Demyelinating, Degenerative, Genetic, And Toxic Disease Dr. Martin Flashcards
Multiple Sclerosis (MS)
demyelination autoimmune
= neurologic deficit relapsing and remitting episodes, gradual partial recovery
1. unilateral visual impairment (optic neuritis)
2. ataxia, nystagmus, motor and sensory impairment
3. loss of bladder control
MS genetic and environmental factors
- 1st degree relatives (DR2 gene, IL2 + IL7 receptors gene)
2. higher farther away from equator (VitD association)
MS inflammation is caused by what
- CD4 Th1 + Th17 cells —-> myelin Ag
(Th1 —-> INF-g = activate M)
(Th17 —-> bring leukocytes)
X-ray MS looks like
sharp boarders, next to lateral ventricles, corpus callosum, optic nerves*, spinal cord
MS plaques look like
gray brown plaques usually around occipital horn and lateral ventricles
how to stain for
- active demyelinating plaque :
- Complete lack of myelin :
- axons are preserved :
- Active demyelinating plaque : Lipid laden Macrophages seen
- Complete lack of myelin : fast blue PAS stain
- Axons are preserved : Neurofilament immunostain
if axons are not preserved then what is the cause usually
Infarction
stain for Macrophages
CD68
active plaque ongoing myeling breakdown
what is going on
- foamy M, lipid rick
- PAS+ (myelin debri)
- axons preserved (oligodendrocytes die)
inactive plaque ongoing myelin breakdown
what is going on
- no inflammation
- decrease in axons
- astrocytes proliferate and gliosis
shadow plaque
boarder between normal and affected white matter (not will circumscribed) = abnormal thinned out myelin sheaths
CSF test for MS
- mild elevate Protein
- Some pleocytosis
- increase IgG** oligoclonal
Neuromyelitis Optica (NMO)
bilateral optic neuritis + Spinal cord demyelination
= not good recovery from first attack
= many develop MS
Neuromyelitis Optica (NMO) prevalence
F > M even more then MS
CSF Neuromyelitis Optica (NMO) looks like
- high Neutrophils
- high opening pressure
- turbid looking like bad meningitis
Neuromyelitis Optica (NMO) happens due to what
Ag against Aquaporin-4 on astrocyte footprocesses
= breaks BBB
Neuromyelitis Optica (NMO) TX
decrease by plasmapheresis
= actue —-> glucocorticosteroids or plasma exchange
Acute Disseminated Encephalomyelitis (ADEM)
happens in 1 distinct area in brain unlike MS
= demyelinating after viral or rarely viral immunization
Acute Disseminated Encephalomyelitis (ADEM) SXs AND PROGRESSION
- 1-2 WEEK SAFTER INFECTION
- headache, coma, fatigue
- 20% die, survivors recover completely
Acute Disseminated Encephalomyelitis (ADEM) looks like what on the brain and if staining
- gray discoloration around white matter
- preservation of axons
- monophasic lesions*
- lipid laden macrophages (myelin debri)
Acute Necrotizing Hemorrhagic Encephalomyelitis ANHE
CNS demyelination similar to ADEM
= young children and young adults
= after recent upper respiratory infection (from cytokine storm)
= usually fatal
Acute Necrotizing Hemorrhagic Encephalomyelitis ANHE TX
intravenous immunoglobulins (giving high dose steroids can increase the infection)
Central Pontine Myelinolysis other name and what happens
Osmotic Demyelination Syndrome = Myelin loss symmetrically on pontine tegmentum and basis (central pontine) = axon preservation = no inflammation = paralysis, dysphagia, LOC
Central Pontine Myelinolysis happens due to
overly rapid correction of hyponatremia
happens 2-6 days after
how fast should Na be increased
no more then 8 mEq/L in 24hrs
no more then 0.5 mEq/L per hour
HD protein aggregate
Polyglutamine repeats
Alzhiemers protein aggrugates
A B-amyloid, neurofibrillar tangels,
