cns degeneration, demyelination and tumors
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Demyelinating Diseases
• Selective loss of myelina) MS is demyelinating, whereasb) necrosis, etc. is not
demyelinating• Leukodystrophies reflect inherited disturbances in formation and preservation of myelin
a) metachromatic leukodystrophyi) most common
leukodystrophyii) autosomal recessive
disorder of myelin metabolism
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- characterized by of a cerebroside
(galactosyl sulfatide) in white matter of brain and PNS
iii) predominates in infancyiv) lethal within several years
b) Krabbe diseasei) fatal, early months of lifeii) deficiency of
galactocerbroside ß- galactosidase
iii) autosomal recessivewww.freelivedoctor.comwww.freelivedoctor.com
iv) almost complete loss of oligodendroglia and myelinv) presence of gobloid cells
found around blood vessels
c) adrenoleukodystrophy (ALD)i) x-linked inherited disorder of adrenal cortex and
demyelination of nervous system
ii) children 3-10 yrsiii) levels of very long chain
FA in tissues and body fluids www.freelivedoctor.comwww.freelivedoctor.com
iv) enzyme mutation-impairs capacity to
degrade VLCFA’sv) more severe demyelination
in cortical white matter- parieto-occipital regions
d) Alexander diseasei) rare neurological diseaseii) infants and childreniii) loss of myelin in brainiv) accumulation of irregular,
extracellular fibers (Rosenthal fibers) www.freelivedoctor.comwww.freelivedoctor.com
v) psychomotor retardation, progressive dementia,
paralysis deathvi) mutation of gene encoding
GFAP Rosenthal fibers
vii) deposited around blood vessels
Multiple Sclerosis (MS)
a) chronic demyelinating diseaseb) most common chronic CNS
disease of young adults in USAwww.freelivedoctor.comwww.freelivedoctor.com
c) affects sensory and motor functionsd) acquired disease, mean age ~
30yrsi) women 2:1
e) etiology remains obscurei) genetic predisposition
f) colder climates riskg) immune factors
i) chronic MS perivascular lymphocytes,
macrophages and CD4+ and CD8+ T cells
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h) infectious agentsi) wide variety of viruses
- mumps, rubella, herpes simplex and measels
(via vaccination)I) demyelinated plaque is hallmark
of MSi) usually in white matterii) preference for optic nerves, chiasm
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iii) neurons are spared, while axons degenerate when
next to plaque!iv) MS has “focal” areas of injuryv) demyelination is complete
when in presence of plaquevi) old MS plaque exhibit gliosis (“scar”) impairs structural integrity of axons
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J) clinicali) onset 30-40 yrsii) PNS are uniformly sparediii) usually begins with
symptoms in optic nerves, brainstem or spinal cord (loss of vision in one eye usually presenting complaint)
iv) lesions in spinal cord leg weakness or numbness
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v) disease usually follows chronic relapsing and remitting course develop permanent lesions
vi) death usually from respiratory paralysis or UTI while in terminal comavii) survival 20-30 yrs
following initial symptoms• MS variants
a) neuromyelitis optica (Devic disease)
i) Asianswww.freelivedoctor.comwww.freelivedoctor.com
ii) present as bilateral optic neuritis and spinal cord involvement
iii) lesions similar to MS but more destructive - grey matter involvement
b) Acute MS (Marburg form)i) young individualsii) fulminant course over
several months
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• Acute disseminated encephalomyelitis
a) follow eitheri) viral infection orii) viral immunization
b) symptoms develop 1-2 weeks following (i or ii above) c) clinical
i) headacheii) lethargy oriii) comaiv) these occur rather than
focal findingswww.freelivedoctor.comwww.freelivedoctor.com
v) symptoms progress rapidly fatal in 20% and remaining
cases complete recovery• Acute necrotizing hemorrhagic encephalomyelitis
a) fulminant syndrome of CNS demyelinationb) usually preceded by upper respiratory infection
i) mycoplasma pneumoniaeii) most times of
indeterminate causewww.freelivedoctor.comwww.freelivedoctor.com
iii) highly fatal• Central pontine myelinolysis
a) loss of myelinb) preservation of neurons and
axonsc) believed to be caused by rapid correction of hyponatremia
i) also to extreme hyperosmolarity orii) other metabolic imbalances
d) clinicali) rapidly developing
