B119 Primary diseases of myelin, and acquired metabolic and toxic distrubances of the brain

Question 1

Multiples sclerosis, general characteristics

Answer 1

Autoimmune focal demyelinating disease

Remitting, relapsing periods of distinct focal neurological deficits.

Due to episodes of autoimmune damage against myelin.

The most common demyelinating disorder.

Onset can occur any age, but is rare in children and after age 50.

2:1 female preference.

Question 2

Presentation of MS and classifications of disease,

progression and prognosis

Answer 2

In all types, it progresses with slow, steady accumulation of neurological deficits based on where the MS plaques form. There are typically many lesions present and often they are asymptomatic, with some of them regressing back to normal tissue during the disease course.

Cognitive changes are not frequent, and usually they are sensory, motor deficits.

Treatments are aimed at suppressing the autoimmune response, to decrease the frequency and severity of relapses.

There is no cure or recovery of lost functions from treatment.

relapsing-remitting: most common form of multiple sclerosis, 85%. This form usually eventually transforms to secondary progressive

secondary-progressive; symptoms steadily worsen with few or no periods of remission

primary progressive; ~10% slowly progressing symptoms with no remessions from the start

progressive-relapsing: steadlily progressing, no remission, with acute phases of severe symptoms ‘relapses’

Question 3

MS pathogenesis and morphology and histology

Answer 3

Pathogenesis:

• Caused by genetic predisposition and environmental event inducing loss of self tolerance to myelin antigens.
• HLA variants, HLA-DR, DR2 allele
• Polymorphisms in IL-2 and IL-7
• CD4 Th Th1 and Th17 cells likely drive, with damage also from CD8 Tc and B cells.
• Lesions appear in the brain and spinal cord.

Morphology:

• Gross appearance shows lesions as brown/red areas in what should be white matter.
• The lesions are called plaques, have a sharp but irregular border. and are slightly depressed.
• Common sites:
  
  • around the brain ventricles
  • optic nerves and optic chiasm
  • brain stem
  • cerebellum
  • spinal cord tracts.
• CSF shows increased protein, mostly of immunoglobulins, and normal glucose
• Oligoclonal bands of immunoglobulins are typcial, indicating that there are many antigenic targets causing the disease and not a specific one or two.

Histology:

• Active plaques: Active plaques come in 4 types, but only one type of active plaque is seen in an individual patient
  
  • Type 1: macrophage infiltrate and sharp margins
  • Type 2: macrophages, sharp margins, and complement deposition
  • Type 3: no macrophages, ill-defined borders, and oligodendrocyte apoptosis
  • Type 4: non-apoptotic oligodendrocyte loss.
• Inactive, Queiscent plaques.
  
  • No inflammation
  • Little to no myelin
  • Astrogliosis and scar formation is evident.

Question 4

What are conginital primary diseases of myelin,

what is their general morphology and histology

Answer 4

Leukodystrophies

Morphology:

• White matter is not white, but gray, translucent, and smaller than normal
• Some cause patchy lesions early on, or begin in the occipital lobe
• eventually all of the white matter is affected.
• Brain becomes atrophic, ventricles enlarge
• Secondary gray matter changes due to atrophy

Histology

• Loss of myelin
• Degenration, death of oligos
• activation of astrocytes, microglia
• macrophage infiltration, stuffed with lipid accumulations, and inclusion bodies specific to the certain disorders.

Question 5

What are the other acquired primary diseases of mylein?

Answer 5

Immune mediated demyelination can occur uncommonly after many kinds of systemic infectious illnesses, and causes a diffuse inflammation against the mylelin, probably due to cross reactivity of myelin antigens with antibodies against the pathogens.

Acute disseminated encephalomyelitis, - symptoms 1-2 weeks after infection. They progress rapidly and is fatal in up to 20%. Headache, lethargy, coma. If the patient survives, it is self resovleing and there is total recovery

Acute necrotizing hemorrhagic encephalomyelitis - a rare and devastating post infectious autoimmune response, does what its name says, and usually affects young adults and children.

Neuromyelitis optic, NMO - Inflammation of the optic nerves, and spinal cord. An Antibody-mediated disorder resulting from autoantibodies against AQP4. An aquaporin limited in its expression to those regions.

Progressive multifocal leukoencephalopathy, from JC polyoma virus infection of the oligodendrocytes

Central pontine myelinolysis - aka Osmotic demyelination syndrome induced by overly-rapid correction of hyposmolarity. Causes most demyelination over the pons.

Question 6

Acquired toxic disturbances of the brain:

Answer 6

Nutritional deficiencies:

• Wernicke Korsakoff syndrome, B1 thiamine deficiency
• B12 megaloblastic pernicious anemia
  
  • Subacute combined degeneration of the spinal cord.
  • both ascending and descending tracts are demyelinated over the course of a few weeks.
  • vitamin replacement halts the disease, but if paraplesia/parapareisis has developed, recovery is poor.

Metabolic disorders:

• Hypoglycemia:
• Hyperglycemia
• Hepatic encephalopathy

Toxic disorders

• Metals - diffuse encephalopathy and neuronal/mitochondrial damage
• Organophosphates - nerve agents
• Methanol -retinal damage and blindness
• carbon monoxide and diffuse hypoxia
• ethanol - chronically: cerebellar dysfunciton and vermis atrophy, events of acute metabolic dysregulation and brain swelling.
• ionizing radiation - can cause areas of focal coagulative necrosis with adjacent inflammation and edema. Can occur days, months, or even years after treatment.