PD protein aggrugates
a- synuclein
AD SX and prevalence
impaired higher intelligence, mood and behavior changes, memory loss, —-> disabled immobile mute (after 5-10years)
= usually after 50yo,
AD CSF
increased phosphorylated TAU
+ decreased A-beta
AD effects what location and what happens
global cortical atrophy = TEMPORAL = Frontal = parietal (most common)
when cortex shrinks —-> Hydrocephalus ex vacuo
degree of dementia in AD is shown by
number of Neurofibrillary tangles
Amyloid plaques vs neurofibrillary tangles
Amyloid plaques : aggregates of A-beta
Neurofibrillary tangles : aggregates of tau
what is the initial thing causing AD to happen
A-beta amyloid deposits
mutation causing frontotemporal lobar degeneration
MAPT gene = encoding Tau
gene that as strong association with earlier and more severe AD and what chr
CHR 19 ApoE - 4 gene
AD staining neuritic (SENILE) plaques
Congo Red for the amyloid core —-> staining the APP (amyloid precursor protein)
AD DIFFUSE PLAQUES
no amyloid core
= just early stage plaque development
Down syndrome and AD
they have APP gene on Chr 21 so they get AD 2nd and 3rd decade
AD stain neurofibrillary tangles
Bielschowsky stain (Silver stain)
2 things seen in AD histology
- Granulovacuolar degeneration = small vacuoles with granules —-> normal aging however many in AD (hippocompi + olfactory bulb)
- Hirano Bodies = glassy eosinophilic bodies (actin stain in hippocampus)
Cerebral Amyloid Angiopathy CAA is what and stain and similar to
with AD
- A-beta 40 on vessels walls
congo red
Frontotemporal Lobar degenerations FTLDS is what, looks like, and includes what inclusions causing what diseases
- frontotemporal dementia
- looks similar to AD
- FTLD-TAU (no A-beta) = Picks, progressive supranuclear palsy
- TDP-43 = ALS
Pick Disease is what and location and what happens
- early onset behavior and personality changes (F), language changes (T)
= progressive Dementia - Asymmetric atrophy of frontal and temporal lobe (NOT Post 2/3 of superior temporal gyrus**)
- knife edge thin gyri
Picks Disease cells seen
- Pick cells = swollen cells
2. Pick bodies = cytoplasmic filamentous inclusions stain with silver
Progressive Supranuclear Palsy (PSP)
- inclusion
- what are sx
- what happens
- FTLD - TAU (4R TAU tangles)
- truncal ridgitity, frequent falls, cant move eyes, ,abnormal speech, progressive mild dementia
- Globus pallidus, subthalamic nuclei, substantia nigra, dentate nucleus gliosis
Progressive Supranuclear Palsy (PSP) other names and prevalence
- Atypical Parkinsonian Syndrome
+ Parkinson Plus Syndrome
= PD + Dementia - men , fatal in 5-7 years
vascular Dementia is what and what happens and tx
vascular injury causing dementia
= subcortical infarcts like in CADASIL or in HTN
= gait probs, dementia, pseudobulbar sign
= if vasulitis then tx that and pt imporves
Basal Ganglia + Brainstem
Abnormal posturing + chorea + rigidity
Basal Ganglia part that does motor pathway and is effected in parkinsons
esp Nigrostriatal pathway
Parkinsonism SX
- decrease facial expressions
- slow voluntary movements
- Festinating gait (shuffled)
- Ridgid
- Pill-rolling tremor
Damage to Nigrostriatal Dopaminergic system 5 diseases
- parkingsons Disease
- Multiple System Atrophy
- Postencephalitic Parkinsonism
- {rogressive Supranuclear Palsy
- Corticobasilar Degeneration
- MPTP : a type of heroin causing this
PD happens due to
- a-synuclein protein accumulation and aggregation + mitochondrial abnormalities + neuronal loss in substantia nigra
- Loss of dopamine
what do you give PD pt
Carbidopa