quadriplegiaii) lesion in basis pontis
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iii) can occur during setting of:
- alcoholism- severe
electrolyte/osmolar imbalances
- orthopic liver transplantation
• Marchiafava – Bignami diseasea) rare disorder of myelin
i) corpus callosum andii) anterior commissure
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Degenerative Diseases
• Parkinson Diseasea) Common movement disorderb) Characterized by loss of neurons (substantia nigra)
i) accumulation of Lewy bodiesc) Tremors at restd) Muscle rigiditye) Expressionless
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• Epidemiologya) 6-8 decadesb) more than 2% in North
America develop diseasec) men more than womend) most cases are sporadic
i) missense mutations cause rare autosomal
dominant e) most are idiopathic, exceptions
i) induced following viral encephalitis- Von Economo
encephalitiswww.freelivedoctor.comwww.freelivedoctor.com
ii) toxin intake- MPTP (1-methyl-4-
phenyl- 1,2,3,6-tetrahydropyridine)
f) substantia nigra relays information to basal ganglia through Dopaminergic synapses
i) aging dopamineii) exaggerated in PDiii) Lewy bodies are
filamentous aggregates seen in substantia nigra
- also other areas
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iv) oxidative stress (of catecholamines) during
melanin formation injures neurons in substantia nigra
g) loss of pigmentation in substantia nigra and locus ceruleus and formation of inclusion bodies (Lewy bodies)
h) clinical:i) slowness of all voluntary movement and muscle
rigidity - disappears with usewww.freelivedoctor.comwww.freelivedoctor.com
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ii) coarse tremor of distal extremities
- at restiii) face is expressionless (mask-like)
- reduced rate of swallowing (leading to drooling)
iv) incidence of depression/dementia (~10-
15%)www.freelivedoctor.comwww.freelivedoctor.com
v) early PD tx with L-dopa- after several years
becomes ineffectivevi) neural transplantation
(dopaminergic) into striatum
vii) deep brain stimulation can provide relief of motor symptoms of PD
• Multiple system atrophya) rare disorderb) mimics PD
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c) less severe changes in substantia nigra and locus ceruleus
d) associated with Shy-Drager disease and
olivopontocerebellar atrophy (i.e., these are known as
multiple system atrophy)i) patients usually have
symptoms of both diseasese) 2 principle symptoms
i) PD www.freelivedoctor.comwww.freelivedoctor.com
ii) Autonomic dysfunction orthostatic hypotension
f) when present as isolated lesion
i) Shy-Drager ii) Striatal degenerationiii) Presentation of isolated ataxic disorder with cerebellar dysfunction olivopontocerebellar
atrophy
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• Amyotrophic lateral sclerosis (ALS)a) leads to profound weakness
and deathb) affects motor neurons of
brain and spinal cordc) worldwide disease
i) 1:100,000d) peaks in incidence in 5th decadee) ~ 2:1 incidence in menf) Guam, Papua new guinea
and parts of Japanwww.freelivedoctor.comwww.freelivedoctor.com
i) Chomoro people in Guam disease is rich in tau NFT
now classified as “neurodegerative
taupathiesg) familial cases i) autosomal dominant (gene 21q)
ii) ~ 5 % of all casesiii) missense mutation
that codes for SOD1iv) disease not due to SOD activity
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h) affects motor neurons (3 locations)
i) anterior horn cells of cordii) motor nuclei of brainstem
- hypoglossal nucleiiii) upper motor neurons of
cerebral cortexiv) loss of large motor neurons accompanied by
mild gliosis- may cause inclusions
sphenoids www.freelivedoctor.comwww.freelivedoctor.com
v) loss of pyramidal “Betz” cells in motor cortex
vi) loss of myelinated fibers in lateral corticospinal tracts
vii) anterior nerve roots are atrophic and affected
muscles are pale and shrunkenI) clinical
i) begins as weakness and wasting of muscles
- hand (often with painful cramps)www.freelivedoctor.comwww.freelivedoctor.com
- irregular rapid contractions of muscles that do not move limbs (fasciculations)
- progressive disease- speech unintelligent- respiratory weakness- intellectual capacity is
preserved- clinical course usually does
not extend beyond 10 years
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• Huntinton diseasea) inherited autosomal dominant diseaseb) progressive movement
disorders and dementiac) degeneration of striatal
