Pathoma Central Nervous System Pathology Flashcards
What is wrong in Dandy-Walker syndrome? How will it appear on MRI?
Agenesis of the cerebellar vermis
- > presents as 4th ventricle being too big -> enlarges into posterior fossa
- > most of the cerebellum will be absent
What is the key complication of Dandy-Walker syndrome?
Obstructive (noncommunicating) hydrocephalus due to enlargement of the 4th ventricle
How does Chiari Malformation type I present and what causes it?
Herniation of cerebellar tonsils (1 structure) -> presents as headaches + cerebellar symptoms in adulthood
-> associated with syringomyelia
How does Chiari Malformation type II present and what causes it?
Herniation of cerebellar tonsils + vermis (2 structures) -> 2x as bad, presents in infancy
- > associated with lumbosacral meningomyelocyele
- > ALSO causes aqueductal stenosis -> hydrocephalus in infancy
What is the main way we distinguish ALS from severe syringomyelia?
ALS involves only the motor system
Syringomyelia will cause pain / temperature sensation loss.
What is Werdnig-Hoffman disease similar to? What’s the difference?
Similar to poliomyelitis. Difference is that polio occurs due to infection and causes an asymmetrical LMN degeneration, while SMA I causes a symmetrical degeneration
What is the most common familial ALS mutation, and what is the most common cause overall?
Familial ALS - superoxide dismutase 1 (SOD1) -> leads to free radical injury of neurons
-> overall, usually idiopathic
What is the most common hereditary ataxia in the Western world? What causes it?
Friedreich’s ataxia
- Trinucleotide repeat “GAA”
- Frataxin gene - iron binding protein in mitochondria causing free radical damage - chromosome 9
- > damage to multiple spinal cord tracts, ataxia with hypertrophic cardiomyopathy
- > presents in childhood as kyphoscoliosis
What germ layer gives rise to the meninges? Include the two special terms for meninges.
Leptomeninges - pia / arachnoid mater - neural crest
Pachymeninges - dura mater - mesoderm
What germ layer gives rise to each type of glial cell?
Neuroectoderm -> Macroglia, including astrocytes, oligodendrocytes, and ependymal cells
Mesoderm -> microglia (macrophages are derived from mesenchyme, like blood vessels)
What are the causes of diffuse hypoxic / ischemic injury in the brain (global stroke)?
- Global ischemia -> failure of systemic circulation (i.e. cardiogenic shock, atherosclerosis)
- Systemic hypoxia -> anemia, CO poisoning, or respiratory issue
- Hypoglycemia -> systemic, i.e. due to insulinoma (brain needs glucose)***** very high yield to know!
What neurons in the brain are most susceptible to ischemic infarct during diffuse ischemic injury?
- Pyramidal neurons of cortex in layers 3, 5, and 6
- > cortical laminar necrosis - Pyramidal neurons of hippocampus in Sommer’s sector (CA1)
- Cerebellar Purkinje cells
- Watershed zones
What is the definition of stroke? TIA?
Acute neurologic dysfunction developing over minutes / hours which rapidly progresses, due to parenchymal damage due to a vascular process. Continues for more than 24 hours
TIA will have symptoms resolve in less than 24 hours (no lasting damage)
When is development of a secondary hemorrhagic infarct common?
Embolic (rather than thrombotic, superimposed on vessel) stroke, where the embolus is broken up by the body so the organ is reperfused.
What is a lacunar stroke and why do they generally occur?
A small infarct (<1cm) which occurs due to small vessel occlusion.
Commonly due to hyaline arteriolosclerosis secondary to chronic benign hypertension or diabetes
-> occurs in lenticulostriate arteries most commonly
What is the timeline of histological changes which occur in ischemic stroke?
12 hours: Red dead neurons - eosinophilic cytoplasm with pyknosis
24-72 hours: Necrosis + neutrophilic acute inflammation
3-5 days: Microglial infiltration + liquefaction, inflammatory edema peaks
1-2 weeks: Gliosis with increased astrocytes / progressive liquefaction and removal of necrotic debris
Weeks later: Fluid-filled cystic cavitation surrounded by gliosis
What are the two types of intraparenchymal hemorrhage? Where do they each occur?
- Ganglionic - “deep” - occurs in basal ganglia (lenticulostriate arteries), thalamus, pons, or deep cerebral hemisphere
- Lobar - superficial in cerebral lobes, not as severe
What are the causes of each type of intraparenchymal hemorrhage?
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Ganglionic - typically secondary to chronic hypertension -> arteriosclerosis of small vessels with formation of Charcot-Bouchard aneurysms -> massive rupture / bleed
Lobar - May also be secondary to hypertension, but often due to cerebral amyloid angiopathy, vascular malformations, coagulopathies, or vasculitis
Where in the brain does subarachnoid hemorrhage usually occur and what are two important causes?
