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NMSP 1 > Demyelinating, Neurodegenerative Diseases > Flashcards

Demyelinating, Neurodegenerative Diseases Flashcards

1
Q

True or False: demyelinating diseases are acquired conditions that preferentially damage myelin, with relative preservation of axons

A

True

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2
Q

True or False: demyelinating diseases can be immunologic or inherited

A

True.

Example: leukodystrophies are inherited; MS is immunologic

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3
Q

Describe the temporal and spatial occurrences of the neurological deficits in MS.

A
  • episodes of neurological deficits are separated in time
  • episodes attributed to separated white matter lesions
  • relapsing and remitting episodes of varying duration
  • freq. decreases during course
  • neuro deterioration, in general, occurs steadily
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4
Q

What commons signs and symptoms of MS?

A
  • unilateral vision impairment (frequently first symptom)
  • -10-15% of pts with optic neuritis develop MS
  • brainstem: ataxia, nystagmus
  • spinal cord: motor/sensory impairment of trunk/limbs, spasticity, dysfunction of bowel/bladder control
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5
Q

How is genetics involved in MS?

A
  • -occurrence 15x higher in pts w/ 1st degree relative
  • -DR2: genetic linkage of MS susceptibility
  • -IL-2 and IL-7 receptor genes
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6
Q

Describe the inflammation of MS.

A

–initiated by CD4+ Th1 and Th17 cells secreting cytokines and reacting against self myelin Ag’s

  • Th1 secrete IFN gamma to activate macrophages
  • Th17 recruit leukocytes

–plaque infiltrate is mainly CD4+ T-cells

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7
Q

What is the gross morphology of MS?

A
  • multiple circumscribed, slightly depressed, glassy, gray/tan irregularly shaped plaques, commonly adjacent to the lateral ventricles or in the optic nerves
  • plaques are sclerosed (firmer than surrounding area)
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8
Q

What is the histology of active plaques in MS where myelin breakdown is ongoing?

A

–abundant macrophages that contain lipid-rich, PAS+ debris (myelin)

–mononuclear inflammatory infiltrate located perivascular at the outer edge of the plaque

–depletion of oligodendrocytes, but axons preserved

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9
Q

What is the histology of inactive plaques?

A
  • inflammatory cells have disappeared
  • little to no myelin anymore
  • reduced number of oligodendrocytes and axons
  • -instead, astrocyte proliferation and gliosis
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10
Q

What are the CSF findings in MS patients?

A
  • mildly elevated protein
  • moderate pleocytosis (increased WBC count in CSF)
  • IgG increased
  • -oligoclonal IgG bands in gamma region (B cell clones)
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11
Q

What is Neuromyelitis Optica?

A
  • -B/L optic neuritis and spinal cord demyelination
  • -Ab’s against aquaporin-4 (important in astrocytes)
  • –however, the foot processes are NOT damaged
  • -much more common in females
  • -neutrophils, turbid CSF; increased opening pressure
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12
Q

What is the treatment for Neuromyelitis Optica?

A

-therapies that target reduction of the Ab load, such as plasmapharesis or an anti-CD20 Ab to deplete B cells

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13
Q

What is Acute Disseminated Encephalomyelitis?

A
  • a diffuse monophasic demyelinating dz
  • follows a viral infection (or rarely, an immunization)
  • symptoms: HA, lethargy, coma (non-focal findings)
  • 20% die, 80% fully recover
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14
Q

What is the morphology of Acute Disseminated Encephalomyelitis (ADEM)?

A
  • -gray discoloration around the white matter vessels
  • -loss of myelin w/ axons preserved
  • -early infiltrates are PMN’s, late are monocytes
  • -lipid-laden macrophages d/t myelin breakdown
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15
Q

What is Acute Necrotizing Hemorrhagic Encephalomyelitis (ANHE)?

A
  • fulminant syndrome of CNS demyelinization
  • follows upper respiratory infection
  • typically affects children and young adults
  • fatal in most; deficits present in survivors
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16
Q

What is Central Pontine Myelinolysis (Osmotic Demyelination Syndrome)?

A

-symmetric loss of myelin in the basis pontis and portions of the pontine tegmentum

  • no evidence of inflammation
  • occurs 2 to 6 days after rapid correction of hypoNa+
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17
Q

What are the symptoms of Central Pontine Myelinolysis (Osmotic Demyelination Syndrome)?

A
  • -acute paralysis
  • -dysphagia and dysarthria
  • -diplopia
  • -loss of consciousness
  • -“locked-in” syndrome
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18
Q

What are the major characteristics of neurodegenerative diseases?

A
  • -diseases of grey matter, w/ progressive neuron loss
  • -affects groups of functionally-related neurons
  • -accumulation of protein aggregates (inclusions)
  • –aggregates are usually resistant to degradation
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19
Q

What is Alzheimer Disease?