neuronsd) movement disorder chorea i) jerky
ii) hyperkineticiii) sometimes dystonic
movementsiv) affecting all parts of body
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e) progressivei) course ~ 15 years
f) HD gene 4p16.3 encodes a protein
i) huntingtinii) repeat mutation (“trinucleotide” repeat
disorder)iii) greater the # of repeats
earlier onset of disease
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g) clinicali) 4-5th decade at onsetii) motor symptoms usually
precede cognitive disorders (in ~ 50% of patients)
iii) movement disorders are chorioform
- jerky, involuntary movement of all parts of body
- risk of suicide (genetic screening)
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Spinocebellar ataxias• loss of neurons and neural tracts
in cerebellum, brainstem and spinal
corda) ataxiab) intention tremorc) rigidityd) tremore) loss of deep tendon reflexes
andf) vibration sense andg) pain
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• Friedreich ataxiaa) most common inherited
ataxiab) autosomal recessivec) onset of symptoms less than
25 yearsd) hallmark is
i) combined ataxia of both upper and lower limbsii) Systemic abnormalities
of skeletal system- scoliosis- pes cavus www.freelivedoctor.comwww.freelivedoctor.com
- hypertrophic cardiomyopathy
which commonly causes death
- diabetes mellituse) genetic defect
i) chromosome 9ii) lack of “frataxin”
productioniii) triplet expansion (GAA
repeat expansion)- confirms diagnosis www.freelivedoctor.comwww.freelivedoctor.com
DEGENERATIVE DISEASES (AD) (Alzheimer Disease)• principle cause of “so-called” senility• worldwide disease• most common cause of dementia in aged
a) more than half of all cases• age prevalence
a) before age 65 years 1-2 %b) after 85 years ~ 10%c) women 2:1d) most cases are sporatici) familial variant is recognized
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e) 2 associationsi) amyloid -protein (A)
- deposition in neuritic
plaques of AD- plaques in cerebral cortex
ii) NFT
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Alzheimer Disease1.- amyloid β-protein (Aβ)
a) evidence points to in neuritic plaques of Aβi) located in cerebral
cortexii) linked to intellectual functioniii) constant feature of AD
b) neurons and glial cells also accumulate Aβ in walls
of cerebral blood vesselswww.freelivedoctor.comwww.freelivedoctor.com
2.- Neurofibrillary tangles (NFT)
a) microtubule-associated protein
i) abnormal helical form which is termed
“tau”b) in AD phosphorylation of
tau in certain areas of brain form NFT
c) mutations of tau gene on chromosome 17 causes
familial dementia and parkinsonism
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d) most cases of AD are associated with lots of LEWY bodies
e) genetic association
• Pathology of AD:a) during course of AD
i) neurons are lostii) gliosis occursiii) gyri narrowiv) sulci narrowv) cortical atrophy
- bilateral and symmetricalwww.freelivedoctor.comwww.freelivedoctor.com
b) microscopic findingsi) senile plaquesii) NFTiii) neuron lossiv) Lewy bodies and
granulovacuolar degeneration• Clinical:
a) patients usually present with:i) gradual loss of memory andii) cognitive functioniii) difficulty with languageiv) changes in behavior
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b) AD is progressivei) previously intelligent and
productive persons- become demented- mute- incontinent- bed ridden- bronchopneumonia
usually cause of death• Pick disease
a) loss of functionb) dementia
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c) difficult to distinguish from ADd) most cases are sporadice) occurs in mid adult life
i) progress to death in 3-10 yrs
f) cortical atrophyi) initially unilateral
- bilateral with progressionii) localized to frontotemporal
g) severe atrophyi) gyri reduced to thin edge
- “knife-blade” atrophywww.freelivedoctor.comwww.freelivedoctor.com
h) inclusions contain tau and argentophilic and are
referred to as “Pick bodies”i) densely aggregated straight filaments
TUMORS
• annual incidence 10-17 per 100,000a) 1-2 per 100,000 for intraspinal
• 50-75% are primary tumorsa) remainder are metastatic
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• rarely metastatic outside of CNS• classes:
a) gliomasb) neuronal tumorsc) poorly differentiatedd) meningiomas
1.- GLIOMAS (astrocytomas, oligodendrogliomas, ependymomas)
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a) Astrocytomai) fibrillary astrocytomaii) glioblastomaiii) pilocytic astrocytomaiv) pleomorphic
