abscess, 176t
clinical findings, 176
diagnostic workup, 176–177
etiology, 176
presentation of, 177f
treatment, 177
Brain, contrast-enhanced computed tomographic scan of, 162f
Brain death, 24–25
clinical diagnosis of, 25
Brain ischemia
embolism, 114
systemic hypoperfusion, 114
thrombosis, 113–114
Brainstem dysfunction, 16
Brainstem lesion, 38
Brainstem reflexes, 19, 20t
Broca aphasia, 91–93
Brudzinski sign, 174, 174f
Bruxism, 109

C
Calculation ability, 3
Carbamazepine (Tegretol), 128t
Cardiac arrhythmias, 62–63
Carotid dissection, 116
Carotid hypersensitivity, 63
Caudal basilar pontine lesion, 30f
Central cord lesions, 192
Central (transtentorial) herniation, 145
Central nervous system empyema, 177
Central nervous system tumors
causes and genetics, 156–157
clinical features, 157
demyelinating diseases of, 165–170
diagnostic evaluation, 157
epidemiology, 156
primary brain tumors. See Primary brain tumors
secondary (metastatic) brain tumors, 162–163
Central pontine myelinolysis (CPM), 150
Central vertigo, 60
cerebral infarct or hemorrhage, 60–61
demyelinating lesions, 61
migraine, 61
Cerebellar ataxia, 68
symptoms and signs in, 67t
Cerebellar herniation, 10
Cerebellar lesion, 38
Cerebellar strokes, 67
Cerebral hemispheres and brainstem disorders
associated signs and symptoms, 48
differential diagnosis, 48
imaging studies, 48
pattern of weakness, 47, 47f
Cerebral herniation, 10
Cerebral hypotonia, 223
Cerebral infarct or hemorrhage, 60–61
Cerebral palsy (CP), 217
classification, 217
clinical manifestation, 217
diagnostic evaluation, 217
primitive reflexes, 219t
treatment, 218
Cerebral vasculitis, 87
Cerebrospinal fluid (CSF) analysis, 26
findings in common neurologic diseases, 11t
findings, interpretation of, 11t
interpretation of results, 10
safety, tolerability, and complications, 10–11
technique, 10
Cerebrovascular disease, 74
Cervicogenic headaches, 89
Channelopathies, 213
Charles Bonnet syndrome, 32–33
Chorea, 6, 137
Chronic migraine, 81
Circadian rhythms, 108
Clobazam (Onfi), 128t
Clonazepam, 138
Clumsy hand syndrome, 116
Cluster headache, 84, 84f
 abortive treatments, 84
preventive treatments, 84
CMAP (compound muscle action potential), 16
CN III deficit, 36
CN IV deficit, 37
CNs. See Cranial nerves
CN VI deficit, 37–39
Color vision, 35
Coma
approach to, 19f
clinical approach, 18–19
definition, 18
differential diagnosis, 21–22
examination, 20–21
laboratory and radiologic studies, 22–23
treatment and prognosis, 23–24
Common ischemic stroke syndromes, 115
anterior circulation, 115
arterial dissection, 116
lacunar syndromes, 115–116
posterior circulation, 115
Complete cord transection, 192
Complex partial seizures, 25
Compound muscle action potential (CMAP), 16
Computed tomography and magnetic resonance imaging
clinical utility, 12–13
safety, tolerability, and complications, 13
technical considerations, 12
Concussion, 143
Conditions of note, 204–205
Conduction aphasia, 94
Conduction velocity, 16
Confusion, 25
Confusional arousals, 109
Congenital muscle disorders, 212
dystrophic
Duchenne and Becker muscular dystrophies, 213–214
Emery-Dreifus muscular dystrophy, 214
facioscapulohumeral muscular dystrophy, 214
limb-girdle muscular dystrophy, 214
myotonic dystrophy, 214
nondystrophic
channelopathies, 213
metabolic myopathies, 213
Conscious state, 24t
Constipation, 134
Conus and cauda equina lesions, 193
Conventional angiography, 14
Conventional cerebral angiogram, 14f
Coordination, 21
Coordination of limbs, 8
Copaxone. See Glatiramer acetate
Cortical (language) centers, 92f
Cranial nerves (CNs), 4–5, 4t, 20
Creutzfeldt-Jakob disease, 10
CSF analysis. See Cerebrospinal fluid analysis
CT angiography (CTA), 14
CT scanning, 13
Cystometry, 73
Cystourethroscopy, 73

