Demyelinating/Degenerative/Genetic/Toxic Diseases Flashcards
(184 cards)
1
Q
What causes multiple sclerosis?
A
- Autoimmune demyelinating disorder
- Genetics –> 15 fold higher incidence in first degree relative
2
Q
What is seen in multiple sclerosis?
A
- Distinct episodes of neurologic deficits, separated in time due to lesions of white matter separated in space
3
Q
What do the lesions of MS cause?
A
- Relapsing and remitting episodes of variable duration
- Neurological deficits are followed by gradual partial recovery
4
Q
What happens to the relapses in MS?
A
- Frequency tend to decrease during course, but there is a steady neurologic deterioration
5
Q
What are some common neurological symptoms of MS?
A
- Unilateral visual impairment –> frequently initial symptoms
- Brainstem symptoms –> CN signs, ataxia, nystagmus, and internuclear ophthalmoplegia
- Spinal cord symptoms –> Motor and sensory impairment of trunk and limbs, spasticity, and loss of bladder control
6
Q
Who is most likely affected by MS?
A
- Any age but rare in children
- Women are twice as often
7
Q
What gene mutations are seen in MS?
A
- DR2 –> genetic linkage of MS susceptibility
- IL-2 and IL-17 receptor genes
8
Q
What are some environmental causes of MS?
A
- Higher number of cases are seen farther away from the equator
- May be due to lower levels of Vit D
9
Q
How could chronic inflammation cause MS?
A
- Disease initiated by CD4+TH1 and TH17 cells that react against self myelin antigens and secrete cytokines
10
Q
What inflammatory cells are seen in MS?
A
- TH1 cells –> secrete IFN gamma which activate macrophages (CD68+)
- TH17 cells promote recruitment of leukocytes
11
Q
What causes the plaque infiltrates in MS?
A
- T cells –> mainly CD4+
12
Q
What does MS look like grossly?
A
- Multiple well circumscribed
- Slightly depressed
- Glassy, gray tan, irregularly shaped plaques
13
Q
Where in the CNS does MS affect?
A
- Adjacent to lateral ventricles
- Corpus callosum
- Optic nerves and chiasm
- Brainstem
- Ascending and descending fiber tracts
14
Q
What is an active plaque in MS?
A
- Ongoing myelin breakdown
15
Q
What is seen with the active plaque in MS?
A
- Abundant foamy macrophages contain lipid rich, PAS+ debris
- Perivascular (small veins) inflammatory infiltrate at outer edge of plaque
- Relative preservation of axons within plaque and depletion of oligodendrocytes
16
Q
What is an inactive plaque in MS?
A
- Quiescent
- Inflammation disappears
17
Q
What is seen with an inactive plaque in MS?
A
- No myelin
- Decrease oligo and axons
- Astrocyte proliferation and gliosis prominent
18
Q
What is a shadow plaque in MS?
A
- Border between NL and affected white matter not sharply circumscribed
19
Q
What is seen in a shadow plaque in MS?
A
- Abnormally thinned out myelin sheaths
- Partial and incomplete remyelination by surviving oligos
20
Q
What does the CSF look like in MS?
A
- Mildly elevated protein
- Moderate pleocytosis in 1/3 cases
- IgG increased
- Oligoclonal IgG bands in immunoelectrophoresis
21
Q
What is neuromyelitis optica?
A
- Synchronous bilateral optic neuritis and spinal cord demyelination
22
Q
Who is affected by neuromyelitis optica?
A
- Women more than men
- 10-50% people with optic neuritis develop MS
23
Q
What does the CSF look like in neuromyelitis optica?
A
- Neutrophils
- Increased opening pressure
- Can be turbid
24
Q
What occurs in neuromyelitis optica?
A
- Vascular deposition of immunoglobulin and complement
- Antibody to aquaporins –> maintain astrocyte foot processes
25
What is the long term treatment for neuromyelitis optica?
- Attempt to decrease antibody burden via plasmapheresis
26
What can be used for acute attacks of neuromyelitis optica?
- Glucocorticoids or plasma exchange
27
What is acute disseminated encephalomyelitis (ADEM)?
