Pathology of Demyelinating Diseases Flashcards
What stain is used for myelin?
Luxol Fast Blue
Define Demyelination
loss of myelin sheath surrounding axons of nerves, with relative preservation of the axons. Can affect nerves of CNS and PNS
What causes demyelination?
damage to myelin sheath and the cells that produce the myelin
What is the functional importance of myelin?
crucial for proper nerve conduction
How is neuronal function affected by loss of myelin?
interruption of nerve transmission leading to neurological deficits
What is the most common demyelinating disorder?
Multiple Sclerosis
What is a vascular cause of demyelination?
Binswanger disease
What are autoimmune causes of demyelination?
- MS
- Acute Disseminated encephalomyelitis [ADEM]
- Guillain Barre Syndrome
- Chronic Inflammatory Demyelinating polyneuropathy
What is an infectious cause of demyelination?
Progressive Multifocal Leukoencephalopathy
What are metabolic causes of demyelination?
- CO poisoning
- Vitamin B12 deficiency
- Mercury poisoning
- Central pontine myelinolysis
- Hypoxia
- Radiation
- Alcohol
What clinical findings are suggestive of a primary demyleinating disorder?
- Diffuse/Multifocal neurological deficits
- Sudden/Subacute onset in young adults
- Onset after infection/vaccination
- Deficits that wax and wane
- Specific [unexplained optic neuritis, Ophalmoplegia]
What is neuromyelitis Optica?
A syndrome with synchronous bilateral optic neuritis and spinal cord demyelination
Describe the lesions seen in Neuromyelitis Optica
- Necrosis
- Inflammatory infiltrate
- Vascular deposition of immunoglobulin and complement
What would investigations of Neuromyelitis Optica reveal?
- Presence of a pathogenic antibody
- Areas of demyelination show loss of aquaporin 4
- WBC and Neutrophils in CSF
Epidemiology of Neuromyelitis Optica
- More prevalent in women
- poor recovery
What is Acute Disseminated Encephalomyelitis (ADEM)\?
Diffuse demyelinating disease that follows viral infection or immunization
What is the pathophysiology of Acute Disseminated Encephalomyelitis (ADEM)?
possibly an acute autoimmune reaction to myelin
Describe the clinical presentation of Acute Disseminated Encephalomyelitis (ADEM)
- Symptoms develop 1-2 weeks after viral infection or immunization
- Rapid clinical course, with most patients recovering completely
- Mortality is 20%
What is similar to Acute Disseminated Encephalomyelitis (ADEM)?
- Lesions similar to those induced by immunization of animals with
- Myelin components
- Rabies vaccines prepared from brains of infected animals
What is the prognosis of Acute Necrotizing Hemorrhagic Encephalomyelitis?
- Causes severe damage
- usually fatal
- Significant neurological deficits in survivors
Describe the histological appearance of ADEM and Acute Necrotizing Hemorrhagic Encephalomyelitis?
Hemorrhage and inflammation in lesion
Epidemiology of Acute Necrotizing Hemorrhagic Encephalomyelitis?
In children and young adults, following a URTI
What is associated with Central Pontine Myelinolysis?
Severe electrolyte disturbance
Osmolar imbalance
What is the clinical presentation of a patient with Central Pontine Myelinolysis?
- Rapid clinical presentation
- Quadriplegia
- Severe long-term deficits
- Locked in syndrome
syndrome arises 2-6 days after rapid correction of hyponatremia
Describe the appearance of Central Pontine Myelinolysis?
Symmetric loss of myelin in the base of the pins and portions of the pontine tegmentum
Pathophysiology of Central Pontine Myelinolysis
damaged oligodendrocytes [due to rapid increase in osmolarity], with preserved neurons and axons. [no inflammation]
What’s is the clinical term for Central Pontine Myelinolysis?
Osmotic demyelination syndrome
Progressive multifocal leukoencephalopathy (PML)
reactivation of JC virus in oligodendrocytes of immunocompromised patient [HIV1/2, etc.]
