Neuro 3 Flashcards
What are the demyelinating diseases
MS, neuromyelitis optica, acute disseminated myeloencephalitis, acute necrotizing hemorrhagicmyeloencephalitis, central pontine myelitis
In demyelinating disease the _ is damaged and the _ is not
Myelin
Axon
White matter or gray matter is damaged by autoimmune MS
White
Where are plaques in MS
Periventricular white matter
Characterization of MS
Distinct episodes of neurologic deficits separated in time due to white matter lesions that are separated in space with varying lengths between them with recovery but overall get decline.
NEED ultiple episodes of neurological deficits to diagnose MS
What is the most common demyelinating disease
MS
Men or women get MS more
Women
Onset of MS
Children
Over 50 is rare
Why get MS
Env and genetic
15x greeter if 1st degree relative
DR2 MHC DRB1*1501 3x
In MS how i myelin attacked
TH1 TH17 against myelin antigens
The plaque haas CD4 8 and macrophages
Describe an MS lesion
Firm, circumscribed, depressed glassy grey tan irregularly shaped plaqu next to lateral ventricles, optic nerve, brainstem, ascending tracts, cerebellum and spinal cord
SHARPLY DEFINED BORDERS
Describe an active plaque
Myelin breakdown, macrophages containing lipid rich PA positive debris
Perivascular cuffs of lymphocytes and monocytes
Near small veins
Gliosis
Describe inactive plaques
Inflammatory cells mostly gone
No myelin
Axons and oligodendrocytes numbers are reduced leading astrocytes proliferation and gliosis
What is a shaddow plaque
Border between normal and affected white matter is not well defined bc some remyelinationof sirvuvung oligodendrocytes
Clinical presentation of MS
OPTIC NEURITIS-unilateral visual disturbances
MULTIPLE episodes of neurologic deficits
INO from MLF damage
Cranial nerve signs, ataxia, nystagmus, spinal cord lesions(motor and sensory disturbances), spasticity, bladder
CSF MS
Elevated protein
Some increase WBC
IgG up oligoclonal bands (active B cell zones (self reactive)
Neuromyelitis optica
Bilateral optic neuritis and spinal cord demyelination with poor recovery from first attack
Neuromyelitis optica women or men
Women
Characteristic sign of neuromyelitis optica
Antibodies to aquaoprin 4 which is the water channel of astrocytes
And
Necrosis, neutrophils and vascular deposition of Ig and complement in white matter
CSF neuromyelitis optica
White cells and neutrophils up1
Acute disseminated encephalomyelitis
Acute, immune, similar to MS, in young, abrupt onset may be rapidly fatal
Monophasic demylinating disease
What causes acute disseminated encephalomyelitis
1-2 weeks After antecedent infection or viral infection or viral immmunization
Presentation of acute disseminated encephalomyelitis
Diffuse..headache, lethargy, coma
Difference between MS and acute disseminated encephalitis symptoms
Ms focal ADME diffuse
Prognosis acute disseminated encephalomyelitis
20% die rest fully recover
Morphology acute disseminated encephalomyelitis
Grey vessels in white matter Myelin lost axon ok Early-neutrophils Later-mononuclear Abundant lipid laden macrophages from myelin breakdown
All lesions look similar MONOPHAsiC
Acute necrotizing hemorrhagic encephalomyelitis (of Weston hurst)
Sudden, fulminant CNS demyelination
Who gets acute necrotizing hemorrhagic encephalomyelitis
Kids young adults
What causes acute necrotizing hemorrhagic encephalomyelitis
Preceded by URI or unknown cause
Prognosis acute necrotizing hemorrhagic encephalomyelitis
Fatal and survivors have lasting effects
FULIMEND of adem
Morphology acute necrotizing hemorrhagic encephalomyelitis
Around vessels like ADEM but more severe-kills the vessels
Necrosis of grey and white matter with acute hemorrhage, fibrin deposition and lots of neutrophils
Scattered lymphocytes
Central pontine myelinolysis/osmotic demyelination disorder
Acute. Symmetric los of myelin in basis pontis and pontine tegmentum
What causes central pontine myelinysis
Rapid increase in osmolarity 2-6 days after hyponatremia correction
Associated with severe electrolyte imbalances (imbalance kill oligodendrocytes)
WATER INCREASE!!! Cerebral edema espicially in white matter
What is spared in central pontine myeliniolysis
Perivascular
Prognosis central pontine myelinolysis
Rapid quadriplegia white may be fatal or locked in syndrome
How does tau aggregation cause neurodegenerative disorders
Loss of function bc depletes neurons of tau but also toxic gain of function as hyperphosphorylated tau aggregate protein in the neuron
What is the most common dementia in older adults
Alzheimer’s
Clinical presentation AD
Insidious impairment of higher cognitive functions
Then deficit sin memory, visuospatial orientation, judgement, personality and language
How long does it take for AD patient to become very disabled
5-10 years
Fundamental cause of AB
AB then tau tangles plaques from excessive production inefficient removal
What causes AB aggregates
APP is cleaved by a secretase and then y -> soluble nontoxic fragment
But
APP cleaved by B secretase then y secretase-> AB peptides that aggregate and form the amyloid cores that elicit a microglial and astrocyte can’t response to form neurotic plaques
Where do AB aggregate? Where do tau aggregates?
Neuropil
Intracellulary(remain after death)
What is the problem with AB and tau aggregates
Stress response, directly toxic to neurons, behave like prions
What disease are only associated with tau and not AD
Frontotemporal lobar degeneration
Progressive supranuclear palsy
Corticobasal degeneration
Genetics of AD
Genetic defects in APP protein , protease complex, trisomy 21 (APP on chronometer 21)APOE on 19, E4 (E2 protective)
The __ reaction in AD caused by protein aggregates by microglia and astrocytes to remove protein also damages everything around it and may lead to tau becoming aggregated
Inflammation
What is tau
Microtubule binding protein causes tangles
What factors determine bad prognosis for AD
Cognitive-TAU tangles (more) and AB plaques (more so that senile plaques)
Tangles more that AB
Loss of choline acetyltransferase, synaptophysin immunoreactivity and amyloid burden
Biomarkers for AD
AB with 18-F labeled amyloid binding compounds
Increased phosphorylated tau and decreased AB in CSF
Why get hydrocephalus ex vacuo with AD
Compensatory ventricular widening from variable cortical atrophy with widening of the sulci espicially the frontal temporal and parietal lobed
What part of the brain is effected first in AD and what symptoms does this cause
Medial temporal lobe (hippocampus, entorhinal cortex, amygdala)
MEMORY
What area of the brain do plaques and tangles stay away from
Primary motor and sensory cortices
What is a neurotic senile plaque
AB40 and 42
What is a diffuse plaque
AB42
What is a diffuse plaque
AB with surrounding neurotic processes, in cerebral cortex, basal ganglia, and cerebellar cortex. Early phase of plaque development
What is the difference between AB40 and 42
Same N terminus and differs in length by 2 aa at C terminus
Describe a plaque
Focal, spherical dilation of tortuous neuritis processes (dystrophic neuritis) that surround a central amyloid core. May be clear halo around
What is in periphery of plaques
Microglial cells and reactive astrocytes
What can you stain amyloid core with to see AB
Congo red
Describe a tangle
Tau bundles of filaments in cytoplasm that displace or encircle the nucleus of the neurons
Elongated flame shape in pyramidal cells and are rounder (globose tangles ) in runner cells
Visible as basophils fibrils with HE staining or silver staining
In entorhinal and pyramidal cells of hippocampus amygdala, basal forebrain and raphe nuclei
Ghost or tombstone tangles
Insoluble and resistant to clearance in Vito and remain visible in tissue sections after death of parent neuron
Who has cerebral amyloid angioplasty
AD but not all people with CAAhave AD
What is cerebral amyloid angiopathy
Bleeding into peripheral cortex
Vascular amyloid AB40
Genetic cerebral amyloid angiopathy
E2 and E4 (E2 is protective AD)
Clinical cerebral amyloid angiopathy
Slow progression takes 10 yearshistology in advance of symptoms 1-memory problems 2.lanuage and math skills 3. Motor skills 4. Can’t walk, incontinent mute
What kills people with cerebral amyloid angiopathy
Pneumonia
Frontotemporal lobar degeneration
TAU, focal degeneration of frontal and/or temporal lobes
Clinical frontotemporal lobar degeneration
Changes in personality, behavior, and language BEFORE memory change (AD is memory first)
Only some get extrapyramidal motor loss
Frontotemporal lobar degeneration occurs at the same frequency as AD under _
65
What do aggregates in frontotemporal lobar degeneration look like
Some like tangles in AD some smooth contoured inclusions known as Pick bodies
Characteristic of frontotemporal lobar degeneration for pick disease version
Pick bodies andstereotypic lobar restriction
