DSA 31 Demyelinating Diseases Flashcards
identify: autoimmune demyelinating disorder with distinct clinical episodes separated in time due to white matter lesions separated in space.
multiple sclerosis
identify: this disease is initiated by Th1 and Th17 cells that react against myelin antigens and secrete cytokines.
multiple sclerosis
where do most plaques commonly occur in MS?
adjacent to lateral ventricles
identify: ongoing myelin breakdown, abundant macrophages with lipid-rich PAS-positive debris. also preservation of axons and depletion of oligodendrocytes.
active plaque in MS
where do active plaques usually form?
centered on small veins
identify: little/no myelin, decreased oligodendrocyte nuclei. instead, astrocyte proliferation and gliosis.
inactive plaque in MS
what is a shadow plaque in MS?
border between normal and affected white matter is not sharply circumscribed
identify: CSF has mild increase in proteins, moderate pleocytosis, increased IgG leves, oligoclonal IgG bands.
multiple sclerosis
what is neuromyelitis optica?
syndrome with synchronous (or near synchronous) bilateral optic neuritis and spinal cord demyelination
identify: this syndrome has antibodies against aquaporin 4 which then injure astrocytes via complement-dependent mechanism.
neuromyelitis optica
what is the genetic linkage in MS?
HLA-DR2
what demographic is predominantly affected by MS?
young adults, mostly women, 20s-30s
what is the clinical presentation of MS?
scanning speech, incontinence, INO, nystagmus–think SIIN. can also have optic neuritis
identify: diffuse demyelinating disease occurring after viral infection or (rarely) viral immunization. no focal deficits in presentation.
acute disseminated encephalomyelitis
identify: fulminant demyelinating syndrome that affects young adults and children after upper respiratory infection.
acute necrotizing hemorrhagic encephalomyelitis
identify: acute disorder with myelin damage without inflammation in basis pontis and pontine tegmentum → spastic paresis.
central pontine myelinolysis
identify: this disease is commonly associated with rapid correction of hyponatremia. can also occur due to electrolyte abnormalities or after liver transplant.
central pontine myelinolysis
what is the most common cause of dementia in the elderly?
Alzheimer’s disease
what is the gross morphology of Alzheimer’s disease?
cortical atrophy with narrow gyri and wide sulci, especially in the frontal, temporal, and parietal lobes
what is the significance of the apolipoprotein e4 allele in alzheimer’s disease?
associated with greater risk and younger age
what is the significance of Aß peptides?
they readily aggregate and can be directly neurotoxic → synaptic dysfunction
in amyloid precursor protein processing, sequential cleavage by _______ (alpha/beta/gamma) secretase and _______ (alpha/beta/gamma) secretase results in Aß generation → amyloid fibrils.
beta, gamma
in amyloid precursor protein processing, cleavage by _______ (alpha/beta/gamma) secretase → non-amyloidogenic peptide fragments.
alpha
identify: round, homogeneous neuronal cytoplasmic inclusions that stain intensely with silver stain.
Pick bodies
which lobes are spared in Pick disease?
parietal and occipital
what is the clinical progression of Pick disease?
behavior and language symptoms arise early, eventually progresses to dementia
identify: group of disorders that share clinical features including progressive deterioration of language and changes in personality corresponding to temporal and frontal lobe degeneration.
frontotemporal dementias
identify: disorder with loss of vertical gaze, truncal rigidity, disequilibrium, loss of facial expression, and mild dementia.
progressive supranuclear palsy
what demographic is primarily affected by progressive supranuclear palsy?
men older than 50 years
true or false: progressive supranuclear palsy does not have MAPT mutations
true
identify: neurons exibit tau (-) ubiquitin (+) inclusions in dentate gyrus and superficial temporal and frontal lobes.
FTD without tau pathology
what is vascular dementia?
multifocal infarction and injury due to hypertension, atherosclerosis, or vasculitis
identify: disease of the elderly characterized by extrapyramidal rigidity.
corticobasal degeneration
what is clinical presentation of corticobasal degeneration?
asymmetric motor disturbances and sensory cortical dysfunction
in corticobasal degeneration, what is seen in the motor, premotor, and anterior parietal cortices?
neuronal loss, gliosis, and ballooned neurons
in corticobasal degeneration, what is seen in astrocytes and oligodendrocytes?
tau immunoreactivity present in astrocytes (tufted astrocytes) and coiled bodies in oligodendrocytes
in corticobasal degeneration, what is seen in the substantia nigra and locus coeruleus?
loss of pigmented neurons and agyrophilic inclusions
what is the morphology of Parkinson’s disease?
pallor of substantia nigra, lewy bodies composed of alpha-synuclein filaments
what is the pathogenesis of Parkinson’s disease?
dopamine deficiency from strial neurons which project to the striatum and stimulate muscular movements
what is the clinical presentation of Parkinson’s disease?
