¾ Central nervous system ¾ Peripheral nervous system Pathology of the Nervous System

JANTIMA TANBOON,MD

27/10/51 Jantima Tanboon, MD 2

Normal cells

ƒ Neuron

ƒ Glia Macroglia: ectoderm Microglia: mesoderm

ƒ Choroid plexus

ƒ Neuropil

ƒ Meningothelial cells Virchow-Robin space 27/10/51 missinglink.ucsf.eduJantima Tanboon, MD /www.lab.anhb.uwa.edu.au3 27/10/51 Jantima Tanboon, MD 4

Neuron

ƒ Nuclei, ganglia

ƒ Cell body (perikaryon), processes

ƒ Eccentric nucleus

ƒ Prominent nucleolus

ƒ Abundant Nissl substance

ƒ Microtubule, neurofilament, prominent golgi, rER, synaptic specialization

ƒ NFP, NeuN, synaptophysin 27/10/51NFP, NeuN, synaptophysinJantima Tanboon, MD 5 27/10/51 Jantima Tanboon, MD 6

1 Glia Astrocytes

ƒ Round-oval nuclei ƒ Macroglia <- neuroectoderm ƒ Pale chromatin

Astrocytes,Oligodendrocytes, Ependyma ƒ Gray/white matter

ƒ Protoplasmic: gray ƒ Microglia <- bone marrow ƒ Fibrous: gray/white ƒ Inflammation, repair, fluid balance, energy ƒ Star shape ƒ GFAP, Golgi method metabolism

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Astrocytes Oligodendrocytes

Processes ƒ Processses wrap neural axons DNeuron ƒ Like Schwann cells in PNS ƒ Metabolic buffers ƒ Multiple internodes ƒ Small round lymphocyte-like nuclei ƒ Detoxifiers ƒ Linear arrays ƒ Nutrient suppliers ƒ Electrical insulator DCapillaries ƒ Barriers: blood, CSF, brain Repair, scar formation/ fibroblast 27/10/51 Jantima Tanboon, MD 9 27/10/51 Jantima Tanboon, MD 10

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2 Ependymal cells

ƒ Line ventricular system

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Microglia

ƒ Mesoderm- bone marrow

ƒ Macrophages of CNS Injury response

1. Proliferation

2. Developing elongated (rod cells)- syphillis

3. Microglial nodules

4. Neuronophagia

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Reaction of neurons to injury Acute neuronal change (red neuron)

ƒ Acute neuronal change (red neuron) ƒ Acute CNS hypoxic/ ischemic ƒ Subacute and chronic neuronal injury (degeneration) ƒ H+E 12-24 hrs ƒ Axonal reaction ƒ Shrinkage cell body ƒ Subcellular alteration in organelles and cytoskeletal ƒ Nuclear pyknosis ƒ Neurodegenerative changes ƒ Loss of nucleolus

ƒ Loss of Nissl substance

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3 Subacute and chronic neuronal injury (degeneration)

ƒ Cell loss ƒ Reactive gliosis (early detect) Axonal reaction

ƒ Regeneration of axon->Axonal spheroids ƒ Increase protein synthesis-> sprouting ƒ Enlarge, round up cell body ƒ Peripheral nuclear displacement ƒ Dispersion of Nissl substance to periphery ƒ Central chromatolysis 27/10/51 Jantima Tanboon, MD 19 27/10/51 Jantima Tanboon, MD 20

Subcellular alteration in organelles and Reaction of Astrocytes to injury cytoskeletal

ƒ Lipofuscin, proteins, CHO ƒ Gliosis***-indicator of CNS injury ƒ Viral inclusion ƒ Cellular swelling z Intranuclear

z Intracytoplasmic ƒ Rosenthal fibers

Neurodegenerative changes ƒ Corpora amylacea

ƒ Neurofibrillary tangles-Alzheimer ƒ Glial cytoplasmic inclusion ƒ Lewy body- Parkinson ƒ Alzheimer type II astrocyte ƒ Abnormal vacuolation- CJD