What allows tau to bind each other
Hyperphosphorylation
What causes tau to aggregate genetically
More phosphorylation genetic mutation
Genetic change in tau isoform leading to aggregation
FTLD-tau atrophy vs Alzheimer’s disease degeneration
ATLD-tau-frontal and temporal lobes , maybe nigra
AD-medial temporal lobe without frontal lobe involvement
Signs of atrophy in FTLD-tau
Neuronal loss, gliosis, presence of tau containing tangles (but to AB)
Pick disease
Best known FTLD-tau
Similar to AD but less memory loss more behavioral changes
Pick disease morphology
Asymmetric atrophy of frontal and temporal lobes that spreaders the posterior 2/3 of superior temporal gyrus
-knifelike gyrus atrophy of frontal and temporal lobes and relative sparing of parietal and occipital lobes
In pick disease where is neuronal loss most severe
Outer 3 layers of cortex
What do surviving neurons in pick disease look like
Swollenpick cells
Or
Some contain pick bodies (cytoplasmic, round/oval , filamentous, stein well with silver, weakly basophils)
FTLD-TPD43
Initial behavior or language not memory TPD43 aggregates(RNA binding protein)
Genetics for FTLD-TPD
Hexanucleotide repeat in 5’ UTR of C9orf72(also ALS associated)
Gene encoding progranulin (not ALS, it expressed in glia and neurons and is linked to inflammation)
Morphology TDP43
Atrophy of frontal and temporal lobes(striatum and dentate gyrus)
TPD which is normally in nucleus will be in nucleus, cytoplasm, or neuritis and i phosphorylated and ubiquinated
UBIAUINATED AND PHOS
*strong association of needle like nuclear inclusions and progranulin mutation
Parkinson Disease
Hypokinetic movement form loss of dopaminergic neurons from substantia nigra, but the pathogenesis of the disease starts in the brainstem and then moves to the cerebral cortex
How diagnose parkinson disease
Symptomatic L DOPA response decreases over time
Central triad of PD
Tremor, rigidity, and bradykinesia in absence of toxic or known underlying etiology
Clinical features PD
Diminished facial expression (masked fancies), stooped posture, slowing of voluntary movement (bradykinesia), destinations gait(short fast seps), pill rolling tremor, rigidity
In PD clinical features are directly proportional to __ defiency
Dopamine
What increases risk of PD whatdecreases risk of PD
Pesticides
Nicotine and caffeine
Morphology PD
Protein accumulation and aggregation, mitochondrial abnormalities, and neuronal loss in substantia nigra
Lewy body
What is diagnostic hallmark ofPD
Lewy body, of which a synuclein is a major component
Inheritance of PD when a synuclein is mutated or amplified
AD 4q21
Gene dosage effect
(A synuclein is an abundant lipid binding protein normally associated with synapses
Most common genetic cause of PD
Mutated LRRK2
Also seen in sporadic
How does PD spread
A synuclein like prion
Genetic mitochondrial PD problem
AR defect in DJ-1, PINK1 and parkin
What does DJ1 do
Goes to mitochondria to protect it from damage when oxidative stres
PINK1
Kinase that is degraded in the mitochondria and when there are problems with the mitochondria recruit parkin to help clear the bad mitochondria through mitophagy
What is parkin
E3 ubiquitin ligase
PD morphology
Pallor of substantia nigra and locus ceruleus from loss of pigmented catacholaminergic neurons
Lewy bodies in neurons and may contain a synuclein
Lewy bodies in PD
In remaining neurons and are cytoplasmic, eosinophilia, round to elongated, dense core and pale halo
Densely packed in the core but then taper out towards the edges and contain a synuclein
Found in basal nucleus of meanest which is also depleted of neurons (espicially in patients with cognitive decline)
Areas of neuron loss also show gliosis
Parkinson and dementia
10-15% of patients with PD get dementia
With fluctuating course, hallucinations and frontal signs
Get evidence of AD
FROM LEWY BODIESSSSS in cortex and brainstem and spreading (prion)
Composition of Lewy bodies
A synuclein
Cortical Lewy bodies in dementia
Less distinct that’s brainstem but have same composition of a synuclein
Lewy neuritis
Abnormal neuritis that stain positive with immunohistochemical techniques for a synuclein protein aggregates
What are the atypical Parkinsonism syndromes
Progressive supranuclear palsy
Corticobasal degeneration
Multiple system atrophy
Progressive supranuclear palsy
TAU
Progressice truncus rigidity, disequilibrium with falls, and difficulty with voluntary eye movements
Also nuchal dystonia, pseudobulbar palsy, and a mild progressive dementia
Onset of progressive supranuclear palsy
40-60
Prognosis progressive supranuclear palsy
5-7 years you will die
Hallmark of progresssive supranuclear palsy
Presence of tau containing inclusions in neurons and glia
Progressive supranuclear palsy morphology
Widespread neuronal loss in the globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter, and dentate nucleus of the cerebellum
Globose fibrillary tangles
In progressive supranuclear palsy
They are found in affected regions (neurons and glia)
In progressive supranuclear palsy what are straight filaments
Straight filaments composed of 4R tau (tau for tangles)
Corticobasal degeneration
TAU
Extrapyramidal rigidity, asymmetric motor disturbances (jerking) and impaired higher cortical function
Later in course get cognitive decline
PSP and CBD
PSP-greater burger of tau containing lesions in brainstem and deep gray matter
CBD0balance is shifted more toward cerebral cortical involvement
Multiple system atrophy
Sporadic disease that affects several functional systems in the brain
Hallmark of multiple system atrophy
Cytoplasmic occlusions of a synuclein in oligodendrocytes
Glial cells affected and loss of white matter tracts
Neuronal degeneration but no inclusion
What ar the neuroanatomical circuits effected by multiple system atrophy
Striatonigral circuit (parkinsoiasm) Olivopontocerebellar (ataxia) Loss of AND function (ORTHOSTATIC HYPOTENSION)
Pathogenesis of multiple system atrophy
A synuclein is major component of the inclusions
O genetics but polymorphism near gene increase risk
When a synuclein is in oligodendrocytes what happens
More sensitive to oxidative stress
Morphology multiple system atrophy
Regions of the inclusions in effected regions
AND problems from catecholaminergic neurons lost in medulla and intermediolateral cell column of the spinal cord
Diagnosis of multiple system atrophy
Glial inclusions found in oligodendrocytes and contain a synuclein and ubiquitin with silver stains
Huntington disease
AD progressive movement disorder and dementia that is caused by degeneration of striatum neurons
Clinical symptoms Huntington
Jerky, hyperkinetic, dystonia, (CHOREA)
Can get bradykinesia and rigidity in latera years
Prognosis Huntington
Fatal 15 years
How get huntington
Polyglutamate trinucleotide repeat expansion disease (CAG repeats at N terminus) of HTT gene on chromosome 4p16.3 that encodes Huntington
More repeats earlieronset
Anticipation
Repeat expansion of HTT occurs during spermatogenesis so that paternal transmission is associated with early onset
Is there sporadic Huntington’s disease
No
Huntington is a _ of function
Gain
Hallmark of HD
Intranuclear inclusions of the mutated Huntington and may look like prion
Also have mitochondrial and oxidative stress and brain derived neurotrophic factor (growth factor) pathways may also be associated with HD
What atrophies in huntington
Caudate nucleus, putamen, globus pallidus, frontal lobe, dilated lateral and third ventricle
What ventricles are dilated in huntington disease
Lateral and third
Caudate nucleus and huntington
Loss of striatum neurons, espicially in the caudate nucleus (espicially the tail and next to the ventricles)
In Huntington, medial to lateral pathological changes happen in the __ and dorsal to ventral in the ___
Caudate
Putamen
In huntington what is the best preserved portion of the striatum
Nucleus accumbens
Striatum huntington
Small neurons lost first followed by the large neurons
Medium spiny neurons using GABA, encephalitis, dynorphin, and substance P are espicially affected
In huntington neurons that are diaphorase-positive that express NO synthase and cholinesterase positive neurons are __
Spared. Both appear to serve as local ninterneurons
There is a direct relationship between the amount of ___ degeneration and clinical signs and symptoms of Huntington
Striatum
Clinical features of Huntington
Choreoathetosis (loss of medium striatum neurons) dysregulation of the basal ganglia (cant dampen motor systems
Jerky involuntary movements of all parts of the body
PD vs HD
PD loss of initiation
HD loss ofinhibition
HD affects mainly the __ ___ and __ __
Caudate nucleus
Basal gangli
Why get cognitive changes with huntington
Loss in cortexwhich begins with forgetfulness and eventually leads to full dementia
Age onset HD
40-60
Causes of death from HD
Suicide but most commonly infection