D
Deep tendon reflexes, 7
Deep venous sinus thrombosis, 87f
Deficits, 2
Delirium, 25
Dementia
Alzheimer disease, 99–101
causes of, 99
clinical manifestations, 96
diagnostic evaluation, 96–97
epidemiology, 96
frontotemporal lobar degeneration, 102–103
human immunodeficiency virus, 104
Huntington disease, 103
Lewy body dementia (LBD), 102
metabolic causes of, 104
Parkinson disease, 103
prion-related diseases, 103–104
progressive supranuclear palsy, 103
vascular dementia, 101
Demyelinating diseases of central nervous system, 165
clinical course and prognosis, 167
clinical manifestations of, 165–166
diagnostic evaluation, 167–168, 168f
epidemiology of, 165
multiple sclerosis, 166t, 167f
pathology, 169
treatment, 169–170
Demyelinating lesions, 61
Demyelinating neuropathies, 17t
Demyelinating plaque, 168f
Depakote. See Valproic acid
Depressed consciousness, 23
diffuse causes of, 22
structural causes of, 21
Dermatome, 197
Detrusor hyperreflexia, 74
Developmental venous anomalies (DVAs), 119
Diabetic neuropathies, 148, 202t
Diffuse axonal injury, 144, 144f
Diffusion-weighted imaging (DWI), 12
Dilantin. See Phenytoin
Dimethyl fumarate (Tecfidera), 169t
Diplopia, 32
Direct visualization of optic nerve, 3
Dissociated sensory loss, 52
Dix-Hallpike maneuver, 57, 57f
Dopamine transporter SPECT (DaT scan), 15
Dorsal columns, 49
Double vision, 32
Drowsiness, 18
Droxidopa, 63
Drug-induced movement disorders, 135–136
Duchenne and Becker muscular dystrophies, 213–214
DVAs (developmental venous anomalies), 119
DWI (diffusion-weighted imaging), 12, 13f
Dysarthria, 66, 116
Dysdiadochokinesia, 66
Dysdiadochokinesis, 8
Dysesthesias, 51
Dysmetria, 66
Dystonia, 137–138
DYT-TOR1A dystonia, 138

E
Edinger-Westphal nucleus (EWN), 28, 31f
EEG. See Electroencephalogram/electroencephalography
18-fluorodeoxyglucose positron emission tomography (FDG-PET) scans, 15
Electroencephalogram/electroencephalography
clinical utility, 15–16
frequencies, 15f
technique, 15
Electrographic seizures, 16
Electrolyte, mineral, and nutritional factors, 150
Electromyography (EEG), 23
clinical utility, 17
in neurogenic and myopathic disorders, 17t
technique, 16–17
Emery-Dreifus muscular dystrophy (EDMD), 214
Encephalopathy, 25
Endocrine dysfunction, 148–149
Ependymoma, 160
Epidural hematoma, 142, 142f
Epilepsy syndromes, 126t
Epileptic myoclonus, 138
Episodic ataxia, 68
Epley maneuver, 58f
Erythema migrans, 180f
Essential myoclonus, 138
Ethosuximide (Zarontin), 128t
Evoked potentials, 16
Extracranial Doppler sonography, 14
Extraocular movements, 3
Eye alignment, 35–36
Eyelid abnormalities, 33
Eye misalignment, 37t
terms used to define, 37
Eye movements, 38
abnormalities, 30f

F
Facial pain, 88
head and neck disorders, 89
trigeminal neuralgia, 89
Facial sensation, 49
Facial weakness, 180, 180f
Facioscapulohumeral muscular dystrophy (FSHD), 214
Fingolimod (Gilenya), 169t
First aid for seizures, 129–130
FLAIR (fluid-attenuated inversion recovery), 12
Fludrocortisones, 63
Fluid-attenuated inversion recovery (FLAIR), 12
Focal brain disorders, 25
Focal seizures, 122–123, 123f
characteristics of, 127t
with impaired awareness, 123–124
Focal signs, presence of, 21
Fortification spectrum, 81
Foster-Kennedy syndrome, 34–35
Friedreich ataxia (FRDA), 68
Frontal gait, 69
Frontal lobe function, 3
Frontal sinusitis, 177f
Frontotemporal lobar degeneration (FTLD), 102–103
Fundoscopy, 3
Fungal infections, 182–183
CNS signs of, 183t
cryptococcal meningitis, 183

