NS II 2016 Pathology II Dr. Mohammed Alorjani. MD EBP

Demyelinating Diseases

Definition: A group of diseases in which there is preferential loss of myelin, most severe in white matter, with relative preservation of axons in early stages. Peripheral nervous system is relatively spared Loss of myelin interferes with electric impulse transmission along axons

Types: Inherited Acquired A- Inflammatory B- Metabolic C- Autoimmune Multiple Sclerosis

Inherited Diseases: Diseases involving myelin synthesis & turnover (oligodendrocytes)  Dysmyelinating Diseases/LEUKODYSTROPHIES CLINICAL: A variety of inherited diseases with variable age of onset (usually in childhood) and rate of progression, which typically result in diffuse severe dysfunction.

PATHOGENESIS: AR mutations in enzymes & proteins related to myelin structure or metabolism. Few are X-linked. Examples: Metachromatic LD (Arylsulfatase A def.), AdrenoLD (Peroxisomal defects) & Krabbe disease PATHOLOGY: - Degeneration of the white matter - Demyelination and glial reaction - Some show defects of lipid metabolism → accumulation of various cerebrosides e.g. Krabbe disease (β-galactosidase def.)

ACQUIRED DEMYELINATING DISEASES:  Viral infection by JC virus  PML  Acute disseminated encephalomyelitis  Acute necrotizing hemorrhagic encephalomyelitis  Central Pontine Myelinolysis  Neuromyelitis optica  Multiple Sclerosis

1- Acute Disseminated Encephalo- myelitis Post- or parainfectious encephalomyelitis (viral) OR Post-vaccinial encephalomyelitis Autoimmune mechanism starts within 1-2 weeks of initial trigger Result: Diffuse brain demyelination  non-localizing S. & S. Coma & death in up to 20% Hemorrhagic Necrotizing: similar, more severe & usually in children

2- Central Pontine Myelinolysis Causes: Rapid correction of hyponatremia & Acid Base imbalance Alcohol-induced Pathology: Cellular edema, caused by fluctuating osmotic pressures → compression of fiber tracts → demyelination in center of PONS & other areas in brain Rapidly evolving quadriplegia.

3- Neuromyelitis Optica Cause: Immune: Antibodies to water channel aquaporin-4 (diagnostic & pathogenic) Pathology: Inflammatory demyelinating. Optic nerves and spinal cord affected.

3- Multiple Sclerosis 2 nd commonest cause of neurological disability in early-middle adulthood, after trauma. Most common demyelinating disorder. Characteristics: Course is relapsing-remitting or progressive Lesions are typically separated in time and in space. Pathology: Inflammation - demyelination - gliosis

Epidemiology: Prevalence is about 1/1000, F:M - 2:1 Age of onset typically  rates in Europe, Canada, USA..(1/1000) Low rates in Asia, Africa, Middle East Migrants adopt the risk of their new environment if they move before age 15y

Pathogenesis: Immunologic mechanisms: Initiating agent: ?Infectious Autoreactive T-lymphocytes to Myelin basic protein (MBP) Autoantibodies against myelin antigens such as myelin oligodendrocyte glycoprotein (MOG) Viral Triggers ? molecular mimicry between viruses and myelin antigens

Genetic predisposition: Disease risk is 15 times higher in people with affected first degree relative ~ 25% concordance rate for monozygotic twins HLA-DR2  risk of MS Polymorphisms in R for IL-2 & IL-7, which have known effect on T-cells Acquired environmental factors  contribute to the Immune insult

MS: pathology Different stages, different dates: Patchy demyelination in periventricular white matter, optic nerves & chiasm, brain stem, ascending & descending fiber tracts, cerebellum and spinal cord - Acute stage ‘Active’ plaque :Soft pink Myelin breakdown  phagocytosis, perivascular lymphocytic infiltration, and edema

Chronic stage ‘inactive’ plaques Hard grey: Total myelin loss, no inflammation, loss of oligodendrocytes and reactive gliosis

Findings in lesions:  CD4 (T H 17 & T H 1) & CD8 T lymphocytes in lesions  AB against myelin components + complement are identified in lesions  CSF  Oligoclonal band of IgG against myelin antigens, mild  protein,  lymphocytes  OB is absent in serum  Classic MRI findings

Oligoclonal bands in multiple sclerosis cerebrospinal fluid: An update on methodology and clinical usefulness Journal of Neuroimmunology Volume 180, Issues 1?

