CNS - Demyelinating disorders, dementia, and degenerative disorders Flashcards
(23 cards)
Basic principles of demyelinating disorders
Myelin insulates axons, improving the speed and efficiency of conduction
- oligodendrocytes –> myelinate the CNS
- schwann cells –> myelinate the PNS
Demyelinating disorders are characterized by destruction of myelin or oligodendrocytes
- axons are generally preserved
Leukodystrophies
Inherited mutations in enzymes necessary for production or maintenance of myeline
3 types
- Metachromatic leukodystrophy
- Krabbe disease
- Adrenoleukodystrophy
Metachromatic leukodystrophy
Due to a deficiency of arylsulfatase
- most common leukodystrophy
- autosomal recessive
- sulfatides cannot be degraded and accumulate in the lysosomes of oligodendrocytes = lysosomal storage disease
Krabbe disease
Due to a deficiency of galactocerebrosidase
- autosomal recessive
- galactocerebroside accumulates in macrophages
Adrenoleukodystrophy
Due to impaired addition of coenzyme A to long chain fatty acids
- x linked defect
- accumulation of fatty acids damages adrenal glands and white matter of the brain
Multiple Sclerosis
Autoimmune destruction of CNS myelin and oligodendrocytes
- most common chronic CNS disease of young adults (20-30 yrs), more common in women
- associated with HLA-DR2
- more commonly seen in regions away from the equator
Clinical presentation of MS
Presents with relapsing neurologic deficits with periods of remission –> multiple lesions in time and space
- blurred vision in one eye –> demyelination of optic nerve
- vertigo and scanning speech mimicking alcohol intoxication –> brainstem
- internuclear ophthalmoplegia –> medial longitudinal fasciculus
- hemiparesis or unilateral loss of sensations –> cerebral white matter, usually periventricular
- lower extremity loss of sensation or weakness –> spinal cord
- bowel, bladder and sexual dysfunction –> ANS
Dx and treatment of MS
Dx –> made by MRI + lumbar puncture
- MRI reveals plaques = areas of white matter demyelination
- lumbar puncture shows
- –> increased lymphocytes
- –> increased immunoglobulins with oligoclonal IgG bands on high resolution electrophoresis
- –> myelin basic protein
Gross examination shows gray appearing plaques in the white matter
Treatment
- acute attacks –> includes steroids
- long term tx –> interferon beta slows progression of disease
Subacute sclerosing panencephalitis
Progressive, debilitating encephalitis leading to death
- due to slowly progressing, persistent infection of the brain by measles virus
- infection occurs in infancy; neurologic signs arise years later (during childhood)
- characterized by viral inclusions within neurons (grey matter) and oligodendrocytes (white matter)
Progressive multifocal leukoencephalopathy
JC virus infection of oligodendrocytes (white matter)
- immunosuppression leads to reactivation of the latent virus
- presents with rapidly progressive neurologic sings –> visual loss, weakness, dementia, leads to death
Central pontine myelinolysis
Focal demyelination of the pons –> anterior brain stem
- due to rapid IV correction of hyponatremia
- occurs in severely malnourished patients (e.g. alcoholics and patients with liver disease)
- classically presents as acute bilateral paralysis = locked in syndrome
Basic principles of dementia
Characterized by loss of neurons within the gray matter –> often due to accumulation of protein which damages neurons
- degeneration of the cortex leads to dementia
- degeneration of the brainstem and basal ganglia leads to movement disorders
Alzheimers disease
- clinical features
Degenerative disease of the cortex –> most common cause of dementia
- slow onset memory loss (begins with short term memory loss and progresses to long term memory loss) + progressive disorientation
- loss of learned motor skills and language
- changes in behavior and personality
- patients become mute and bedridden –> infection is a common cause of death
- focal neurologic deficits are not seen in early disease
Alzheimers disease
- early onset AD
- genetic associations
Most cases are sporadic and seen in the elderly (>95%)
- risk increases with age –> doubles every 5 years after the age of 60
- E4 allele of apolipoprotein E is associated with increased risk, E2 allele is associated with decreased risk