- Perivenous encephalomyelitis
| - Diffuse monophasic demyelinating disease that follows either viral infection, or rarely viral immunization
28
What are some symptoms of acute disseminated encephalomyelitis (ADEM)?
- Follows 1-2 weeks after antecedent event
- Headache
- Lethargy
- Coma
29
What is the morphology of ADEM?
- Grayish discoloration around white matter vessels
- Myelin loss with relative preservation of axons
- Lesions are monophasic
- Accumulation of lipid-laden macrophages
30
What is acute necrotizing hemorrhagic encephalomyelitis (ANHE)?
- Fulminant syndrome of CNS demyelination
| - Similar to ADEM
31
Who is most likely affected with ANHE?
- Young adults and children
| - Usually seen after a recent upper respiratory infection
32
What is the usual result seen with ANHE?
- Fatal in most
| - Survivors have significant deficits
33
What is central pontine myelinolysis?
- Loss of myelin roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum
34
What is seen in central pontine myelinolysis?
- Myelin loss without evidence of inflammation
| - Neurons and axons well preserved
35
What are the symptoms of central pontine myelinolysis?
- Acute paralysis --> may have locked in syndrome
- Dysphagia
- Dysarthria
- Diplopia
- LOC
36
What is the cause of central pontine myelinolysis?
- Overly rapid correction of hyponatremia
| - Severe electrolyte or osmolar imbalance
37
What is dementia?
- Progressive loss of cognitive function independent of the state of attention
- NOT A PART OF NORMAL AGING
38
What is seen in Alzheimer disease?
- Insidious impairment of higher intellectual function with alterations in mood and behavior
39
What happens in late Alzheimer disease?
- Progressive disorientation
- Memory loss
- Aphasia
- All due to severe cortical dysfunction
40
When is Alzheimer disease usually seen?
- After 60 usually
| - Incidence doubles every 5 years
41
What is needed for a definitive diagnosis of Alzheimer disease?
- Combination of clinical assessment and current radiologic methods allows accurate premortem diagnosis
- Now possible to demonstrate Abeta deposition through imaging
42
How can Abeta be seen radiologically?
- Using 18F-labeled amyloid-binding compounds
43
What can be seen in CSF in Alzheimer disease?
- Presence of increased phosphorylated tau
| - Reduced Abeta
44
What does the cortical atrophy look like in Alzheimer disease?
- Global cortical atrophy
- Widening of sulci
- Frontal, temporal, and parietal lobes most prominently
45
What could be a compensatory side effect of Alzheimer disease?
- Hydrocephalus ex vacuo due to decreased brain parenchyma
46
What are the two pathologic hallmarks of Alzheimer disease?
- Amyloid plaques
| - Neurofibrillary tangles
47
What helps correlate to the degree of dementia in AD?
- Number of neurofibrillary tangles more than number of neuritic plaques
48
What are plaques in AD?
- Deposits of aggregated Abeta peptides in the neuropil
49
What are the tangles in AD?
- Aggregates of the microtubule binding protein tau
- Develop intracellularly
- Persist extracellularly after neuronal death
50
What is the critical initiating event for the development of AD?
- Abeta generation
51
What genetic locus has a strong influence on the risk of AD?
- Ch 19 which encodes Apolipoprotein E
52
What is seen on histology in AD?
- Neuritic plaques
| - Diffuse plaques
53
What are neuritic plaques?
- Focal spherical collections of dilated tortuous neuritic processes around amyloid core
54
Where are neuritic plaques seen?
- Hippocampus
- Amygdala
- Neocortex
- Reactive astrocytes and microglial in periphery
55
What stain can be used to visualize neuritic plaques?
- Congo red due to amyloid core --> Abeta 40 and 42
56
How are diffuse plaques different from neuritic plaques?
- No amyloid core --> Abeta 42
57
Where are diffuse plaques typically seen?
- Superficial cortex
- Basal ganglia
- Cerebellar cortex
58
How is Down syndrome associated with AD?
- The gene that encodes for APP is on Ch 21
| - Causes early onset
59
What is seen with neurofibrillary tangles histologically?