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Gliosis

ƒ Astrocyte: hypertrophy hyperplasia

ƒ Nucleus: eccentric, enlarged vesicular, prominent nucleolus

ƒ Scant->bright pink cytoplasm

ƒ Gemistocytic astrocyte

ƒ Glial fibrils

ƒ Bergmann gliosis

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4 Rosenthal fibers Corpora amylacea

ƒ Thick elongated brightly eosinophilic ƒ Concentrically lamellated round faintly basophilic, ƒ Irregular contour within astrocytic process PAS positive 5-50µm ƒ Long standing gliosis ƒ Heat shock protein, ubiquitin ƒ Pilocytic astrocytoma ƒ Astrocytic end process ƒ Craniopharyngioma z Subpial ƒ Syrinx cavities z Perivascular zone ƒ Alexander disease ƒ Advance age ƒ αB-crystallin, hsp27, ubiquitin ƒ Adult polyglucosan body ƒ Lafora body (cytoplasm) 27/10/51 Jantima Tanboon, MD 25 27/10/51 Jantima Tanboon, MD 26

Alzheimer type II astrocyte

ƒ Gray matter ƒ Nucleus 2-3 times> normal ƒ Pale staining central chromatin ƒ Unrelated to Alzheimer disease ƒ Hyperamonemia ƒ Chronic liver disease ƒ Wilson disease ƒ Hereditary disorder of Urea cycle

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Cerebral edema

Vasogenic edema ƒ Disrupted normal BBB ƒ vascular permeability ƒ Intercellular space ƒ Localized/generalized Cytotoxic edema ƒ Neuronal/glial/endothelial injury ƒ Intracellular ƒ Generalized hypoxic/ischemic

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5 Increase intracranial pressure Subfalcine (cingulate)herniation

Herniation ƒ ACA compromised

ƒ Subfalcine (cingulate)

ƒ Transtentorial Tonsillar herniation (uncinate, mesial temporal) ƒ Life-threatening ƒ Tonsillar herniation Life-threatening ƒ Brain stem compression

ƒ Respiratory and cardiac center in medulla

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Transtentorial (uncinate, mesial temporal) herniation

ƒ CNIII compressed -> pupil dilate

z Impair ipsilateral ocular movement

ƒ PCA compressed->primary visual cortex

z Contralateral peduncle compress

z Kernohan’s notch

z Ipsilateral hemiparesis

ƒ Hemorrhage in midbrain, pons

z Secondary brain stem (Duret hemorrhage) 27/10/51 Jantima Tanboon, MD 33 27/10/51 Jantima Tanboon, MD 34

Hydrocephalus

Accumulation of excessive CSF ƒ Impaired flow ƒ Impaired absorption ƒ Overproduction ƒ Hydrocephalus ex vacuo

CSF Produced: Choroid plexus Absorbed: Arachnoid granulation

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6 Noncommunicating hydrocephalus Neural tube defects ƒ Congenital malformation 1. Anencephaly ƒ Tumor ƒ Inflammation 2. Encephalocele ƒ Hemorrhage 3. Spina bifida*(spinal dysraphism)

4. Myelomeningocele Communicating hydrocephalus ƒ Maternal blood: AFP, acetylcholinesterase ƒ Subarachnoid hemorrhage ƒ Folate deficiency ƒ Meningitis ƒ Metastasis to subarachnoid space ƒ Subsequent pregnancy 4-5% 27/10/51 Jantima Tanboon, MD 37 27/10/51 Jantima Tanboon, MD 38

Forebrain anomaly

1. Polymicrogyria

2. Megalencephaly

3. Microencephaly*

4. Lissencephaly

5. Neuronal heterotopia

6. Holoprocencephaly

7. Agenesis of corpus callosum

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Posterior fossa anomaly

ƒ Arnold-Chiari malformation

z Type I: less severe, tonsils

z Type II: vermis

z Small posterior fossa, large foramen magnum, low insertion of tent

z caudal displacement of medulla, tectum malformation, aqueduct stenosis, cerebralheterotopia, hydromyelial ƒ Dandy-Walker malformation

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7 Arnold- Chiari malformation Dandy-Walker malformation