G
Gabapentin (Neurontin), 128t
Gait ataxia, 8, 66
Gait disorders, 68–69
akinetic-rigid gait, 69
frontal gait, 69
psychogenic gait, 69–70
sensory ataxia, 69
spastic gait, 69
waddling gait, 69
Gaits, abnormal, 69t
Ganglioglioma, 161
GCA (giant cell arteritis), 35, 87
GCS (Glasgow Coma Scale), 18, 145, 145t
Generalized motor seizures, 124
Generalized seizures
absence seizures, 124–125
generalized motor seizures, 124
Gerstmann syndrome, 95–96
Giant cell arteritis (GCA), 35, 87
Gilles de la Tourette syndrome, 139
Glasgow Coma Scale (GCS), 18, 145, 145t
Glatiramer acetate (Copaxone), 169t
Glioblastoma multiforme, 157–158
Gliomas, 157
Global aphasia, 94
Guillain-Barré syndrome, 41, 67

H
Headache
cluster. See Cluster headache
diagnosis, 78
features of, 80t
history, 78
management, opioids in, 85
migraine. See Migraine
neurologic exam, 79
short-lasting unilateral neuralgiform headaches. See Short-lasting unilateral neuralgiform headaches
tension-type. See Tension-type headache
trigeminal autonomic cephalalgias, 83–84
Head imaging, 23
Head impulse test (HIT), 59f
Head trauma
computed tomographic scan of, 142f, 143f
epidemiology, 142
Glasgow Coma Scale, 145, 145t
herniation syndromes, 144
central (transtentorial) herniation, 145
subfalcine herniation, 145
uncal herniation, 145
increased intracranial pressure, 145–146
initial assessment of, 145
types of
concussion, 143
diffuse axonal injury, 144, 144f
epidural hematoma, 142, 142f
postconcussion syndrome, 143–144
posttraumatic seizures and epilepsy, 144
subdural hematoma, 142–143, 143f
Hearing, 3
Hemangioblastoma, 161
Hemicord lesions, 192
Hemicrania, 85
abortive and preventive treatment, 85
Hemispheric syndromes, 96
Hereditary syndromes, 156t
Herniation syndromes, 144
central (transtentorial) herniation, 145
subfalcine herniation, 145
uncal herniation, 145
Histoplasma, 183
HIT (head impulse test), 59f
HIV-associated dementia, 184–185
Homunculus of motor strip, 47f
Horizontal gaze center, 30f
Horners syndrome (HS), 34
HSV encephalitis, 182f
Human immunodeficiency virus (HIV), 104
Huntington disease (HD), 103
clinical manifestations, 136–137
diagnostic evaluation, 137
pathology, 137
therapeutic strategies in, 134t
treatment, 137
Hyperesthesia, 51
Hyperventilation, 16
Hypoesthesia, 51
Hypoglycemia, 64
Hypothalamic fibers, 37f
Hypothyroidism, 149, 150
Hypovolemia, 62

I
Individual movements, power testing of, 6f
Indomethacin trial, 85
INO (internuclear ophthalmoplegia), 30f
Intention tremor, 66
Interferon beta-1a (Avonex), 169t
Interferon beta-1b (Betaseron), 169t
Interictal epileptiform, 16
Internuclear ophthalmoplegia (INO), 30f
Intracerebral hemorrhages, 86, 86f, 113, 116f
Intracerebral hypotension, 88
Intracranial hemorrhage, 22
intracerebral hemorrhage (ICH), 119
subarachnoid hemorrhage (SAH), 118, 118f
Intracranial hypotension, 88, 88f
Intracranial tuberculoma, 179
Intravenous immunoglobulin (IVIG), 67
Ischemic optic neuropathies, 35
IVIG (intravenous immunoglobulin), 67

J
Jerk nystagmus, 39

K
Keppra. See Levetiracetam
Kernig sign, 174, 174f
Ketogenic diet, 129
Korsakoff syndrome, 151