xanthoastrocytomav) all these have histological
characteristics, distribution, age and clinical course
vi) mean survival time is ~ 5 yrs
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A) Fibrillary astrocytomai) ~ 80 % of adult primary
tumorsii) found in cerebral hemispheresiii) 4-6th decade may occur in cerebellum, brainstem,
spinal cordiv) most common presenting
sign is- seizures- headache- focal neurological deficits
v) grading predicts prognosis- WHO classification- grades 1-4
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- low grade astrocytoma show inactivation of tumor suppressor gene p53- high grade astrocytoma
show inactivation of p53 as well
as RB gene, p16/CDKNZA gene and tumor suppressor gene
on chromosome 19qB) Glioblastoma
i) prognosis very poor- 8 to 10 months following Dx
ii) 2 distinct clinical histories
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1. - short, rapidly progressive, arising without preexisting low grade tumor - typically in older patients
(primary glioblastoma2.
- younger patients- previously diagnosed low grade astrocytoma (secondary astrocytoma)- p53 mutations
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C) Pilocytic astrocytomai) young adultsii) relatively benigniii) mainly cerebellum
- may occur in floor of 3rd ventricle, optic nerves, and
occasionally in cerebral hemispheres
iv) often cystic lookingv) grow slowlyvi) WHO grade 1vii) rare p53 mutations
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• Oligodendroglioma a) 5-10 % of gliomasb) most common in 4th and 5th decades
i) may have had many years of complaints
- seizuresc) lesions found most often in cerebral hemispheres
i) mainly white matter
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d) most common genetic defecti) involves chromosome 1
and 19qe) clinical:
i) better prognosis re: astrocytomasii) average survival 5 to 10
years
• Ependymomasa) arise next to ependyma-lined ventricular system
i) also central canal of cordwww.freelivedoctor.comwww.freelivedoctor.com
ii) first 2 decades of life- near 4th ventricle- 5-10 % of primary
tumors in this age groupiii) in adults spinal cord most
common locationb) clinical
i) posterior fossa ependymoma
- often with hydrocephalus,
secondary to obstruction, rather than invasion
ii) poor prognosis
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- CSF dissemination is common- average survival ~ 4
yearsiii) several other tumors occur
- lining of ventricles- other cells that form wall of ventricles choroid plexus (rare)
iv) benign low grade tumor- except the rare choroid plexus carcinoma
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• Subependymomasa) solid
i) sometimes calcifiedb) slow growing nodules
i) attached to ventricular lining
ii) protrude into ventricles c) usually asymptomatic
i) may cause hydrocephalusd) most often found in lateral and
4th ventriclesi) difficult to removeii) have distinct histology
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• Choroid plexus papillomas a) occur anywhere along choroid plexusb) most common in children
i) lateral ventriclesii) 4th ventricle in adults
c) usually present with hydrocephalus • Colloid cyst of 3rd ventricle
a) non-neoplastic lesionb) young adultsc) attached to roof of 3rd ventricle
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i) causes noncommunicating hydrocephalus
- may be rapidly fatald) headache (sometimes
positional) important symptom
NEURONAL TUMORS
• Several types contain mature appearing neurons (ganglion cells)
a) gangliocytoma i) comprised only of ganglion
cells
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b) more commonly exist as admixture
i) with glioma neoplasm- lesion termed
“ganglioglioma” - usually presents with seizures
c) most slow growingi) glioma part may progress
rapidlyd) dysembryoplastic
neuroepithelial tumori) low grade, distinct tumor
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ii) childhood- presents with seizures
iii) slow growth- good prognosis after Tx
iv) located- superficial temporal lobe
• Tumors with only neuronal elements
a) cerebral neuroblastomai) rareii) childreniii) hemispheres
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iv) rapid and aggressive growth
b) central neurocytomai) low gradeii) lateral and 3rd ventricle
POORLY DIFFERENTIATED NEOPLASMS
• most common is medullablastomaa) ~ 20% of brain tumors in
childrenb) exclusive to the cerebellumc) largely undifferentiated
