n1 31 roy neuropathology 2010.ppt - beat the boards! · neuropathology book 2, section 12 roy ©...

Neuropathology Book 2, Section 12

Roy © 2010

www.BeatTheBoards.com 877-225-8384 1

Neuropathology

SubhojitSubhojit Roy, MD, PhDRoy, MD, PhD

UCSD Neurosciences and PathologyUCSD Neurosciences and Pathology

[email protected]@ucsd.edu

2

CME Financial Disclosure Statement

I, or an immediate family member including I, or an immediate family member including spouse/partner, have at present and/or have spouse/partner, have at present and/or have had within the last 12 months, or anticipate had within the last 12 months, or anticipate NONO financial interest/arrangement or financial interest/arrangement or affiliation with one or more organizations affiliation with one or more organizations that could be perceived as a real or apparent that could be perceived as a real or apparent conflict of interest in context to the design, conflict of interest in context to the design, implementation, presentation, evaluation, implementation, presentation, evaluation, etc of CME activities etc of CME activities –– Roy Subhojit, MDRoy Subhojit, MD


Roy © 2010


Lecture Content

�� What is normal?What is normal?

�� What is abnormal?What is abnormal?

�� Specific neuropathologic examples relevant Specific neuropathologic examples relevant

to board examsto board exams

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The Organization of Nervous

System

�� Central Nervous System (CNS)Central Nervous System (CNS)

��BrainBrain

��Spinal CordSpinal Cord

�� Peripheral Nervous System (PNS)Peripheral Nervous System (PNS)

��Nerves and nerve rootsNerves and nerve roots

��GangliaGanglia

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Courtesy: WUSM tutorial

Basic Neuroanatomy

Basic motor pathwayBasic motor pathway Basic sensory pathway (touch)Basic sensory pathway (touch)

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Basic Neuroanatomy

Courtesy: WUSM tutorial

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Principal Cell Types of the Nervous

System

�� CNS:CNS:

�� NeuronNeuron

�� AstrocyteAstrocyte

�� OligodendrocyteOligodendrocyte

�� MicrogliaMicroglia

�� EpendymalEpendymal

�� PNSPNS

�� NeuronNeuron

�� Schwann cellSchwann cell

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Cerebral cortex

Basic Patterns of Reaction

“Red neurons”“Red neurons”——acute hypoxiaacute hypoxia“Gliosis”“Gliosis”——astrocytic astrocytic

activation, indicative of nonactivation, indicative of non--

specific injury specific injury

“Microglial nodules”“Microglial nodules”——

indicative of infections (viral) indicative of infections (viral)

“Rosenthal fibers”“Rosenthal fibers”——indicative of nonindicative of non--specific injury, also specific injury, also

seen in “Alexander’s disease” (GFAP mutations)seen in “Alexander’s disease” (GFAP mutations)“Neuronophagy” of anterior horn cells“Neuronophagy” of anterior horn cells——ppolioolio8


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Cerebral Infarction

�� Arterial Arterial

��Regional distribution Regional distribution (MCA/ICA/brainstem etc)(MCA/ICA/brainstem etc)

��General pathology (gross/microscopic)General pathology (gross/microscopic)

�� Specific examples (lacunar, Binswanger’s)Specific examples (lacunar, Binswanger’s)

�� VenousVenous

��Usually secondary to infectionUsually secondary to infection

��Specific examples (sagittal sinus, vein of Specific examples (sagittal sinus, vein of

Galen)Galen)

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Regional Distribution Most common sites:Most common sites:

•• Internal carotid Internal carotid

(with PCA)= 30%(with PCA)= 30%

•• AA--CommComm= 30%= 30%

•• MCA= 30%MCA= 30%

Berry aneurysms

Remote MCA infarct

Cuccurullo, PMR Board review

Basic circulation of brainBasic circulation of brain

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General Infarct Pathology (Gross)

Early hypoxic changes “laminar necrosis”Early hypoxic changes “laminar necrosis”