- Pyramidal nucleus
- Round nucleus
- Basophilic fibrillary structures --> silver stain
- Persist after neuron death
60
What is granular degeneration in AD?
- Small clear intraneuronal cytoplasmic vacuoles which contain argyrophilic granules
- Normal to be found in aging but abundant in AD
61
What are hirano bodies in AD?
- Elongated glassy eosinophilic bodies
- Paracrystalline arrays of beaded filaments --> actin major component
- Hippocampal pyramidal cells
62
What are frontotemporal lobar degenerations?
- Heterogenous group of disorders with focal degeneration of frontal and/or temporal lobes
- Share clinical features with AD but need to look postmortem to differentiate
63
What is pick disease (FTLD-Tau)?
- Progressive dementia
| - Mostly sporadic, but some familial forms identified
64
When does pick disease develop?
- Early onset of behavioral changes with alterations in personality (frontal lobe signs) and language disturbances (temporal lobe signs)
65
What does pick disease look like?
- Asymmetric atrophy of frontal and temporal lobes with sparing of the posterior 2/3 of superior temporal gyrus
- Knife like thin gyri
66
What are pick cells and pick bodies seen in pick disease?
- Pick cells --> swollen cells
| - Pick bodies --> cytoplasmic filamentous inclusions that are weakly basophilic and stain strongly with silver
67
What is seen in progressive supranuclear palsy?
- Progressive truncal rigidity with disequilibrium
- Difficulty with voluntary eye movements --> including vertical gaze palsy progressing to difficulty with all eye movements
- Nuchal dystonia
- Pseudobulbar palsy and abnormal speech
68
When is the onset of progressive supranuclear palsy? Who does it affect most?
- 5th-7th decades
| - Men more than women
69
How fatal is PSP?
- Fatal within 5-7 years of onset
70
What tangles are seen in PSP?
- Globose neurofibrillary tangles --> 4R tau straight filaments
71
What are the clinical symptoms of parkinson's disease?
- Diminished facial expression
- Stooped posture
- Slowness of voluntary movement
- Festinating gait
- Rigidity
- Pill rolling tremor
72
What is parkinson disease associated with?
- Protein accumulation and aggregation
- Mitochondrial abnormalities
- Neuronal loss in the substantia nigra
73
What causes the hypokinetic movement disorders?
- Loss of dopaminergic neurons from substantia nigra
74
What can help determine parkinson disease from other hypokinetic movement disorders?
- Response to L-dopa
| - If there is no response, than it is not PD
75
What gene is in mutated in PD?
- SNCA --> encodes for alpha-synuclein (Ch 5)
76
What may be the cause in autosomal recessive forms of PD?
- Mitochondrial dysfunction
| - Genes that encode for DJ-1, PINK1, and PARKIN
77
What is the most common cause of AD PD?
- LRRK2
78
Where in the brain becomes more pale in PD?
- Substantia nigra
| - Locus ceruleus
79
What are the lewy bodies seen in parkinson disease?
- Could be single or multiple cytoplasmic, eosinophilic round-elongated inclusions that have a dense core surrounded by a pale halo
80
What is dementia with lewy bodies?
- Parkinson disease that is accompanied by cognitive dysfunction
81
What are the symptoms of dementia with lewy bodies?
- Fluctuating course
- Hallucinations
- Prominent frontal signs
82
What is lewy neuritis?
- Dystrophic processes that contain alpha-synuclein aggregated protein
83
What symptoms are seen in corticobasal degeneration?
- Extrapyramidal rigidity
- Asymmetric motor disturbances
- Impaired higher cortical function
84
Where does corticobasal degeneration affect in the brain?
- Cerebral cortex instead of the brainstem and deep gray matter like PSP
85
What is the most specific pathologic finding in CBD?
- Tau-positive threads in gray and white matter
86
What is multiple system atrophy?
- Sporadic disorder that affects a number of different systems in the brain
87
What three systems are involved in multiple system atrophy?
1. Striatonigral circuit --> parkinsonism
2. Olivopontocerebellar circuit--> ataxia
3. ANS --> autonomic dysfunction (orthostatic hypotension)
88
How is Huntington disease inherited?