Spinocerebellum ataxia
Group of genetic disorders that present with signs and symptoms involving the cerebellum (progressive ataxia), brainstem, spinal cord, and peripheral nerves
Characterization of spinocerebellum ataxia
Neuron loss and secondary loss of the corresponding white matter tracts all leading to progressive ataxia
Genetics spinocerebellum ataxia
Polyglutamine diseases, CAG expansion leading to intranuclear inclusions in the neurons
SCA1, 2, 3, (machado-Joseph disease) SCA6, SCA7 (visual impairment too) SCA17
And dentatorubropallidoluysian atrophy DRPLA
Genetic SCA Expansion of non coding region repeats in spinocerebellum ataxia
SCA8, 10, 12, 31, 36
Genetic SCA point mutations
10 more types code for proteins that are expressed extra neuronally
Friedreich ataxia clinical
Progressive ataxia, spacicity, weakness, sensory neuropathy, and cardiomyopathy
Onset friedreich ataxia
First decade with gait ataxia then hand clumsiness and dysarthria, depressed/absent DTR (extensor plantar reflex is typically present), impaired proprioception/vibration, sometimes loss of pain/temp
Prognosis friedreich ataxia
Pens cavus and kyphoscoliosis and are wheelchair bound within 5 years
Won’t live past 50
Death cause of friedreich ataxia
Cardiomyopathy
__ is found in 25% of patients with friedreich ataxia
Diabetes
Genetics friedreich ataxia
AR
Expansion GAA in the intron for the mitochondrial protein frataxin (9q13)
What is frataxin
Inner mitochondrial membrane protein involved with oxphos
Oxidative damage friedreich ataxia
More free fe in mitochondria with less frataxin that can lead to more oxidative damage
Morphology friedreich ataxia
Loss of axons and gliosis in the posterior columns, corticospinal tracts, and the spinocerebellum tracts which accounts for loss of pan/temperature and motor disturbances
What is there degeneration in in friedreich ataxia
Neurons in spinal cord (Clarke column), CN nuclei VIII, X, and XII, the cerebellum (dentate nucleus and purkinje cells o the superior vermis), and the beta cells of the motor cortex
Dorsal root ganglion friedreich atazia
Ganglion cells decreased in number and there is loss of their white matter tracts
Heart and friedreich ataxia
Cardiomyopathy
Enlarged and may have pericardial adhesions
Multifocal destruction of myocardial fibers with inflammation and fibrosis
Ataxia telangiectasia
AR
Ataxic-dyskinetic syndrome that begins early childhood (dilated small BV like rosacea)
Subsequent development of telangiectasis in conjunctiva and skin and immunodefiency
Genetic ataxia telangiectasia
ATM gene is mutated (11q22-q23)
What does ATM encode
DsDNA break repairs Facilitation of apoptosis Maintence of telomeres Mitochondrial homeostasis Response to oxidative stress Maintence of the ubiquitin-proteosomal degradation system
ataxia-telangiectasia problems are mainly from what
Cerebellum with loss of purkinje and granule cells
Also degeneration of dorsal columns, spinocerebellum tracts, anterior horn cells and a peripheral neuropathy
Telangiectasia lesions are found in the __, __ and __
CNS, conjunctiva, and skin of face/neck/arms
And pituicytes
These are called amphicytes
Lymph nodes ataxia telangiectasia
Thymus, gonads are hypoplasia fro IMMUNODEFIENCY
Clinical features of ataxia telangieectasia
Initial signs and symptoms include cinopulmonary infections and unsteady walking
Speech then becomes dysarthria and there are eye movement issues
Many patients develop lymphoid neoplasms, commonly T cell leukemia
Progressice and leads to death in 20s
Amyotrophic lateral sclerosis (ALS)
Progressive disease that is marked by loss of upper motor neurons in the cerebral cortex and lower motor neurons int he spinal cord and brainstem often in association with evidence of toxic protein accumulation
ALS is a purely __ disease
Motor
In ALS what leaves to muscle enervation
Neuron loss
Familial ALS accounts for what percent of ALS and how is it inherited
20%
AD
Males of females ALS
Males
Onset of ALS
50
Genetics ALS
AV4 mutation of SOD1 is most common (rapid progression doesn’t affect UMN)
Mutation of C9orf72, TDP43, or FUS can lead to FTLD and ALS
Morphology ALS
Anterior roots of the spinal cord are thin from loss of LMN fibers, loss of anterior horn neurons and reactive gliosis
Precentral gyrus (primary motor cortex) may be strophic in espicially severe cases
Neuron loss and gliosis in the hypoglossal, amniguus, and motor trigeminal nuclei and the remaining neurons show PAS positive cytoplasmic inclusions called burina bodies
Loss of UMNs leads to loss of the. CST
Muscles show neurogenic atrophy (loss LMN innervation)
Precentral motor gyrus is atrophied in severe cases
Clinical features ALS
Asymmetric weakness of hands , cramping/spasticity of the arms and legs
With time muscle strength and bulk decreases and fasciculations begin
Eventually affect the respiratoy msucles leading to recurrent bouts of pulmonary infections
Most patients of ALS have both _ and _ involvement
UMN
LMN
Primary lateral sclerosis
Mostly UMN
Progressive muscular atrophy
Mostly LMN involvement
Progressive bulbar palsy (bulbar ALS)
Brainstem cranial nerve nuclei degeneration occurs early and progresses rapidly
Problems with deglutition and phonation dominate and patients die in 1-2 years
Bulbar =brainstem
ALSneurons with extraocular muscles are the last to be affected
CNIII, SOIV, LRVI
When can ALS look like FTLD
Cerebral decline
Spinal and bulbar muscular atrophy (Kennedy’s disease
X linked polyglutamine repeat expansion in the androgen receptor gene
Characterization of spinal bulbar muscular atrophy
Distal limb amyotrophic and bulbar signs like atrophy and fasciculations of the tongue and dysphagia, associated with degeneration of lower motor neurons in the spinal cord
Androgen receptor and spinal and bulbar muscular atrophy
Androgen insensitivity, gynecomastia, testicular atrophy, oligospermia-related to androgen receptor
Intranuclear inclusions of spinal and bulbar muscular atrophy Kennedy
Contain androgen receptor
Damage from spinal and bulbar muscular atrophy
From androgen binding to the bad receptor and subsequent binding to DNA
Spinal muscular atrophy
Group of genetically linked childhood diseases with marked loss of LMN that result in progressive weakness
Spinal muscular atrophy type 1 (werdnig Hoffman disease)
Most severe with onset in 1st year and dead by 2
Spinal muscular atrophy type II (kugelberg-welander disease)
Motor problems appear in latera childhood and adolescence
In spinal muscular atrophy II, signs and symptoms are directly related to what
Amount of SMN protein
In spinal muscular atrophy type II, patients have decreased what
Nuclear puncta containing SMN
Neuronal storage disease
AR accumulation of missing enzyme substrate in the lysosomes leading to neuronal death, loss of cognitive function, and seizures
Tau sachs
Sphingolipids
Neimann pick
Gangliosides
Mucopolsaccharidoses
Mucopolysaccharides or mucolipids
Cerio lipofuscinoses
Lipid pigments accumulate in neurons that lead to blindness, cognitive and motor detonation and seizures
Leukodystrophies
Inborn errors of metabolism involving lysosomal or perxisomal enzymes that affect white matter extensively and cause myelin loss and abnormal accumulations of myelin from failure of generation, maintence, or catabolism of myelin
Leukodystrophies
AR, diffuse involvement of white matter leading to deterioration in motor skills, spasticity, hypotonia, or ataxia
Presentation of leukodystrophies
Insidious and progressive loss of cerebral function
Present at younger ages
Associated with diffuse and symmetric changes on imaging studies
There are no discrete plaques of demyelination
Krabbe disease
AR leukodystrophy resulting from a defect in galactocerebroside B-galactosidase (galactosylceramidase)
Normal galactocerebroside from galactocerebroside B galactosidase
Turns to ceramics and galactose
Krabbe disease galactocerebroside
Shunted to an alternate pathway to make galactosylsphingosine
Accumulation of galactosylsphingosine
Cytotoxic/neurotoxic
Symptoms krabbe disease
Rapidly progressive motor signs of stiffness and weakness that appears between 3-6 m of life
Prognosis krabbe
Death by 2
Morphology krabbe
Brain and peripheral nerve cells show a loss of myelin and cells that make it, while the neurons and axons are spared
Diagnostic features
Aggregations of engaged macrophages called globose cells in the brain parenchyma and around blood vessels
Metachromic leukodystrophy
AR leukodystrophy that comes from a defiency of lysosomal enzyme arylsulfatase A
What does arylsulfatase do
Cleaves sulfatides (sulfate containing lipids) as the first step in their degradation
Accumulation of sulfatides in metachromic leukodystrophy (espicially cerebroside sulfate)
Leads to inhibition of oligodendrocytes differentiation and elicits an inflammatory response throughout the white matter.