“wedge shaped” infarct“wedge shaped” infarct

Old cystic changes Old cystic changes

following infarctfollowing infarct“Laminar” necrosis in hippocampus“Laminar” necrosis in hippocampus

Lacunar infarcts associated Lacunar infarcts associated

with hypertensionwith hypertension

<4h: subtle changes<4h: subtle changes 44--12 h12 h-- red neuronsred neurons

2424--72 hours: enter inflammatory cells72 hours: enter inflammatory cellsCourtesy: UCSF Neuropathology

General Infarct Pathology (Micro)

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11--2 weeks: proliferation of inflammatory cells2 weeks: proliferation of inflammatory cells

33--4 weeks: reactive astrocytes4 weeks: reactive astrocytes

>3 months: cavity>3 months: cavity

Courtesy: UCSF Neuropathology

General Infarct Pathology (Micro)

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Hemorrhage

�� Epidural and subduralEpidural and subdural

�� SubarachnoidSubarachnoid

��Vascular malformationsVascular malformations

�� Berry aneurysmsBerry aneurysms

��Inflammatory/infective mycoticInflammatory/infective mycotic

�� IntraparenchymalIntraparenchymal

��HypertensiveHypertensive

��AmyloidAmyloid

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Epidural Vs. Subdural

�� EpiduralEpidural

��Usually secondary to trauma (skull fracture)Usually secondary to trauma (skull fracture)

��Arterial, MM Arterial, MM arteryartery

�� Subdural hemorrhageSubdural hemorrhage

��Movement of brain inside skull, elderlyMovement of brain inside skull, elderly

��Rupture of bridging Rupture of bridging veinsveins

Bone

Dura

Arachnoid

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General Hemorrhage Pathology

(Gross)

Epidural hemorrhageSubdural hemorrhageSubdural hemorrhage

Subarachnoid hemorrhageSubarachnoid hemorrhage16


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General Hemorrhage Pathology

(Gross)

“Lobar” hemorrhage“Lobar” hemorrhage-- CAACAA

Duret hemorrhagesDuret hemorrhages

Vascular malformationVascular malformation17

Trauma�� Intracranial hemorrhage (epidural, Intracranial hemorrhage (epidural,

subdural, subarachnoid, subdural, subarachnoid,

parenchymal)parenchymal)

�� Diffuse brain injuryDiffuse brain injury

Contrecoup injuriesContrecoup injuries

Axonal accumulationsAxonal accumulationsGliding contusion, diffuse axonal injuryGliding contusion, diffuse axonal injury

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Herniation

Cingulate herniationCingulate herniation

Uncal herniationUncal herniation

Tonsillar herniationTonsillar herniation

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Infections

�� BacterialBacterial�� Meningitis (bacterial, fungal)Meningitis (bacterial, fungal)

�� AbscessAbscess

�� Protozoal/helminthicProtozoal/helminthic�� Amoebic meningoencephalitisAmoebic meningoencephalitis

�� ToxoplasmosisToxoplasmosis

�� CysticercosisCysticercosis

�� ViralViral�� ADEM/AHLADEM/AHL

�� PMLPML

�� HIVHIV

�� CMVCMV

�� Rabies, polioRabies, polio

Opaque meningesOpaque meninges

Inflammatory cells in meningesInflammatory cells in meninges20


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Generic Pathologic Changes——Infection

Temporal lobe Temporal lobe

hemorrhages hemorrhages

(herpes)(herpes)

Brain abscessBrain abscess——grossgross

Microglial nodules—viral infections21

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Viral InfectionsProgressive multifocal Progressive multifocal

leukoencephalopathyleukoencephalopathy

Myelin stain showing “punched out” Myelin stain showing “punched out”

demyelinated areasdemyelinated areas

Intranuclear inclusions with JC virusIntranuclear inclusions with JC virus

Intranuclear inclusions with CMV virusIntranuclear inclusions with CMV virus

Rabies virus neuropathologyRabies virus neuropathology

“Neuronophagy” of “Neuronophagy” of

anterior horn cellsanterior horn cells

Intranuclear inclusions Intranuclear inclusions

“Negri bodies”“Negri bodies”

