1

DEMYELINATING
&
DEGENERATIVE
DISEASES
DEMYELINATING DISEASES
DEMYELINATING DISEASES
INTRODUCTION:

 Acquired conditions
 Preferential damage to myelin
 Relative preservation of axons
 Clinical deficit due to effect of myelin
loss on transmission of electrical
impulses along axons
DEMYELINATING DISEASES

DISEASES INCLUDED ARE:

Multiple sclerosis
Multiple sclerosis variants
Acute disseminated encephalomyelitis
Central pontine myelinolysis
Progressive multifocal leukoencephalopathy
JC virus infection of oligodendrocytes
Metabolic disorders e.g Leukodystrophies
MULTIPLE S C L E R O S I S (MS)

“An autoimmune demyelinating disorder

characterized by distinct episodes of neurologic
deficits, separated in time, attributable to white
matter lesions that are separated in space”.
Any age, rare in children & old
Women affected twice
Variable time intervals between relapses and
remissions
PATHOGENESIS–MS

Exact not known

Environmental influence
Role of virus e.g Epstein Barr Virus(EBV)
Genetic influence:
 Susceptibility to DR2, haplotype of MHC
 15 folds greater risk when disease
present in first degree relative
 Greater magnitude(150 folds) for
monozygotic twins
PATHOGENESIS–MS
(continued)

Immune mechanisms
Cell mediated damage:
Role of CD4,+ D8+ T- cells & macrophages
CD4 interact with self myelin which has become
antigenic due to microbes and susceptible genes
CD4 secrete cytokines such as IFN gamma
Activation of macrophages by IFN gamma
Demyelination caused by macrophages, leukocytes
and their injurious products
Antibody mediated damage.
MORPHOLOGY–MS

Grossly, evidence found in pons &

spinal cord
Areas involved are: brain stem,
pons, optic nerve, optic chiasma
and spinal cord
Well circumscribed, depressed,
glassy, gray-tan irregular plaques
Firmer in consistency – Sclerosis
MORPHOLOGY–MS

Active plaques

Myelin breakdown

Macrophages with lipid rich debris

Lymphocytes, perivascular cuffs
Depletion of oligodendrocytes
Preservation of axons
 MORPHOLOGY –
MULTIPLE SCLEROSIS
MORPHOLOGY–MS
Inactive plaques
Little or no myelin
Prominent gliosis and astrocytes
Severe depletion of myelin.
Shadow plaques
Border between normal and affected white
matter not sharply circumscribed
Partial or incomplete myelin loss
Remyelination by surviving oligodendrocytes
CLINICAL FEATURES – MS

MS lesions anywhere in the CNS

Wide range of clinical manifestations
Unilateral visual impairments
Ataxia, nystagmus, ophthalmoplegia
Spasticity, sensory impairment and
autonomic disturbances
CLINICAL FEATURES – MS (contd)

Motor & sensory impairment – Trunk &

Limbs
Spasticity, loss of voluntary control of
urinary bladder
CSF – mildly raised proteins, moderate
pleocytosis & increased gamma globulins
DEGENERATIVE DISEASES
Affecting cerebral cortex; Alzheimer disease,
Pick disease
Affecting Basal ganglia & Brain Stem;
Parkinsonism, Huntington disease
Spinocerebellar degeneration; Freidreich
Ataxia & Ataxia Telangiectasia
Affecting Motor Neurons; Motor neuron
disease & Bulbospinal atrophy
ALZHEIMER DISEASE
Most common cause of
dementia in elderly
Insidious impairment of
higher intellectual functions.
Progressive disorientation,
memory loss, aphasia, loss
of mathematical skills,
incontinence and immobility.
Mostly sporadic whereas 5
to 10% are familial
MORPHOLOGY – ALZHEIMER DISEASE

Gross examination
Cortical
atrophy: pronounced in
frontal, temporal and
parietal lobes
Sulci
widened, deep and gyri
narrow
Ventricular enlargement
MORPHOLOGY – ALZHEIMER DISEASE