ƒ Enlarged posterior fossa, ƒ Agenesis of vermis, ƒ Midline cyst

Type I Type II

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Direct parenchymal injury ƒ Hydromyelia

ƒ Syringomyelia Contusion: bruising Laceration: tearing ƒ Syringo bulbia

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Contusion

Plaque jaune

Contusion

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8 Diffuse axonal injury Diffuse axonal injury

ƒ Deep centroaxial white matter region

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Traumatic vascular injury

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Epidural hematoma Subdural hematoma

¾ Associated skull fracture ƒ Potential spaces-> Bridging veins Elder, infant ¾ Middle meningeal artery ¾ Acute subdural hematoma ¾ Chronic subdural hematoma ¾ Lucid interval

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9 Chronic subdural hematoma Subarachnoid hemorrhage

Multiple episode of rebleeding ƒ Trauma Organizing ƒ Aneurysm/Vascular malformation ƒ 1wk -> Clot lysis ƒ 2wks -> Fibroblast from meninges to hematoma ƒ 2-3 months -> Early development of hyalinized connective tissue

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Trauma sequele Cerebrovascular disease

ƒ Post traumatic hydrocephalus Cerebrovascular accident (CVA) ƒ Punch-drunk syndrome (dementia pugilistica) Ischemia and infarction

z Hydrocephalus z Global cerebral ischemia z Thining of corpus callosum z Focal cerebral ischemia z DAI z Neurofibrillary tangles Intracranial hemorrhage z Diffuse Aβ-plaque z Intraparenchymal (intracerebral) hemorrhage ƒ Epilepsy z Rupture Berry aneurysm ƒ Brain tumor (meningioma) ƒ Infectious disease z Vascular malformation ƒ Psychiatric disorder Hypertensive cerebrovascular disease 27/10/51 Jantima Tanboon, MD 57 27/10/51 Jantima Tanboon, MD 58

Global cerebral ischemia

ƒ Diffuse hypoxic/ischemic encephalopathy

ƒ Low flow

ƒ Respirator brain

ƒ Border zone (watershed) infarction

ƒ Most susceptible

z Pyramidal cells of Sommer sector (CA1) of the hippocampus, Purkinje cell of cerebellum,

27/10/51 pyramidal neuronJantima in Tanboon,neocortex MD 59 27/10/51 Jantima Tanboon, MD 60

10 1. Early change: 12-24 hrs Red neuron Neutrophils 2. Subacute change: 24hrs-2 wks Necrosis Macrophage Vascular proliferation Gliosis 3. Repair: after 2 weeks Remove all necrotic tissue Loss normal organized CNS structure Gliosis Pseudolaminar necrosis 27/10/51 Jantima Tanboon, MD 61 27/10/51 Jantima Tanboon, MD 62

Focal cerebral ischemia

MCA* Embolization*

z Cardiac mural thrombi: MI, valvular disease, AF

z Thromboemboli: atheromatous plaque

z Paradoxical emboli

z Emboli associated with Sx

z Other material (tumor, fat, air) In situ thrombosis

z Atherosclerosis: carotid bifurcation, origin of MCA, basilar artery

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Non hemorrhagic infarcts

ƒ First 6 hrs: difficult ƒ 48 hrs: pale soft swollen, indistinct GW junctio ƒ 2-10 days: gelatinous, friable, distinct ƒ 10-3 wks: liquefies, fluid filled cavity Hemorrhagic infarcts

ƒ Reperfusion: collaterals, dissolution of intravascular occlusion

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11 Bone marrow embolization Intraparenchymal hemorrhage

ƒ HT ¾ ¾ Fat embolism ƒ Putamen* thalamus pons cerebellar hemisphere ¾ ¾ Fractures ƒ Charcot-Bouchard aneurysm Fusiform Basal ganglia ƒ Ganglionic hemorrhage Basal ganglia Thalamus ƒ Lobar hemorrhage

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Lobar hemorrhage

ƒ Hemorrhagic diathesis

ƒ Neoplasms

ƒ Drug abuse

ƒ Infectious vasculitis

ƒ Non infectious vasculitis

ƒ Cerebral amyloid angiopathy

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Aneurysm

Saccular (berry) abeurysm MC subarachnoid hemorrhage Congenital Atherosclerosis Fusiform aneurysm, Basilar a Mycotic Traumatic Dissecting Anterior ciculation