- AD
| - Polyglutamine trinucleotide repeat --> CAG
89
What is Huntington disease?
- Progressive movement disorder and dementia
90
What movements are seen in Huntington disease?
- Chorea
91
What is chorea?
- Jerky, hyperkinetic, sometimes dystonic movements involving all parts of the body
92
When does Huntington disease present? Who does it affect?
- Onset is 4th-5th decade
| - More repeats mean the younger the onset
93
How does anticipation affect Huntington disease?
- Repeat expansions during spermatogenesis leads to earlier onset
94
What causes the motor symptoms in HD?
- Loss of medium spiny striatal neurons which leads to dysregulation of basal ganglia
95
What causes the cognitive changes in HD?
- Neuronal loss from cortex
96
What happens to the brain in HD?
- Striking atrophy of caudate nucleus then later, the putamen
- Globus pallidus secondarily atrophied
- Atrophy in frontal lobes --> less in parietal
- Severe loss of striatal neurons --> most marked in caudate nucleus
97
What are the seven types of polyglutamine disease?
- SCA1, SCA2, SCA3, SCA6, SCA7, SCA17
98
What is the polyglutamine disease similar to?
- HD since it is linked to expansion of a CAG repeat
99
What are the five types of expansion of noncoding repeats?
- SCA5, SCA8, SCA10, SCA12, SCA31, and SCA36
100
What is the inheritance of friedreich ataxia?
- AR
| - GAA trinucleotide repeat
101
What protein is mutated in friedreich ataxia?
- Frataxin
102
When does friedreich ataxia present?
- Begins in first decade with gait ataxia followed by hand clumsiness and dysarthira
103
What symptoms are seen in friedreich ataxia?
- DTRs depressed or absent --> but extensor plantar reflex is positive
- Joint position and vibratory sense is impaired
- Sometimes loss of pain, temperature, and light touch
- Pes cavus and kyphoscoliosis
104
What does friedreich ataxia do to the heart?
- Increases cardiac arrhythmias and congestive heart failure
105
What is the cause of death most often seen in friedreich ataxia?
- Intercurrent pulmonary infections and cardiac disease
106
What is ataxia-telangiectasia?
- AR
| - Ataxic-dyskinetic syndrome that begins in early childhood
107
What symptoms are seen in ataxia-telangiectasia?
- Telangiectasias in CNS, conjunctiva, skin of face, neck, and arms
- Many develop lymphoid neoplasms
- Immunodeficiency --> recurrent sinopulmonary infections
108
What gene is mutated in ataxia-telangiectasia?
- ATM gene on Chr 11
109
What does a mutated ATM gene do?
- Increased sensitivity to Xray induced chromosome abnormalities
- Fails to remove cells with DNA damage
110
What happens in ALS?
- Loss of lower motor neurons in spinal cord and brainstem
| - Loss of upper motor neurons in cerebral cortex
111
Who is most likely affected with ALS?
- Seen in men more than women
| - Usually around the fifth decade
112
What mutations are the most common cause of familial ALS?
- SOD1 --> 20%
- C9ORF72 --> 40%
- TDP-43 and FUS proteins
113
How does ALS affect the CNS?
- Anterior roots are thin
- Precentral gyrus is atrophic
- Decreased number of anterior horn neurons
114
What do the neurons contain in ALS?
- PAS+ cytoplasmic inclusions --> Bunina bodies
115
What are some early symptoms of ALS?
- Asymmetric weakness of hands --> dropping objects or difficulty with fine motor tasks
- Cramping and spasticity of arms and legs
- Fasciculations
- Recurrent pneumonia
- Progressive muscular atrophy
- Primary lateral sclerosis
116
What is progressive bulbar palsy?
- Degeneration of lower brainstem
- Cranial motor nuclei occurs early and progresses rapidly
- Deglutination and phonation difficulties (speaking and swallowing)
117
What is spinal and bulbar muscular atrophy?
- X-linked polyglutamine repeat expansion disease
| - Repeat in first exon of the androgen receptor
118
What does the repeat do in spinal and bulbar muscular atrophy?