HIV encephalitisHIV encephalitis

Non-Viral InfectionsRadiologic features of toxoplasmosisRadiologic features of toxoplasmosis

Neuropathology of toxoplasmosis (bradyzoites)Neuropathology of toxoplasmosis (bradyzoites)

Aspergillosis (note 90Aspergillosis (note 90°° branching)branching)

CryptococcosisCryptococcosis

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Demyelination/Dysmyelination

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GrossGross——foci of foci of

periventricular periventricular

demyelination in demyelination in

multiple sclerosismultiple sclerosis

Histology:Histology:

1.1. Accumulation of inflammatory Accumulation of inflammatory

cells (macrophages)cells (macrophages)

2.2. Loss of myelin with relative Loss of myelin with relative

preservation of axons (d/d with preservation of axons (d/d with

infarction)infarction)26


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Preservation of axonsPreservation of axons——silver silver

stainstain

Patchy loss of myelin (myelin Patchy loss of myelin (myelin

stain)stain)

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“Gaucher cells”“Gaucher cells”——

Gaucher’s diseaseGaucher’s disease

Accumulation of Accumulation of

“Rosenthal fibers”“Rosenthal fibers”——

Alexander’s diseaseAlexander’s disease

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Classification of Tumors of the

Nervous System

�� HistologyHistology

�� LocationLocation

��Intra vs. extraIntra vs. extra-- parenchymalparenchymal

��Supra vs. infraSupra vs. infra-- tentorialtentorial

�� Patient agePatient age

��Adult vs. pediatricAdult vs. pediatric

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Pediatric Vs. Adult Brain Tumors

�� Pediatric: about 70% posterior fossa:Pediatric: about 70% posterior fossa:

��Pilocytic astrocytomaPilocytic astrocytoma

��MedulloblastomaMedulloblastoma

��EpendymomaEpendymoma

�� Adult: about 70% supratentorial:Adult: about 70% supratentorial:

��Metastatic carcinomaMetastatic carcinoma

��GlioblastomaGlioblastoma

��Meningioma Meningioma 30


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Grading of CNS Tumors

�� Grade I: discrete, well circumscribed, Grade I: discrete, well circumscribed,

potentially amenable to complete surgical potentially amenable to complete surgical

excisionexcision

�� Grad II: low grade malignancy. Invades Grad II: low grade malignancy. Invades

surrounding brain. Not amenable to surrounding brain. Not amenable to

complete surgical excisioncomplete surgical excision

�� Grade IIIGrade III--IV: high grade malignancy. IV: high grade malignancy.

Invades surrounding brain and Invades surrounding brain and

histologically anaplastichistologically anaplastic

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Features Suggesting a Low Grade Tumor

�� Long history of seizuresLong history of seizures

�� Cyst with an enhancing mural noduleCyst with an enhancing mural nodule

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Meningioma

MeningotheliaMeningothelia

l “whorls”l “whorls” Intranuclear Intranuclear

inclusionsinclusions33

Pilocytic Astrocytoma

�� Grade IGrade I

�� Circumscribed, nonCircumscribed, non--infiltratinginfiltrating

�� Cyst with enhancing mural noduleCyst with enhancing mural nodule

�� Common location:Common location:

��CerebellumCerebellum

��Third ventricleThird ventricle

��Optic nerve/tractOptic nerve/tract

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DDx of cyst with mural nodule:

-Pilocytic (child)

-Hemangiopericytoma (adult)

-Glioma


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Pilocytic Astrocytoma

�� Histology: bipolar Histology: bipolar

astrocytes with delicate astrocytes with delicate

“hairlike” processes“hairlike” processes

�� Loose microcystic spongy Loose microcystic spongy

areas alternating with areas alternating with

compact fibercompact fiber--producing producing

spindle cell areasspindle cell areas

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Rosenthal fibers: eosinophilic

intracytoplasmic inclusions

Fibrillary Astrocytoma——Grading

�� Prognostically important histologic features:Prognostically important histologic features:

��Nuclear pleomorphismNuclear pleomorphism

��Mitotic activityMitotic activity

��Endothelial proliferationEndothelial proliferation

��NecrosisNecrosis

�� 1 feature1 feature——grade IIgrade II

�� 2 features2 features——grade IIIgrade III

�� 3 features3 features——grade IVgrade IV36


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Low Grade Fibrillary Astrocytoma

�� WHO grade IIWHO grade II

�� Peak incidence 4Peak incidence 4thth decadedecade

�� Life expectancy <10 yearsLife expectancy <10 years

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Anaplastic Astrocytoma

�� WHO Grade IIIWHO Grade III

�� Peak incidence 5Peak incidence 5thth

decadedecade

�� Life expectancy 2Life expectancy 2––3 3

yearsyears

�� High cellularityHigh cellularity

�� Greater nuclear atypiaGreater nuclear atypia

�� Mitotic activityMitotic activity

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Glioblastoma Multiforme

�� Peak incidence 5thPeak incidence 5th––66thth decadesdecades

�� Life expectancy <1 yearLife expectancy <1 year

�� Anaplastic astrocytoma with endothelial Anaplastic astrocytoma with endothelial

proliferation or necrosisproliferation or necrosis

�� Highly variable histologic appearanceHighly variable histologic appearance

�� Multiple molecular pathwaysMultiple molecular pathways

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Endothelial Proliferation

�� Abnormal vessels Abnormal vessels

with endothelial cell with endothelial cell

hyperplasia lack a hyperplasia lack a

bloodblood--brain barrier brain barrier

and are the histologic and are the histologic

correlate of contrast correlate of contrast

enhancement in enhancement in

diffuse diffuse giomasgiomas

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Pseudopalisading Necrosis

�� The presence of The presence of

necrosis adjacent to necrosis adjacent to

densely cellular and densely cellular and

actively proliferating actively proliferating

tumor is characteristic tumor is characteristic

of glioblastomaof glioblastoma

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Pseudopalisading Necrosis Vs.

Radiation Necrosis

PseudopalisadingPseudopalisading RadiationRadiation--inducedinduced

Note “geographic” necrosis

Lack of atypical cytology44


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Molecular Biology

�� Secondary glioblastomaSecondary glioblastoma——arise from arise from

progression of low astrocytomaprogression of low astrocytoma

��TP53 mutationTP53 mutation

��Rare EGFR amplificationRare EGFR amplification

�� Primary glioblastomaPrimary glioblastoma——no clinical or no clinical or

pathologic evidence for prepathologic evidence for pre--existing low grade existing low grade

astrocytomaastrocytoma

��EGFR amplificationEGFR amplification

��LOH LOH chrchr 1010

��Rare mutations of TP53Rare mutations of TP5345

Other brain tumors

Oligodendroglioma Medulloblastoma (“rosettes”)

Ganglioglioma

Craniopharyngioma- “picket

fence” and “wet keratin”

Rosenthal fibers


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Neurofibroma Vs. Schwannoma

NeurofibromaNeurofibroma

SchwannomaSchwannoma

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Tau positive inclusions Tau positive inclusions --

composed predominantly of: composed predominantly of:

PiDPiD

FTDPFTDP--1717

Neuropathological Examination of Frontotemporal Dementia Neuropathological Examination of Frontotemporal Dementia

PatientsPatients

NFTsNFTs

3R/4R3R/4R--tautau

Neuronal/glialNeuronal/glial

inclusionsinclusions

4R4R--tautau

ADAD

LBVADLBVAD

TPSDTPSD

AGD*AGD*

FTDPFTDP--1717

CBDCBD

PSPPSP

FTDPFTDP--1717

Pick bodiesPick bodies

3R3R--tautau

Absence of tau positive inclusions Absence of tau positive inclusions

UbiquitinatedUbiquitinated

TDPTDP--43+43+


NeurofilamentNeurofilament


Absence ofAbsence of


FTDFTD--MNDMND

+/+/-- MNDMNDNFIDNFID DLDH/FTLDDLDH/FTLD

OtherOther

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General Principles of

Neurodegenerative Diseases

�� Selective vulnerabilitySelective vulnerability

�� Reactive gliosisReactive gliosis

�� Protein aggregation that leads to specific Protein aggregation that leads to specific

intracellular inclusion bodies or intracellular inclusion bodies or

extracellular depositsextracellular deposits

�� Familial forms, some with known genetic Familial forms, some with known genetic

mutationsmutations

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Alzheimer’s Disease

PlaquePlaque--

amyloidamyloidTangleTangle

-- tautau

Atrophy

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Pathological Hallmarks of AD