L
Labyrinthitis, 58
Lacosamide (Vimpat), 128t
Lacunar syndromes, 115–116
Lambert-Eaton myasthenic syndrome, 211
Lamictal. See Lamotrigine
Lamotrigine (Lamictal), 128t
Landau-Kleffner syndrome, 220
Language, 2
LBD (Lewy body dementia), 102
Lemtrada. See Alemtuzumab
Lethargyx, 18
Leukoencephalopathies, 171
Levetiracetam (Keppra), 128t
Lewy body dementia (LBD), 102
Lightheadedness, 62
autonomic causes, 63
cardiac arrhythmias, 62–63
hypovolemia, 62
metabolic causes, 64
postural tachycardia, 63–64
Limb-girdle muscular dystrophy, 214
LMN (lower motor neuron), 46f
Locked-in syndrome, 24
Lower motor neuron (LMN), 46f
Low-grade gliomas, 158–159
Lumbar puncture (LP), 10, 23, 41
optimal positioning, 10
radiologic contraindications to, 10
Lumbosacral plexus, 200f
anatomy, 44
Lumbosacral spine, 178f
Lyme disease, 179
clinical findings, 180
diagnostic workup, 180
serologic testing for, 181f
treatment, 180–181
Lyrica. See Pregabalin

M
Magnetic resonance angiography (MRA), 14, 14f
Magnetic resonance imaging (MRI), 12, 12f
Magnetic resonance spectroscopy, 15
Magnetic resonance venography (MRV), 14
Marchiafava-Bignami disease, 151
Marcus Gunn pupil, 34
MCA (middle cerebral arteries), 112
MCS (minimally conscious state), 24
Medial lemniscal system, 51f
Medial longitudinal fasciculus (MLF), 29, 30f
Medical Research Council (MRC) scale, 6, 6t
Medication overuse headache (MOH), 89
Medulloblastoma, 160–161, 160f
Memory, 2
Ménière disease, 58–59
Meningioma, 159–160
Meningitis
causes of, 175t
forms of, 175t
Menses, 81
Mental status
formal, 25
neurologic examination, 2–4
testing, 20
Metabolic causes, 64
Metabolic derangements, 64
Metabolic disorders, 150–151
Metabolic myopathies, 213
MFS (Miller Fisher syndrome), 67
Middle cerebral arteries (MCA), 112
Midodrine, 63
Migraine, 61
with aura, 81
chronic, 81
complications associated with, 81
and menses, 81
prophylaxis oral medications, 82t
status migrainosus, 81
stroke risk associated with, 81
without aura, 79–81
Migraine with brainstem aura, 61
Miller Fisher syndrome (MFS), 67
Minimally conscious state (MCS), 24
Miosis, 34
Mixed incontinence, 74
Mixed transcortical aphasia, 94
MOH (medication overuse headache), 89
Mononeuropathies, 10, 43, 203t
Motor exam, neurologic examination, 5–6
Motor tone, 20
Movement disorders
ballism, 137
drug-induced movement disorders, 135–136
dystonia, 137–138
Huntington disease. See Huntington disease
myoclonus, 138
Parkinson disease. See Parkinson disease
 paroxysmal dyskinesias, 140
Stiff-person syndrome, 140
tics, 138–139
tremor, 136
Wilson disease, 139
Movements, 10, 43t
Multiple periventricular hyperdensities, 168f
Multiple sclerosis, 166t, 167f
clinical course of, 167f
clinical features of, 166t
treatment of, 169t
Muscles of mastication, 3
Muscle stretch reflexes, 7, 7f, 21, 44t
Myasthenia gravis, 208–210
Myoclonus, 138
Myotome, 197
Myotonic dystrophy, 214

