Demyelinating, Metabolic & Degenerative Diseases of the CNS

Demyelinating diseases of the CNS Acquired diseases characterized by: Preferential damage to myelin Relative preservation of axons Reduced impulse conduction Later in the Natural History secondary damage to axons may occur Remember: the CNS has limited capacity to regenerate myelin

Mechanism of Demyelination Self-study The upper part of the figure depicts a neuron with a myelinated axon. At the right corner, the neuron is magnified and cut in cross section, demonstrating the concentric lamellar structure of myelin. The middle of the figure shows a neuron with a myelinated axon forming a synapse with another neuron. Two oligodendrocytes are shown; each cell myelinates multiple segments of more than one axon. The bottom neuron has been partially demyelinated, and it is surrounded by T cells, which secrete inflammatory cytokines (interleukin-2 [IL-2], interferon gamma [IFN-and tumor necrosis factor- [TNF- ]), and by macrophages, which are stripping myelin from the axon. The macrophages contain myelin debris in phagocytic vacuoles. Conduction in the demyelinated axon is blocked. A blood vessel shows T cells adhering to the lumen and crossing from the vessel into the brain.

Effect of Demyelination on Nerve Conduction Demyelination reduces the Velocity of Nerve conduction Axonal degeneration reduces the Amplitude of Nerve conduction Normal Amplitude - Low Velocity Normal Normal Velocity – low amplitude Time in Milliseconds

Multiple Sclerosis (MS) Autoimmune demyelinating disease Distinct episodes of neurologic deficits Separated in Time (the episodes) Space (the white matter lesions) Remember: You need Two separate Episodes that affect Two different areas of the CNS to clinically diagnose MS

Multiple Sclerosis (MS) – Features The Most common disease in this category Risk higher as one moves away from Equator 1/1000 persons (US, Europe); Rare in Asians Age: 20 to 50 years (peak = 30); rare in children Gender: Women twice as men Relapsing and remitting episodes are typical Gradual, partial recovery of neurological function Intervals: weeks to months

M S – Pathogenesis Cellular immune response against components of myelin Influenced by genetic/environment Risk 15x if present in 1st degree relative Risk 50x for monozygotic twins Genetic linkage to HLA DR2

M S – Pathogenesis

M S – Pathogenesis Initiated by reaction of CD4+ TH1 against self myelin Ag due to microbial triggers? susceptibility genes? Secretions of cytokines (e.g. IFN-gamma) Activation of Macrophages  damage to myelin

MS – Morphology Macro: Well circumscribed, irregular tan-gray plaques Firmer consistency than surrounding white matter (sclerosis) Microscopic foci to confluent & large

M S – Location of plaques Commonly beside lateral ventricles Also frequent in: Optic nerve and chiasm Brainstem tracts Cerebellum Spinal cord

M S – Histopathology Sharply defined lesions Abundance of inflammatory cell (mainly Ma with PAS+ debris) especially around blood vessels (perivascular cuffs) and at the outer edge of the lesion Depletion of myelin (illustrated by LFB stain) Preservation of axons Depletion of oligodendrocytes

M S – Clinical course Wide range of clinical manifestation Certain patterns more common Optic neuritis (Retro-Bulbar neuritis): Frequent initial manifestation Unilateral visual impairment 10-50% develops MS (after the 1st episode) MS variants: Neuromyelitis Optica (Devic Disease) Acute MS (malignant MS; Marburg variant)

Neuromyelitis Optica (Devic Disease) Especially Asians Presents as: Bilateral optic neuritis Prominent spinal cord involvement Three clinical forms: Rapidly progressive Relapsing-Remitting Single episode Plaques appear more destructive Eugene Devic (1858-1930)

Encephalomyelitis Acute disseminated encephalomyelitis (ADEM) Monophasic demyelinating disease Followed a week or two after: Viral infection Viral immunization (rarely) Acute necrotizing hemorrhagic encephalomyelitis (ANHE) Fulminant syndrome of CNS demyelination Children and young adults Preceded by URTI (e.g. Mycoplasma Pneumoniae) Usually fatal

ADEM – Clinical Features Diffuse (Not Focal) brain involvement Headache Lethargy Coma 20% rapid progression & death 80% complete recovery

Other causes of Demyelination Nutritional / metabolic Machiafava-Bignami disease (in alcoholics) subacute combined degeneration In Vit B-12 deficiency central pontine myelinolysis Complication after severe burns Toxic Others - HIV-1 myelopathy

Subacute Combined Degeneration In subacute combined degeneration this is caused by vitamin B12 deficiency. Similar demyelination pattern can be found in HIV-1 myelopathy (the cause in this demyelination is unknown) Symptoms & Signs Tingling Numbness Paresthesias Unsteady gait loss of vibration sense loss of position sense Leg weakness & Pyramidal signs

Uncommon Diseases Leukodystrophies are Inherited disorders of myelin synthesis & turnover PML (progressive multifocal leukoencephalopathy) Due to JC virus infection of oligodendrocytes Results in loss of myelin

Inherited Demyelinating diseases Secondary to a genetic defect in various metabolic and biochemical pathways Breakdown of abnormal or immature myelin Peripheral nervous system myelin involved in some of these disorders Mostly pediatric, although adult forms exist

Inherited demyelinating diseases: 2 Examples Metachromatic leukodystrophy caused by a deficiency of the enzyme arylsulfatase A. MLD is a lipid storage disease, resulting in the toxic build-up of lipids in cells in the nervous system, liver, and kidneys. Symptoms: muscle wasting & rigidity, developmental delays, loss of vision, convulsions, paralysis, and dementia Spongiform leukodystrophy caused by a deficiency of the enzyme acetylaspartase aspartate builds up in the neurons accumulation of the aspartate in the white matter  leads to increased osmotic pressure there with consequent drawing of water & damage Symptoms (Start in Infancy): mental retardation, feeding difficulties, abnormal muscle tone, poor head control, and abnormally enlarged head. Later – paralysis, blindness, or hearing loss

Acquired Metabolic Disorders

Acquired Metabolic Disorders – Classification with Examples syndrome of confusion, stupor, or coma Hypoglycaemia Hypoxia / Hypercapnia Hepatic Encephalopathy Azotaemia psychosis or dementia Cushing disease and steroid encephalopathy Hyperthyroidism Hypothyroidism progressive extra-pyramidal syndrome Hyperbilirubinemia and kernicterus cerebellar ataxia Hypothyroidism

Degenerative Diseases of CNS Lastly, Degenerative Diseases of CNS

Degenerative Diseases Two outstanding characteristics: (1) selective involvement of anatomically and physiologically related systems of neurons (2) begin insidiously and worsen gradually over many years, often a decade or longer

Syndromic Classification - 1 progressive dementia Alzheimer disease progressive dementia with other signs Huntington chorea “Parkinson’s Plus” disordered posture and movement Parkinson disease Familial tremors progressive ataxia Spinocerebellar ataxias (early onset) Friedreich ataxia Cerebellar cortical ataxias muscular weakness & atrophy (slow onset) motor system disease

Stephen Hawking - A famous Scientist with Motor system disease

Syndromic Classification - 2 Hereditary neuropathies peroneal muscular atrophy progressive blindness or ophthalmoplegia retinitis pigmentosa Progressive external ophthalmoplegia neurosensory deafness Hereditary hearing loss

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