think TRAPS–tremor, rigidity, akinesia/bradykinesia, postural instability, shuffling gait
what is the significance of when dementia occurs in the history of Parkinson’s disease?
dementia is a common feature of late disease. if it occurs early, this suggests Lewy body dementia → dementia, hallucinations, Parkinsonian features
identify: group of disorders characterized by atrophy in specific CNS regions associated with glial tubular cytoplasmic inclusions composed of alpha-synuclein, ubiquitin, and alpha-beta crystallin.
multiple system atrophy
identify: Parkinsonism, atrophy of substania nigra and striatum
striatonigral degeneration
identify: atrophy of cerebellar peduncles, basis pontis, and inferior olives
olivopontocerebellar atrophy
what is clinical presentation of olivopontocerebellar atrophy?
cerebellar ataxia, eye and somatic movement abnormalities, dysarthria, rigidity
identify: autonomic dysfunction with loss of sympathetic neurons of intermediolateral column of spinal cord.
Shy-Drager syndrome
what is the pathogenesis of Huntington’s disease?
autosomal dominant mutation of HD gene which encodes huntingtin protein. trinucleotide repeat disorder (more than 35 copies CAG)
Hungtington’s disease involves degeneration of which neurons?
GABAergic neurons in the caudate nucleus
what is morphology of Huntington’s disease?
atrophy of caudate, putamen, and frontal lobes.
enlarged ventricles.
gliosis
true or false: motor features precede cognitive features in Huntington’s disease.
true
what is the age of onset for Huntington’s disease? what is the onset related to?
age onset: 35-45. related to number of CAG repeats
what is the inheritance pattern of Friedreich ataxia?
autosomal recessive
what is the clinical presentation for Friedreich ataxia?
wheelchair within 5 years. gait ataxia, hand clumsiness, dysarthria, depressed DTRs, sensory loss. also likely to develop cardiomyopathy–think of my frat brother Freidreich stumbles and falls but has a big heart.
what is the genetic cause for Friedreich ataxia?
GAA repeat in gene coding frataxin (inner mitochondrial membrane protein involved in iron regulation) on chromosome 9. decreased frataxin is associated with generalized mitochondrial dysfunction
identify: axonal loss and gliosis in posterior columns of the spinal cord, distal corticospinal, and spinocerebellar tracts
Friedreich ataxia
what structures are degenerated in Friedreich ataxia?
CN 8, CN 9, CN 10, CN 12, dentate nucleus,Purkinje cells of superior vermis, and dorsal root ganglia
what is the presentation of Friedreich ataxis in childhood?
presents with kyphoscoliosis
what is the inheritance pattern of ataxia telangiectasia?
autosomal recessive
what is the clinical presentation of ataxia telangiectasia?
present in childhood with cerebellar dysfunction, telangiectactic lesions in the skin and conjunctiva. hypoplastic lymph nodes and thymus → immunodeficiency
what is the mutation involved in ataxia telangiectasia?
mutation in ATM
what degeneration is seen in ataxia telangiectasia?
cerebellar, granule, and Purkinje cells lost. degeneration of dorsal columns, spinocerebellar tract, and anterior horn cells (differs from Friedreich ataxia)
identify: congenital degeneration of anterior horns of spinal cord → LMN lesion.
spinal muscular atrophy
what is the clinical presentation of spinal muscular atrophy?
floppy baby, marked hypotonia and tongue fasciculations
what is the inheritance pattern for spinal muscular atrophy?
autosomal recessive
true or false: ALS has sensory and oculomotor deficits.
false, ALS is a motor neuron disease
what is the clinical presentation of ALS?
upper motor neuron loss → spasticity, brisk DTRs
lower motor neuron loss → muscles atrophy
brainstem motor neuron loss → abnormal speech, impaired swallowing, later respiratory failure
what is the inheritance pattern of bulbospinal atrophy?
x-linked
identify: atrophy associated with androgen insensitivity (→ gynecomastia), testicular atrophy, and oligospermia (→ male infertility).
bulbospinal atrophy
what is the genetic cause for bulbospinal atrophy?
expansion of CAG/polyglutamine trinucleotide repeat in androgen receptor gene. intranuclear receptor aggregation
what drug when given to ALS patients increases survival by decreasing presynaptic glutamate release?
riluzole
identify: lysosomal storage disorders characterized by neuronal accumulation of lipofuscin. results in blindness, mental and motor deterioration, seizures.
neuronal ceroid lipofuscinoses
what causes Krabbe disease?
deficiency of galactocerebrosidase → stiffness and weakness by 3-6 months of age.
identify: glycolipid-engorged macrophages around blood vessels.
globoid cells, characteristic of Krabbe disease
what causes metachromatic leukodystrophy?
deficiency of arylsulfatase → sulfatides cannot be degraded and accumulate in the lysosomes of oligodendrocytes
what is the inheritance pattern of metachromatic leukodystrophy?
autosomal recessive
identify: myelin loss and gliosis with macrophages containing metachromatic material.
metachromatic leukodystrophy
identify: myelin loss and adrenal insufficiency attributale to the inability to catabolize long chain fatty acids. atrophy of the adrenal cortex is present
adrenal leukodystrophy
what will present in the serum of patient with adrenal leukodystrophy?
high VLCFA
describe the genetics of Pelizaeus-Maerzbacher disease.