PD gene + chr involved in making lewy body and mit dysfunction from AR or AD
- SNCA encoding the a-synuclein on chr 4q21
- DJ-1, PINK1, PARKIN (AR)
- LRRK2 (AD)
PD histology
- pale substantia nigria + locus ceruleus
- Lewy bodies : long elongated inclusions that have dense core (a-synuclein) surrounded by a pale halo
- some paler cholinergic cells
Dementia with Lewy body is what
Dementia + PD
- hallucinations + frontal lobe problems
- Lewy bodies are all over cortex + SN + CL
- lewy neurites : have a-synuclein
- depigmented SN + CL only
Dementia with Lewy bodyvs Alzhiemers
preservation of cortex, hippocampus, amygdala (only CL + SN affected)
Atypical Parkinsonian Syndromes or Parkinson-plus syndromes 3 types and difference to PD
- Progressive Supranuclear palsy
- Corticobasal degeneration
- multisystem atrophy
= have more sx + no response to L-dopa
Corticobasal Degeneration CBD
progressive taupathy
- jerking, cortical impaired (Apraxia), cognitive decline
- TAU in cerebral cortex
Corticobasal Degeneration CBD histology and cells found
- Tau+ threads in gray + white matter**
- ballooned neurons = gliosis
- tufted astrocytes + coiled bodies , astrocytic plaques
Multiple System Atrophy causes what 3 things
- Striatonigral circuit = (parkinsonism)
- Olivopontocerebellar circuit = ataxia
- Autonomic NS = autonomic dysfunction like orthostatic htn
Multiple System Atrophy what happens
many brain regions involved
= a-synuclein in oligodendrocytes
autonomic sx caused by what brain part
medulla, catecholaminergic nuclei
HD
- inherited how
- sx
- due to what mutation **
- AD
- progressive movement + dementia problems : jerky, hyperkinetic chorea, slurred speech, behavior changes
- Polyglutamine trinucleotide CHR4p16.3 —-> huntington protein = CAG REPEATS **
HD effects what part of the brain and neurons
Striatal neurons
HD common cause of death (Ave 15years after dx)
- pneumonia
- suicide
- starvation (they need more food due to many movements)
HD onset has to do with
CAG repeat extension during spermatogenesis (paternal transmission)
neurons that die in HD and normal function of these
- Spiny neurons of striatal neurons
= they dampen motor activity - cortex neurons = behavior changes
- caudate nucleus + putamen = frontal and cortex
brain slice in HD
stiatum atrophy + ventricular dilation
Spinocerebellar degeneration are what and effects what location and 2 types
- spinocerebellar ataxia
- cerebellum , spinal cord, peripherial nerves
- Friedreich ataxia + ataxia telangiectasia
Spinocerebellar ataxia mutations and gene involved
- CAG repeats like in HD
2. SCA genes
Friedrich ataxia is inherited how and sx
- AR
2. progressive ataxia, weakness, sensory probs, cardiomyopathy
Friedrich ataxia GENE + repeat
- GAA
2. CHR9q13 = Frataxin protein = changes mitochondria
Friedrich ataxia sx start when and what PE sx do you find
1st decade in life
- low reflex EXCEPT IN PLANTAR REFLEX
- loss of pain, temp
- pes cavus + kyphoscoliosis
- joint position abnormal
Friedrich ataxia COD and increase risk of getting
- Cardiac arrythmia + CHF + DM
2. COD : pulmonary infections + cardiac disease
Ataxia telangiectasia
- inheritance
- sxs
AR
1. telangiectasias : CNS + conjunctiva, skin on face + neck + arms
Ataxia telangiectasia mutation and start of sx and death age
childhood, death at 2nd decade of life
1. ATM gene CHR 11q22-q23 = cant remove double stranded breaks
Ataxia telangiectasia cause of death
- lymphoid neoplasm, gliomas, carcinoma
2. immunodeficiency —-> recurrent sinopulmonary infections
Amyotrophic Lateral Sclerosis what happens and which decade in life `
