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Primary Diseases of Myelin Demyelinating diseases: Damage to previously normal myelin Immune-mediated injury: multiple sclerosis Viral infection of oligodendrocytes Drugs and other toxic agents Dysmyelinating diseases (Leukodystrophy): Abnormal myelin synthesis / turnover

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Multiple Sclerosis Relapsing/remitting episodes of neurologic deficits, separated in time, white matter lesions separated in space Women affected twice as often (20 40 years) Environmental/genetic: loss of tolerance to myelin antigens (CD4 T cells react against self antigens in myelin sheath) 15-fold risk if disease present in first-degree relative

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Morphology Plaques: multiple, well-circumscribed, gray-tan lesions Microscopic: Active plaque - myelin breakdown, macrophages containing myelin debris, perivascular lymphocytes Small lesions on small veins, axons relatively preserved Quiescent /inactive plaques - Gliosis, no inflammation, little to no myelin left

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Multiple Sclerosis

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Clinical Features Relapses followed by remissions Sensory dysfunction: paresthesias, loss of pain/ temperature / vibratory sensations UMN dysfunction: spasticity, DTRs, muscle spasm, Babinski, weakness Autonomic dysfunction: urge incontinence; sexual dysfunction; bowel motility dysfunction Optic neuritis, Bilateral internuclear ophthalmoplegia Cerebellar ataxia SIN: scanning speech, intention tremor, nystagmus Flexion of neck produces an electrical sensation down the spine

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A 45-year-old man with worsening weakness in his right leg and double vision Horizontal diplopia during lateral gaze in both eyes

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Diagnosis & Treatment CSF : Mildly elevated protein level with increased -globulin, Oligoclonal bands, moderate pleiocytosis in 1/3rd cases MRI: for distribution of lesions during active disease Treatment Acute relapse - High dose methylprednisolone Chronic (a) Disease modifying drugs-e.g., interferon-beta (b) Monoclonal antibody-natalizumab (c) Cytotoxic-cyclophosphamide; methotrexate; azathioprine Prognosis 70% of patients alive 25 years after diagnosis

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Non-immune process Loss of myelin in center of pons Follows rapid correction of hyponatremia In alcoholism and severe electrolyte imbalance - rapidly evolving quadriplegia Central pontine myelinolysis

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Leukodystrophies Abnormal myelin, mostly autosomal recessive Morphology: White matter diffusely abnormal in color (gray and translucent) and volume (decreased) Brain atrophy, ventricles enlarge, secondary changes in gray matter Loss of myelin

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Metabolic DisorderInheritanceAbnormality Metachromatic leukodystrophy AR Arylsulfatase A deficiency Krabbe diseaseAR Galactocerebroside -galactosidase deficiency AdrenoleukodystrophyX-Recessive Peroxisomal defects; elevated very long chain fatty acids Canavan diseaseAR Aspartoacylase deficieny Pelizaeus-Merzbacher disease X Mutations in proteolipid protein Vanishing white matter disease AR Translation initiation factor Alexander diseaseAR Mutations in GFAP

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Summary Diseases of myelin - widespread, severe neurologic deficits Demyelinating (normal myelin is broken down) Dysmyelinating (abnormal myelin) Multiple sclerosis: most common demyelinating disease, autoimmune, affects young adults, relapsing-remitting course with progressive neurologic deficits

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Nutritional Diseases - Thiamine Deficiency Beri Wernicke encephalopathy : confusion, abnormal eye movement and ataxia Korsakoff syndrome: profound memory disturbances Causes: chronic alcoholism, gastric carcinoma, chronic gastritis Treatment: Thiamine

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Nutritional Diseases - Thiamine Deficiency Morphology Hemorrhage and necrosis in mammillary bodies Lesions in medial dorsal nucleus of thalamus correlate with memory disturbance in Korsakoff syndrome

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Vitamin B 12 deficiency Pernicious anemia Sub-acute combined degeneration of spinal cord Initially ataxia/numbness/tingling can progress to paraplegia Clinical improvement with vitamin replacement therapy

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Degenerative Diseases and Dementias Primary Neurodegenerative Disorders Alzheimer disease Pick disease, frontotemporal degenerations Parkinson disease, diffuse Lewy body disease Progressive supranuclear palsy Huntington disease Motor neuron disease Infections Prion-associated disorders (Creutzfeldt-Jakob disease, fatal familial insomnia, others) HIV encephalopathy (AIDS dementia complex) Progressive multifocal leukoencephalopathy Miscellaneous forms of viral encephalitis Neurosyphilis Chronic meningitis Vascular and Traumatic Diseases Multi-infarct dementia, chronic vascular disorders Global hypoxic-ischemic brain injury Chronic subdural hematomas Metabolic and Nutritional Diseases Thiamine deficiency (Wernicke-Korsakoff syndrome) Vitamin B 12 deficiency Niacin deficiency (pellagra) Endocrine diseases Miscellaneous Brain tumors Neuronal storage diseases Toxic injury (mercury, lead, manganese, bromides)

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Alzheimer Disease Most common cause of dementia in elderly 1.Impaired higher intellectual functions with mood/behavior alterations 2.Progressive disorientation, memory loss, and aphasia 3.Disabled, mute, immobile Prominent early sign is decline in short-term memory Accumulation of amyloid (A) in brain Death from pneumonia/other infections

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Alzheimer Disease Sporadic early onset - related to apolipoprotein gene E Familial early onset type of AD (