Demyelinating Disorders Christina Catherine - PowerPoint Presentation

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Demyelinating Disorders

Christina CatherinePGY-II10/3/16

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Demyelinating disorders

Can be divided between congenital and acquiredCongenital disorders include:Adrenoleukodystrophy

Metachromatic

leukodystrophy

Krabbe’s

disease

Alexander’s disease

Canavan’s disease

Pelizaeus-Merzbacher

disease

Acquired disorders include:

MS

MS variants (

tumefactive

MS, Marburg type,

Balo’s

concentric sclerosis,

Schilder’s

disease, NMO, ADEM, acute hemorrhagic

leukoencephalitis

)

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Case 1:

Sam is a 20 yo college student who presents to the neuro clinic for progressive weakness and numbness in his lower extremities. He reports that he first started to notice the weakness about 2 months ago after going on several alcohol binges. He has stopped drinking but continued to notice worsening weakness in both legs that has made it difficult for him to walk up stairs to class and walk around campus. He has also noticed mildly decreased sensation in his feet and calves associated with burning pain. A1c 5.1. No illnesses around the time that his symptoms started. Exam is notable for 4/5 strength in BLEs, 4+/5 strength in BUEs, reflexes were brisk in the LEs, and Babinski was present bilaterally.

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More info….

Further history elucidates that his mom also has mild lower extremity weakness and difficulty ambulating requiring a walker to get around that was diagnosed 2 years ago (when she was 48). He doesn’t remember what her diagnosis was though. LP was unremarkable. A brain MRI was obtained and showed:

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What is the most likely diagnosis?

Multiple sclerosisCIDPDistal symmetric polyneuropathyKrabbe’s

disease

Adrenoleukodystrophy

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Adrenoleukodystrophy

Most common inherited leukodystrophyGene: X-linked (defect in ABCD1)

Mechanism

: accumulation of VLCFAs in cell membranes 2/2

peroxismal

disorder of myelin/myelin-producing cells

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Phenotypes:

Males: earlier onset and more severe diseaseChildhood cerebral (31-35%): onset 3-10 yo

Adolescent (4-7%): onset 11-21

yo

Adrenomyeloneuropathy

(40-46%): onset >19yo

Adult cerebral (2-5%)

Olivopontocerebellar

(1-2%): onset in adolescence or adulthood

Addison’s only

Females: heterozygotes with later disease onset

Asymptomatic: most women <30yo

Mild myelopathy: 50% by 40

yo

Mod-severe myelopathy: ~15% at 40

yo

Cerebral form (2%)

Adrenal insufficiency (1%)

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Clinical features:

Males:Childhood cerebral: deficits in behavior, cognition, vision, hearing, motor. May initially be confused w/ ADHD, total disability w/in 3 yrs.Adolescent

: slower progression of childhood form

Adrenomyeloneuropathy

(AMN): progressive spastic

paraparesis

, decreased vibration, dysesthesias, sphincter disturbances

Adult cerebral

: dementia, including

fronto

-subcortical dementia and seizures

Olivopontocerebellar

: cerebellar and brainstem

sx

Females:

Mild myelopathy

: increased DTRs, distal sensory changes

Mod-severe myelopathy

: similar to AMN but milder and later onset

Cerebral form

: may show psychiatric

sx

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Radiologic features:

(A) Childhood cerebral form with classic posterior pattern of T2 lesions beginning in the splenium with symmetric spread to

parieto

-occipital lobes. (B) Cerebral involvement can also have a frontal pattern. In both patterns, there is relative

sparing

of arcuate fibers.

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Gross findings:

Confluent symmetric lesions esp in parieto-occipital lobes

Severe myelin loss in deep white matter with relative sparing of myelin near gray-white junction

Brownish discoloration of: cerebral white matter, corpus callosum, post. internal capsule, optic fibers

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Histologic findings:

Common findings:(A) Perivascular lymphocytic inflammation with T cells., macrophages & astrocytes (B) Macrophages contain myelin debris in areas of active myelin breakdown (PAS+). (C) Myelopathy w/ degeneration of

asc

. posterior columns &

desc

. CST

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Case 2:

Alex is a 23 yo w/ no significant PMH who presents to the neurology clinic with c/o slurred speech, frequent choking and abnormal “shaking” movements when he walks or tries to grab things. His exam is notable for dysarthria,

hypophonia

, weak masseters, inability to puff his cheeks,

dysmetria

on FTN and a broad-based, ataxic gait.

AchR

antibodies are normal. No change in amplitude on repetitive stim. An MRI shows a single subcortical cyst. Genetic testing is pending.

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What is the diagnosis?