Neurofibrillary Tangles:
Bundles of filaments in the
cytoplasm of neurons that
displace or encircle the
nucleus. These are
elongated “flame” shape.
MORPHOLOGY – ALZHEIMER DISEASE

Neuritic Plaques: Focal

spherical collections of
dilated, tortuous, silver-
staining neuritic processes
(dystrophic neurites)
surrounding an amyloid core
Amyloid angiopathy
Granulovacuolar
degeneration
 PATHOGENESIS & MOLECULAR
GENETICS – ALZHEIMER DISEASE
Role of amyloid (Aß)
Role of presenilins 1 & 2
Role of apolipoprotein-E
PATHOGENESIS – ALZHEIMER DISEASE
ALZHEIMER DISEASE- CLINICAL COURSE

Slow progression
Initial symptoms are forgetfulness
Other symptoms emerge as language
deficit , loss of mathematical skills and
loss of learned motor skills
Finally individual may become
incontinent, mute and unable to walk
Terminal event is intercurrent infection
like pneumonia
 PARKISONISM
“A clinical syndrome
characterized by
diminished facial
expression, stooped
posture, slowness of
voluntary movements,
festinating gait (shortened,
accelerated steps), rigidity
& pill-rolling tremors
associated with decreased
function of the nigrostriatal
system”.
 PARKISONISM
Principal diseases are:-
• Idiopathic Parkinson disease
• Progressive supranuclear palsy
• Corticobasal degeneration
• Multiple system atrophy
• Postencephalitic Parkinsonism
PARKISONISM
ETIOLOGY

Idiopathic

Drugs: Dopamine antagonists - MPTP

Toxins: pesticide exposure

PARKISONISM
PATHOGENESIS
Degeneration of dopaminergic neurons
projecting from Substantia nigra to Corpus
striatum
Reduction in dopamine striatal content
Severity proportional to dopamine deficiency
Acute Parkinson syndrome follows exposure to
psychoactive mepridine analogs
Autosomal dominance inheritence - Mutation in
the gene alpha- synuclein
PARKISONISM
PATHOGENESIS:
Lewy body which contains;
Alpha synuclein
Parkin
Ubequitin
 IDIOPATHIC PARKINSON DISEASE
(PARALYSIS AGITANS)

Absence of toxic or
other known etiology
Occurs in later life
Pallor of substantia
nigra & locus ceruleus
Deficiency of dopamine
IDIOPATHIC PARKINSON DISEASE (PARALYSIS AGITANS)

Loss of dopaminergic neurons and

gliosis

Lewy bodies, bright pink,

eosinophilic ,single or multiple,
round to elongated (intracytopasmic
inclusion) in remaining neurons

Dense core of filaments surrounded

by clear halo
IDIOPATHIC PARKINSON DISEASE (PARALYSIS AGITANS)
 PARKISONISM

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INFECTIONS OF CNS
BACTERIAL
– Acute pyogenic
– Chronic
VIRAL
FUNGAL
– Normal persons
– Immunocompromised
PARASITIC
M E N I N G I T I S
Definition
“An inflammatory process of the leptomeninges and CSF within
the subarachnoid space”

Meningoencephalitis
Inflammation of the meninges and brain parenchyma

Meningeal carcinomatosis
Infiltration of subarachnoid space by carcinoma

Meningeal lymphomatosis
Infiltration of subarachnoid space by lymphoma
M E N I N G I T I S
ACUTE
Pyogenic (bacterial)
Aseptic (viral & Chemical)
CHRONIC
 Bacterial (Tuberculous, Spirochaetes)
 Fungal (Cryptococcus neoformans, Candida
albicans, Aspergillus fumigatus, Mucormycosis)
 Parasitic (Acanthamoeba – chronic
granulomatous, Toxoplasma gondii, Naegleria)
ACUTE (PYOGENIC) MENINGITIS