i) glial and neuronal markers occasionally
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d) clinicali) highly malignantii) very radiosensitiveiii) prognosis also depends on amount of tumor resectediv) total resection plus
radiation- 5 year survival ~ 75 %
• Atypical teratoid/rhabdoid tumorsa) highly malignantb) young childrenc) posterior fossad) presence of rhabdoid cells is Dx
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e) clinicali) occur prior to 5 years of ageii) death within a year
following diagnosis
OTHER PARENCHYMAL TUMORS
• primary CNS lymphomasa) ~ 2 % of extra nodal
lymphomasi) ~ 1 % of intracranial tumors
b) most common CNS neoplasm in immunosuppressed patients
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c) in nonimmunosuppressed i) occurs after age 60
d) often presents at multiple sitese) extra CNS involvement is rare
i) denotes late stageii) NHL arising outside CNS rarely invades brain parenchyma
f) majority are B-cell origini) in immunosuppressed
patients all neoplasms appear to
contain EBV genome
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g) very aggressivei) poor response to treatment compared to peripheral lymphomas
• Germ cell tumorsa) primary brain germ cell tumor
i) most commonly occur along midline
- pineal- suprasellar
b) young (90% in first 2 decades) www.freelivedoctor.comwww.freelivedoctor.com
c) teratomasi) most common tumor that
- presents as congenital tumor
d) in pineal regioni) male predominanceii) not seen in suprasellar
region as male predominance
e) unlike lymphomasi) CNS germ cell tumors not uncommon
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ii) similar classification to seminoma in testis
- termed “germinoma”• pineal parenchymal tumors
a) arise from pineocytesb) differentiation
i) well – pinocytomaii) undifferentiated (high
grade)- pineoblastoma- highly aggressive- more common in children- in pts. with
retiniblastoma
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c) Gliomas also found in pineal region
• meningiomaa) benignb) occur in adultsc) usually attached to durad) clinical
i) slow growingii) uncommon in childreniii) small female
preponderance- 3:2- 10:1 with spinal
meningioma
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• metastatic tumorsa) mostly carcinomas
i) 25-50 % of hospitalized patients
b) sites (accounts for 80% of all metastatic tumors)
i) lungii) breastiii) skin (i.e., melanoma)iv) kidneyv) GI
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c) meninges frequent site of metastatic tumorsd) present as mass lesion
• paraneoplastic syndromesa) major underlying mechanisms
i) systemic development of immune response
against tumor antigenb) may be T-cell mediated
neuronal injury in some settings www.freelivedoctor.comwww.freelivedoctor.com
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BOARD QUESTIONSBOARD QUESTIONS
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Which of the following disorders affecting myelin is most likely to be found in a 30-year-old woman? (A) multiple sclerosis (B) Krabbe disease (C) Alexander disease (D) metachromatic leukodystrophy
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A disease characterized by widespread patches of demyelination with less prominent axis cylinder destruction and glial overgrowth is (A) syphilis (B) poliomyelitis (C) multiple sclerosis (D) pernicious anemia (E) amyotrophic lateral sclerosis
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Reactive astrocytes surrounding eosinophilic fibers radiating from a central core which stains for amyloid is characteristic of (A) Alzheimer disease (B) amyotrophic lateral sclerosis(C) olivopontocerebellar atrophy (D) Parkinson disease (E) Wilson disease
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Lewy bodies are most commonly encountered in
(A) idiopathic Parkinsonism (B) post-encephalitic Parkinsonism (C) rabies (D) Tay-Sachs disease (E) herpes simplex encephalitis
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The most radiosensitive primary intracranial neoplasm is (A) ependymoma(B) glioblastoma(C) medulloblastoma (D) oligodendroglioma
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A child presents with nausea and vomiting, a recent onset of ataxia, and a posterior fossa tumor. The most likely diagnosis is (A) craniopharyngioma (B) medulloblastoma (C) meningioma (D) neuroblastoma (E) pinealoma
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