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12 Hypertensive cerebrovascular Vascular malformations disease

1. Arteriovenous malformations* ƒ Lacunar infarction (<15mm)

2. Cavernous hemangiomas Basal ganglia, thalamus. Internal capsule, deep white matter, pons 3. Capillary telangiectasia

4. Venous angiomas ƒ Slit hemorrhage ƒ Hypertensive encephalopathy Diffuse cerebral dysfunction headache, confusion, vomitting, convulsion-> coma

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Lacunar infarction 27/10/51 Jantima Tanboon, MD 75 27/10/51 Jantima Tanboon, MD 76

Tumors Gliomas

ƒ Subtle histologic distinction ƒ Astrocytoma ƒ Low grade lesion sometimes infiltrate ƒ Anatomic site -> prognosis Pilocytic, Anaplastic, Glioblastoma ƒ Spread through subarachnoid spaces 1. Gliomas ƒ Oligodendroglioma 2. Neuronal tumors ƒ Ependymoma 3. Embryonal tumors 4. Meningioma 5. Metastasis

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13 Fibrillary (diffuse) astrocytoma

ƒ 80% of adult primary brain tumor

ƒ 4th-6th decades

ƒ Cerebral hemisphere

ƒ Histology <-> prognosis

ƒ II/IV Diffuse astrocytoma

ƒ III/IV Anaplastic astrocytoma

ƒ IV/IV Glioblastoma

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Glioblastoma

ƒ Palisading necrosis

ƒ Vascular proliferation

ƒ Glomeruloid body

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Pilocytic astrocytoma

ƒ Children, young adult ƒ Cerebellum*, floor-wall of 4th ventricle ƒ Optic nerve, cerebral hemisphere Gross: Cystic with mural nodule ƒ Solid well circumscribed Micro: Hair-like process ƒ Rosenthal fibers ƒ Eosinophilic granular bodies ƒ Microcysts

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14 Oligodendroglioma

ƒ 4th-5th decades

ƒ Cerebral hemisphere: white matter

ƒ Better prognosis>astrocytoma Gross: Infiltrative, gelatinous gray mass Micro: Similar to normal oligodendrocyte

ƒ Clear cytoplasmic halo

ƒ Delicate capillary network

ƒ Calcifications (~90%) 27/10/51 Jantima Tanboon, MD 85 27/10/51 Jantima Tanboon, MD 86

Ependymoma

ƒ 1st two decades: 4th ventricle

ƒ Adults: spinal cord

ƒ Supratentorial, spinal better>cerebellum Gross: papillary/ circumscribed solid Micro: Rosettes Perivascular pseudorosettes

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Perivascular27/10/51 pseudo rosetteJantima Tanboon, MD 89 Homer-Wright27/10/51 pseudo rosetteJantima Tanboon, MD 90

15 Embryonal tumor: Medulloblastoma

ƒ 20% of pediatric brain tumor ƒ Cerebellum* ƒ Undifferentiated ƒ Highly malignant, dismal prognosis ƒ Radiosensitive-> 5 yr survival 75% Gross: ƒ Children midline of cerebellum ƒ Adult: lateral Micro: Small blue cells, rosette Flexner27/10/51 Wintersteiner rosetteJantima Tanboon, MD 91 27/10/51 Jantima Tanboon, MD 92

Meningioma

ƒ Meningothelial cell (arachnoid) ƒ External surface, ventricle ƒ Loss of 22q (NF2 22q12) ƒ Slow growing ƒ Parasagittal convexity, lateral convexity, wing of sphenoid, olfactory groove, foramen magnum ƒ F:M = 3:1 (10:1, spinal cord) ƒ Rapid growth during pregnancy ƒ MIB1 (Ki67) 27/10/51 Jantima Tanboon, MD 93 27/10/51 Jantima Tanboon, MD 94

Encapsulated mass, en plaque Grade I – IV

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16 Metastatic tumors Metastatic tumors