N
Natalizumab (Tysabri), 169t
NCS. See Nerve conduction studies
Neglect, 2, 96
Nerve conduction studies (NCS)
clinical utility, 17
technique, 16–17
Nerve root disorders, 44
Nervous system
complications of HIV infection, 183–184
effects of alcohol on, 151t
Neurally mediated syncope, 63
Neurocysticercosis, 184, 185t
Neurogenic bladder, 74t
Neuroleptic malignant syndrome, 136
Neurologic examination, 1
commonly performed elements of, 3t
coordination, 7
cranial nerves, 4–5
gait, 8
mental status, 2–4
motor exam, 5–6
patterns of sensorimotor abnormalities, 2t
principles, 1–2
reflexes, 7
sensory exam, 7–8
Neurologic manifestations, 148
diabetic neuropathies, 148
electrolyte, mineral, and nutritional factors, 150
endocrine dysfunction, 148–149
examples of, 149
of hypothyroidism, 150
metabolic disorders, 150–151
 paraneoplastic phenomena, 152
rheumatologic diseases, 153
toxic metabolic encephalopathy, 153–154
toxins, 151
Neuromuscular junction (NMJ), 16
acquired muscle disorders. See Acquired muscle disorders
associated signs and symptoms, 42
describing, 208
differential diagnosis, 42
laboratory studies, 42
Lambert-Eaton myasthenic syndrome, 211
myasthenia gravis, 208–210
pattern of weakness, 42
Neuromyelitis optica (NMO), 171
Neurontin. See Gabapentin
Neuro-ophthalmology, 28
anatomy of visual paths, pupils, and oculomotor nerves, 28–31, 28f–30f
causes of visual loss, 36t
CN III deficit, 36
CN IV deficit, 37
CN VI deficit, 37–39
diplopia, 32
eye alignment and movements, 35–36
eyelid abnormalities, 33
eye misalignment, 37t
history of, 32
nystagmus, 38t
optic disc, 34–35
peripheral nystagmus, 39t
positive and negative visual phenomena, 32–33
pupil, 33–34
vision, 35
Neurophysiologic studies, 73
Nightmares, 109
NMJ. See Neuromuscular junction
NMO (neuromyelitis optica), 171
Nystagmus, 38t, 39, 57, 66

O
Obstructive sleep apnea (OSA), 109
Obtundation, 18
Ocrelizumab (Ocrevus), 169t
Ocrevus. See Ocrelizumab
Oculocephalic maneuver (doll’s eye test), 36
Oculomotor apraxia, 39
Olfaction, 3
Oligodendroglioma, 159
One-and-a-half syndrome, 30f
Onfi. See Clobazam
Optic disc, 34–35
Optic nerve function, 3
Orientation, 2
Orthostatic hypotension, 63
Orthostatic intolerance, 64
OSA (obstructive sleep apnea), 109
Otoliths, 36, 56–57
Overflow incontinence, 74
Oxcarbazepine (Trileptal), 128t