- May see androgen insensitivity
- Gynecomastia
- Testicular atrophy
- Oligospermia
119
What is seen in spinal and bulbar muscular atrophy?
- Distal limb amyotrophy and bulbar signs
- Atrophy and fasciculations of the tongue and dysphagia
- Associated with degeneration of LMNs in the spinal cord and brainstem
120
What happens in neuronal storage diseases?
- Mostly AR
| - Defect in catabolism of sphingolipids, mucopolysaccharides or mucolipids --> causes accumulation of substrate
121
What do the defects in neuronal storage diseases cause?
- Loss of cognitive function
| - Possible seizure activity
122
What are leukodystrophies?
- Myelin abnormalities
| - Generally lack neuronal storage defects
123
What happens in leukodystrophies?
- Diffuse involvement of white matter
| - Deterioration of motor skills, spasticity, hypotonia, or ataxia
124
What are mitochondrial encephalomyopathies?
- Oxidative phosphorylation disorders
| - Mutations in mitochondrial or nuclear genomes
125
What do mitochondrial encephalomyopathies involve?
- Gray matter and skeletal muscle
126
What gene is involved in Tay Sachs?
- HEXA
127
What enzyme is involved in Tay Sachs?
- Hexosaminidase A
128
What accumulates and never goes away in Tay sachs?
- GM2 gangliosides
129
What happens in Tay sachs?
- Kid is fine for the first year and then degenerating mentally and physically until year 2 or 3
130
What is seen in Tay sachs?
- Cherry red spots in maculae
131
What defect is seen in Krabbe disease?
- Galactocerebroside B galactosidase
132
How does galactocerebroside toxic?
- The accumulation is not toxic
| - An alternative catabolic pathway removes a fatty acid generating galactosylsphingosine
133
What does galactosylsphingosine do?
- Toxic to oligodendroglia and astrocytes
134
What does Krabbe disease do?
- Rapidly progressive and fatal
| - Motor signs (stiffness and weakness) with gradually worsening difficulties feeding
135
What does histology look like in Krabbe disease?
- Loss of myelin and oligodendroglia in the CNS and PNS
| - Neurons and axon relatively spared
136
What is a unique diagnostic feature of Krabbe disease?
- Aggregation of engorged macrophages in parenchyma and around blood vessels
137
What is the defect in metachromatic leukodystrophy?
- Arylsulfatase A --> cerebroside sulfate accumulates (toxic to white matter)
138
What is seen in the late infantile and juvenile form of metachromatic leukodystrophy?
- Late infantile most common
- Motor symptoms and progress gradually
- Death in 5-10 years
139
What is seen in the adult form of metachromatic leukodystrophy?
- Psychiatric and cognitive initially
| - Motor later
140
What is the treatment of metachromatic leukodystrophy?
- Bone marrow stem cell transplant beneficial if started before neurological deficits
141
What does histology look like in metachromatic leukodystrophy?
- Demyelination with resulting gliosis
| - Macrophages scattered in white matter --> have vacuolated cytoplasm
142
What can happen in the brain in metachromatic leukodystophy?
- Brain stained with metachromatic dye
143
How is adrenoleukodystrophy inherited? What gene?
- X-linked recessive
| - ABCD1 gene
144
What happens in adrenoleukodystrophy?
- Progressive myelin loss of the CNS and PNS with adrenal insufficiency
145
What happens to the adrenals in adrenoleukodystophy?
- Very long chain fatty acids accumulate (VLCFAs)
146
What happens in the early onset of adrenoleukodystrophy?
- More rapid course
| - Young boy presents with behavioral changes and adrenal insufficiency
147
What happens in the late onset of adrenoleukodystrophy?
- Adults slowly progressive for decades
| - Peripheral nerves predominantly
148
What is the inheritance of pelizaeus-merzbacher disease?
- X-linked
| - PLP and DM20
149
What is pelizaeus-merzbacher disease?
- Invariably fatal leukodystrophy
150
What are some early symptoms in pelizaeus-merzbacher disease?
- Pendular eye movements
- Hypotonia
- Choreoathetosis
- Pyramidal signs
151
What are some late symptoms in pelizaeus-merzbacher disease?