Usually occurs at the base of the brain where the Circle of Willis lies
- Saccular “berry” aneurysm
- Congenital arteriovenous malformation
What conditions predispose to berry aneurysms and where do they often occur?
- Autosomal dominant polycystic kidney disease
- Marfan syndrome
Often occur at branch points in the circle of willis:
- Anterior communicating/ACA junction**
- Posterior communicating / MCA junction
- MCA/lenticulostriate junction
How do the associated syndromes of berry aneurysm predispose to forming them and what is the #1 factor for their progression? What will be seen on lumbar puncture?
Congenital loss of the tunica media at the branch points
- > # 1 factor for progression is hypertension
- > hypertension of upper extremities also associated with coarctation of the aorta
Lumbar puncture shows xanthochromia (yellow) or blood depending on how soon after the event it’s taken
What are the two types of transtentorial herniations? What might cause them?
These involve displacement of brain structures through tentorium cerebelli opening (incisure)
- Central - bilateral and symmetric, leading to caudal displacement and compression of entire brainstem -> i.e. due to diffuse brain swelling
- Uncal - unilateral, with herniation of medial temporal lobe into midbrain
- > i.e. due to supratentorial hemorrhage
What are the clinical complications of the two types of transtentorial herniations?
- Central - tends to cause Duret hemorrhages which are fatal
- Uncal - generally compresses ipsilateral CNIII - down-and-out pupil, as well as ipsilateral PCA (contralateral homonymous hemanopsia + macular sparing), + contralateral Crus cerebri problem. May cause Duret hemorrhage as well
What is a tonsillar herniation and what is the usual clinical result?
Herniation of cerebellar tonsils into foramen magnum
Compression of brain stem (medulla) leads to cardiopulmonary arrest
What enzyme is deficient in Metachromatic leukodystrophy and what will accumulate? How is it inherited? Is it common?
Arylsulfatase A - galactocerebroside sulfate will accumulate in Schwann cells / oligodendrocytes (a major component of myelin membranes)
It is an autosomal recessive lysosomal storage disease
It is the MOST COMMON leukodystrophy
How is metachromatic leukodystophy diagnosed / was classically diagnosed?
“metachromasia” in urine spot test due to presence of sulfatides in urine
Also from imaging scans showing demyelination of white matter.
Nerve biopsy showing metachromatic granules
What is defective in Krabbe’s disease? Inheritance pattern?
Galactocerebrosidase -> it is the last step in the galactocerebroside sulfate breakdown pathway, so we know it’s going to be toxic to neurons (like metachromatic leukodystrophy)
it is another autosomal recessive lysosomal storage disease
What are the key symptoms of Krabbe’s disease?
Accumulation of galactocerebroside and psychosine leads to:
- Developmental delay
- Optic atrophy
- “Globoid cells” - multinucleated macrophages filled with lipid material
Buzz words baby
What is defective in X-linked adrenoleukodystrophy and what are symptoms?
Disrupted transport of VLCFA into peroxidsomes -> excessive buildup in nervous system, adrenal glands, and testes
- > damage to adrenal glands -> Addison’s disease -> adrenal crisis
- > damage to nervous system -> “leuko” -> demyelination
Obviously seen more in boys
What is Charcot’s triad of MS?
SIN
S - scanning speech (pauses between words) -> due to brainstem involvement (looks like drunkness)
I - intention tremor, incontinence (neurogenic bladder), internuclear ophthalmoplegia
N - nystagmus
How does location affect your susceptibility to MS? Who tends to get it / HLA association?
More common farther from the equator (temperate climates)
-> depends on your geographic location prior to age 15. I.e. no increased susceptibility if you lived near equator until 15 then moved to Canada.
Particularly common in Caucasian females aged 20-30 years old with HLA-DR2 (multiple hay pastures have dirt)
Why does MS cause optic neuritis but Guillain-Barre doesn’t?
Optic nerve (CN2) is the only cranial nerve innervated by oligodendrocytes (arises directly from the diencephalon) -> can be affected by demyelination of CNS / spinal cord (oligodendrocytes)
GBS will not affect CN2 but can affect all other cranial / peripheral nerves by attacking Schwann cells.
What is the role of methylprednisolone in MS?
Used to SHORTEN acute exacerbations
-> has no affect on disease progression, or SEVERITY of exacerbation, just length.
What is meant by panencephalitis in SSPE?
Viral inclusions will be seen within neurons in both gray and white matter (oligodendrocytes + neurons) -> PANencephalitis
How is A-beta amyloid formed? How is it usually cleared?