Morphology metachromic leukodystrophy
Demyelination gliosis and macrophages with vacuolated cytoplasm scattered throughout the white matter
The vacuoles contain complex crystalloid structures composed of sulfatides
Metachromatic leukodystrophydiagnosis
Toluidine blue since sulfatides use metachromasia to shift the absorbance spectrum of the dye and can be found in peripheral nerves and urine
UA
Adrenoleukodystrophy
X linked recessive leukodystrophy that is from a mutation in the ATP binding cassette transported family proteins ABCD1 that transports molecules into the peroxisome
Who gets adrenoleukodystrophy
Young males
Presentation of adrenoleukodystrophy
Young males present with behavioral changes and adrenal insuffiency (kennedy disease also has dysregulation of the adrenal receptor signaling )
Characterization of adrenoleukodystrophy VLCFA
Inability to break down very long chain fatty acids within peroxisomes leading to elevated serum VLCFA
Progressice loss of myelin in the CNS and PNS , gliosis, and lymphocyte infiltration
Morphology in adrenoleukodystrophy
Of adrenal cortex with VLCFA accumulation in remaining cells of adrenal gland
Adrenomyeloneuropathy
More mild allergic form can happen in females and males
Pelizaeus Merzbacher disease
Defec in gene coding for myelin formation
Alexander Disease
Defect in intermediate filament proteins like GFAP
Vanishing white matter leukoencephalopathy
Defect in genes for subunits of translation initiation factor elF2B
Mitochondrial encephalopathies
Disorders of oxidative phosphorylation
Gray matter is more severely affected than white matter (related to metabolic demands)
Heteroplasmy
There can be god and bad mitochondrial in each cell and the ratio of them depends on what the severity will be for each cell
Seen in mitochondrial disease
Mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes (MELAS)
Recurrent episodes of acute neurological dysfunction, cognitive changes, and evidence of muscle involvement with weakness and lactic acidosis
MELAS stroke like symptoms are associated with __ deficits that do not correspond with discrete vascular areas
Reversible
MELAS mutation
MTTL1 gene encoding mitochondrial tRNA leucine
Areas of infarction MELAS
With vascular proliferation and focal calcification
In MELAS both neurons and vascular smooth muscle cells have altered expression of ___ __ ___, evading to metabolic disturbance
Cytochrome c oxidase
Myoclonus epilepsy and ragged red fibers (MERRF)
Maternally transmitted, myoclonus, seizure disorder, myopathy, ragged fibers in the muscle and ataxia
Genetic MERRF
Associated with mutations in tRNAs other than MELAS ones
Leigh syndrome
Infancy that causes death in 1-2 years
Clinical Leigh syndrome
Lactic academia, arrest of psychomotor development, feeding problems, seizures, extraocular palsies, and weakness with hypotonia
Morphology Leigh syndrome
Symmetric brain destruction with a spongiform appearance and a proliferation of blood vessels (espicially in the thalamus, brainstem nuclei, and hypothalamic)
Genetics Leigh syndrome
Mutations in OxPhos system
Clinical vignette Leigh syndrome
1 year old lactate plasma increased plasma lactate
Muscle strength poor
Brain MRI multifocal abnormalities with loss of tissue in periventricular regions of midbrain pons medulla
Thiamine B1 defiency /wernicke encephalopathy
Acute appearance of psychotic symptoms and ophthalmoplegia
Are wernicke symptoms reversible
If treated early , but if left untreated can lead to korsakoff syndrome which is marked mainly by problems in short term memory and confabulation
Who gets wernicke
Chronic alcoholics, gastric carcinoma, chronic gastritis, persistent vomiting
In wernicke where are there foci of hemorrhage and necrosis
In mammillary bodies and the walls of the 3rd and 4th ventricles
Morphology wernicke
Foci of hemorrhage and necrosis in mammillary bodies and the walls of the 3rd and 4th ventricle
Early on there are lesions with dilated capillaries that become leaky to create the hemorrhagic area
Eventually macrophages come in and create a cystic space with hemosiderin macrophages
These spaces are then chronic and lead to problems, espicially in the dorsomedial nucleus of the thalamus (9for memory and confabulation)
Vitamin B12 defiency
Subacute combined degeneration of the spinal cord of both ascending and descending spinal tracts from a defect in myelin formation
Symptoms b12 defiency
Over a few weeks with initial slight symmetrical numbness and tingling leading to spastic weakness int he lower extremities, with quadriplegia occurring if there is not prompt treatment
Morphology b12 defiency
Swelling in myelin layers that produces vacuoles and eventually the axons will die off
Prognosis B12 defiency
Good with supplementation but gets worse as the disease progresses
Pernicious anemia /macrocytic anemia
B12 defiency from chronic gastritis, IF defiency, poordiet
Hypoglycemia and the brain
Initial-selective injury to large pyramidal neurons in cerebral cortex that can lead to pseudolaminar necrosis (espicially deeper layers) in severe cases
Can also be damage to the sommer sector (CA1) of the hippocampuswith loss of the pyramidal neurons and loss of purkinje calls of the cerebellum-theses are very sensitive neurons
More widespread with more neuron loss
Hyperglycemia is caused by what
Most commonly from uncontrolled diabetes melitus
What is hyperglycemia associated with
Ketoacidosis or hyperosmolar coma
Hyperglycemia symptoms
Does not effect brains tructure, but can lead to severe dehydration that leads to confusion, stupor, and coma
Rehydration consideration with hyperglycemia
Slowly or get cerebral edema
Hepatic encephalopathy
From impaired liver function
Elevated ammonia and inflammatory cytokine levels lead to astrocyte with enlarged nuclei an minimal reactive cytoplasm (ADII cells) which are found mainly in cerebral cortex and the basal ganglia
Carbon monoxide why toxic
Lack of O2 binding to heme, but also may inhibit cytochrome C oxidase in OxPhos
Injury from CO
Selective injury to neurons in layers III and V, sommer sector of the hippocampus CA1 and purkinje cells(very sensitive)
Also bilateral necrosis of the globus pallidus
Also demyelination of white matter tracts
Methanol toxicity
Mostly affects the retina by killing off the retinal ganglion cell to cause blindness, but there can also be bilateral necrosis of the putamen and foal white matter necrosis
How does methanol damage
Don’t by metabolite of methanol called formate (formic acid) when ingesting something like moonshine
Methanol->formic acid+formaldehyde
Ethanol (from nutritional aspects) causes what
Cerebellar dysfunction occurs in about 1% of chronic alcoholics that results in atrophy and loss of granule cells in the and anterior vermis of cerebellum (—>ataxia)
Severe ethanol toxicity
Loss of purkinje cels and proliferation of hte adjacent astrocytes (Bergman gliosis) in the cerebellum
Clinical ethanol toxicity
Patient will rpesent with truncated and gait ataxia, unsteady gait, and nystagmus
Clinical vignette ethanol
Alcohol abuse, severe and constant motor problems over the past 5 years
Radiation toxicity
High levels can cause intractable nausea, confusion, convulsions, and rapid onset of coma and then death
Clinical delayed effects of radiation
Headaches, nausea, vomiting and papilledema and can happen years after exposure
Years after radiation
Sarcomas, gliomas, and meningiomas can appear
Pathology radiation
Large areas of coagulation necrosis, primarily in the white matter and edema int he surrounding tissue
There will be vascular fibrinoid necrosis and eventual sclerosis
Exposure of methotrexate at the same time as radiation