�� Senile plaqueSenile plaque

�� Neurofibrillary Neurofibrillary

tangletangle

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Genes Associated with

Alzheimer’s Disease

�� Amyloid Precursor Protein (APP)Amyloid Precursor Protein (APP)

�� Presenilin 1Presenilin 1

�� Presenilin 2Presenilin 2

�� Apolipoprotein EApolipoprotein E

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Parkinson’s Disease

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Neuropathology in Other

Neurodegenerative Diseases

Picks diseasePicks disease——frontotemporal dementiasfrontotemporal dementias

Huntington’s disease Huntington’s disease

(caudate atrophy)(caudate atrophy) Amyotrophic lateral sclerosis (CS Amyotrophic lateral sclerosis (CS

tract degeneration)tract degeneration)

Tau positive Tau positive

inclusions in inclusions in

hippocampal hippocampal

dentate neuronsdentate neurons

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Skeletal Muscle Diseases

�� Normal muscle biopsyNormal muscle biopsy

��Uniform, polygonal fibers, no central nuclei Uniform, polygonal fibers, no central nuclei

(~95%), delicate endomysial tissue, no (~95%), delicate endomysial tissue, no

adipocytes.adipocytes.

��Roughly equal number of type 1 and type 2 Roughly equal number of type 1 and type 2

musclesmuscles

Type 1: light, Type 2: dark, ATPase stainType 1: light, Type 2: dark, ATPase stainRegular H&E stainRegular H&E stain55

Pathologic Changes in Muscle

Fibers

�� Variations in size and shapeVariations in size and shape--angulated, angulated, hypercontractedhypercontracted

�� Atrophy and hypertrophyAtrophy and hypertrophy

�� Predominance or deficiency of a fiberPredominance or deficiency of a fiber--typetype

�� Structural anomaliesStructural anomalies——nuclear, split fibers nuclear, split fibers (hypertrophy), necrotizing change (myopathic (hypertrophy), necrotizing change (myopathic process), basophilic fibers (regenerating), process), basophilic fibers (regenerating), “target fibers” (neurogenic), inclusions, “target fibers” (neurogenic), inclusions, vacuoles, “ragged red” (mitochondrial), vacuoles, “ragged red” (mitochondrial), interstitial changes interstitial changes

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Muscle Diseases

(Neurogenic)

Acary Souza Bulle OliveiraI; Roberto Dias Batista PereiraII

Clustering of fiberClustering of fiber--type type

(“grouping”)(“grouping”)

Target Target

fibersfibers57

Muscle Diseases (Myogenic)

�� Inflammatory myopathiesInflammatory myopathies

��DermatomyositisDermatomyositis

��PolymyositisPolymyositis

��Inclusion body myositisInclusion body myositis

�� Genetic myopathiesGenetic myopathies

��Muscular dystrophyMuscular dystrophy——DuchenneDuchenne

��Congenital myopathiesCongenital myopathies——nemaline myopathy, nemaline myopathy,

centralcentral--core diseasecore disease

��MetabolicMetabolic——mitochondrial, lipid, steroid, drugs mitochondrial, lipid, steroid, drugs