Describe the morphology of Subacute combined degeneration of spinal cord
Loss of myelin in posterior and lateral columns
Describe the clinical presentation of a patient with Subacute combines degeneration of Spinal cord
- Progressive sensory abnormalities
- Ascending paresthesias
- Weakness
- Ataxia
- Loss of sphincter control
- Gait impairment
- Megaloblastic anemia
What is the pathophysiology of Subacute combined degeneration of the spinal cord?
Vitamin B12 deficiency
Accumulation of methylmalonyl CoA causes a decrease in myelin synthesis
What is the cause of tabes dorsals?
Trypanosoma pallidum [as a manifestation of tertiary syphilis]
Describe the morphology of Tabes dorsalis
Demyelination of dorsal column of spinal cord, with no inflammatory reaction and absence of Trypanosoma pallidum
Etiology of Hypoxic-ischemic demyelination
Severe small vessel disease:
• Hypertension
• Diabetes
• Old age
Global brain hypoxia:
• Cardiac arrest
• Asphyxia
• Drug overdose
What structures are affected in Hypoxic-ischemic demyelination?
Globus pallidus + white matter
What is the presentation of Hypoxic-ischemic demyelination?
Acute:
• Headache, Myalgia, Dizziness, Coma
• Psychological impairment
Chronic:
• Delayed personality changes, Cognitive deficit, Dementia, Parkinsonism.
What is the morphology of Hypoxic-ischemic demyelination??
Acute:
• Cherry red discoloration of white matter
Chronic:
• Necrosis of globus pallidus
• Demyelination of white matter
How does hypoxia affect the brain?
ussually causes necrosis, but if it primarily affect the oligodendrocytes then we’d have demyelination
List the Peripheral Nervous System Demyelination Disorders
- Acute Inflammatory Demyelinating Polyradiculoneuropathy
- Chronic Inflammatory Demyelinating Polyradiculoneuropathy
- Anti-Myelin Associated Glycoprotein (MAG) Neuropathy
- POEMS Syndrome
- Charcot Marie Tooth Disease
Describe the clinical presentation of a patient of GBS
Ascending Symmetric Weakness and paresthesias
Weakness maximal at 3 to 4 weeks then resolves.
Loss of deep tendon reflexes
Sphincters spared
What is the most common cause of acquired inflammatory neuropathy?
GBS
What is the etiology of GBS?
Unknown etiology, but possibly autoimmune as it starts 5-21 days after infection, surgery and vaccination
What is the most common hereditary neuropathy?
Charcot marie tooth disease [Type 1 and Type X]
What is the pathophysiology of Chronic Inflammatory Demyelinating polyradiculoneuropathy?
T-cell mediated or humoral immunity
Anti-Myelin Associated Glycoprotein (MAG) Neuropathy
Associated with IgM monoclonal gammopathy against MAG (transmembrane glycoprotein)
What environmental factors are associated with MS?
Geographic variation
role of low vitamin d level
What genetic factors are associated with MS?
Higher incidence in first degree relative and affected monozygotic twins
Strong association with DR haplotype of MHC
Association with IL-2 and IL-7 receptor genes
Associations with genes encoding proteins involved in the immune response
What is MS?
autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits that are separated in time and are attributable to patchy white matter lesions that are separated in space
Describe the gross appearance of MS lesions
Multiple well circumscribed lesions with sharp border.
lesions are firmer than surrounding white matter
Where would MS lesion be found?
adjacent to lateral ventricles
Corpus callous
Optic nerves and chiasm
Brainstem fibers
SC
What is the immune mechanism in MS?
TH1 secrete IFNγ, which activates macrophages
TH17 promote recruitment of leukocytes
activated leukocytes and their chemical products cause demyelination
What inflammatory cells are found in MS plaques?
Macrophages, T-Lymphocytes [CD4+, CD8+ [few]]
What is the microscopic morphology of MS lesions?
o Active plaque:
§ Myelin absent
§ Macrophages and lymphocytes § Centered on small veins
§ Axons relatively preserved
o Inactive plaques
§ No inflammatory infiltrate § Loss of myelin
§ Reactive gliosis
§ Damage to axons
What findings are found in the CSF of a patient with MS?
Elevated protein
Normal glucose
Lymphocytes
Macrophages
Plasma cells
Increased IgG
Oligoclonal IgG bands on immunoelectrophoresis