ƒ ¼- ½ of intracranial tumors ƒ Sharply demarcated ƒ 5 MC primary site (80%): ƒ Gray-white junction z Lung ƒ Edema, reactive gliosis, central necrosis z Breast ƒ Meningeal carcinomatosis: z Skin (melanoma) z Brain, spinal cord, intracranial nerve root z Kidney Brain, spinal cord, intracranial nerve root

z GI tract z Lung: small cell CA, adenoca

ƒ Choriocarcinoma z Breast CA ƒ Intraparenchyma, meninges

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Schwannoma

ƒ Syn: Neurilemmoma

ƒ Schwann cell

ƒ Symptoms: local compression

ƒ NF2

ƒ CP angle, vestibular branch of VIII

ƒ Acoustic neuroma (vestibular schwannoma)

ƒ Gross: Circumscribed

ƒ Micro: Antoni A (Verocay body), Antoni B 27/10/51 Jantima Tanboon, MD 99 27/10/51 Jantima Tanboon, MD 100

Antoni A: Neurofibroma cellular area, nuclear free zone, Verocay bodies ƒ Skin: cutaneous neurofibroma Antoni B: Loose cellular, microcysts, ƒ Peripheral nerve: solitary neurofibroma myxoid changes ƒ Sporadic or associated with NF1 Elongated cells, oval nuclei Degenerative change: ƒ Skin: nodules (pedunculated, hyperpigmented) nulcear pleomorphism, ƒ Plexiform neurofibroma: NF1-> malignant xanthomatous change, vascular hyalinization

27/10/51 www.robbinspathology,wwwJantima Tanboon, MD .cumc.columbia.edu101 27/10/51 Jantima Tanboon, MD 102

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Malignant peripheral nerve sheath tumor

ƒ MPNST ƒ De no vo: Neurofibroma, plexiform ƒ Associate with NF1 ƒ NF1, p53, p16 ƒ Highly malignant ƒ Local invasive, recurrence, metastasis ƒ Triton tumor

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Traumatic neuroma Traumatic neuroma

ƒ Morton’s neuroma

ƒ Non neoplastic proliferation

ƒ Response to injury

ƒ Disorganized proliferation of proximal stump

ƒ Firm nodule, tender, painful Gross: circumscribed white gray nodules Micro: haphazard proliferation of nerve fascicles

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18 Type 1 Neurofibromatosis

ƒ AD

ƒ Neurofibromas (plexiform, solitary)

ƒ Gliomas of the optic nerve

ƒ Lisch nodules (iris)

ƒ Café au lait spots

ƒ Tend to have malignant transformation

ƒ NF1 17q11.2 tumor suppressor: neurofibromin

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Type 2 Neurofibromatosis Type 2 Neurofibromatosis

ƒ AD ƒ Heterotopia of Schawann cells, glial cells

ƒ < NF1 ƒ Nonsense mutation, missense mutation

ƒ Bilateral vestibular (acoustic) schawannoma ƒ NF2 22q12: merlin

ƒ Multiple meningiomas

ƒ Gliomas, Ependymoma of the spinal cord

ƒ Schwannosis (spinal cord)

ƒ Meningioangiomatosis

ƒ Glial hamartia 27/10/51 Jantima Tanboon, MD 111 27/10/51 Jantima Tanboon, MD 112

Tuberous sclerosis Tuberous sclerosis

ƒ AD AD ƒ Disruption of tumor suppressor gene Hamartomas and benign neoplasms ƒ TSC1: hamartin ƒ CNS (cortical tubers, subependymal hamartomas)-> epilepsy, mental retardation ƒ TSC2: tuberlin ƒ Renal angiomyolipoma, retinal glial hamartomas, cardiac rhabdomyomas ƒ Cysts: liver kidney pancreas ƒ Cutaneous lesion: angiofibroma, shagreen patches, ash-leaf patches, subungual fibroma

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19 Von Hippel-Lindau Disease