APP is normally cut by alpha-secretases
If APP is cut by beta-secretases -> Amyloid-beta fragments stay in the cell membrane and can form aggregates. This can be further processed by gamma secretases.
It is neurotoxic and usually degraded and cleared by proteosomes of astrocytes
How does the course of vascular dementia vs diffuse Lewy body disease vs Alzheimer’s differ?
Alzheimer’s - steady decline
Vascular dementia - Stepwise decline
Lewy body disease - waxes and wanes on its way down
What are the Tauopathies? Why does it precipitate?
Disorders of tau protein accumulation
-> precipitates due to hyperphosphorylation
Alzheimer’s, Pick disease, progressive supranuclear palsy
What are neurofibrillary tangles? How do they appear on electron microscopy? Does this cause the cell death?
Intracellular, hyperphosphorylated tau protein (a microtubule-associated protein) in association with other neurofilaments in the cytoplasm of neurons.
Appear as paired helical filaments on EM
Unclear if this causes cell death or is just associated with it.
What are neuritic plaques?
Also called senile plaques, they are extracellular zones of disrupted neuropil containing axons and dendrites with a Beta-amyloid core.
What is seen pathologically in Pick disease?
Frontotemporal atrophy “knife-blade atrophy”
Microscopic - “Pick bodies” - ROUND aggregates of tau protein in neurons of the cortex (vs irregular tangles of Alzheimer’s)
What are the causes of iatrogenic CJD?
Patients receiving human pituitary-derived growth hormone supplements, dural / corneal grafts, and contaminated neurosurgery instruments
What are the characteristic physical exam findings and EEG findings of CJD? MRI / CSF
Physical exam - rapidly progressive dementia with startle myoclonus
EEG findings - periodic sharp waves
MRI - enhancement of basal ganglia (startle myoclonus)
CSF - 14-3-3 protein
What occurs pathologically in Lewy body dementia?
Deposition of eosinophilic inclusions of alpha-synuclein (Lewy bodies) primarily in the cortex, causing a dementia (if Lewy bodies were in basal ganglia, it would primarily cause Parkinsonianism)
How do you tell Parkinson’s disease from Lewy body dementia?
In Parkinson’s, dementia is a late feature - typically 10+ years after clinical disease onset
In Lewy body dementia, dementia often appears before Parkinsonian symptoms (early-onset)
What treatments can slow disease progression in Alzheimer’s?
Memantine - NMDA receptor antagonist
Vitamin E - antioxidant supplementation
-> sporadic forms seem to be inflammation-mediated
What is Pick disease? What are the symptoms?
Frontotemporal dementia
Frontal lobe effects - behavioral symptoms, especially disinhibition
Temporal lobe - aphasia (language effects)
What compound is known to induce Parkinson’s and how?
MPTP - a contaminant in the production of the opiate drug MPPP
MPTP is converted by MAO-B to MPP+ in dopaminergic neurons, which is toxic and causes their death.
What is the pattern of spread of neuronal loss in Parkinson’s? What symptoms does this explain?
“Braak Stages” - Starts in medulla and moves its way up to eventually involve the cortex.
Parkinson’s development exists on a spectrum, and at least 50% of dopaminergic neurons need to be lost in order to have disease
Explains early symptoms
- > anosmia - anterior olfactory nucleus involved early
- > constipation - dorsal motor nucleus of X affected early in medulla
What are the features of postural instability in Parkinsonism?
- Flexed posture - shoulders bent over
- Festination - shuffling gait, walking forward quickly to catch weight
- Retropulsion - difficulty balancing oneself when pulled backward, need to take a few steps back (walking backward)
What is bradykinesia vs hypokinesia? When else could these occur?
Bradykinesia - Slowness of movement, also caused by psychomotor retardation or deliberate slowing if you’re ataxic
Hypokinesia - Reduction in number of movements and AMPLITUDE of movement - can also occur in lethargy or frontal akinesis
When does further expansion of the Huntington trinucleotide repeat occur?
During spermatogenesis -> leads to anticipation
What is chorea vs athetosis?
Chorea - proximal / distal rapid, dancing movements
Athetosis - snake-like, writhing, slow movements, especially of fingers
Honestly its hard to remember
Why are the symptoms of normal pressure hydrocephalus seen?
Lack of CSF resorption (chronic communicating hydrocephalus) -> ventricles expand to maintain normal pressure -> corona radiata are stretched -> wet, wobbly, wacky
Wet - Urinary incontinence
Wobbly - Ataxia - with magnetic gait
Wacky - Cognitive dysfunction
Treat with shunt.
What gene is mutated in autosomal recessive Parkinson’s inheritance and what is the clinical picture?