CAUSES
Neonates – Escherichia coli & Group B-
Streptococci
Infants/children – Haemophilus influenzae
type-B
Adolescents – Neisseria meningitidis,
Streptococcus pneumoniae
Elderly – Streptococcus pneumoniae &
Listeria monocytogenes
Immunocompromised – klebsiella, Anaerobes
ACUTE ASEPTIC MENINGITIS
CAUSES
VIRAL
Enterovirus, Echovirus, Coxsackie virus &
nonparalytic poliomyelitis virus. Herpes
simplex, Herpes zoster, Influenza
CHEMICAL
- Drugs
- Rupture of epidermoid cyst
MENINGITIS
Routes of infection
Haematogenous spread
Septicemia
Retrograde venous spread from veins of face
Direct implantation
Traumatic
Iatrogenic
Local extension
Sinusitis, infected tooth, osteomyelitis, chronic otitis media,
mastoiditis
Peripheral nervous system
Viruses: Rabies & Herpes simplex
ACUTE MENINGITIS - MORPHOLOGY

CSF
Cloudy, purulent
GROSSLY
Purulent exudate over surface of
brain, meningeal vessels
congested, ventriculitis

MICROSCOPY
ACUTE PYOGENIC; Neutrophilic
infiltrate: perivascular, wall of
veins, cerebritis
ACUTE VIRAL; Lymphocytes,
plasma cells & macrophages –
perivascular lymphocytic cuffing
TUBERCULOUS MENINGITIS
Source; tuberculosis of lung or vertebral bodies
Gelatinous / fibrinous exudate at base of brain
Discrete tubercles/granules over meninges
Diffuse meningoencephalitis
Chronic caseating granulomata
Obliterative endarteritis – infarction
Adhesions and fibrosis
Obliteration of cistern
Hydrocephalus
Tuberculoma
CLINICAL FEATURES - MENINGITIS
Headache, photophobia, irritability
Malaise
Fever
Vomiting
Mental confusion
Neck stiffness
Kernig’s sign - positive
 CSF FINDINGS
Parameters Ac.Bacterial Acute viral Tuberculous
(pyogenic)
Appearance Turbid, purulent Clear & colourless Opalescent or
clear
Coagulum Nil Nil Spider-web clot

Cell count Very high Increased Increased

Type of cells Neutrophils Mostly Mostly

lymphocytes lymphocytes

Protein level Markedly raised Moderately raised Markedly raised

Glucose Very low or absent Normal Moderately

content reduced or
normal
Gram’s stain Bacteria ± No organism No organisms

Z.N stain No AFB No AFB AFB may be seen

COMPLICATIONS OF MENINGITIS

Adhesive arachnoiditis
Obliterations of cistern
Hydrocephalus
Involvement of cranial nerves
Meningoencephalitis
Brain abscess
Tuberculoma
Calcification
 BRAIN ABSCESS
SOURCE OF INFECTION
By direct implantation
Local extension
Haematogenous spread

PREDISPOSING CONDITIONS
Acute bacterial endocarditis,
Cyanotic congenital heart
disease, Chronic pulmonary
sepsis (bronchiectasis)
B R A I N A B S C E S S (Contd)
ORGANISMS
Staphylococci, Streptococci, Anaerobic bacteria
REGIONS AFFECTED
Frontal lobe, parietal lobe and cerebellum
MORPHOLOGY
Central liquefactive necrosis, neovascularization,
oedema, fibrosis and reactive gliosis
EFFECTS
Increased intracranial pressure – herniation
Rupture – ventriculitis
Meningitis
Venus Sinus thrombosis- infarction
Focal neurological deficits
Death
BRAIN ABSCESS
N E U R O S Y P H I L I S
Treponema pallidum gains access to the CNS
by haematogenous spread.
Primary & secondary stages - clinically silent
meningitis
Tertiary stage – meningeal thickening
causing cranial nerve palsies
Gummas(plasma cells rich mass), causing
cerebral or spinal compression
Tabes dorsalis due to degeneration of dorsal
spinal columns
General paresis of the insane’ is due to
cerebral atrophy.
V I R A L I N F E C T I O N S OF C N S

