Neuro2: Disorders Of White Matter And Spinal Cord

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Presentation of demyelinating disorders and differential

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UNIL or BIL facial numbness, gait imbalance, confusion, difficulty thinking, vision problems

DDx: vasculitis, primary CNS lymphoma

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What to get for any suspected white matter disease

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Stereotactic biopsy and froxen section of tissue

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Frozen section properties in demyelinating disease

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Chronic inflammation, reactive astrocytes, macrophages and edema

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CNS myelination and implications

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Oligodendrocytes are myelinating glia that myelinate MANY axons.

Therefore a loss of a single oligodendrocyte causes a reduction of conduction velocity in many axons. Multiplicative (Schwann in PNS innervate far less axons/cell)

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Stain to evaluate demyelinating disorders

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Luxol Fast Blue (LFB)-PAS staining

Normal CNS (brain and cord) myelin stains turquoise and normal PNS myelin stains violet

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Value of a foramlin and paraffin frozen section, what does hypercellularity mean

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MORE resolution and shows cellularity. perivascular chronic inflammation and gliosis

Hypercellularity means that there is something contributing it that needs to be distinguished (vasculitis, vs primary CNS lymphoma, vs demyelinating disease)

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Special Stains to determine cell type CD3, CD20, CD68

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CD3/T-cell marker - brown is +

CD20/B-cell marker - brown is +

In CNS lymphoma only one or other is positive NOT both. Usually B cell

CD68/macrophage marker - identifies LAMP4 lysosomal protein

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What stains needed to diagnose demyelinating disease

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LFB-PAS to show myelin is not present

Neurofilament/axon stain to show axons relatively preserved

Lose both in stroke

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Immune mediated, Infectious and Genetic causes of Demyelinateive CNS disease

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Immune mediated - MS, Acute disseminated encephalomyelitis, Acute hemorrhagic leukoencephalitis

Infectious - Progressive Multifocal Leukoencephalopathy, Subacute Sclerosing Panencephalitis, Rubella, AIDS

Genetic - Leukodystrophies

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MS overview, epidemiology population, etiolgy, gross findings, microscopic finding

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Overview - disease of relapse and remissions due to gradual accumulation and residual impairment. ONLY 10% have steady progression. VERY heterogeneous

Population: 30 year old onset, women slightly more

Etiology: Unclear, involves genetics, environment and infectious agent thought

Gross findings - foci of demyelination (PLAQUES=hallmark) in PERIVENTRICULAR WHITE MATTER AND jxn of cortex and digitate white matter. CAN occur in gray matter but less common.

Reactive plaques are pinkish (active) and chronic plaques are gray, gelattinous appearing and firm (sclerotic). May have DAWSON"S FINGERS extensions of demyelination in veins intering plaque. Can affect cranial nerves leading to transient blindness

Microscopic finding - in active plaques have hypercellularity, foamy macrophages, loss of myelin. In chronic macrophages clear and some remyelination

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MS targeting of myelin sheath

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Myelin sheath is the primary target in MS and the mature oligodendrocyte body is not so can get some remyelination.

Some argue it is oligodendrocytes and O2A progenitor is the target

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Demyelination primary locations in MS

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White matter in periventricular areas, ascending and descending tracts of brainstem including cerebellar peduncles

Optic nerve and other cranial nerves

Subpial region of spinal cord

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Progression to chronic inactive plaques in MS

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Cycles of demyelination and remyelination leave virtually no oligodendrocytes in the plaque. Just axons and gliosis

Permanent compromised, can get axonal spheroids and no possible neurologic recovery

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Lesion progression in Optic Neuritis of MS

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Relapse: surge of inflammation, decrease in evoked potential amplitude (conduction block/slowing), visual loss. THought to be due to inflammatory cells releasing cytokines to interfere with ion channels

Remission: vision improves, loss of enhancement (inflammation subsides), evoked potentials delayed but block relieved (remyelination)

Remyelination: secure conduction restored, some axon loss but enough residual activity that it is not clinically/ evident

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4 MS variants

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Differ from the classic chronic relapsing-remitting MS (CHARCOT FORM)

Acute MS (Marburg Disease): monophasic MS rapidly fatal (days to months)

Devic's disease: Acute MS in adults targeting optic nerves and spinal cord with extensive destruction (often fatal)

Balo's concentric sclerosis: Rapidly fatal acute MS occurring in children and young adults, concentric wavelike pattern of loss

Schilder's disease: Resembles acute MS, but demyelinates very large areas in cerebral hemispheres. MORE PROLONGED COURSE

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Acute Disseminated Encephalomyelitis Pathophysiology, Presentation, Course

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aka perivenous or postinfectious encephalomyelitis. ACUTE, MONOPHASIC demyelinative disease

Pathophysiology: Sleeve-like perivascular demyelination surrounding small veins (definitive), hard to biopsy.