- Lower motor neurons loss in spinal cord + brainstem
- upper motor neuron loss in cortex
= 5th decade (AD)
Amyotrophic Lateral Sclerosis mutation and chr and what happens
- SOD1 superoxide dismutase on CH21
2. C9orf72 = ALS + FTLD (TDP-43 + FUS)
Amyotrophic Lateral Sclerosis what nerves are involved
- Anterior roots in spinal cord (thin)
- Precentral gyrus (Atrophic)
- skeletal muscle atrophy
- Upper motor neuron
Amyotrophic Lateral Sclerosis stain and histology cells
PAS+
= Bunina Bodies
= can have TDP-43
ALS early sx
- asymmertric weakness on hands , dropping objects , cramping,
- recurrent pneumonia
- progressive bulbular palsy
= sclerosis + atrophy of upper and lower neurons
Bulbar ALS
Progressive bulbar palsy
= progress fast, deglutination+ phonation problems
Kennedy Disease other disease other name and what happens
- X-linked polyglutamine repeat expansion
- LMN + brainstem degeneration
= BOLBAR signs + androgen insensitivity
neuronal storage diseases
- inheritance
- effects what
- what happens + SX
- AR (children get this)
- catabolism of sphingolipids, mucolipids —-> enzyme substrates accumulate in lysosomes = cell death
- Loss of cognitive function, seizures
Leukodystrophies
- inheritance
- what happens
- SXs
- imaging
- AR (children get this) X-linked
- Myelin problems (lysosome + enzymes)
- deterioration of motor skills, spasticity, ataxia, hypotonia
- diffuse symmetric in imaging (different then in demyelinating dz)
mitochondrial encephalomyopathies include what areas + inheritance + type of disease
- grey matter + skeletal muscles
- mother
- heteroplasmy
Tay-sachs (neuronal storage disease)
- gene involved + enzyme dysfunction
- sx and when they start
- hallmark finding during PE
- what never goes away
- HEXA gene = Hexosaminidase A
- start at 1yo, then mentally + physically degenerate (death at 2yo-3yo)
- Cherry red spot in maculae
Krabbe Disease (Leukodystrophy)
- gene involved + enzyme thats deficient
- what accumulates as a result
- sx start and sx
- 14q31 + Galactocerebroside B-galactosidase
- galactocerebroside accumulates (not toxic) —-> galactosylphingosine** Toxic to oligodenroglia
- 3-6mo (die at 2yo)
- stiff + weak motor, X feeding
Krebbe Disease histology hallmark + TX
los of myelin and oligodendroglia in CNS + PNS
(Macrophages called globoid cells** HALLMARK around BVs)
TX : with cord blood pre sxs
Metachromatic Leukodystrophy
- gene and enzyme and accumulation
- sx start when and sx
- CHR 22q many mutations , Arylsulfatase A deficiency —-> Cerebroside sulfate* accumulation in white matter which inhibits oligidendroglia proliferation
- late infant / juvenile : motor problems progress (death 5-10yr)
Adult form : psychiatric + cognitive then motor problems
Metachromatic Leukodystrophy
- histology
- tx
- BM stem cell trasplant
2. gliosis from demyelination (Metachromasia in mitochondria)
Adrenoleukodystrophy
X-linked
ABCD1 gene
(ATP -binding cassette transporter family) = VLCFAs accumulate (very long FA chains)
1. myelin loss CNS + PNS
2. adrenal insufficiency
3. behavioral changes (more rapid progression in early onset)
Pelizaeus- Merzbacher Disease
X-linked (PLP protein and DM20 protein) = same locus as SPG2 spastic paraplegia
= fatal leukodystrophy after birth or early childhood
- pendular eye movement, hypotonia, choreoathetosis
- spasticity, dementia, ataxia later
Pelizaeus- Merzbacher Disease histology sees
loss of myelination in patches = TRIGOID PATTERN (tiger looking) when stained
Canavan Disease
- chr and gene and protein
- what happens
- Sx
CHR17 deacetylating enzyme ASPARTOACYLASE = accumulation of N-acetylaspartic acid