Can exacerbate the problems and are often seen adjacent to the lateral ventricles but can be seen throughout the white matter and brainstem
Act synergistically
Axons in the vicinity of the lesions will also show dystrophic mineralization
Most common primary brain neoplasm in adults
Infiltrating astrocytoma (glioblastoma multiforme, IV/IV) in a cerebral hemisphere
Most common type of primary CNS lymphoma
Large B cell lymphoma
Most common primary malignant neoplasms of the brain in children in posterior fossa
- pilocystic (cystic cerebellar) astrocytoma (I/IV)-slower growing and has a better overall prognosis that glial neoplasms in adults
- medulloblastoma-often occur in the cerebellum midline, composed of round blue cells, and has a poor prognosis
Medulloblastomas and ependymomas can seed int he __
CSF
Myxopapillary variant of ependymoma is more common in __ than __
Adults children
Children ependymomas
Most often arise in floor of 4th ventricle and can obstruct the flow of CSF
Adults ependymomas
Most often found in the spinal cord
Schwannomas
Benign
Most often involve CNVIII
Bilateral acoustic neuromas-NF2
70% of all kid tumors arise in the __ __
Posterior fossa
70% of adult tumors appear where
In their cerebral hemispheres above the tenrorium
How may a tumor spread through the CSF
If they encroach upon the subarachnoid space (where CSF circulates)
Grading tumours
I-IV
Lesions of different grade are always given distinct names
When a tumor recurs, it is typically of a higher level since it was from the original tumor
Most common primary brain tumors
Gliomas
How do gliomas arise
From a glial cell progenitor cell that just happens to go down one of the cellular lineages
Examples of gliomaswhy are there no neuron progenitors
Astrocytoma, oligodendrogliomas, ependymomasneurons are permanent tissues in adult
Glioblastomas
Occur in older adults as a primary glioblastoma in new disease settings
Secondary glioblastomas
Typically a progression of a lower grade tumor in younger patients
What are the 2 types of astrocytomas
Infiltrating astrocytomas and localized astrocytomas
When and where are astrocytomas
Any age and anywhere
Infiltrating astrocytoma (glioblastoma IV/IV)
80% of tumours in US!
Found in the cerebral hemispheres but can also be found in the cerebellum, brainstem or spinal cord
Who gets astrocytoma
Usually 40-70
I astrocytoma
Does not exist
II astrocytoma
Diffuse astrocytoma
Infiltrating astrocytomas III
Anapalstic astrocytoma
Infiltrating astrocytoma IV
Glioblastoma (this is malignant)
IV infiltrating astrocytomas
Glioblastoma malignant
Genetics classic subtype of glioblastoma *most common type of primary glioblastoma
Mutations in PTEN
Deletion of chromosome 10
Amplification EGFR(leading to increased RTK->sustained proliferation signaling)
Focal deletions 9p21 (hemizygous deletion of CDKN2A tumor suppressor gene that directly or indirectly inhibits RB and p35 function)
Proneural type of glioblastoma (*most common type of secondary glioblastomas TP53 and IDH1 and IDH2
TP53 and point mutations in IDH1 and IDH2(also found in low grade gliomas (grade II and III astrocytomas))
Molecular signature is carried forward as the neoplasm evolves to the higher grade, secondary glioblastomas
Glioblastoma proneural type PDGFRA
Overexpression of the receptor for PDGFRA
Leads to increased RTK signalling->sustained proliferation signaling
Glioblastoma neural type
Characterized by higher levels of expression of neuronal markers like NEFL, GABRA1, SYT1, and SLC12A5
Glioblastoma mesenchymal type
Characterized by deletion of NF1 gene on chromosome 17 (neurofibramotosis type I), which results in lower expression of NF1 protein
There is also overexpression of genes in the TNF and NF-KB pathways in mesenchymal glioblastoma
What genetic defect in glioblastoma is associated with better prognosis?
Among higher grade astrocytomas (WHO grades II and IV), the presence of the mutant form of IDH1 is associated with significantly better outcomes than in tumors with wild type IDH1
Diffuse astrocytoma morphology II/IV
Poorly defined grey tumors that vary in size and can appear well demarcated but they always infiltrate past their obvious boundary
May have cystic degeneration
They have a cellular density that is greater than normal white matter
Between the tumor cell nucle there is an extensive network of GFAP positive astrocytes processes to make a fibrillary background appearance
There are variable degrees of nuclear polymorphism
Anaplastic astrocytoma morphology
More densely cellular and have greater nuclear polymorphism with mitosis figures
Gemistocytic astrocytoma: the predominant neoplasticism astrocyte shows a brightly eosinophilia cell body with lots of stout processes
Glioblastoma morphology/glioblastoma multiforma
Appearance varies
Looks like anaplastic astrocytoma with necrosis and vascular/endothelial cel proliferation
-vascular cell proliferation causesthere to be tufts of cells to pile up and bulge into lumen
-with increasing proliferation, the tufts forms a ball like structure called the glomeruloid body
-the proliferation is from the malignant astrocytes and the hypoxia they are experiencing
Glioblastoma often occurs in a __ pattern in areas of hypercellularity
Serpentine
Pseudo-palisade get
Tumor cells collect along the edges of the necrotic regions
Gliomatosis cerebri
Diffuse glioma with lots of infiltration into multiple regions of the brain
Widespread infiltration+ aggressive course=grade III/IV
Life expectancy of infiltrating astrocytomas
Well differentiated astrocytomas that are diffuse have a mean survival of 5 years since they are slow growing and mostly stable
Infiltrating astrocytomas problems
Cell decides to evolve into a higher grade tumor
Higher grade tumors have leaky vessels that allow them to be seen with contrast easier since their blood brain barrier is more permeable
Prognosis for glioblastoma
Very poor with 15 month average survival and time is decreased if the tumor is large and non respectable or have poor prognosis
Pilocytic astrocytoma grade I
They are relatively benign and grow very slowly
Who gets pilocytic astrocytoma
Kids and young adults
Where are pilocytic astrocytomas
Located in cerebellum most often, but can also be found in the floor/walls of the 3rd ventricle, optic nerves, and sometimes the cerebral hemisphere
Genetic pilocytic astrocytomas
NOOO Mutations in TP53 or other molecular signatures of infiltrating astrocytomas
HAVE BRAF mutationa
Pilocytic astrocytoma in patients with NF type I
Show functional loss of neurofibromin
Growth of pilocytic astrocytoma
Grow slowly, treated by resection
Symptomatic recurrence of incompletely resented lesions is often associated with cyst enlargement rather than growth of solid component
Ok
Biphasic pilocytic astrocytoma
Bipolar with cystic and fibrillary areas in the same tumor-biphasic
Where are the pilocytic astrocytoma
In cerebellar hemisphere and appear as a cystic mass with a mural nodule and tumor cells with hair like processes
If a pilocytic astrocytoma if solid, the tumor is genereally well circumscribed and rarely infiltrates the __ like other astrocytomas
Brain
What is a pilocytic astrocytoma composed of
Bipolar cells with long, thin, processes that are GFAP positive
Characteristic findings of pilocytic astrocytoma
Rosenthal fibers and eosinophilia granular bodies
Biphasic pilocytic astrocytoma
With both loose “microcytic and fibrillary areas
Pilocytic astrocytoma vascular
Increase in number of vessels that have thickened walls and vascular cell proliferation
Prognosis pilocytic astrocytoma
Limited infiltration of the surrounding brain-prognosis good!