A
  • -most common cause of dementia in elderly
  • -impairment of higher intellectual function
  • -alterations in mood and behavior
  • -rarely symptomatic prior to age 50 (40% over age 85)
  • -most cases are sporadic (only 5-10% familial)
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20
Q

What are the symptoms of Alzheimer Disease?

A
  • progressive disorientation, memory loss, and aphasia
  • become profoundly disabled, mute, and immobile
  • cortical atrophy and widened sulci
  • frontal, temporal, and parietal lobes
  • definitive Dx comes from pathology exam postmortem
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21
Q

What are neuritic plaques in the histology of Alzheimer Disease?

A

-focal spherical collections of dystrophic neurites around an amyloid core, which stains with Congo Red and contains abnormal AB40 and AB42 proteins

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22
Q

What are diffuse plaques in the histology of Alzheimer Disease?

A

-found mainly in superficial cerebral cortex, basal ganglia, and cerebellar cortex

  • no amyloid core
  • only contain AB 42
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23
Q

What are neurofibrillary tangles in the histology of Alzheimer Disease?

A
  • cytoplasmic bundles of filaments containing tau
  • displace or encircle nucleus
  • found in cortical neurons, hippocampus, amygdala
  • shape of the tangle depends on the cell’s shape
  • -“flame” in pyramidal neuron; “globose” in round cells
  • basophilic in H and E stain
  • better seen with silver stain (Bielschowsky)

-resistant to clearance in vivo, leaving “ghost tangles”

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24
Q

Which correlates better with the degree of dementia, number of tangles or number of plaques?

A

number of tangles

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25
Q

What is granulovacuolar degeneration in the histology of Alzheimer Disease?

A
  • small, clear intraneuronal cytoplasmic vacuoles containing argyrophilic granules
  • normal in aging; MORE ABUNDANT in Alzheimer Dz in hippocampus and olfactory bulb
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26
Q

What are Hirano Bodies in the histology of Alzheimer Disease?

A
  • elongated, glassy, eosinophilic bodies
  • paracrystalline arrays of beaded filaments
  • -major component is ACTIN
  • present in hippocampal pyramidal cells
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27
Q

What is Cerebral Amyloid Angiopathy?

A
  • invariably present in Alzheimer Disease
  • -but can be seen outside of Alzheimer Disease
  • AB40 amyloid protein (stains w/ Congo Red)
  • thick vessel walls
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28
Q

What is Pick Disease (rare), one of the Frontotemporal Dementias with tau pathology?

A
  • progressive dementia

- EARLY ONSET of behavior changes (frontal lobe sign) and language disturbances (temporal lobe sign)

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29
Q

What is the morphology of Pick Disease?

A
  • -asymmetric atrophy of frontal and temporal lobes
  • -posterior 2/3rds of superior temporal gyrus spared
  • -“knife-edge” thin gyri w/ deep and wide sulci
  • -Pick Cells (swollen cells)
  • -Pick Bodies (cytoplasmic filamentous inclusions, weakly basophilic, stain strongly with silver stain)
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30
Q

What is Progressive Supranuclear Palsy?

A

-widespread neuron loss in globus pallidus, subthalamic nucleus, substantia nigra, dentate nucleus

  • onset in 40’s-60’s, men 2x as likely as women
  • fatal within 5-7 years

-globose neurofibrillary tangles made of 4R tau straight filaments

31
Q

What are the symptoms of Progressive Supranuclear Palsy?

A

-TRUNCAL RIGIDITY w/ dysequilibrium and nuchal dystonia

  • abnormal speech
  • ocular disturbances (vertical gaze palsy)
  • mild progressive dementia
32
Q

What is Vascular Dementia, a progressive cognitive disorder that is associated w/ vascular injury?

A

–improves w/ Tx if d/t vasculitis

  • widespread areas of infarction (cortical microinfarcts, lacunar infarcts, cortical laminar necrosis)
  • diffuse white matter injury (HTN, CADASIL aka Cerebral Autosomal Dominant Arteriopathy w/ Subcortical Infarcts and Leukoencephalopathy)
  • strategic infarcts (usually embolic): hippocampus, dorsomedial thalamus or cingulate gyrus
33
Q

What category of disorders are associated with degenerative diseases of the basal ganglia and brainstem?

A

movement disorders
-rigidity, abnormal posturing, chorea

-basal ganglia (esp. nigrostriatal pathway) plays a role in modulating feedback from thalamus to motor cortex

34
Q

What are the symptoms of Parkinson Disease?

A
  • DIMINISHED FACIAL EXPRESSION
  • stooped posture
  • SLOWNESS of voluntary mvmt
  • festinating gait (accelerated steps)
  • rigidity
  • “PILL-ROLLING” tremor
35
Q

What is the treatment for Parkinson Disease?