X-linked inheritance, mutations in genes encoding myelin proteins
identify: myelin may be in the hemispheres. patches may remain giving a tigroid appearance to tissue sections stained for myelin.
Pelizaeus-Merzbacher disease
identify: megalocephaly, severe mental deficits, blindness, and signs/symptoms of white matter injury beginning in early infancy. spongy degeneration of the white matter
Canavan disease
identify: accumulation of N-acetylaspartic acid due to loss of function mutation in the gene encoding the deacetylating enzyme aspartoacetylase located on chromosome 17.
Canavan disease
what is the clinical presentation of lehigh syndrome?
arrest of psychomotor development. feeding problems. seizures, extraocular palsy, and weakness of hypotonia.
identify: bilateral damage with vascular proliferation and spongiform changes involving the midbrain, periventricular gray matter, pontine tegmentum, thalamus, and hypothalamus.
lehigh syndrome
what is characteristic of leigh syndrome?
lactic acidemia
where does the mutation occur in mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS)?
tRNAs
what is the clinical presentation of myoclonic epilepsy and ragged red fibers (MERRF)?
patients have myoclonus (seizure disorder), evidence of myopathy, and ataxia
identify: sporadic disorder most often associated with large mitochondrial DNA deletion/rearrangement. degeneration of cerebellum is most common.
Kearn-Sayre syndrome
identify: neurologic symptoms with evidence of hepatic dysfunction. hepatitis and bile duct proliferation.
Alpers disease
what is clinical progression of Alpers disease?
severe seizures followed by developmental delay, hypotonia, ataxia, and cortical blindness
what causes Wernicke-Korsakoff syndrome?
thiamine (B1) deficiency which can result from alcoholism or gastric disease
describe Wernicke encephalopathy.
suddent onset of psychosis and/or ophthalmic symptoms (e.g. nystagmus). focal hemorrhage and necrosis of mammilary bodies and walls of 3rd and 4th ventricles.
describe Korsakoff syndrome.
chronic, can follow Wernicke encephalopathy. memory disturbance and confabulation. lesions in dorsomedial nucleus of thalamus.
what does B12 deficiency cause?
subacute combined spinal cord degeneration
what is the clinical presentation of B12 deficiency?
slight ataxia with lower extremity parethesias. spastic weakness and pareplegia (progresses later in the disease)
what is the morphology of B12 deficiency?
vacuolar swelling of myelin which affects the ascending and descending tracts starting at the mid-thoracic cord
identify: atrophy and granule cell loss in anterior cerebellar vermis → Bergmann gliosis (Purkinje cell dropout and astrocyte proliferation).
ethanol
identify: this toxic disorder causes intractable nausea, confusion, convulsions, and rapid onset of coma. delayed effects are papilledema and headaches.
radiation
what is the effect of methanol on the retina?
degeneration of ganglion cells → blindness
which cells are sensitive to hypoglycemia?
large cerebral pyramidal cells, hippocampal pyramidal cells, and Purkinje cells
in hyperglycemia, what are the physical manifestations of hyperosmolar state?
dehydration, confusion, stupor, and eventually coma
what is the cause of hepatic encephalopathy?
liver failure
identify: Alzheimer type II cells evident in cortex and basal ganglia in response to injury.
hepatic encephalopathy
what is the most common damage seen in carbon monoxide poisoning?
bilateral necrosis of the globus pallidus
in combined methotrexate and radiation induced injury, where are focal areas of coagulative necrosis often seen?
adajcent to lateral ventricles
how will neuromyelitis optic differ from MS on MRI?
NMO will not show plaques in the brain particularly around periventricular areas, which is characteristic of MS.
what is the pathogenesis of multiple system atrophy?
alpha-synuclein accumulation kills oligodendroglial cells
what is the age of onset for Friedreich’s ataxia?
childhood
what findings are not a hallmark of ALS?
lymphocytic and macrophage infiltrates
what is the etiology of Pick disease?
abnormality of tau protein
what is the clinical presentation of frontotemporal lobar degenerations (FTLDs)?
altered personality, behavior, and speech (aphasia) precede memory loss
what is a possible partially effective treatment for Wernicke-Korsakoff syndrome?
vitamin B1–will likely help the acute Wernicke portion of the syndrome
what is the clinical presentation of Huntington’s disease?
choreiform movements, aggression, depression, dementia