Where and who get pleomorphic xanthoastrocytoma
Temporal lobe of kids and young adults
Pleomorphic xanthoastrocytoma grade II
5 year survival is 80%
Presentation of pleomorphic xanthoastrocytoma
History of seizures
What is pleomorphic xanthoastrocytoma composed of
Astrocytes that are sometimes filled with lipids and can express neuronal and glial markers
Has lots of reticulum deposits, relative circumscription, chronic inflammatory cell infiltrates, and lots of nuclear atypia
NO absence of necrosis and mitosis activity
Brainstem glioma
Subgroup of astrocytomas
Age that people that people get brainstem glioma
0-20
Genetics brainstem glioma
K27M 9lysine to methionine) mutation in histone H3.1 or H3.3
This position is subject to acetylation and methylation events-epigenetics
Intrinsic pontine gliomas
Aggressive and short survival, most common of the brainstem gliomas
Cervicomedullary junction tumors
Exophytic, less aggressive
Dorsally exophytic gliomas
More benign and arise in the rectum, pons, or medulla
Oligodendroglioma
Infiltrating gliomas (grade II/IV) that are most common between 30-50 years of
Clinical presentation oligodendroglioma
Patients may have had several years of neurologic complaints (espicially seizures)
Morphology oligodendroglioma
Lesions are mostly found in the cerebral hemisphere, with predilection for white matter
Oligodendroglioma genetics
90% have mutations in IDH1 or IDH2
80% have co deletion of chromosome 1p and 19q that allows them to be more sensitive to chemotherapy
They can progress onto anaplastic oligodendrogliomas (III/IV) with loss 9p, 10q, and mutations in CDKN2A
(In contrast to high grade astrocytes tumors, EGFR gene amplification is not seen, even though many tumors still have increased EGFR protein levels
Better prognosis IDH1 IDH2
Better
Oligodendroglioma morphology Grade II
Well circumscribed tumors that often have cysts, focal hemorrhage and calcification
Composed of sheets of regular cells with spherical nuclei containing finely granular chromatin surrounded by a clear halo of vacuolated cytoplasm
Typically contains a delicate network of anastomosing capillaries
What infection also displays calcification
CMV
Perineuronal satellitosis
Grade II oligodendroglioma
Tumor cell infiltrating the cerebral cortex often collect around neurons
Grade II oligodendrogliomas prognosis
Good bc mitosis activity is minimal or absent , proliferation indices are low
Anaplastic oligodendrogliomas morphology
Grade III
Greater cell density, nuclear anaplastic, detectable mitosis activity, and necrosis
Can sometimes be found within nodules of na otherwise grade II tumor
H
High grade oligodendroglioma tumors can show patterns that are indistinguishable from glioblastoma-this is bad
Classified as glioblastomas
Ependymomas
Most commonly arise next to ependymal lined ventricular system, including the central canal of the spinal cord
Where fo ependymomas arise
In the ventricular system, often int he fourth ventricle, to cause obstruction to CSf flow
When and where do people get ependymomas
0-20
Near 4th ventricle
In adults what is the most common location of ependymomas
Spinal cord
Who is ependymomas common in
NF2
Ependymoma genetics
NF2 gene is commonly mutated in spinal cord ependymomas,
No TP53 like most infiltrating gliomas
2 subtypes of ependymoma genetics
Mesenchymal subtype
Other subtype
Mesenchymal subtype of ependymoma
Younger patients more likely to develop metastases and worse prognosis
Other subtype ependymoma
Involves the destruction of most or all of some hchromosome and tends to have a Better prognosis
Ependymoma most common
Most are grade II
Grade II ependymoma
Increased cell density, high mitosis rates, areas or necrosis, and less evident ependymal differentiation
Grade III ependymoma
Increased cell density, high mitosis rates, areas of necrosis, and less differentiation
Morphology ependymoma
Cells with regular, round to oval nuclei and lots of granular chromatin
Between the nuclei, there is a variably dense fibrally background
Tumors often form gland like round or elongated structures (rosettes, canals) that resemble the embryonic ependymal canal, with long, delicate processes extending into a lumen
Perivascular pseudorosettes ependymoma
Tumor cells are arranged around vessels with an intervening zone consisting of thin,, ependymalprocesses directed toward the wall of the vessel
GFAP expression is found in most ependymomas
Ok
4th ventricle ependymoma
Typically solid. Or papillary masses arising from the floor and even though they are well circumscribed, their location next to brainstem nuclei make them difficult to remove
Myxopapillary ependymomas morphology
Distinct but related lesions that occur int he film terminals
What do myxopapillary ependymomas contain
Papillary elements in a myxoid background, admired with ependymoma-like cells that contain neutral and acid MPSs
Cuboidal cells myxopapillary ependymomas
Sometimes with clear cytoplasm are arranged around papillary cores CT and vessels
Prognosis myxopapillary ependymomas
Depends on completeness of surgical resection
Recurrence myxopapillary ependymomas
If processes have extended into he subarachnoid space and surrounded the roots of the cauda equina, recurrence is likely
Clinical ependymomas
Posterior fossa tumors often lead to hydrocephalus secondary to obstruction of the th ventricle
If tumor disseminated I th e csf the prognosis is not good-drop metastases
Posterior tumors have the worst prognosis, espicially in kids as there is only a fifty percent five year survival rate
Subependymomas
Solid, sometimes calcified, slow growing nodules attached to the ventricular lining and protruding into the ventricle
When do subependymomas cause problems
No problems unless they happen to grow in the wrong spot and may lead to obstruction and hydrocephalus
Incidental on autopsy usually
Appearance of subependymomas
Characteristic appearance with clusters of ependymal appearing nuclei scattered in a dense fine glial fibrillary background
The rare choroid plexus papilloma
Anywhere along choroid plexus
Kids choroid plexus papillomas
Lateral ventricles
Adult choroid plexus papillomas
Fourth ventricle
What do choroid plexus papillomas look like
Choroid plexus
Why do people with choroid plexus papillomas present with hydrocephalus
Due to obstruction of the ventricular system by tumor or overproducing of CSF
Choroid plexus carcinoma
Rare
Resemble adenocarcinoma
Primary carcinoma of the choroid is usually found in kids, what are they in adults
Differentiated from metastatic carcinoma
Colloid cyst of third ventricle
Non neoplastic enlarging cyst that most commonly affects young adults
Where is a colloid cyst of the third ventricle
Attached to the roof of the third ventricle where it can obstruct one or both foramina of monro to create non communicating hydrocephalus
Most important clinical sign of colloid cyst of third ventricle
Headache sometime positional
Morphology colloid cyst of the third ventricle
Thin fibrous capsule and a lining of low to flat cuboidal epithelium containing gelatinous proteinaceous material
Neuronal tumors
Less common than glial
More often in younger adults and often presented with seizures
Gangliomas
Most common neuronal tumors of the CNS
Where are gangliomas found
Temporal lobe with a cystic component
What are gangliomas composed of
Mixture of neuronal and glial cells
Morphology gangliomas
Irregularly clustered with random orientation of neurites
In gangliomas, superficial lesions the Present with seizures. How fix
Resection of tumor resolves
Growth of gangliomas
Most grow slowly but can speed up if the glial component becomes anaplastic
Gangliomas more likely to come back
If have mutation in BRAF gene
What other tumor has mutated BRAF
Pilocytic astrocytomas
Dysembryoplastic neuroepithelial tumor
Rare low grade I tumor in kids that presents as a seizure disorder
Good prognosis with surgery
Location of dysembryoplastic neuroepithelial tumor
Located in superficial temporal lobe with attenuation of the overlying skull indicating that the tumor has been around a while
Dysembryoplastic neuroepithelial tumor lesions form intracortical nodules