P
Palate elevation, 5
Papilledema, 34
Papillitis, 35
Paramedian pontine reticular formation (PPRF), 29
Paraneoplastic antibodies, 152t
Paraneoplastic cerebellar degeneration (PCD), 67
Paraneoplastic phenomena, 152
Parasitic infections of nervous system
neurocysticercosis, 184, 185t
toxoplasmosis, 183–184, 184f
Parasympathetic fibers, 28
Parasympathetic pathway, 31f
Paresthesias, 51
Parinaud syndrome, 38
Parkinson disease (PD), 8, 103
clinical manifestations, 133–134
epidemiology, 133
pathology, 133
pharmacologic treatment of, 135t
treatment, 134–135
Parkinsonian syndromes, 133t
Parkinsonism, 135
Paroxysmal dyskinesias, 140
Paroxysmal kinesigenic dyskinesia, 140
Paroxysmal nonkinesigenic dyskinesias, 140
Parsonage-Turner syndrome, 199
PCD (paraneoplastic cerebellar degeneration), 67
PCNSL (primary CNS lymphoma), 161
PD. See Parkinson disease
Pediatric autoimmune neuropsychiatric disorders, 139
Pediatric neurology
attention deficit-hyperactivity disorder, 224
autistic spectrum disorders. See Autistic spectrum disorders
cerebral palsy. See Cerebral palsy
chromosomal abnormalities, 220t
developmental delay, 219
developmental regression, 221
development and maturation, 217, 218t
hypotonia, 223–224
inherited neurodegenerative disorders, 222t
intellectual disability, 219
lysosomal disorders, 221–222
 neurocutaneous disorders, 223
neurocutaneous syndromes, 223t
peroxisomal disorders, 222
Peripheral nerve diseases, 76
Peripheral nerve disorders
associated signs and symptoms, 43
commonly tested movements, 43t
differential diagnosis, 43
laboratory studies, 43
pattern of weakness, 43
Peripheral nerves and mono and polyneuropathies
anatomy and terminology, 201
diagnosis, 203–204
pathophysiology, 201
symptoms and signs, 201–202
Peripheral nerve ultrasound, 15
Peripheral nervous system (PNS), 1
Peripheral neuropathy, classification of, 201
Peripheral nystagmus, 39t
Peripheral vertigo, 56–57
acoustic neuroma, 59–60
medications, 60
Ménière disease, 58–59
vestibular neuritis and labyrinthitis, 58
Persistent vegetative state, 24
Phenobarbital, 128t
Phenytoin (Dilantin), 128t
Physiologic myoclonus, 138
Plexus and plexopathies
anatomy, 198–199, 199f, 200f
diagnosis, 200
pathophysiology, 199
symptoms and signs, 200
Plexus disorders
associated signs and symptoms, 45
differential diagnosis, 45
laboratory studies, 45
pattern of weakness, 44–45
PMC (pontine micturition center), 72
PML (progressive multifocal leukoencephalopathy), 185–186
PNS (peripheral nervous system), 1
Polyneuropathy, 10
Polyradiculoneuropathy, 205t
Polyradiculopathy, 44
Polysomnography (PSG), 107–108
Pontine micturition center (PMC), 72
Postcentral cortex, 49
Postconcussion syndrome, 143–144
Posterior circulation, 115
Posterior cord (dorsal column) lesions, 193
Posterior reversible encephalopathy syndrome (PRES), 171
“Postganglionic” sympathetic fibers, 37f
Postinfectious cerebellitis, 67
Posttraumatic seizures and epilepsy, 144
Postural instability, 134
Postural tachycardia syndrome (POTS), 63–64
Posturing, 8, 21f
POTS (postural tachycardia syndrome), 63–64
Pott’s disease, 179
Power testing of individual movements, 6f
PPRF (paramedian pontine reticular formation), 29
Pregabalin (Lyrica), 128t
“Preganglionic” sympathetic fibers, 37f
PRES (posterior reversible encephalopathy syndrome), 171
Primary brain tumors
ependymoma, 160
ganglioglioma, 161
glioblastoma multiforme, 157–158
gliomas, 157
hemangioblastoma, 161
low-grade gliomas, 158–159
medulloblastoma, 160–161
meningioma, 159–160
oligodendroglioma, 159
primary CNS lymphoma, 161
schwannoma, 161
sellar and suprasellar tumors, 162
Primary CNS angiitis, 87
Primary CNS lymphoma (PCNSL), 161
Primary headache disorders, location of pain, 80f
Primary muscle disorders, 42
Primitive reflexes, 3
Prion-related diseases, 103–104
Progressive multifocal leukoencephalopathy (PML), 185–186, 186f
Progressive supranuclear palsy (PSP), 103
Prophylaxis, 101
Proprioception, 8
Prosopagnosia, 94
Pseudoathetosis, 66
PSG (polysomnography), 107–108
PSP (progressive supranuclear palsy), 103
Psychogenic gait, 69–70
Psychogenic nonepileptic seizures, 131
Ptosis, 33
Pupillary dilation, 37f
Pupillary dysfunction, 28
Pure motor lacune, 115
Pure sensory lacune, 116

R
Radiculopathy, 44
anatomy, 197
 diagnosis, 198
pathophysiology, 197
symptoms and signs, 197–198
Radiofrequency (RF) pulses, 12
Rapid eye movement (REM) sleep, 107, 107f
Red flags, 79
Reflexes, 6
Relative afferent pupillary defect (RAPD), 34
REM (rapid eye movement) sleep, 107, 107f
REM sleep-related parasomnias, 109
Restless legs syndrome (RLS), 108–109
Retinal axons, 28
Rheumatologic diseases, 153
RLS (restless legs syndrome), 108–109
Romberg sign, 8
Root syndromes distribution of abnormalities, 198t