Myasthenia gravisLambert-EatonAlexander’s diseaseADEMMS

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Alexander’s disease

Genetics: autosomal dominant, often de novo mutation in GFAP geneIncidence

: rare

Pathophysiology

: causes excessive accumulation of GFAP -> diffuse or focal demyelination

Pathology

: abundant Rosenthal fibers

Phenotypes

:

Infantile form: universally fatal, p/w macrocephaly, ataxia, and

sx

of bulbar dysfunction

Adult form: onset in 20-50s, 10% of cases, p/w bulbar dysfunction and ataxia

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Alexander’s disease: Gross pathology

(Infantile form) Broadening of the gyri

Extensive white matter involvement w/ frontal predominance

Subcortical cysts

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Alexander’s disease: Microscopic path

Diffuse GFAP staining and abundant Rosenthal fibers

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Case 3:

A 21 yo woman p/w acute onset of paresthesias in her right arm, dysarthria and blurred vision. Last year, she had been diagnosed with optic neuritis that had improved. MRI at that time only showed a few scattered T2

hyperintensities

in the deep cortical white matter. Repeat MRI today shows new T2 lesions in her occipital lobe and brainstem. LP results are pending.

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What are the diagnostic criteria of MS?

At least 2 different T2 lesions on MRI with one known attack2+ lesions with at least one new lesion, +CSFA short segment spinal cord lesion following a viral illnessA family h/o MS w/ CSF + for

oligoclonal

bands

Isolated optic neuritis

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Multiple sclerosis

Sx: paresthesias, monocular vision loss, gait abnormalities, weakness, double vision, urinary issues, cognitive dysfunction, fatigue

Incidence

: increases w/ distance from Equator (

except

in Native Americans)

Risk factors

: smoking, vitamin D deficiency, EBV exposure, +/- BMI

Types

:

Relapsing-remitting: sporadic attacks w/ new or worsened

sx

Primary progressive: progressive accumulation of disability w/o relapses

Secondary progressive: conversion of R-R to PP

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Diagnosis of MS

CSF: mild elevation of protein + mononuclear cellsOligoclonal bands w/ elevated IgG index

MRI:

Periventricular,

infratentorial

,

juxtacortical

or cortical white matter T2

hyperintensities

“Black holes: on T1 images

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MS: Gross pathology

Moderate cerebral atrophy, hydrocephalus ex vacuo, thinning of the corpus callosum, gray-glistening patches of myelin loss

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What patterns of demyelination can be seen?

T-cell mediated onlyT-cell mediated, T-cell antibody-mediated, and/or oligodendrocyte dystrophyOligodendrocyte dystrophyVirus-induced demyelination

Destruction of astrocytes

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MS: microscopic pathology

Ventricular plaques adjacent to ependymal lining/hippocampus

Spinal cord plaque

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MS: microscopic pathology

Chronic inactive plaque: hypocellularity, severe loss of oligodendrocytes,

astrocytosis

, NO macrophages

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MS: microscopic pathology

Chronic active plaque (CAP):

Shadow plaque (SP): reduced myelin,

remyelinated

lesion

NAWM (normal white matter)

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Case 4:

A 26 yo woman from China presents to the ED with acute onset headache, aphasia and AMS. Per her family, she had been in her normal state of health until earlier that week. No recent illnesses or travel. She was afebrile with normal VS. Exam was notable for decreased sensation in LUE, a left visual field cut, and non-fluent aphasia. An MRI brain was obtained…..

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MRI:

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What type of demyelinating d/o is this?

ADEMMarburg type of MSNMOBalo’s concentric sclerosis

Adrenoleukodystrophy

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Balo’s Concentric Sclerosis:

Acute MS defined by the presence of concentric rings of normal white matter alternating w/ zones of demyelination.Seen more commonly in people from Southeast Asia

Sx

: headache, aphasia, cognitive dysfunction, behavioral abnormalities, loss of function in affected cortical area(s), +/- ICP

Dx

:

MRI: lamellar lesions, may have contrast enhancement

Pathologic: alternating bands of preserved myelin (narrow) surrounded by bands of demyelination, macrophages at the edges of lesions

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Balo’s Concentric Sclerosis: micro

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Balo’s concentric sclerosis: micro

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Summary

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Summary:

Adrenoleukodystrophy: Most common

leukodystrophy

X-linked defect in ABCD1 gene -> accumulation of VLCFAs

Majority of cases affect young adult males and are

a/w

spastic

paraparesis

, brisk reflexes and abnormal sphincter tone +/- adrenal dysfunction

Key path terms

: perivascular lymphocytic inflammation

Alexander’s disease

:

Autosomal dominant

Excess GFAP accumulation

P/w ataxia and bulbar dysfunction

Key path terms

: Rosenthal fibers, +GFAP staining w/ accumulation

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Summary

MS:Most common form of demyelinating diseaseWide variety of symptoms at presentation

Time & space criteria for definition, MRI + CSF findings for dx

Key terms

: Dawson’s fingers, T2 periventricular

hyperintensities

, T1 black holes, T-cell mediated demyelination + oligodendrocyte dystrophy, foamy macrophages containing myelin

Balo’s

concentric sclerosis

:

Concentric rings of myelination (thin) and demyelination

p/w headache, confusion, behavioral abnormality, similar to mass-like lesion

Key path terms

: lamellar lesions that alternatively stain + for myelin

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Questions?

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References:

Material taken from Neuropathology by Prayson, 2012