Of small round cells that makes columns and are associated with a myxoid background
Surrounding the nodules, there may be focal cortical dysplasia
Dysembryoplastic neuroepithelial well differentiating floating neuronscentral neurocytoma
Sit in the pools of MPS rich myxoid backgrounf
Grade II
Tumor found within hte ventricualr system )lateral or third)
Characterized by evenly spaced, round, uniform nuclei and neuropil island
What is the most common poorly differentiated brain tumor
Medulloblastoma
Twenty percent of all brain tumours in kids
Medulloblastoma
Grade IV
Prognosis medulloblastoma
Very malignant and will often kill quickly, but is very radiosensitive
Who gets medulloblastoma
In kids and exclusively appears in the cerebellum
Blue cell tumors
Medulloblastoma in pediatric populations
Where do medulloblastoma occur
Cerebellum
Midline
Medulloblastoma and CSF
Can seed into CSF->drop metastases
What else can seed CSF
Glioblastoma (adult) and ependymoma can seed the CSf
WNT genetic medulloblastoma
Mutation in WNT
Occurs in older kids
Monosomy of chromosome 6 and expression of B catenin
Prognosis WNT medulloblastoma
Best with 90% five year survival
SHH type medulloblastoma
In infants or young adults
Defect SHH
May have MYC amplification
Prognosis SHH medulloblastoma
MYC amplification confers to a goo prognosis bc there is molecular target therapy
2nd best prognosis
Group 3 medulloblastoma -who gets it
Infants and kids
Genetic group 3 medulloblastoma
MYC amplification and isochrromome 17 (i17q)
Histology group 3 medulloblastoma
Classic or large cell
Prognosis group 3 medulloblastoma
Worst prognosis
Group 4 medulloblastoma
Isochromosome 17 (i17q)
Classic or large cell histology
No MYC amplification, but sometimes MYCN amplification
3rd worse prognosis
A mutation in what gene makes a medulloblastoma more resistant to chemotherapy and has a worse prognosis
I17q, restricted to groups 3 and 4
Medulloblastoma is located where in kids and where in adults
Midline of cerebellum for kids
Lateral in adults
Rapid growth of medulloblastoma leads to ___
Hydrocephalus
Describe a medulloblastoma
Tumors well circumscribed and friable and can involve the leptomeninges (pia and arachnoid)
Densely cellular with sheets of anaplastic cells that are small with little cytoplasm
Have hyperchromatic nuclei that are elongated or crescent shaped
Lots of mitosis events and markers lie Ki-67
Can express neuronal granules, form homer Wright rosettes, and express glial markers (GFAO)
Drop metastases medulloblastoma
Can disseminate through the CSF and give rise to nodular masses at some distance from the primary tumor
Morphology medulloblastoma nodular desmoplastic variant
Characterized by areas of stromal response marked by collagen and reticular deposition that form pale islands with more neuropil and neuronal markers
Medulloblastoma large cell variant morphology
Characterized by large irregular vesicular nuclei, prominent nucleoli and frequent mitosis and apoptotic cells
Atypical teratoid/rhabdoid tumors
Grade IV tumor or young kids 9very malignant , poor prognosis)
Where do atypical teratoid/rhabdoid tumors
Posterior fossa and supratentorial compartments in nearly equal proportions
Characterization of atypical rhabdoid tumors
Epithelial, mesenchymal, neuronal, and glial components
Genetic atypical teratoid/rhabdoid tumors
Chromosome 22 is hallmark
-hsNF5/INI1
Atypical teratoid/rhabdoid tumors morphology
Large tumors that spread along the surface of the brain
Lot of mitosis activity
Diagnostic cells of atypical teratoid/rhabdoid tumors
Rhabdoid cell contains intermediate filaments and is immunosuppressive for epithelial membrane antigen and vimentin
- smooth muscle actins and keratin may also be positive
- desmin and myoglobin are not present
What are cells of atypical teratoid/rhabdoid tumors at reset
Rest of the cells are a mix of mesenchymal, epithelial and neurological
Clinical features atypical teratoid.rhabdoid tumors
AGGRESSIVE tumors (grade IV) of kids younger that’s 5 and they only live for about a year
Primary CNS lymphoma
Most common CNS tumor in AIDS patients and those who are immune suppressed
Where is primary CNS tumor and where does it spread
Multifocal int he brain and spread outside of the CNS is late and rare
Secondary CNS lymphoma
Rare to get inside CNS
Immunosuppressed patients and primary CNS lymphoma
Cells in nearly all primary brain lymphomas are latently infected by EBV-they are B cells
Organ transplantation and primary CNS lymphoma
Associated with post transplantation lymphoproliferative disorder
Non immnosuppresssed primary CNS lymphoma
Show a phenotype typical or post germinal center B cell differentiation
Prognosis primary CNS lymphoma
Aggressive and have worse outcomes than tumor of comparable histology occurring at non CNS sites
Morphology primary CNS lymphoma
Typically many lesions within the brain parenchyma (multifocal) and they surround vessels
They are relatively well defined with central necrosis
Diffuse large cell B lymphomas are the most common group
HOOPING: the infiltrating cells are separated from one another by silver staining material;characteristic of primary brain lymphoma
Intravascular lymphoma
Large cell lymphoma that grows in vessels of the brain and other places in body
Presentation intravascular lymphoma
Doesn’t present as a mass lesion, but rather as an occlusion of small vessels and widespread microscopic infarcts
Leads to widespread microscopic infarcts that result in non localizing neuro symotoms like dementia
Primary germ cell tumors
Occur first two years
More commonly in JAPANESE
Primary germ cell tumors in pineal region
Males
Primary germ cell tumors in suprasellar region
Both males and females
Prognosis primary clerk cell tumors
To CNS is common
But exclusion of a non CNS primary tumor must be made prior to diagnosing a primary germ cell tumor of the CNS
Markers of primary germ cell tumor
Markers a fetoprotein and B-hcg (as with all germ cell tumors)
Pineal parenchymal tumors
Arise from Pinochet’s in the pineal gland that have features of neuronal differenation
Pineocytomas and pineoblastomas
Pineocytomas
Low grade tumor
- affects adults
- more neuronal differentiation
- areas of neuropil, cells with small round nuclei, no evidence of mitosis or necrois
Pineoblastomas
High grade tumor
Affects kids
Occurs with increased frequency in individuals with the germline mutations in RB
Little differentiation, densely packed small cells and frequent mitosis figures
Highly aggressively spreads throughout CSF
Meningiomas
Grade I
Benign that are attached to the dura of adults
Where do meningiomas arise
Meningothelial cells of the arachnoid
Can be found along any of the external surfaces of the brain or within the ventricular system
Potential cause of meningiomas
Associated with prior radiation therapy to the head and neck decades earlier
Genetics meningiomas
NF2 gene on chromosome 22q that encodes merlin
Often happens in setting of NF2 but also sporadic
Associated with higher grade tumors
Other mutations seen are in TNF receptor 7 (TNFR7)
Meningioma amorphology
Rounded masses with well defined and easily separateable bases from the dire
They will sometimes grow into the brain, but it doesn’t change their grading
-benign neoplasms can be lethal if they are space occupying and impinge on vital structures
-the surface of the mass is encapsulated by thick fibrous tissue and may have a bosselated or polyploid appearance
They can also grow en plaque in which the tumor spreads in a sheet like fashion along the dura (sommonly associated with hyperostoitic reactive Changes in the adjacent bone
May contain multiple CALCIFIED PSAMMOMA BODIES
NECROSIS AND LIMITED HEMORRHAGE
Immunoreactive for epithelial membrane antigen
What signs increase risk of recurrence of meningioma
Brain invasion is associated with increased risk of recurrence but does not alter the histologic grade of the lesion
Atypical meningiomas
Grade II
More aggressive and may require radiation therapy in conjunction to surgery
Morphology atypical meningiomas