ƒ AD

ƒ Hemangioblastoma: cerebellum, retina, brainstem, spinal cord

ƒ Pheochromocytoma

ƒ Cysts; pancreas kidney, liver

ƒ Tend to develop renal cell carcinoma

ƒ Missense mutation in VHL tumor suppressor

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Primary disease of myelin Multiple sclerosis (MS)

ƒ MC* demyelinating disorder Disruption of neuronal communication MC* demyelinating disorder ƒ Autoimmune: env+genetic White matter disorders ƒ New symptoms (relapse) -> remission (incomplete)

¾ Demyeliniating disease: acquired: MS ƒ Accumulation of increasing neurologic deficit

ƒ Any age, F:M = 2:1 ¾ Dysmyelinating disease: mutation: ƒ HLA-DR2 leukodystrophy ƒ T-cell, macrophage

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20 Multiple sclerosis (MS) Plaque: well-circumscribed,irregular shape, White matter disease slightly depressed glassy gray-tan lesion Plaques:

z Ventricles*

z optic nerve, chiasm, brainstem,tracts, cerebellum, spinal cord. Active plaques:

z Macrophage+myelin debris

z Perivascular cuffs

z Axon preserved

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Multiple sclerosis (MS) Central pontine demyelinolysis

Inactive plaques: ƒ Loss myelin/preserve axons, neurons ƒ Rapid correction of hyponatremia z No inflammation ƒ Pons*, elsewhere z Little-no myelin ƒ Rapidly evolving quadriplegia z Prominent astrocytic proliferation+ gliosis Shadow plaques:

z Not circumscribed border

z Thinned out myelin sheaths

z Incomplete loss/partial remyelination 27/10/51 Jantima Tanboon, MD 123 27/10/51 Jantima Tanboon, MD 124

Degenerative diseases Alzheimer disease

ƒ Gray matter disease MC* cause of dementia in elderly

ƒ Progressive neuronal loss Affecting cerebral cortex

ƒ Secondary change in white matter tracts ƒ Forgetfulness ƒ Insidious impairment of intellectual function 1. Cortex ƒ Alterations in mood and behavior 2. Basal ganglia and brain stem ƒ Progressive disorientation 3. Spinocerebellar ƒ Memory loss 4. Motor neurons ƒ Aphasia ƒ Profounded disabled in next 5-10 yrs 27/10/51 Jantima Tanboon, MD 125 27/10/51 Jantima Tanboon, MD 126

21 Alzheimer disease Aβ:

ƒ Pathologic examination -> definite Small aggregates: ƒ Alter neuronal ƒ Clinical + modern radiologic methods transmission ƒ Sporadic> familial (5-10%) ƒ Toxic to neurons ƒ Rare before age of 50 and synaptic ƒ Amyloid precursor protein (APP) endings

ƒ Chromosome 21 (Down syndrome>45 yr)

ƒ Apolipoprotein (ApoE4) Chr 19 -> early onset

ƒ SORL1_> late onset 27/10/51 Jantima Tanboon, MD 127 27/10/51 Jantima Tanboon, MD 128

Aβ: Alzheimer disease

Large aggregates: Gross: cerebral atrophy ƒ Form plaques ƒ Frontal/temporal/ temporal ƒ Neuronal death ƒ Spare occipital ƒ Local inflammatory response ƒ Hydrocephalus ex vacuo ƒ Cell injury ƒ Alter region-to-region commnication through mechanical effect ƒ Form tangles (Hyperphosphorelate tau protein )

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Granulovacuolar degeneration: Major microscopic abnormalities: ƒ Normal aging 1.Neuritic (senile) plaques ƒ AD: hippocampus, olfactory bulb Hirano bodies Diffuse plaques ƒ Major compotent: actin 2.Neurofibrillary tangles ƒ Hippocampal pyramidal cells 3.Amyloid angiopathy

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22 Parkinsonism Parkinsonism

ƒ Mask facies Idiopathic Parkinson disease ƒ Stooped posture ƒ Sporadic>familial (AD/AR) ƒ Slowness voluntary movement ƒ α- synuclein/parkin ƒ Festinating gait ƒ Dopaminergic neuron in substantia nigra ƒ Rigidity ƒ MPTP/ pesticide exposure ƒ Pill-rolling tremor ƒ Caffeine/ nicotine -> protective ƒ 10-15%->dementia (fluctuating courses/hallucination) ƒ RX -> L-dihydroxyphenylalanine (L-DOPA) ƒ Pathologic evidence of Alzheimer disease