S
SAH (subarachnoid hemorrhage), 118, 118f
Sarcoidosis, 153
Schwannoma, 161
SE (status epilepticus), 129
Secondary angiitis, 87
Secondary (metastatic) brain tumors, 162–163
Secondary headache disorders, 85–86
infectious or inflammatory causes, 88
intracerebral pressure disorders, 88
medication causes, 88
neoplastic causes, 88
traumatic causes, 88
vascular causes, 86–88
Second-order neurons, 28
Seizures
antiseizure drugs and pregnancy, 131
classification, 122
clinical manifestations
history, 126
physical examination, 126
diagnostic evaluation
brain imaging, 127
electroencephalography, 127–128
laboratory studies, 127
and driving, 131
epidemiology and etiologies, 125–126
epilepsy syndromes, 126t
first aid for, 129–130
focal seizures, 122–123, 123f
with impaired awareness, 123–124
generalized seizures
absence seizures, 124–125
generalized motor seizures, 124
 management of status epilepticus, 130t
psychogenic nonepileptic seizures, 131
status epilepticus, 129
sudden unexpected death in epilepsy, 130–131
treatment
antiseizure drugs, 128t
drugs, 128–129
ketogenic diet, 129
surgery, 129
vagus nerve stimulation, 129
types of, 122t, 123f
unclassified, 125
unknown onset, 125
Sellar tumors, 162
Semicircular canals, 36
Sensorimotor abnormalities, localizing patterns of, 1, 2t
Sensorimotor lacune, 116
Sensory ataxia, 69
Sensory cortex, 52f
Sensory dermatomes, 53f
Sensory exam, 7–8
Sensory loss, patterns of, 54, 54t
Sensory system
anatomy of, 49, 50f, 51f, 52f
approach to patient with sensory loss, 52–54, 53f
examination of, 49–52
patterns of sensory loss, 54t
Sensory testing, 21
Sexual dysfunction
anatomy and physiology, 75–77
causes of, 77
diagnostic evaluation, 77
treatment, 77
Short-lasting unilateral neuralgiform headaches, 84–85
abortive treatment, 85
preventive treatment, 85
Single-photon emission computed tomography (SPECT), 15
Single radiculopathies, 44
Sinusitis, 89
Sleep
apnea, 110
paralysis, 109
stages of, 107, 107f
terrors, 109
Sleep disorders, 107
arousal disorders, 109
circadian rhythms and, 108
physiology of, 107
polysomnography, 107–108
REM sleep-related parasomnias, 109
restless legs syndrome, 108–109
 sleep apnea, 110
sleep-wake transition disorders, 109
Sleep-related dissociative disorders, 109
Sleep-wake transition disorders, 109
Somatosensory-evoked potentials (SSEPs), 16
Somnambulism, 109
Spasmodic dysphonia, 138
Spastic gait, 69
Spasticity, 47
Spinal cord
anatomy, 189–191
corticospinal tract from cortex, 190f
diagnostic tests, 195
injury, phases of, 47
posterior view of vertebral bodies, 190f
transverse section of, 190f
Spinal cord diseases, multiple sclerosis, 75
Spinal cord disorders
associated signs and symptoms, 47
differential diagnosis, 47
laboratory studies, 47
pattern of weakness, 45–46, 46f
Spinal cord dysfunction, 191
causes of, 193–195
Spinal cord syndromes, 192
central cord lesions, 192
complete cord transection, 192
conus and cauda equina lesions, 193
hemicord lesions, 192
posterior cord (dorsal column) lesions, 193
Spinal epidural abscess
clinical findings, 177–178
diagnostic workup, 178
etiology, 178
treatment, 178
Spinothalamic tract (STT), 49
SSEPs (somatosensory-evoked potentials), 16
Status epilepticus (SE), 129
management of, 130t
Status migrainosus, 81
Sternocleidomastoid strength, 5
Stiff-person syndrome, 140
Strength, 5–6
Stress incontinence, 74
STT (spinothalamic tract), 49
Stupor, 18
Subarachnoid hemorrhage (SAH), 118, 118f
Subcortical aphasias, 94
Subdural hematoma, 142–143, 143f
Subfalcine herniation, 145
Sudden unexpected death in epilepsy (SUDEP), 130–131
Suprasellar tumors, 162
Supraspinal diseases
cerebrovascular disease, 74
Parkinson disease, 74–75
Sympathetic fibers, 28
Symptomatic myoclonus, 138
Syringomyelia, 192f
Systemic lupus erythematosus (SLE), 153