4 or more mitosis per 10 high powered fields or at least 3 atypical features (increased celularity, small cells with high nuclear to cytoplasmic ratio, prominent nucleoli, pattern less growth , or necrosis)clear cell and choroid patterns are associated with more aggressive behavior and thus grade II
Anaplastic meningiomas
Grade III highly aggressive tumor with hte appearance of a high grade sarcoma
Papillary and rhabdoid
Mitosis are typically greater than 20 mitosis per 10 high power fields
Papillary meningioma
Pleomorphic cells arranged around fibrovascular cores
Rhabdoid meningioma
Sheets of tumor cells with hyaline eosinophilic cytoplasm containing intermediate filaments
Clinical features meningiomas
Present with vague non localizing signs and symptoms or with focal findings due to brain compression
Growth or meningiomas
Slow
Where do meningiomas occur
Parasagittal aspect of the brain convexities, dura over the lateral convexities, wing of the sphenoid, olfactory groove, sella turncia, and foramen magnum
Who gets meningiomas
Uncommon in kids and affect more females (espicially spinal meningiomas)
Singular lesions of meningiomas
Think of NF2 if there are multiple, espicially if there are acoustic neuromas or glial tumors too
Multiple lesions are much more likely to represent dissemination from a single tumor than clonally distinct tumors
Meningiomas often express progesterone receptors and may grow more rapidly during __
Pregnancy
What tumors metasticize to the brain
Carcinomas
Where do tumors that metasticize to the brain spread from
Lung, breast, skin (melanoma), kidney, and GI tract
Where does brain tumor spread
Meta STIs is to the grey white junction is the most common location (where the vessels narrow and branch out)
___ (rare) is very,likely to go to the brain but __ __ (common) almost never goes to the brain
Choriocarcinoma
Prostatic adenocarcinoma
What improves the quality of patients remaining life with metastatic tumors
Localized treatment of solitary brain metastases
IntraParenchymal metastases morphology
Form sharply demarcated massses at the junction between the grey and white matter surrounding by a zone of edema
MELANOMA DOESNT FOLLOW RULE
Region of edema around it with reactive gliosis and central necrosis
Morphology of metastasis to brain
_ and __ cancers are associated with meningeal carcinomatosis with tumor nodules along the surface of the brain, spinal cord, and intramural nerve toors
Lung breast
Paraneoplastic syndromes
Development of an immune response with cross reactivity between a tumor antigen in CNS or PNS
Subacute cerebellar degeneration
Destruction of purkinje cells, gliosis, and mild chronic inflammatory cell infiltrate
Biomarker of subacute cerebellar degeneration
Circulating PCA1 antibody (anti-yo) which recognized cerebellar purkinje cells
Who gets subacute cerebellar degeneration
Women with ovarian, uterine, or breast cancer
Limbic encephalitis
Autoimmune inflammation of the brain
Characterized by subacute dementia, perivascular inflammatory cuffed, microglial nodules, some neuronal loss, and gliosis
Where is there Limbic encephalitis
Anterior and medial portions of the temporal lobe-Limbic structures are there
Signs of Limbic encephalitis
Circulating ANNA-1 antibody (anti-Hu) that attacks neuronal nuclei in the CNS and PNS and is associated with small cell carcinoma of the lung 9the smoking one)
Antibody agaisnt NMDA receptor that cross reacts with hippocampal neurons and is associated with ovarian teratomas
Antibodies against voltage gated potassium channel (VGKC) complex
If signs of Limbic encephalitis look for a tumor why
Paraneoplastic syndrome is often seen first
Eye movement disorders(uncontrolled eye movement)
Opsoclonus
Opsoclonus
In association with cerebellar and brainstem dysfunction
What are eye movement disorders associated with
Neuroblastoma in kids
What are eye movement disorders accompanied by
Myoclonus
Subacute sensory neuropathy
May be found by itself or with Limbic encephalopathy
Loss of sensory neurons fro the dorsal root ganglia in association with lymphocytic inflammation
Lambert Eaton myasthenic syndrome
Caused by antibodies against the voltage gated Ca channel in the presynaptic element of the NMJ
May be seen without cancer too
Weak muscles trouble walking
Which paraneoplastic syndromes respond better to immunotherapy (removal of circulating antibodies and immunosuppression)
VGKC and NMDAR (plasma membrane reactive antibodies) respond better than ANNA-1 and PCA-1 (intracellular antigens)
Cow den syndrome
Dysplasia gangliocytoma of the cerebellum (lhermitte-duclos dz) caused by mutations in PTEN resulting in PI3K/AKT signaling activity
Li-Fraumeni syndrome
Medulloblastomas caused by mutations in TP53
Turcot syndrome
Medulloblastomas or glioblastoma caused by mutations in APC or mismatch repair genes
Goblin syndrome
Medulloblastoma caused by mutations int he PTCH gene resulting in up regulation of SHH
Tuberous sclerosis complex
AD
Characterized by development of hamartomas and benign tumors int he brain or other tissue
Symptoms tuberous sclerosis complex
Seizures, autism, metal retardation
Morphology tuberous sclerosis
Cortical tubers and subependymal nodules
Tuberous sclerosis complex subependymal giant cell astrocytomas
Can develop from hamartomatous nodules in the same location
Tuberous sclerosis complex cysts
May also be found in liver, kidneys, and pancreas
Renal angiomyolipomas, renal cysts, subungal fibromas, and cardiac rhabdomyoams
Tuberous sclerosis complex cutaneous lesions
Like angiofibromas, localized leathery patches (shagreen patches), hypopigmented areas (ash lead patches), and subungual patches
Genetics tuberous sclerosis complex
TSC1 (hamartin 9q34) and TSC2 (tuberin 16p13.3) mutated and prevent them from coming together and inhibiting the kinase mTOR
Is TSC1 or TSC2 more commonly mutated
TSC2
What is mTOR
Key regulator of protein synthesis and other aspects of anabolic metabolism -mTOR regulates cell size and the tumors associated with tuberous sclerosis are all large
Cortical and subependymal tubers
Intact copy of wild type allele
Subependymal giant cell astrocytoma
Biallelic loss
Tuberous sclerosis complex morphology
Firm
Composed of randomly arranged neurons that lack normal laminar organization of the neocortex
Some large cells have characteristics that are between neurons and glial cells so that they express both neurofilament and GFAP
What to tuberous sclerosis complex stain for
Tuberoinfundibular and hamartin
Candle guttering tuberous sclerosis complex morphology
Large astrocyte like cells will cluster beneath the ventricular surface and are called candle guttering
Cortical tubers tuberous sclerosis complex morphology
Hamartomas of neuronal and glial tissue
Von hippel-lindau disease
AD, tumors and cysts in many parts of the body early childhood
Develop hemangioblastomas of the CNS (espicially cerebellum and retina) and cysts of the pancreas, liver, and kidneys
Hemangioblastomas
Uncommon neoplasms arising in the cerebellum often with vHL disease and associated with polycythemia
What are people with Von hipped Linda more likely to develop
Renal cell carcinoma and pheochromocytoma
Von hipped Linda’s disease genetics
VHL gene (3p25.3 tumor suppressor) that normally downregulates HIF1( a transcription factor) and thereby down regulated VEGF, EPO and other growth factors
Downregulated EPO
Leads to polycythemia observed in association with hemangioblastomas
Von hipped Linda’s disease stains for what
Inhibin
Von hipped Lindau morphology
Hemangioblastomas are very vascular neoplasms that occur as a mural neoplasm associated with a large fluid filled cyst
The lesion is composed of a small sized vessels with intervening stromal cells characterized by vacuolated, lightly PAS positive, lipid rich cytoplasm
Neurofibromatosis
AD
NF1 and NF2
Characterized by tumours in PNS and CNS
NF1
Neurofibromas of the peripheral nerve, gliomas of the optic nerve, pigmented nodules of the iris and CUTANEOUS HYPERPIGMENTED SPOTS (cafe au last spots)
NF2
Bilateral schwannomas of the vestibulocochlear nerves (CNVIII) and multiple meningiomas is virtually pathogenic
Gliomas can also occur as ependymomas of the spinal cord