Parkin gene - functions as an E3 ubiquitin ligase and proteasome regulator
- Early Parkinson’s (20s) but slow progression
- Patients do NOT have Lewy bodies
What is variant CJD?
Bovine spongiform encephalopathy
-> as opposed to sporadic CJD, which is the most common form
What are common sources of metastatic cancer to the brain? Where do they appear?
Lung carcinoma, breast carcinoma, malignant melanoma
Others: Kidney, GI tract
Appear as single or multiple well-circumscribed masses at the gray-white junction
What is the most common benign CNS tumor in adults and who tends to get it? What is the cell of origin?
Meningiomas - more commonly seen in women because it expresses the estrogen receptor
Cell of origin - arachnoid cells (neural crest derived)
What is the microscopic morphology of meningioma?
Spindle cells concentrically arranged in a whorled pattern
-> also forms calcified “psammoma bodies”
What is the classic clinical presentation of oligodendroglioma and what is seen on imaging? What area of the brain is usually involved?
Clinical presentation - slow-growing tumor in young adults which may contain calcifications. Most often in frontal lobe, causing seizures.
How does pilocytic astrocytoma appear grossly and microscopically? What cell marker will be +?
Grossly - cystic lesion with nodular mass which grows adjacently on its wall.
Microscopically - Rosenthal fibers -> thick, eosinophilic aggregates of alpha-B-crystalline which accomulates in processes of astrocytes
GFAP+ since astrocyte origin
What tumor is characterized by perivascular pseudorosettes? Why does it form this pattern?
Ependymoma - tumor of ependymal cells which form rosettes around vasculature -> similar to choroid-plexus type function
Where do ependymomas tend to grow, and what is their clinical presentation?
Typically children with hydrocephalus - grows out from a stalk into the 4th ventricle, obstructing CSF flow -> symptoms of increased ICP
Has poor prognosis
What is the microscopic appearance of medulloblastoma?
Homer-Wright Rosettes - small round blue cells wrapping radially around pink neuritic processes (neuropil).
What is the origin of medullablastoma and can it metastasize?
It is an embryonal tumor of the neuroectoderm, only actual neural tumor
Disseminates into subarachnoid space and even outside CNS
Commonly a drop metastasis:
Metastasis to cauda equina -> lower spinal cord
-> spread of medulloblastoma thru CSF
What is the most common sellar tumor in children and what might it be confused with?
Craniopharyngioma - a tumor derived from Rathke’s epithelium. One of the only supratentorial tumors of children. Suspect in a child with bitemporal hemianopsia.
May be confused with pituitary adenoma -> both present with headache, hypopituitarism, and bitemporal hemianopsia (compression of optic chiasm)
What does the pathology of craniopharyngioma look like?
“Adamantinomatous” - squamous epithelium which appears cystic due to fluid accumulation between squamous epithelial cells.
Calcification is extremely common (remember pathoma’s mnemonic about this being derived from mouth and teeth have calcium).
“Wet keratin” - keratin pearls appear overly plump.
What fluid is in the cysts of craniopharyngioma and what is its prognosis?
Cholesterol crystals in a “motor oil”-like fluid
Prognosis is poor -> tumor is locally aggressive and it frequently recurs after surgery (like pleomorphic adenoma)
What are the symptoms of lateral medullary (Wallenberg) syndrome? What causes it?
Don’t pica a horse that can’t eat
-> PICA loss (branch of vertebral), hoarseness and dysphagia are major signs (loss of nucleus ambiguus)
Also loss pain from ipsilateral face, pain from contralateral body (loss of trigeminal nucleus and lateral spinothalamic tract)
Ipsilateral horner syndrome from loss of descending sympathetics
Ataxia / dysmetria from loss of ICP
What type of tumor is a pinealoma and what are its presenting symptoms typically?
Typically a germinoma which arises in the pineal gland -> can produce beta-HCG and lead to precocious puberty
Symptoms:
- Precocious puberty - as previously explained
- Parinaud syndrome - compression of rostral midbrain tectum which controls vertical gaze
- Obstructive hydrocephalus - compression of cerebral aqueduct -> papilledema, headache, vomiting
How do you determine if a lacunar stroke is due to a Charcot-Bouchard aneurysm secondary to HTN, or hypertensive arteriolar sclerosis secondary to hypertension?
Hypertensive arteriolar sclerosis - causes lipohyalinosis and progressive luminal narrowing -> will lead to ISCHEMIC stroke which does not initially appear on CT
Charcot-Bouchard - leads to HEMORRHAGIC stroke
What is Clasp-Knife spasticity and what causes it?
Increased resistance, than rapid decrease in resistance when trying to flex a joint, due to lack of UMN inhibition of reflex arch by Golgi Tendon Organ. #1687
