Transcript ACQUIRED DEMYELINATING DISEASES

NS II 2016
Pathology II
Dr. Mohammed Alorjani. MD EBP
Demyelinating Diseases
Definition:
 A group of diseases in which there is
preferential loss of myelin, most severe
in white matter, with relative
preservation of axons in early stages.
 Peripheral nervous system is relatively
spared
 Loss of myelin interferes with electric
impulse transmission along axons
Types:
 Inherited
 Acquired
A- Inflammatory
B- Metabolic
C- Autoimmune
 Multiple Sclerosis
Inherited Diseases:
 Diseases involving myelin synthesis &
turnover (oligodendrocytes) 
Dysmyelinating
Diseases/LEUKODYSTROPHIES
CLINICAL: A variety of inherited
diseases with variable age of onset
(usually in childhood) and rate of
progression, which typically result in
diffuse severe dysfunction.
 PATHOGENESIS:
AR mutations in enzymes & proteins related
to myelin structure or metabolism.
Few are X-linked.
Examples: Metachromatic LD (Arylsulfatase A def.), AdrenoLD
(Peroxisomal defects) & Krabbe disease
 PATHOLOGY:
-Degeneration of the white matter
- Demyelination and glial reaction
- Some show defects of lipid metabolism →
accumulation of various cerebrosides
e.g. Krabbe disease (β-galactosidase def.)
ACQUIRED DEMYELINATING
DISEASES:
Viral infection by JC virus  PML
Acute disseminated encephalomyelitis
Acute necrotizing hemorrhagic
encephalomyelitis
Central Pontine Myelinolysis
Neuromyelitis optica
Multiple Sclerosis
1- Acute Disseminated Encephalomyelitis
 Post- or parainfectious encephalomyelitis
(viral) OR
 Post-vaccinial encephalomyelitis
 Autoimmune mechanism starts within
1-2 weeks of initial trigger
Result:
 Diffuse brain demyelination  non-localizing
S. & S.
 Coma & death in up to 20%
 Hemorrhagic Necrotizing: similar, more
severe & usually in children
2- Central Pontine Myelinolysis
Causes:
 Rapid correction of hyponatremia &
Acid Base imbalance
 Alcohol-induced
Pathology:
 Cellular edema, caused by fluctuating
osmotic pressures → compression of fiber
tracts → demyelination in center of PONS &
other areas in brain
 Rapidly evolving quadriplegia.
3- Neuromyelitis Optica
Cause:
 Immune: Antibodies to water channel
aquaporin-4 (diagnostic & pathogenic)
Pathology:
 Inflammatory demyelinating.
 Optic nerves and spinal cord affected.
3- Multiple Sclerosis
 2nd commonest cause of neurological disability
in early-middle adulthood, after trauma.
 Most common demyelinating disorder.
 Characteristics:
 Course is relapsing-remitting or progressive
 Lesions are typically separated in time and in
space.
 Pathology:
Inflammation - demyelination - gliosis
Epidemiology:
 Prevalence is about 1/1000, F:M - 2:1
 Age of onset typically 20-40

 rates in Europe, Canada , USA..(1/1000)

Low rates in Asia, Africa, Middle East

Migrants adopt the risk of their new
environment if they move before age 15y
Pathogenesis:
 Immunologic mechanisms:
 Initiating agent: ?Infectious
 Autoreactive T-lymphocytes to Myelin
basic protein (MBP)
 Autoantibodies against myelin
antigens such as myelin
oligodendrocyte glycoprotein (MOG)
 Viral Triggers
 ? molecular mimicry between
viruses and myelin antigens
 Genetic predisposition:




Disease risk is 15 times higher in people
with affected first degree relative
~ 25% concordance rate for
monozygotic twins
HLA-DR2  risk of MS
Polymorphisms in R for IL-2 & IL-7,
which have known effect on T-cells
 Acquired environmental factors 
contribute to the Immune insult
MS: pathology
Different stages , different dates:
Patchy demyelination in periventricular
white matter, optic nerves & chiasm,
brain stem, ascending & descending
fiber tracts, cerebellum and spinal cord
- Acute stage ‘Active’ plaque :Soft pink
Myelin breakdown  phagocytosis,
perivascular lymphocytic infiltration,
and edema
 Chronic stage ‘inactive’ plaques
Hard grey: Total myelin loss, no
inflammation, loss of oligodendrocytes
and reactive gliosis
 Findings in lesions:
 CD4 (TH17 & TH1) & CD8 T lymphocytes
in lesions
 AB against myelin components +
complement are identified in lesions
 CSF  Oligoclonal band of IgG against
myelin antigens, mild  protein,
lymphocytes