A
  • -L-dopa to replace dopamine
  • -Tx doesn’t reverse the changes or stop progression
  • -drug therapy becomes less effective over time
36
Q

What are the molecular genetics that contribute to the autosomal dominant form of Parkinson Disease?

A

–alpha-synuclein was the first gene mutation discovered and it’s a component of the Lewy Body

–mutations of LRRK2 (leucine-rich repeating kinase 2) are a more common cause of autosomal dominant Parkinson Disease

37
Q

What are the molecular genetics of the juvenile autosomal recessive form of Parkinson Disease?

A
  • mutation in the gene for parkin (E3 ubiquitin ligase)
  • mitochondrial dysfunction

-PINK1 and parkin combo clear dysfunctional mitochondria via mitophagy

38
Q

What is the morphology of Parkinson Disease?

A
  • pallor of substantia nigra and locus ceruleus
  • -loss of pigmented catecholaminergic neurons
  • Lewy Bodies: cytoplasmic, eosinophilic inclusions
  • -dense core surrounded by a pale halo
  • -comprised of alpha-synuclein
39
Q

What is Lewy Body Dementia?

A
  • -Lewy neurites contain alpha-synuclein aggregates
  • -depigmentation of substantia nigra, locus ceruleus
  • -Lewy Bodies in cortical locations
  • -HALLUCINATIONS, fluctuating course, frontal signs
  • -10-15% of Parkinson Disease develop dementia
40
Q

What is Multiple System Atrophy?

A

–sporadic disorder characterized by cytoplasmic inclusions of alpha-synuclein in oligodendrocytes

  • -involves three neuroanatomic systems:
    1) striatonigral circuit (Parkinsonism)
    2) olivopontocerebellar circuit (ataxia)
    3) autonomic nervous system (orthostatic hypotension)
41
Q

What is the most notable gross brain morphology in Huntington Disease?

A
  • ATROPHY OF THE CAUDATE NUCLEUS
  • later the putamen atrophies
  • frontal lobe atrophy
42
Q

What is Huntington Disease?

A
  • autosomal dominant mvmt disorder w/ dementia
  • rapidly progressive leading to death within 15yrs

-repeat CAG expansions during spermatogenesis cause anticipation and earlier onset (juvenile form)

43
Q

What are the symptoms of Huntington Disease?

A
  • jerky, hyperkinetic mvmts
  • later … bradykinesia and rigidity
  • sometimes chorea
  • -dystonic mvmts involving the whole body
44
Q

What number of CAG repeats is normal?

A

10-35 normal
40-50 adult onset
>60 juvenile onset

27-35 normal, but children may develop disease

45
Q

What is the pathogenesis of Huntington Disease?

A
  • degeneration of medium spiny striatal neurons that normally dampen motor activity
  • expansions produce a toxic GAIN OF FUNCTION on huntingtin (protein aggregates to form intranuclear inclusion)
46
Q

What is Friedreich Ataxia?

A

-autosomal recessive spinocerebellar degeneration caused by GAA repeat on 9q13 coding for frataxin

47
Q

What are the symptoms of Friedreich Ataxia?

A
  • gait ataxia by age 10; wheelchair by 5yrs after onset
  • clumsy hands
  • dysarthria
  • depressed DTR’s (except extensor plantar reflex)
  • joint position and vibratory sense impaired
  • CARDIAC arrhythmias and CHF
  • 10% have DM
48
Q

What is the common cause of death in patients with Friedreich Ataxia?

A
  • intercurrent pulmonary infections

- cardiac disease

49
Q

What is Ataxia-Telangectasia?

A
  • autosomal recessive spinocerebellar degeneration that begins in childhood d/t mutated ATM gene on 11q22 that encodes a kinase which normally orchestrates the cell’s response to breaks in dsDNA
  • increased sensitivity to X-ray-induced chromosome abnormalities; failure to remove cells w/ DNA damage
50
Q

What are the symptoms of Ataxia-Telangectasia?

A
  • telangectasias in CNS, CONJUNCTIVA, face/neck, arms
  • development of lymphoid neoplasms (mostly T-cell leukemias), gliomas, and carcinomas
  • immunodeficiency and recurrent sinopulmonary infections
  • death by early teens
51
Q

What is Amyotrophic Lateral Sclerosis?

A
  • loss of lower motor neurons in the spinal cord and brainstem that project into the corticospinal tracts
  • loss of upper motor neurons in the cerebral cortex
52
Q

What are the characteristics of ALS?

A
  • slight male predominance
  • onset in 40’s or later
  • familial form (5-10%) is autosomal dominant
  • mutation in superoxide dismutase on chromosome 21
  • -gain of function (ala-val substitution is most common)
53
Q

What can be seen on gross morphology of ALS?