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Dermatomyositis

1.1. Painful, proximal muscle weaknessPainful, proximal muscle weakness

2.2. Cutaneous signs: erythema, 15% Cutaneous signs: erythema, 15%

associated with visceral cancersassociated with visceral cancers

3.3. High CK levelsHigh CK levels

4.4. “Marginal atrophy”“Marginal atrophy”-- atrophy of atrophy of

perifascicular fibersperifascicular fibers

5.5. Ischemic “punched out” vacuoles Ischemic “punched out” vacuoles

and microinfarctsand microinfarcts

6.6. SEPTAL inflammatory infiltrates, SEPTAL inflammatory infiltrates,

mixture of mixture of bothboth B, T (B, T (CD4CD4>CD8) >CD8)

and macrophagesand macrophages

7.7. No significant inflammation in No significant inflammation in

nonnon--necrotic fibersnecrotic fibers

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Polymyositis

1.1. Symmetric, subacute/chronic Symmetric, subacute/chronic

presentationpresentation

2.2. No skin changesNo skin changes

3.3. High CK levels, EMG consistent High CK levels, EMG consistent

with myositiswith myositis

4.4. Endomysial inflammation Endomysial inflammation

surrounding fibers that may look surrounding fibers that may look

only slightly abnormal (nononly slightly abnormal (non--

necrotic) necrotic)

5.5. Predominantly T cells (CD8+) and Predominantly T cells (CD8+) and

large number of macrophageslarge number of macrophages

6.6. No perifascicular atrophy, no other No perifascicular atrophy, no other

ischemic changesischemic changes

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Dermato Vs. Polymyositis

�� Perifascicular atrophy, inflammation confined to Perifascicular atrophy, inflammation confined to septa v/s endomysial, both B and T vs. T only, septa v/s endomysial, both B and T vs. T only, CD4>CD8 T cells, no lymphocytic infiltration in CD4>CD8 T cells, no lymphocytic infiltration in nonnon--necrotic fibers necrotic fibers

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Inclusion Body Myositis�� Most common myopathy >50 yrs, M>FMost common myopathy >50 yrs, M>F

�� Insidious, painless, distal>proximal, CK Insidious, painless, distal>proximal, CK

normal or slightly elevatednormal or slightly elevated

�� PathologyPathology——“rimmed vacuoles”, mild “rimmed vacuoles”, mild

inflammation, mild neurogenicinflammation, mild neurogenic--type atrophy type atrophy

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Genetic——MMuscular Dystrophy

�� Variability (Variability (hypertrophic+atrophichypertrophic+atrophic), rounded atrophic fibers, endomysial ), rounded atrophic fibers, endomysial

fibrosis, loss of dystrophin in Duchenne and Becker fibrosis, loss of dystrophin in Duchenne and Becker

Endomysial fibrosisEndomysial fibrosis Split fibersSplit fibers Dystrophin staining in muscleDystrophin staining in muscle

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Miscellaneous MyopathiesGlycogen storage diseasesGlycogen storage diseases “Ragged red” fibers“Ragged red” fibers——mitochondrial myopathiesmitochondrial myopathies

Drug reactions (eosinophilia)Drug reactions (eosinophilia) Nemaline rod myopathiesNemaline rod myopathies

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Axonal Vs. Demyelinating

Axonal: Axonal:

degenerating and degenerating and

regenerating regenerating

clusters, focal clusters, focal

accumulations in accumulations in

teased preps, teased preps,

demyelination is demyelination is

present but is global, present but is global,

ieie secondary to secondary to

axonal damage. axonal damage.

Examples: diabetes, Examples: diabetes,

neuroaxonal neuroaxonal

dystrophy, toxinsdystrophy, toxins

Demyelinating: Demyelinating:

Remember “onion Remember “onion

bulbs” due to bulbs” due to

repeated bouts of repeated bouts of

degeneration and degeneration and

regeneration of regeneration of

myelin. Examples: myelin. Examples:

CIDP, GB CIDP, GB

syndromesyndrome

Teased prepTeased prep

Teased prepTeased prep

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“Vasculitis”

�� For pathologic diagnosisFor pathologic diagnosis

��Inflammatory cells Inflammatory cells

(lymphocytes and (lymphocytes and

macrophages) surrounding macrophages) surrounding

andand infiltrating vessel wallinfiltrating vessel wall

��“Fibrinoid necrosis” of “Fibrinoid necrosis” of

vessel wallvessel wall

��clinical contextclinical context——very very

important!important!

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