OB is absent in serum

Classic MRI findings
Oligoclonal bands in multiple sclerosis cerebrospinal fluid: An update on methodology and clinical usefulness
Journal of Neuroimmunology Volume 180, Issues 1?2 2006 17 - 28
Clinical features:
 limb weakness 40%
 optic neuritis 20%  unilateral
visual impairment (a frequent initial
manifestation of MS)
 paresthesia 20%
 diplopia 10%
 bladder dysfunction 5%
 vertigo 5%
Disease Course: Many clinical types
 Relapsing/remitting MS (85%)
Secondary progressive MS
 Steady deterioration following RRMS
(50% patients after 15 years)
 Primary progressive MS (15%)

Steady deterioration disease onset
 Prognosis:
 Better if benign variant from start
(<20%)
 Better in women
 Better in patients with  2 attacks in
first year
- Death usually due to a complication e.g
chest or urinary infection….etc.
Degenerative Diseases
 Gradual loss of neurologic function
affecting selected populations of
neurons
 Unknown causes, some familial
 No effective treatment
 Classified according to neurological
manifestation:
 Dementia
 Postural / Movement disorders
 Combined
Dementia
 Global impairment of intellect, reason
and personality without loss of
consciousness
 Classified into:
- Primary degenerative diseases
Alzheimer Disease, Pick disease,
Huntington disease, FTLD etc…
- Secondary:
Infections, Vascular, Traumatic
Metabolic/nutritional, Toxic etc…
1- ALZHEIMER DISEASE:
 Commonest cause of dementia in the
elderly in the west.
 Insidious progressive neurologic
disorder showing gradual loss of
cognitive function.
 Sporadic or familial (5-10%)
Incidence rises with increasing age.
Familial type has earlier age at onset.
Pathogenesis of AD:
 Basic pathogenesis of the disease is
linked to deposition of β amyloid (Aβ)
in the brain by splitting Amyloid
precursor protein (APP) by certain
enzymes.
 Abnormal neurotransmission
 Genetic defects in <5% familial cases
have been identified on chromosomes
21, 19, 14, 12 & 1.
Pathogenesis of AD:
1- Chromosome 21:
 Location of APP gene
 Patients > 40 years of age with
Trisomy 21 (Down Syndrome) have
higher risk of Alzheimer disease
2- Presenelin Mutations
Alzheimer disease (AD) patients with an
inherited form of the disease carry
mutations in the Presenilin 1 or 2 gene or
the APP
APP split by β amyloid converting
enzyme (BACE) / Secretase → β amyloid
Presenilin gene mutation:
 These genes are involved in processing
of APP
 APP α & γ secretase  Soluble
Β & γ secretase  Insoluble Aβ
 Defects result in accumulation of fibrillar
aggregates of β-amyloid (Aβ) that are toxic
to neurons.
3- Tau protein:
Tau is a normal protein involved in
assembly of axonal microtubules & their
stability. Usually parallel.
 Presence of Aβ  Hyperphosphorylation
of tau protein  tau redistributes from
axons into dendrities and cell bodies as
filaments in neurofibrillary tangles.
4- Apolipoprotein E (Apo E4)
Presence of each allele ↑ risk 4 times
↑deposition of fibrillar beta-amyloid
(Aβ) in 30-40% of AD cases
Diagnosis of AD:
 Clinical Picture:
Progressive memory loss with
increasing inability to participate in
daily living activities...
 Radiological methods
 Brain biopsy
 The final diagnosis is made pathologically
by examination of the brain at autopsy.
Pathology:
Gross Changes:
 Cerebral atrophy, mainly in frontal,
temporal, and parietal region, mainly
in hippocampus leading to:
ventricular dilatation (Hydrocephalus
ex vacuo).
Microscopic Changes:
1- Neuritic (Senile) plaques:
- Extracellular location
- Composed of tortuous neuritic
processes surrounding a central
amyloid core of Aß
- Reactive astrocytes and microglia at
the periphery.
Neuritic
Plaque
Neuritic Plaque
2- Neurofibrillary tangles:
- Intracellular location, unless neurons die.
- Insoluble filaments (tau protein) mainly in
pyramidal cells of hippocampus important as
transport system. Initially parallel
- Not specific for AD.
3- Amyloid angiopathy
Neurons with tangles displacing nucleus,
2- VASCULAR DEMENTIA
 Associated with multiple infarcts, hence
the name (Multi-Infarct Dementia)
 Lacunar infarcts
 Cortical microinfarcts
 Multiple embolic infarcts
 MRI - Grey matter lesions rather than
white as in MS
 SECOND commonest form of dementia
after Alzheimer
MULTI-INFARCT DEMENTIA
Other Degenerative Diseases
 Frontotemporal dementias (FTLD):
- FTLD-tau, e.g. Pick disease (tau
mutation).
- FTLD-TD43.
 Lewy body Diseases ± Dementia:
- PARKINSON DISEASE
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