Spread to CNS by haematogenous route or

by retrograde neural transport
Viral meningitis is common & self limiting
illness
Viral encephalitis is less frequent. May result
in death or severe disability.
Reactivation of a latent viral infection
(Herpes zoster) may damage CNS
VIRAL INFECTIONS OF CNS (Contd)
HIV infection is common and is often
associated with other viral, bacterial or
parasitic infections.
‘Slow’ virus infection responsible for
subacute spongiform encephalopathy –
dementia
Acute disseminated encephalomyelitis,
a demyelinating disorder may result
from a virus induced immune reaction.
VIRAL ENCEPHALITIS
Characterized by:-
Mononuclear cells
infiltration: lymphocytes,
plasma cells and
macrophages usually as
perivascular cuffing
Cell lysis and phagocytosis
of cell debris by
macrophages. When
neurons involved e.g in
poliomyelitis called as
neuronophagia
VIRAL ENCEPHALITIS
VIRAL ENCEPHALITIS
(Contd)

Characterized by:-
Viral inclusions: seen in infected neurons
or glial cells “owl-eye” inclusions in
cytomegalovirus and “negri bodies” in
rabies.
Reactive hypertrophy and hyperplasia of
astrocytes and microglial cells – microglial
nodules/clusters
Oedema which is vasogenic type
TYPES OF VIRAL ENCEPHALITIS
Arthropod – borne viral encephalitis –
ourtbreaks of epidemics
Herpes simplex virus (HSV) type - I
(Labialis): most common in children &
young adults.
Herpes simplex virus (HSV-2) – genitalis: in
neonates with H/O vaginal delivery
Herpes zoster: reactivation of latent
infection – distribution of a dermatome
(shingles)
HERPES ENCEPHPHALITIS
 TYPES OF VIRAL ENCEPHALITIS (Contd)
Cytomegalovirus: in utero infection – periventricular
necrosis, microcephaly and periventricular calcification.
Opportunistic in AIDS.

Poliomyelitis
Attack lower motor neurons
and may cause flaccid paralysis.
Inflammatory process confined
to anterior horns
Death due to respiratory muscle
paralysis or myocarditis
RABIES
Due to bite of rabid animals
or exposure to bats
Virus ascends to CNS
along peripheral nerves
from wound
Causes CNS excitibility,
hydrophobia & flaccid
paralysis
Death due to respiratory
center failure.
 R A B I E S (Contd)
Negri bodies found in
hippocampal pyramidal
cells and Perkinje cells
of cerebellum.
Neuronal necrosis &
inflammation in basal
ganglia, midbrain and
medulla.
 HUMAN IMMUNODEFICIENCY VIRUS
(HIV) INFECTION
HIV-1 Aseptic meningitis
– Within 1-2 weeks of
seroconversion. Virus can be
isolated from the CSF
HIV-1 Encephalitis
– Insidious mental slowing, memory
loss and mood disturbances,
ataxia, bladder and bowel
incontinence, Virus containing
microglial nodules and
multinucleated giant cells.
 HIV INFECTION (Contd)
Vacuolar Myelopathy
– destruction of myelinated fibres and
macrophages involving posterior and lateral
columns
Cranial and Peripheral Neuropathies
– Acute & chronic inflammatory demyelinating
polyneuropathies. Inflammatory myopathies.
CNS INFECTIONS - IMMUNOCOMPROMISED
PATIENTS

Atypical mycobacteria
Cytomegalovirus
Papovaviruses
Candida albicans
Aspergillus fumigatus
Cryptococcus neoformans
Toxoplasma gondii
Entamoeba histiolytica
CRYPTOCOCCUS NEOFORMANS
PARASITIC INFECTIONS - CNS

Toxoplasma gondii – may be congenital

Plasmodium falciparum – cerebral malaria
Trypanosome Rhodesiensis – chronic
meningoencephalitis
Entamoeba histiolytica – amoebic abscess
Taenia solium – cerebral cysticercosis
Echinococcus granulosus – hydatid cyst
Toxocara crani – eosinophilic meningitis