- spongy degeneration of white matter (like in CGB)
- megalocephaly, severe mental deficits, blindness
(in infants and die within a few years)
Alexander disease
gene+ accumulaiton of and what happens
- GFAP gene = Rosenthal Fiber accumulation around BVs (in subpial + Subependymal zones) PAS+
- white matter loss (fronto-occipital gradient)
Vanishing White Matter Leukodystrophy
- mutation and protein and what happens
- dx
- EIF2B = white matter injury
- ataxia, seizures
survive only few years - dx by imaging
MELAS
- mutation
- SX
- MTTL1 : the tRNA leucine
- encephalopathy, lactic acid, Stroke like episodes (not corresponding to vascular territories) , weakness, cognitive changes
MERRF
- mutation
- SX
- tRNA mutation
2. Myoclonic (sudden brief) epilepsy, RAGGED RED FIBERS, ataxia,
Leigh syndrome
- other name
- mutation
- SX
- Subacute Necrotizing Encephalopathy
- mito DNA and nuclear DNA
- lactic acid, X psychomotor development, feeding probs, seiures, extra-ocular palsies, Hypotonia (death in 1-2years)
LEIGH SYNDROME histology
Spongiform and vascular proliferation
center and midbrain
Spongiform histology is found in what 4
- CJB
- Canavan disease
- Subacute necrotizing encephalopathy (Leigh syndrome)
- Kearn-Sayre Syndrome (ophthalmoplegia plus)
= B-sheets
Kearn-Sayre Syndrome (ophthalmoplegia plus)
- mutation
- sx
large mito DNA deletion
2. cerebellar ataxia, pigmentary retinopathy, cardiac conduction defect, Ophthalmoplegia , RAGGED RED FIBERS
Kearn-Sayre Syndrome (ophthalmoplegia plus) histology
- spongiform in cerebellum gliosis
Thiamine B1 def (usually from chronic alcoholism)
- wernicke encephalopathy : REVERSIBLE, psychosis, ophthalmoplegia, hemorrhage, necrosis, mamillary bodies + 3rd/4th ventricles
- Korsakoff : IRREVERSIBLE , memory probs, confabulation
- Beriberi : CF
Wernicke syndrome casuses what in the brain BOARDS
foci Hemorrhage + necrosis of Mammillary bodies (and walls of 3rd + 4th ventricles)
B12 def
anemia
= defect in myelin formation
= numbness, tingling, ataxia, spastic weakness, —-> paraplegia late course
B12 hallmark histologic finding
- swelling of myelin in midthoracic spinal cord
BOTH ASCENDING POSTERIOR COLUMNS + DESCENDING PYRAMIDAL TRACTS = subacute combined degeneration of spinal cord
Hypoglycemia
- what part of brain is effected
- what happens
- pyramidal neurons of Sommer’s sector (hippocampus) + Purkinje cells (Cerebellum)
Pseudolaminar necrosis (superficial layer on cortex)
Hyperglycemia causes and what it causes
ketoacidosis or hyperosmolar coma
= dehydrated, confusion, stupor, coma
= GIVE FLUID GRADUALLY to prevent cerebral edema
Hepatic encephalopathy (impaired liver function) what happens and what areas in brain it effects
high ammonia + inflammation —-> Alzheimer type 2 cells in cortex and BG, and other grey matter like globus pallidus
CO poisoning and brain locations and what happens
hypoxia
- layers 3 and 4 of cerebral cortex, Sommer sector (Hippo), Purkinje cells (Cerebellum)
- Bilateral necrosis of GLOBUS PALLIDUM**
+ CHEERY RED COLOR ON SKIN AND ORGANS
Methanol
degeneration of retina ganglion cells
= bilateral putamenal necrosis
ethanol and brain
cerebellar dysfunction = truncal ataxia, nystagmus
= atrophy of granule cells (ANTERIOR VERMIS)
= advanced : purkinji cell loss, BERGMANN GLIOSIS (adjacent astrocytes proliferate)
Radiation and brain
headache + PAPILLEDEMA
= can cause sarcomas, gliomas, meningiomas (effects everything)
= coagulative necrosis, BV HYALINE thickened walls, fibrinoid necrosis + sclerosis
= dystrophic mineralization of axons
= methotrexate and make worse
