CNS Pathology Lecture 4: Demyelinating Diseases

CNS Pathology Lecture (4)

• Lecture covers Demyelinating and Degenerative Diseases

Demyelinating Diseases

• Demyelinating diseases of the central nervous system (CNS) are characterized by myelin damage, with axons relatively preserved.
• These diseases include:
  • Multiple Sclerosis (MS)
  • Acute Disseminated Encephalomyelitis (ADEM)
  • Acute Necrotizing Hemorrhagic Encephalitis

Multiple Sclerosis (MS)

• Definition: An autoimmune demyelinating disorder characterized by distinct, separate episodes of neurological deficits in time, and lesions in different locations in space(separated in space) within the CNS white matter.

• This involves inflammation and damage to the myelin sheath surrounding nerve cells in the brain and spinal cord.

• Prevalence: Approximately 1 per 1000 people in the USA and Europe.

• Clinical Onset: Clinically apparent at any age, but relatively rare in childhood and after age 50.

• Course: Typically begins as a relapsing and remitting illness, progressing to a steady state later.

• Age of Onset: Most common between ages 20 and 50.

• Gender Predominance: More common in women (2:1 ratio).

• Causes:

  • Immune-mediated disease (most accepted).
  • Viral infection (unproven, examples include: mumps, rubella, herpes simplex, and measles).
  • Genetic defects: Abnormalities in the HLA region of chromosome 6 increase the likelihood of developing MS.

• Pathogenesis: A combination of environmental and genetic factors leads to a loss of tolerance towards self proteins.

  • Concordance rate for monozygotic twins is approximately 25% and lower for dizygotic twins.
  • The risk of developing MS is 15-fold higher if a first-degree relative has the disease.

• Experimental Allergic Encephalomyelitis (EAE): An animal model of MS, where inflammation and demyelination are induced by immunizing the animal with myelin or myelin peptides.

  • Damage is caused by the delayed T-cell mediated type IV HSR.
  • Toxic effects of released molecules from immune cells (lymphocytes/macrophages) play a significant role in axonal damage and neuronal death.

• Pathogenesis (MS): involves the loss of oligodendrocytes, the cells responsible for myelin sheath formation leading to interruption of nerve signal transmission. This is followed by breakdown of axons and scar tissue (sclerosis) formation in multiple plaques throughout the CNS.

• Morphology (Active Plaques):

  • Gross: Well-circumscribed plaques with loss of myelin.
  • Microscopic: Myelin breakdown, lipid-laden macrophages, and lymphocytes at the edges of the plaques; relative preservation of axons.

• Morphology (Inactive Plaques):

  • No inflammation.
  • Axons remain unmyelinated.
  • Sclerosis (scar tissue).

• Clinical Manifestations:(Multiple Sclerosis): Neurological symptoms vary according to the affected areas including autonomic, motor, and sensory abnormalities.

• Clinical Manifestations (Example Symptoms):

  • Central: fatigue, cognitive impairment, depression, unstable mood
  • Visual: nystagmus, optic neuritis, diplopia
  • Throat: dysphagia
  • Musculoskeletal: weakness, spasms, ataxia
  • Sensation: pain, hypoesthesias, paraesthesias
  • Bowel: incontinence, diarrhea or constipation
  • Urinary: incontinence, frequency or retention
  • Speech: dysarthria

• Diagnosis (MS):

  • Clinical evaluation
  • Laboratory analysis: high CSF protein, mostly gamma globulin, oligoclonal bands of immunoglobulin. Antibodies present are a marker of disease activity.

Acute Disseminated Encephalomyelitis (ADEM)

• Characteristics: Immune-mediated disorder.
• Cause: Usually follows a viral infection, or rarely, viral immunization.
• Onset: Affects all ages, but most cases are in children and adolescents.
• Morphology: Multiple inflammatory lesions in white matter of the brain and spinal cord, demyelination, and accumulation of lipid-laden macrophages. Mononuclear and polymorphonuclear leukocyte infiltration.
• Clinical Manifestations: Fever, headache, lethargy, and coma.

Acute Necrotizing Hemorrhagic Encephalitis

• Characteristics: More severe and abrupt than MS or ADEM.
• Onset: Seen in young, previously healthy children.
• Causes: Influenza A virus, mycoplasma, Herpes Simplex Virus (HSV), and human herpes virus 6 - potential causative agents.
• Morphology: Hemorrhagic necrosis of white and gray matter.
• Clinical Manifestations: High fever, seizures, and rapidly progressing neurological disturbances.

Degenerative Diseases of CNS

• A group of disorders with unknown etiology and pathogenesis.
• There's degeneration in specific neuronal populations leading to atrophy and neuronal loss.
• Often, gliosis (scarring) follows.

Demyelinating Diseases II

• Associated with mutations affecting myelin formation or synthesis/degradation.
• These diseases include:
  • Alzheimer's disease
  • Pick's disease
  • Huntington's disease
  • Parkinson's disease

Alzheimer's Disease (AD)

• Definition: Senile dementia characterized by progressive memory loss, difficulty with tasks of daily living, and difficulty recognizing familiar individuals.
• Cause: Unknown, but some familial cases are linked to abnormalities on chromosomes 21, 14, 1, and 19.
• Onset: Usually after 50 years of age. Mostly sporadic (90-95%), but some cases run in families.
• Gross Appearance: Cerebral atrophy, predominantly in the frontal, temporal, and parietal lobes. MRI/diagnostics can show these changes.
• Microscopic Features:
  • Fragmentation of neurites (production of "senile plaques"): degenerative synaptic endings.
  • Amyloid material (AB) deposited outside the neurons. Insoluble intracellular twisted filaments (neurofibrillary tangles).
  • Cerebral amyloid angiopathy (CAA).
• Clinical features: Progressive memory loss(dementia), inability to participate in daily activities, and inability to recognize family members.
• Cause of death: Typically aspiration pneumonia.

Pick's Disease

• A frontotemporal neurodegenerative disease, similar to AD.
• Cause: Mutations in the tau protein, which stabilizes microtubules within neurons.
• Gross Appearance: Cerebral atrophy, predominantly affecting the frontal and temporal lobes. The atrophy may be asymmetrical.
• Microscopic Features: Marked loss of cortical neurons with gliosis. Presence of cytoplasmic inclusions (Pick bodies).

Huntington's Disease

• An autosomal dominant disorder.
• Cause: Abnormalities on chromosome 4 (mutation in the huntingtin gene).
• Onset: Typically between ages 20 and 50.
• Morphology: Loss of neurons in the caudate and putamen, with subsequent gliosis. Enlargement of the anterior horns of the lateral ventricles.
• Clinical features: Choreiform movements (involuntary, jerky movements), personality changes.

Parkinson's Disease

• Characteristics: A progressive neurodegenerative disorder.
• Causes: Sporadic (most common) and familial cases with mutations in the alpha-synuclein gene (autosomal dominant) or in the parkint gene (autosomal recessive).
• Morphology:
  • Pallor of the substantia nigra and locus ceruleus.
  • Loss of pigmented neurons.
  • Gliosis.
  • Lewy bodies (abnormal protein aggregates within nerve cells).
• Clinical Features: Diminished facial expression, slow movements, festinating gait, cogwheel rigidity, pill-rolling tremors.

This quiz covers critical concepts related to demyelinating and degenerative diseases of the central nervous system, focusing specifically on Multiple Sclerosis and related conditions. You will explore the characteristics, prevalence, and clinical impact of these disorders on patients, enhancing your understanding of CNS pathology.