Early onset AD –> seen in:
- familial cases –> associated with presenilin 1 and 2 mutations
- down syndrome –> commonly occurs by 40 years of age (beta APP encoded on chromosome 21)
Morphologic features of AD
- cerebral atrophy with narrowing of the gyri, widening of the sulci, and dilation of the ventricles
- neuritic plaques –> extracellular core comprised of AB amyloid with entangled neuritic processes
- –> AB amyloid is derived from amyloid precursor protein (APP), which is coded on chromsome 21
- –> APP normally undergoes alpha cleavage, beta cleavage results in AB amyloid
- –> amyloid may also deposit around vessels, increasing the risk of hemorrhage - neurofibrillary tangles –> intracellular aggregates of fibers composed of hyperphosphorylated tau protein
- –> tau is a microtubule associated protein - loss of cholinergic neurons in the nucleus basalis of Meynert
Diagnosis is made by clinical and pathological correlation
- presumptive dx made clinically after exclusing other causes
- confirmed by histology at autopsy
Vascular dementia
Multifocal infarction and injury due to hypertension, atherosclerosis, or vasculitis
- second most common cause of dementia
Pick disease
Degenerative disease of the frontal and temporal cortex –> spares the parietal and occipital lobes
- characterized by round aggregates of tau protein (pick bodies) in neurons of the cortex
- behavior (frontal lobe) + language (temporal lobe) symptoms arise early –> eventually progresses to dementia
Parkinson disease
Degenerative loss of dopaminergic neurons in the substantia nigra of the basal ganglia
- nigrostriatal pathway of basal ganglia uses dopamine to initiate movement
Common disorder related to aging –> seen in 2% of older adults
- unknown etiology –> historically, rare cases were related to MPTP exposure (a contaminant in illicit drugs)
Clinical features and histology of Parkinson disease
Clinical features = TRAP
- Tremor –> pill rolling tremor at rest; disappears with movement
- rigidity –> cogwheel rigidity in the extremities
- akinesia/bradykinesia –> slowling of voluntary movement; expressionless face
- postural instability and shuffling gait
Histology –> reveals loss of pigmented neurons in the substantia nigra and round, eosinophilic inclusions of alpha synuclein (Lewy bodies) in affected neurons
Dementia is a common feature of late disease
- early onset dementia is suggestive of Lewy body dementia –> cahracterized by dementia, hallucinations and parkinsonian features
- histology reveals cortical lewy bodies rather than substantia nigra
Huntington disease
Degeneration of GABAergic neurons in the caudate nucleus of the basal ganglia
- autosomal dominant disorder (chrom 4)
- characterized by expanded trinugleotide repeats (CAG) in huntington gene
- further expansion of repeats during spermatogenesis leads to anticipation
Presents with chorea that can progress to dementia and depression
- avg age at presentation is 40 years
- suicide is a common cause of death
Normal pressure hydrocephalus
Increased CSF resulting in dilated ventricles
- can cause dementia in adults; usually idiopathic
Presents as triad of urinary incontinence, gait instability and dementia = wet, wobbly and wacky
Lumbar puncture improves symptoms
Treatment is ventriculoperitoneal shunting
Spongiform encephalopathy
Degernative disease due to prion protein –> normally expressed in CNS neurons in an alpha helical configuration
- disease arises with conversion to a beta-pleated confirmation
- conversion can be sporadic, inherited or transmitted
- pathologic protein is not degradable and converts normal protein into pathologic form, resulting in a vicious cycle
- damage to neurons and glial cells is characterized by intracellular vacuoles = spongy degeneration
Creutzfeldt-Jakob disease
Varian CJD
Familial fatal insomnia
Most common spongiform encephalopathy
- usually sporadic; rarely can arise due to exposure to prion infected human tissue
- presents as rapidly progressive dementia associated with ataxia (cerebellar involvement) and startle myoclonus
- –> periodic sharp waves are seen on EEG
- –> results in death, usually in an inherited form of prion disease characterized by severe insomnia and an exaggerated startle response