T
Tabes dorsalis, 193
Tardive dyskinesia (TD), 136
TCD (transcranial Doppler), 14
TD (tardive dyskinesia), 136
TE (time to echo), 12
Tecfidera. See Dimethyl fumarate
Tegretol. See Carbamazepine
Telangiectasias, 119
Temporomandibular joint disorder (TMD), 89
Tension-type headache
abortive treatments, 83
preventive treatments, 83
Teriflunomide (Aubagio), 169t
Thunderclap headache, 86
TIA (transient ischemic attack), 61
Tiagabine (Gabitril), 128t
Tics, 138–139
Time to echo (TE), 12
Time to repetition (TR), 12
TMD (temporomandibular joint disorder), 89
TME (toxic metabolic encephalopathy), 153–154
Tobacco-alcohol amblyopia, 151
Tone, abnormalities of, 5
Tongue protrusion, 5
Tonic (Adie) pupil, 34
Topiramate (Topamax), 128t
Torticollis, 138
Touch sensation, 49
Toxic metabolic encephalopathy (TME), 153–154
Toxins, 151
Toxoplasmosis, 183–184, 184f
TR (time to repetition), 12
Transcortical motor aphasia, 94
Transcortical sensory aphasia, 94
Transcranial Doppler (TCD), 14
Transient ischemic attack (TIA), 61
Tremor, 6, 136
Trigeminal autonomic cephalalgias (TACs), 83–84
Trileptal. See Oxcarbazepine
Truncal ataxia, 66
Tuberculosis
 intracranial tuberculoma, 179
Pott’s disease, 179
tuberculous meningitis, 178–179
Tuberculous meningitis, 178–179
Tuberculous spondylitis, 179f
Tysabri. See Natalizumab

U
UMN (upper motor neuron), 46f
Uncal herniation, 145
Unclassified seizures, 125
Unilateral optic disc swelling, 35
Unknown onset seizures, 125
Upper motor neuron (UMN), 46f
Upside-down ptosis, 33
Urge incontinence, 74
Urinalysis, 25–26
Urinary dysfunction
bladder continence
anatomy and physiology, 72
classification, 74
control of bladder function, 73f
diagnostic evaluation, 72–73
neurogenic bladder, 74t
treatment, 75
Urinary incontinence, treatment of, 76t

V
Vacuolar myelopathy, 185
VA dissection, 116
Vagus nerve stimulation, 129
Valproate, 138
Valproic acid (Depakote), 128t
Vascular anatomy, 112, 113f
anterior circulation, 112
Vascular dementia, 101
Vascular disease
brain ischemia. See Brain ischemia
common ischemic stroke syndromes. See Common ischemic stroke syndromes
diagnostic evaluation, 116–117, 116f–117f
intracranial hemorrhage
intracerebral hemorrhage, 119
subarachnoid hemorrhage, 118, 118f
posterior circulation, 113, 114f
transient ischemic attack, 118
treatment, 117–118
vascular anatomy, 112, 113f
anterior circulation, 112
vascular malformations, 119
Vascular imaging studies, 14–15
Vascular malformations, 119
Vascular territories of brain, 113f
Vasovagal syncope, 63
Vertigo, 56
central vertigo. See Central vertigo
characteristics of causes of, 62t
peripheral vertigo. See Peripheral vertigo
Vestibular function, 3
Vestibular migraine, 61
Vestibular neuritis, 58
Vestibular schwannoma, 59–60, 60f
Vestibulo-ocular reflex (VOR), 36
Vibration, 8
Vimpat. See Lacosamide
Viral infections
encephalitis, 181–182
viral meningitis, 181
Zika virus, 182
Vision, 35
loss, 35
Visual acuity, 3
Visual fields, 3
Visual loss, causes of, 36, 36t
Visual pathways, 29f
Visual phenomena, positive and negative, 32–33
Visuospatial function, 3, 3f
Voluntary micturition, 72
VOR (vestibulo-ocular reflex), 36

W
Waddling gait, 69
Wallenberg (or lateral medullary) syndrome, 61
WD (Wilson disease), 139
Weakness, approach to
cerebral hemispheres and brainstem disorders. See Cerebral hemispheres and brainstem disorders
differential diagnosis, 42
nerve root disorders. See Nerve root disorders
neuromuscular junction problems. See neuromuscular junction
peripheral nerve disorders. See Peripheral nerve disorders
plexus disorders. See Plexus disorders
primary muscle disorders. See Primary muscle disorders
principles, 40–41
spinal cord disorders. See Spinal cord disorders
Wernicke aphasia, 93
Wernicke encephalopathy, 151
Wilson disease (WD), 139
Writer’s cramp, 138

X
Xanthochromia, 10
Z
Zarontin. See Ethosuximide
Zonegran. See Zonisamide
Zonisamide (Zonegran), 128t