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Huntington disease

ƒ AD

ƒ Trinucleotide (CAG) repeated mutation 4p16.3

ƒ huntingtin

ƒ Progressive movement disorder+dementia

ƒ Degenerate striatum (caudate+putamen)

Gross: Pallor of substantia nigra, Locus ceruleus ƒ Chorea:

Micro: Loss of cathecholaminergic neurons,Gliosis ƒ Jerky, hyperkinetic, dystonic movement Lewy body: basal nucleus of Meynert, sympathetic27/10/51 ganglia, cingulate/parahippocampalJantima Tanboon, MD gyrus135 27/10/51 Jantima Tanboon, MD 136

Huntington disease Huntington disease

ƒ 4th-5th decades Gross: ƒ Striking atrophy on caudate/putamen ƒ Depend on length of CAG repeate ƒ Globus pallidus ƒ >70 adolescent Micro: ƒ Motor>cognitive impairment ƒ Severe neuronal loss

ƒ Gliosis

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23 Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis

ƒ ALS ƒ Sporadic>familial (AD 5-10%) ƒ MC form of neurodegeneration involving motor ƒ Chromosome 21 system ƒ Superoxide dismutase (SOD1) ƒ Muscle atrophy ƒ Asymmetric weakness of hands ƒ Hyper-reflexia (loss upper+lower motor neuron) ƒ Cramping/spasticity of arms and legs ƒ Degeneration of the corticospinal tract ƒ Fasciculations ƒ M>F ƒ Respiratory muscles-> death ƒ >5th decades Respiratory muscles-> death ƒ 5 year survival-50%

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Transmissible spongiform Prion disease encephalopathy (Prion disease)

Creutzfeldt-Jakob disease (CJD) ¾ PRNP gene chr 20 PrPc -> PrPsc,PrPres

Variant CJD ¾ Resistant to protease digestion

Gerstmann-Straussler-Scheinker syndrome (GSS) ¾ Other PrPc change Fatal familial insomnia ¾ Low rate -> sporadic Kuru ¾ High rate -> mutation Scrapie: sheep/goat Mink transmissible encephalopathy Chronic wasting disease of deer and elk Bovine spongiform encephalopathy (BSE) 27/10/51 Jantima Tanboon, MD 141 27/10/51 Jantima Tanboon, MD 142

Prion disease Creutzfeldt-Jakob disease (CJD)

ƒ Accumulation of PrPsc in neural tissue -> cell injury Accumulation of PrP in neural tissue -> cell injury ƒ Startle myoclonus, cerebellar dysfunction Creutzfeldt-Jakob disease (CJD) ƒ Fatal in 7 months ƒ Rapidly progressive dementia Spongioform transformation: ƒ 85% sporadic 1: 1,000,000 ƒ Cerebral cortex/deep gray matter structures ƒ Familal form

ƒ 7th decades ƒ Neuronal loss, reactive gliosis

ƒ Subtle changes in memory and behavior -> Rapidly ƒ Expansion of vacuoles -> cyst (status spongiosus) progressive dementia

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24 Variant Creutzfeldt-Jakob disease (vCJD)

ƒ Young adults

ƒ Exposure to BSE (cattle)

ƒ Behavioral disorders in early stage

ƒ Neurologic syndrome progress slowly

ƒ Pathologic/molecular finding: the same

ƒ + Abundant cortical amyloid plaques

27/10/51 Jantima Tanboon, MD 145 27/10/51 Jantima Tanboon, MD 146

Gerstmann-Straussler-Scheinker syndrome Fatal familial insomnia (GSS) Fatal familial insomnia

ƒ Mutation in PRNP gene ƒ Initial stage->Sleep disturbance ƒ <3 yr: neurological signs ƒ Chronic cerebellar ataxia ƒ Ataxia, autonomic disturbance, stupor, coma ƒ Progressive dementia ƒ Fatal sporadic insomnia ƒ Clinical slower than CJD Micro: NO spongioform pathology ƒ Death in several years ƒ Neuronal loss, reactive gliosis