A

-thin anterior roots of the spinal cord d/t loss of anterior horn neurons

  • atrophic precentral gyrus
  • skeletal muscles w/ neurogenic atrophy
54
Q

What features of neurons in ALS can be seen under microscope?

A

-neurons contain PAS+ cytoplasmic inclusions called Bunina Bodies, which are remnants of autophagic vacuoles

55
Q

What are the symptoms of ALS?

A

early: asymmetric hand weakness, DROPPING OBJECTS, difficultly w/ fine motor tasks, arm/leg CRAMPING/spasticity

  • muscle atrophy as dz progresses
  • fasciculations
  • respiratory infections d/t resp. muscle involvement
56
Q

What is the prognosis of ALS?

A

-50% mortality within 2yrs

57
Q

What is Progressive Bulbar Palsy (Bulbar ALS)?

A
  • degeneration of lower brainstem cranial motor nuclei
  • occurs early, progresses rapidly
  • deglutination
  • phonation difficulties
58
Q

What are the major characteristics of neuronal storage diseases?

A
  • mostly autosomal recessive
  • defects in catabolism (sphingolipids, mucolipids, etc.)
  • accumulation of enzyme substrates
  • neuron death
  • cortical involvement, loss of cognitive fxn, seizures
59
Q

What are the characteristics of leukodystrophies?

A
  • mostly autosomal recessive
  • -except adrenoleukodystrophy is X-linked
  • myelin abnormalities
  • lack neuronal storage defects
60
Q

What are the symptoms of leukodystrophies?

A
  • diffuse involvement of white matter
  • -motor skills deteriorate
  • -spasticity
  • -hypotonia or ataxia
61
Q

What are mitochondrial encephalopathies?

A
  • oxidative phosphorylation disorders
  • mutations in the mitochondrial genome
  • involved GREY MATTER and SKELETAL MUSCLE
62
Q

What are the characteristics of Tay-Sachs?

A
  • HEXA gene for hexosaminidase A (chromosome 15)
  • buildup of GM2 gangliosides
  • death by age 3
63
Q

What are the symptoms of Tay-Sachs?

A
  • motor incoordination
  • muscular flaccidity
  • blindness
  • cherry red spot in macula of eye
  • -normal choroid against swollen retinal ganglion cells
64
Q

What are the two tissues most affected by mitochondrial encephalopathies?

A

1) muscle

2) CNS

65
Q

What is Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)?

A

–mutation (most commonly) in mitochondrial tRNA-leucine (MTTL1)

–most common neurologic syndrome caused by mitochondrial abnormalities

66
Q

What are the symptoms of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)?

A
  • -recurrent episodes of acute neurologic dysfunction
  • -cognitive changes
  • -muscle weakness and lactic acidosis

–stroke-like episodes w/ reversible deficits that do NOT correspond to specific vascular territories

67
Q

What is Myoclonic Epilepsy and Ragged Red Fibers (MERRF)?

A

–maternally-transmitted disease associated w/ mutations in tRNA’s other than those in MELAS

  • -Symptoms:
  • myoclonus
  • seizures
  • myopathy (w/ ragged red fibers on biopsy),
  • ataxia d/t cerebellar neuron loss
68
Q

What is Kearn-Sayre Syndrome (“Ophthalmoplegia Plus”)?

A

-sporadic disorder associated w/ large mitochondrial DNA deletion or rearrangement

69
Q

What are the symptoms of Kearn-Sayre Syndrome?

A
  • cerebellar ATAXIA
  • ophthalmoplegia (paralysis of extraocular muscles)
  • progressive inability to move eyes and eyebrows
  • PIGMENTARY RETINOPATHY
  • CARDIAC CONDUCTION DEFICITS
70
Q

What is seen on histology of Kearn-Sayre Syndrome?

A
  • spongiform change in grey and white matter

- cerebellar neuronal loss

71
Q

What is Leigh Syndrome (Subacute Necrotizing Encephalopathy)?

A
  • disease of infancy associated w/ mutations of nuclear and mitochondrial DNA that involve components of oxidative phosphorylation complexes
  • death by age 2
72
Q

What the symptoms of Leigh Syndrome?

A
  • lactic acidemia
  • psychomotor development arrest
  • feeding problems
  • SEIZURES
  • extraocular palsies
  • weakness w/ HYPOTONIA
73
Q

What is the histology of Leigh Syndrome?

A

-multifocal regions of symmetric brain tissue destruction w/ spongiform appearance and vascular proliferation

  • periventricular midbrain grey matter
  • periventricular regions of thalamus and hypothalamus
  • tegmentum of pons

NMSP 1 (9 decks)

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