Pathology Of Demyelinating Diseases Flashcards
How are demyelinating disorders acquired?
Immune-mediated injury and genetic predisposition
Cross-linked autoimmunity after viral infections
Myelin is not properly formed or has higher turnover kinetics
Mutations in the proteins of a normal myelin sheath
Multiple sclerosis
Autoimmune demyelinating disorder that is characterized by episodes of disease activity deprecated in time.
- most common demyelinating disorder especially in Caucasian’s*
- rates are increasing
Rates increase in places that a re further from the equator
- women are 2x more affected then males and most common age group is 20-30 yrs old
Pathogenesis of MS
Autoimmune response against the myelin sheath
- can be genetic or environmental triggers
- also prior viral infections can increase chances of MS (especially EBV)
Genetic component is association with MHC class 2 (HLA-DR2)
*monozygotic twins are highly susceptible to MS *
TH1 and TH17 cells are the main autoimmune cells
- activate leukocytes and forms scarring of the myelin sheaths
Morphology of MS
Multi focal white matter plaques in the brain and spinal cord
- almost never just a focal lesion(s)
- lesions have sharped defined borders in microscopic regions
Plaques = depressed glassy appearing gray/tan colored areas (often close to ventricles)
Active plaques show macrophages that possess myelin debris and lymphocytes
Inactive plaques show no myelin and lots of scarring (gliosis)
Common clinical features of MS
*Shows multiple relapses and episodes or remission in between
Symptoms:
- unilateral visual impairment
- unilateral optic neuritis
- often the first symptom that develops*
- cranial nerve dysfunctions
- nystagmus
- ataxia with wide-based gait
- general idiopathic shooting pains
- INO
- motor and sensory impairment (usually in limbs but can be trunk also)
- bladder and bowl dysfunctions
Tests:
- CSF = elevated proteins with increased immunoglobulin and oligoclonal bands
- MRI = shows diffuse plaques near the ventricle and brain stem
Types fo MS
1) Clinically isolated syndrome (CIS)
- single episode of MS that may or may not progress to true MS
2) Relapsing-remitting MS (RRMS)
* most common*
- disease comes and goes in flares
3) secondary progressive MS (SPMS)
- a RRMS that doesnt stay RRMS and then begins to flare up without relapses
4) primary progressive MS (PPMS)
- mild relapse and remission from the start with worsening neurological function each step
Acute disseminated encephalomyelitis (ADEM)
Post-infectious autoimmune reactions
Symptoms typically develop within 1-2 weeks after infection and are diffuse
(Most common is headache, lethargy, coma)
Symptoms progress rapidly and can be fatal in 20% of cases
sometimes forms acute necrotizing hemorrhagic encephalomyelitis which is rare and affects children
Neuromyelitis optic (NMO)
Antibody-mediated demyelinating disease centered on the optic nerve and spinal cord specifically
Central pontine myelinolysis
Non immune damage to oligodendrocytes after sudden correction of hyponatremia
- demyelination of the pons occurs
- occurs often in malnourished indicates, alcoholics and liver disease patients
Looks like locked in syndrome when it occurs
Progressive multi focal leukoencephalopathy (PML)
is a risk factor in any patient that is using immunosupression medications
Caused by reactivation of a latent JC viral infection
Develops focal and relentlessly progressive neurological signs and symptoms
MRIs show extensive multi focal lesions throughout the cerebellar and cerebrum
- not close to ventricles usually thou
- also borders are poorly demarcated
Subacute sclerosing Panencephalitis (SSP)
Progressive encephalitis most commonly associated with measles virus
- other viruses are associated as well
Virus affects neurons and oligodendrocytes
Infection in infancy, but becomes latent is common
- anti-vaccination populations are at high risk
Leukodystrophies
Inherited dysmyelinating diseases that are caused by abnormal myelin synthesis
Most are autosomal recessive inheritance
- can be X-linked however
Usually show diffuse involvement of white matter which leads to:
- spasticity
- hypotonia
- ataxia
- poor motor skills
- are most often insidious progressive loss of function in younger patients and presents with symmetric changes on imaging*
- krabbe disease is a common one, and present of globin cells in microscopic evaluation is a hallmark of the disease
Prion diseases
A group of infectious diseases caused by abnormal cellular proteins
Includes:
- kuru (humans)
- sporadic/familial/iatrogenic/variant Creutzfeldt-Jakob disease (CJD)
- Scrapie (sheep)
- Bovine spongiform encephalopathy (mad cow disease)
- chronic wasting disease (deer and elk)
Pathogenesis of prion diseases
Causative prion protein (PrP) undergoes a conformational change from its normal shape -> abnormal shape
Normal prion proteins are high in a-helixes, however mutant forms are high in B-sheets
- this makes these proteins resistant to proteolysis
Infects normal prion proteins by interacting with normal prion proteins
Aggregation of mutated prion proteins causes neuronal toxicity and neuron cell death
- proteins are high stable which makes them difficult to cure and stop
- even autoclave doesnt cure it
CJD
Rapidly progressive dementia with ataxia
- wayyy faster than Alzheimer’s, but looks similar
Kills within 1 year with 85% cases being idiopathic
- most common in individuals older than 70 yrs of age and can be spread via familial forms genetically
Causes fatal familial insomnia (FFI)