Clinical features: limb weakness 40% optic neuritis 20%  unilateral visual impairment (a frequent initial manifestation of MS) paresthesia 20% diplopia 10% bladder dysfunction 5% vertigo 5%

Disease Course: Many clinical types Relapsing/remitting MS (85%) Secondary progressive MS Steady deterioration following RRMS (50% patients after 15 years) Primary progressive MS (15%) Steady deterioration disease onset

Prognosis: Better if benign variant from start (<20%) Better in women Better in patients with  2 attacks in first year - Death usually due to a complication e.g chest or urinary infection….etc.

Degenerative Diseases

Gradual loss of neurologic function affecting selected populations of neurons Unknown causes, some familial No effective treatment Classified according to neurological manifestation: Dementia Postural / Movement disorders Combined

Dementia Global impairment of intellect, reason and personality without loss of consciousness Classified into: - Primary degenerative diseases Alzheimer Disease, Pick disease, Huntington disease, FTLD etc… - Secondary: Infections, Vascular, Traumatic Metabolic/nutritional, Toxic etc…

1- ALZHEIMER DISEASE: Commonest cause of dementia in the elderly in the west. Insidious progressive neurologic disorder showing gradual loss of cognitive function. Sporadic or familial (5-10%) Incidence rises with increasing age. Familial type has earlier age at onset.

Basic pathogenesis of the disease is linked to deposition of β amyloid (Aβ) in the brain by splitting Amyloid precursor protein (APP) by certain enzymes. Abnormal neurotransmission Genetic defects in <5% familial cases have been identified on chromosomes 21, 19, 14, 12 & 1. Pathogenesis of AD:

1- Chromosome 21: Location of APP gene Patients > 40 years of age with Trisomy 21 (Down Syndrome) have higher risk of Alzheimer disease

2- Presenelin Mutations Alzheimer disease (AD) patients with an inherited form of the disease carry mutations in the Presenilin 1 or 2 gene or the APP APP split by β amyloid converting enzyme (BACE) / Secretase → β amyloid

Presenilin gene mutation: These genes are involved in processing of APP APP  Soluble  Insoluble Aβ Defects result in accumulation of fibrillar aggregates of β-amyloid (Aβ) that are toxic to neurons. α & γ secretase Β & γ secretase

3- Tau protein: Tau is a normal protein involved in assembly of axonal microtubules & their stability. Usually parallel. Presence of Aβ  Hyperphosphorylation of tau protein  tau redistributes from axons into dendrities and cell bodies as filaments in neurofibrillary tangles.

4- Apolipoprotein E (Apo E4) Presence of each allele ↑ risk 4 times ↑ deposition of fibrillar beta-amyloid (Aβ) in 30-40% of AD cases

Diagnosis of AD: Clinical Picture: Progressive memory loss with increasing inability to participate in daily living activities... Radiological methods Brain biopsy The final diagnosis is made pathologically by examination of the brain at autopsy.

Pathology: Gross Changes: Cerebral atrophy, mainly in frontal, temporal, and parietal region, mainly in hippocampus leading to: ventricular dilatation (Hydrocephalus ex vacuo).

Microscopic Changes: 1- Neuritic (Senile) plaques: - Extracellular location - Composed of tortuous neuritic processes surrounding a central amyloid core of Aß - Reactive astrocytes and microglia at the periphery.

Neuritic Plaque

2- Neurofibrillary tangles: - Intracellular location, unless neurons die. - Insoluble filaments (tau protein) mainly in pyramidal cells of hippocampus important as transport system. Initially parallel - Not specific for AD. 3- Amyloid angiopathy

Neurons with tangles displacing nucleus,

2- VASCULAR DEMENTIA Associated with multiple infarcts, hence the name (Multi-Infarct Dementia) Lacunar infarcts Cortical microinfarcts Multiple embolic infarcts MRI - Grey matter lesions rather than white as in MS SECOND commonest form of dementia after Alzheimer

MULTI-INFARCT DEMENTIA

Other Degenerative Diseases Frontotemporal dementias (FTLD): - FTLD-tau, e.g. Pick disease (tau mutation). - FTLD-TD43. Lewy body Diseases ± Dementia: - PARKINSON DISEASE

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