Cns Pathology Lecture (4)-Demyelinating & Degenerative Diseases PDF

CNS Pathology Lecture (4) II- Demyelinating Diseases & Degenerative Diseases Ahmed Almobarak  Demyelinating Diseases - Demyelinating diseases of CNS Characterized by myelin damage with relative preservation of axons. These diseases include: 1- Multiple sclerosis. 2- Acute...

CNS Pathology Lecture (4) II- Demyelinating Diseases & Degenerative Diseases Ahmed Almobarak  Demyelinating Diseases - Demyelinating diseases of CNS Characterized by myelin damage with relative preservation of axons. These diseases include: 1- Multiple sclerosis. 2- Acute disseminated encephalomyelitis. 3- Acute necrotizing hemorrhagic encephalitis.  Multiple Sclerosis Multiple sclerosis (MS): Definition: is an autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits separated in time, attributable to white matter lesions that are separated in space. inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged or lost.  Multiple Sclerosis MS is the most common demyelinating disorder ( prevalence 1 per 1000 persons in USA & Europe). Clinically apparent at any age, although relatively rare in Childhood & after age of 50 years. It begins as a relapsing and remitting illness, then after sometime becomes steady. Age: between ages 20 - 50.  Multiple Sclerosis Causes: – Immune-mediated disease (the most accepted). – Viral infection: (not proven) as: Mumps, rubella, herpes simplex & measles. – Genetic defects: abnormalities in HLA region in chromosome 6 increase the probability for getting multiple sclerosis  Multiple Sclerosis Pathogenesis of MS is caused by combination of environmental & genetic factors that result in a loss of tolerance to self proteins. Concordance rate for monozygotic twins around 25% with lower rate for dizygotic twins. The risk of developing MS is 15-fold higher when present in a first-degree relative. Immunopathogenesis of MS Experimental allergic encephalomyelitis is an animal model of MS in which demyelination & inflammation induced by immunization with myelin, myelin protein & certain myelin peptides from myelin proteins. Damage induced by T-cell-mediated delayed type IV HSR. Toxic effects of lymphocytes, macrophages & released molecules play a role in axonal injury and may lead to neuronal death.  Multiple Sclerosis Pathogenesis: There is loss of oligodendrocytes, that are responsible for the myelin sheath formation. When the myelin is lost, the neurons can not effectively conduct their electrical signals. This is followed by breakdown of axons. Scar tissue is formed around the damaged axons. This occurs in multiple plaques in the  Multiple Sclerosis Morphology of multiple sclerosis: – Active plaques: Gross: well circumscribed plaques with loss of myelin. Microscopic: myelin breakdown, lipid-laden macrophages, lymphocytes at the edge of plaques, relative axonal preservation. – Inactive plaques: No inflammation. Axons remain unmyelinated. Sclerosis.  Multiple Sclerosis Clinical manifestations: – The patient may present with any neurological manifestations according to the site of affection: Autonomic. Motor. Sensory. – The followings are the main symptoms of multiple sclerosis. MRI showing Multiple Sclerotic areas  Diagnosis of MS 1- Clinical diagnosis. 2- Laboratory diagnosis: a) High CSF protein mostly gamma- globulin. b) Immunoglobulin show oligoclonal bands representing Abs directed against a variety of Antigenic targets. c) Abs represent a marker of disease activity.  Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis (ADEM): Immune-mediated. Cause: usually follows viral infection or, rarely, viral immunization. Affects any age, but most reported cases occur in children and adolescents.  Acute Disseminated Encephalomyelitis Morphology: – Multiple inflammatory lesions in the brain and spinal cord (white matter). – Demyelination. – Accumulation of lipid-laden macrophages. – Mononuclear and polymorph nuclear leukocyte infiltration.  Acute Disseminated Encephalomyelitis Clinical manifestations: – Fever, – Headache, – Lethargy, – Coma.  Acute Necrotizing Hemorrhagic Encephalitis Acute necrotizing hemorrhagic encephalitis: It is more fulminant than the previous diseases. The disease is seen in young, previously healthy children. Cause: influenza A virus, mycoplasma, HSV, and human herpes virus-6 have been reported as common causative agents. Morphology: There is hemorrhagic necrosis of white and gray matter. Clinically, it starts with high fever, seizures, and rapid progressing neurologic disturbances.  Acute necrotizing hemorrhagic encephalitis: Degenerative diseases of CNS: Group of disorders that are of unknown etiology and pathogenesis. There is degeneration in a particular neurons with a particular function which undergo atrophy and are lost. Frequently, there is gliosis later on.  Demyelinating Diseases II - Associated with mutations affecting myelin formation or affecting its synthesis &/or degradation. - The commonest degenerative diseases include: Alzheimer’s disease. Pick’s disease. Huntington’s disease. Parkinson’s disease.  Alzheimer Disease Alzheimer disease (AD): “Senile Dementia”: The cause is unknown. Usually begins after the age of 50 years. Most cases are sporadic. About 5-10% are familial (abnormalities on chromosomes 21, 14, 1, 19).  Alzheimer Disease Gross appearance: – Cerebral atrophy of: Frontal, temporal and parietal lobes. – The following MRI and diagram represent these changes.  Alzheimer Disease Microscopic: – Fragmentation of neurites (neuronal processes), producing the characteristic “senile plaques” , which are degenerative synaptic endings. – Amyloid material (Aβ) is deposited outside the neurons. – Neurofibrillay tangles (insoluble intracellular twisted filaments). – Cerebral amyloid angiopathy. Senile plaques in Alzheimer disease Neurofibrillary tangles in Alzheimer disease  Alzheimer Disease Clinical features: – Progressive memory loss (dementia). – Inability to participate in daily activities. – Lately, inability to recognize family members. The cause of death in this disease is aspiration pneumonia.  Pick’s disease Pick’s disease (fronto-temporal neurodegenerative disease): Similar to Alzheimer disease. 90% of cases are sporadic. The rest are familial. Cause: mutation in tau protein, a protein present in the neurons, which stabilizes microtubules.  Pick’s disease Gross appearance: – There is cerebral atrophy involving the frontal and temporal lobes. – The atrophy may be asymmetrical.  Pick’s disease Microscopic: – There is marked loss of cortical neurons with gliosis. – Pick bodies, are cytoplasmic inclusions seen in the cortex. Pick bodies  Huntington's Disease Huntington’s disease: Autosomal Dominant “AD” disease. The genetic defect is localized on chromosome 4 (abnormal protein called huntingtin). Occurs between ages 20 and 50 years.  Huntington's Disease Morphology in the brain: – Loss of neurons in the caudate and putamen areas with subsequent gliosis. – The head of the caudate becomes shrunken and there is dilatation of the anterior horns of the lateral ventricles. Clinical features: – Choreiform movements. – Character change of personality. Huntington disease  Parkinson’s disease Parkinson’s disease: Most cases are sporadic. Few cases are familial with mutation in the: – Alpha-synuclein gene (autosomal dominant), or – Upquitin-protein ligase (parkin) gene (autosomal recessive).  Parkinson’s disease Clinical features: – Diminished facial expression (mask face). – Slowing of movements. – Festinating gait (rapid accelerating). – Cog-wheel rigidity of limbs. – Pill-rolling tremors.  Parkinson’s disease Morphology in the brain: – Pallor of substantia nigra and locus ceruleus. – Loss of pigmented neurons. – Gliosis. – Lewy bodies: abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease Normal pigmented neurons vs Parkinson disease  Lewy bodies Lewy body, H&E stain Lewy body, IHC stain Thank you