- Spasticity
- Dementia
- Ataxia
152
What do tissues look like when stained for myelin in pelizaeus-merzbacher disease?
- Tigroid pattern
153
What causes canavan disease?
- Loss of function mutation in deacetylating enzyme = aspartoacylase
154
What accumulates in canavan disease?
- N-acetylaspartic acid
155
What happens in canavan disease?
- Spongy degeneration of white matter
156
What are the symptoms of canavan disease?
- Megalencephaly
- Severe mental deficits
- Blindness
- Signs of white matter injury
157
What causes alexander disease?
- Gain of function in gene encoding glial fibrillary acid protein (GFAP)
158
What accumulates in Alexander disease?
- Rosenthal fibers around blood vessels, subpial and subependymal zones
159
What is MELAS?
- Mitochondrial encephalomyopathy, Lactic acidosis, and stroke like episodes
160
What is the most prevalent mutation in MELAS?
- MTTL1 TRNAleucine
161
What symptoms are seen in MELAS?
- Recurrent episodes of acute neurologic dysfunction
- Cognitive changes
- Muscle involvement with weakness and lactic acidosis
- Stroke like episodes that do not correspond well to specific vascular territories
162
What is MERRF?
- Myoclonic epilepsy and ragged red fibers
163
What mutation is seen in MERRF?
- TRNA distinct from MELAS
164
What symptoms are seen in MERRF?
- Myoclonus
- Seizure disorder
- Evidence of myopathy
- Ataxia
165
What stain is used to see the ragged red fibers in MERRF?
- Modified gomori trichrome stain
166
What symptoms are seen in Leigh syndrome?
- Lactic acidemia
- Arrest of psychomotor development
- Feeding problems
- Seizures
- Extraocular palsies and weakness with hypotonia
167
What is seen on histology in Leigh syndrome?
- Multifocal moderately symmetric regions of destruction of brain tissue with spongiform appearance and vascular proliferation
168
What is Kearn-Sayre syndrome?
- Sporadic disorder, often associated with a large mitochondrial DNA deletion/rearrangement
169
What symptoms are seen in Kearn-Sayre syndrome?
- Cerebellar ataxia
- Progressive external ophthalmoplegia
- Pigmentary retinopathy
- Cardiac conduction deficits
170
What does the histology look like for Kearn-Sayre syndrome?
- Spongiform change in gray and white matter
| - Neuronal loss most evident in the cerebellum
171
What happens in the brain in Wernicke encephalopathy?
- Hemorrhage and necrosis in the mamillary bodies
172
What happens histologically in B12 deficiency?
- Swelling of myelin in axons both of the ascending tracts of the posterior columns and descending pyramidal tracts
173
What areas of the brain are affected by hypoglycemia?
- Sommer's sector of hippocampus
| - Purkinje cells of cerebellum
174
What is seen in the brain during hypoglycemia?
- Pseudolaminar necrosis --> also selective for the large pyramidal neurons of cerebral cortex
175
What is hyperglycemia usually associated with?
- Ketoacidosis or hyperosmolar coma
176
What happens to the patient in hyperglycemia?
- Become dehydrated and develop confusion, stupor, and eventually coma
177
What is hepatic encephalopathy?
- Cellular response in CNS that is primarily glial due to elevated ammonia levels
178
Where in the brain does carbon monoxide affect?
- Layers III and IV of cerebral cortex
- Sommer's sector
- Purkinje cells
- Bilateral necrosis of globus pallidi
179
What does CO interact with?
- Heme of cytochrome C oxidase
180
What does methanol do?
- Preferentially attacks the retina
- Degeneration of retinal ganglion cells --> causing blindness
- Selective bilateral putaminal necrosis and focal white matter necrosis
181
What is the major metabolite in methanol poisoning?
- Formate
182
What does ethanol do?
- Directly toxic or secondary to nutritional deficits
183
What signs are seen in ethanol over intake?
- Truncal ataxia
- Unsteady gate
- Nystagmus
184
How is ethanol toxic to the brain?
- Atrophy and loss of granule cells predominantly in the anterior vermis
- Loss of purkinje cells and proliferation of adjacent astrocytes
