Lecture #42: Diseases of Myelin

What is demyelination?

Loss of myelin with relative preservation of axons, distinguishing it from infarction or destructive lesions

How does demyelination affect nerve conduction?

It causes slowed conduction velocity due to loss of saltatory conduction and may cause conduction block

What is the most common demyelinating disease of the CNS?

Multiple sclerosis

What defines multiple sclerosis clinically?

Episodic neurologic deficits separated in time and caused by white matter lesions separated in space

What population is most commonly affected by multiple sclerosis?

Young adults, with women affected more often than men

What is the underlying pathogenesis of multiple sclerosis?

Autoimmune attack against myelin mediated by T lymphocytes and macrophages in genetically susceptible individuals

Which immune cells are most important in MS pathogenesis?

Th1 and Th17 CD4 T cells that activate macrophages and recruit inflammatory cells

What are MS plaques?

Well-circumscribed areas of demyelination in white matter with relative axonal preservation

Where are MS plaques most commonly found?

Periventricular white matter, optic nerves, corpus callosum, brainstem, cerebellum, and spinal cord

What are the gross characteristics of MS plaques?

Firm, gray-tan, irregularly shaped lesions that are often periventricular

What distinguishes active from inactive MS plaques microscopically?

Active plaques contain inflammatory cells and macrophages with myelin debris, while inactive plaques show gliosis and little inflammation

What are common presenting symptoms of multiple sclerosis?

Weakness, optic neuritis, diplopia, sensory loss, ataxia, vertigo, and bladder dysfunction

What is Uhthoff phenomenon?

Worsening of neurologic symptoms with increased body temperature

What is Lhermitte sign?

An electric shock sensation down the spine with neck flexion

What CSF finding supports a diagnosis of multiple sclerosis?

Oligoclonal IgG bands indicating intrathecal antibody production

What imaging modality is preferred for diagnosing MS?

MRI

What is Guillain-Barre syndrome?

An acute immune-mediated demyelinating disorder of the peripheral nervous system

What typically precedes Guillain-Barre syndrome?

A recent viral or bacterial illness

What is the classic pattern of weakness in Guillain-Barre syndrome?

Rapidly progressive ascending paralysis

What reflex changes are seen in Guillain-Barre syndrome?

Areflexia or hyporeflexia

What is albuminocytologic dissociation?

Elevated CSF protein with normal or near-normal cell count

What is the primary pathologic process in Guillain-Barre syndrome?

Segmental demyelination of peripheral nerves with relative axonal preservation

Why is Guillain-Barre syndrome life-threatening?

Respiratory muscle weakness and autonomic instability

What treatments are effective for Guillain-Barre syndrome?

Plasmapheresis and intravenous immunoglobulin

What are leukodystrophies?

Genetic disorders of abnormal myelin formation or stability rather than destruction of normal myelin

When do leukodystrophies typically present?

Infancy or childhood with progressive neurologic decline

What enzyme deficiency causes metachromatic leukodystrophy?

Arylsulfatase A deficiency

What accumulates in metachromatic leukodystrophy?

Sulfatides that are toxic to white matter

What histologic feature characterizes metachromatic leukodystrophy?

Macrophages containing metachromatic sulfatide material and gliosis

What enzyme deficiency causes Krabbe disease?

Galactocerebroside beta-galactosidase deficiency

What toxic metabolite accumulates in Krabbe disease?

Galactosylsphingosine

What is a hallmark histologic feature of Krabbe disease?

Globoid cells around blood vessels

What genetic defect causes adrenoleukodystrophy?

X-linked mutation impairing peroxisomal metabolism of very-long-chain fatty acids

What organs are affected in adrenoleukodystrophy?

CNS, peripheral nerves, and adrenal cortex

What is progressive multifocal leukoencephalopathy?

A demyelinating disease caused by JC polyomavirus infection

Which patients are at risk for PML?

Immunocompromised individuals such as transplant recipients or AIDS patients

Which cells are infected in PML?

Oligodendrocytes

What are the histologic features of PML?

Multifocal demyelination, enlarged oligodendrocyte nuclei with viral inclusions, and bizarre reactive astrocytes

What is the key difference between MS and PML?

MS is autoimmune and relapsing, while PML is infectious and occurs in immunosuppressed patients