Presentation: 2-12 days post viral infection (measles, mumps, rubella) or immunizatoin for rabies or smallpox. Fever, headache, meningeal signs followed by decrease in consciousness, seizures, paraplegia, ataxia, focal signs.

Recovery is rapid and complete usually. BUT mortality is 20-30%.

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Acute Hemorrhagic Leukoencephalitis Pathophysiology, Presentation, Course

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aka Weston Hurst disease

hyperacute form of ADEM

typically fatal, death in 1-5 days

Pathophys: sleeve-like perivenous demyelination around small veins. White matter with many petechial hemorrhages and edema. NECROTIC small veins with reactive macrophages/neutrophils

BBB integrity lost, and this is what kills pt

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Progressive Multifocal Leukoencephalopathy (PML) Pathophysiology, Presentation, Course, Dx

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MOST COMMON INFECTIOUS DEMYELINATION DISORDER

Caused by JC VIRUS!!!

Pathophysiology: A complication of an underlying disease process (lymphoproliferative diseases (Hodgkins), or immunocompromised (HIV, transplant).

Course: SHORT (3-12 month) course of visual, motor, sensory and personality changes that culminate in profound dementia and death

Dx: "Punched out" lesions on LFB-PAS stain, plum colored nuclei on H&E,

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JC virus adults vs child

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Child - hemorrhagic cystitis

Adult - nothing unless immunocompromised or lympoproliferative disease then can get JC virus

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Subacute Sclerosing Panencephalitis (SSPE) Pathophysiology, Presentation, Course

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Pediatric disease

Pathophysiology: early measles in children, oligodendrocytes infected with a defective measles virus, extensive demyelination, leading to death

Demyelination with gliosis, perivascular and parenchymal inflammation and prominent INTRANUCLEAR VIRAL INCLUSION

Rubella form lacks viral inclusions

Death, no treatment

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HIV Leukoencephalopathy key ID vs AIDS (Vacuolar Myopathy)

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LESS INFLAMMATION

MULTINUCLEATE GIANT CELLS, gradual myelin loss,

infiltrative macrophages pile up at end stage


AIDS (Vacuolar Myopathy) - present with symmetrical sensory disturbance of feet that progress to clumsiness and ataxia in weeks. Multifocal vacuolated and demyelinated lesions in the posterior and lateral columns of spinal cord (brain spared)

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Causes of Vacuolar Myopathy

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multifocal vacuolated and demyelinated lesions in the posterior and lateral columns of the spinal cord (brain typically spared)

Associated with HIV infection or Vit B12 def


Present with symmetrical sensory disturbance of feet that progress to clumsiness or ataxia in weeks

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Leukodystrophies Clinical and Pathology, Cause

2 Main subtypes differentiation

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GENETIC CAUSE, NEVER FORM MYELIN

Clinical - variety of individual diseases with variable age of onset (childhood usually) and rate of progression, typically result in diffuse dysfunction ending in vegetative state

Pathology - gross demyelination occurs in large confluent areas with the cerebral hemispheres and other sites. Microscopically show loss of oligodendrocytes and myelin with relative preservation of axons. Often show inclusions or cellular accumulations peculiar to the specific leukodystrophy


Metachromatic Leukodystrophy - Cerebellar loss resembling MS plaque. Loss of central white matter with relative sparing of myelin of U-fibers (gray matter). Macrophages stain brown due to intracellular SUFLATIDES ACCUMULATION

Adrenoleukodystrophy - myelin loss in occipital, parietal and temporal lobes while sparing frontal cortex.

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Leukodystrophy due to arylsulfatase A deficiency

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Metachromatic leukodystrophy

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Leukodystrophy due to ABCD1 transporter protein deficiency

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Adrenoleukodystrophy