Micro: the same ƒ Anterior ventral/dorsomedial nuclei of thalamus

ƒ + numerous amyloid (Kuru) plaques/ tangles ƒ Inferior olivary nuclei 27/10/51 Jantima Tanboon, MD 147 27/10/51 Jantima Tanboon, MD 148

Infection ƒ Meningitis ƒ Meningoencephalitis Routes of infection: ƒ Chemical meningitis ƒ Meningeal carcinomatosis 1. Hematogenous spread ƒ Meningeal lymphomatosis 2. Direct implantation Infectious meningitis

ƒ Acute pyogenic (bacterial) 3. Local extension Acute pyogenic (bacterial) ƒ Aseptic meningitis (viral) 4. Peripheral nervous system ƒ Chronic meningitis (tuberculous, spirochetal, cryptococcal) 27/10/51 Jantima Tanboon, MD 149 27/10/51 Jantima Tanboon, MD 150

25 Acute pyogenic (bacterial) meningitis

ƒ Escherichia coli* ƒ Streptococcus group B* ƒ Streptococcus pneumoniae**-> over convexities ƒ Listeria monocytogenes ƒ Neiseria meningitidis*** ƒ Haemophilus influenza -> basal ƒ Meningeal impairment, stiffness, headache, photophobia ƒ CSF: Protein, ‚ glucose 27/10/51 Jantima Tanboon, MD 151 27/10/51 Jantima Tanboon, MD 152

Aseptic (viral) meningitis Acute focal suppurative infection

Brain abscess: ƒ Less fulminant ƒ direct implant, local extension ƒ Viral, NSAIDS, chemical ƒ Frontal>parietal>cerebellum ƒ CSF: lymphocytosis, protein, sugar <-> ƒ CSF: protein <->sugar ƒ Self limiting, symptomatic treatment Gross: mild edema Micro: mild-mod leptomeningeal L infiltration

27/10/51 Jantima Tanboon, MD 153 27/10/51 Jantima Tanboon, MD 154

Subdural empyema: bacteria, fungus Chronic bacterial meningoencephalitis Extradural / spinal epidural abscess : osteomyelitis Tuberculosis:

ƒ Base of the brain: gelatinous, fibrinous exudate

ƒ Meningoencephalitis*, Obliterative endarteritis, Tuberculoma Cpx: Arachnoid fibrosis -> hydrocephalus Obliterative endarteritis -> infarction

27/10/51 Jantima Tanboon, MD 155 27/10/51 Jantima Tanboon, MD 156

26 Neurosyphilis = Tertiary syphilis

1. Meningovascular neurosyphilis

2. Paretic neurosyphilis

3. Tabes dorsalis Meningovascular:

ƒ Chronic meningitis: base/convexities/spinal cord

ƒ Obliterative (Heubner) endarteritis

ƒ Plasma cell/ lymphocytes

ƒ Cerebral gumma

27/10/51 Jantima Tanboon, MD 157 27/10/51 Jantima Tanboon, MD 158

Paretic neurosyphilis ƒ Invasion T. pallidum ƒ Granular ependymitis ->hydrocephalus ƒ General paresis of the insane: delusion of grandeur, dementia, loss mental/physical Tabes dorsalis ƒ Damage sensory nerves in dorsal root ƒ Loss Joint position sense -> ataxia ƒ Loss of pain sensation -> Chacot joint -> lightning pain ƒ Loss DTR

27/10/51 Jantima Tanboon, MD 159 27/10/51 Jantima Tanboon, MD 160

Viral meningoencephalitis

ƒ Meningoencephalitis

ƒ Encephalomyelitis Histology:

ƒ Perivascular/parenchymal mononuclear cell infiltrates

ƒ Glial reaction: microglial nodule

ƒ Neuronophagia

27/10/51 Jantima Tanboon, MD 161 27/10/51 Jantima Tanboon, MD 162

27 Herpes simplex virus type 1

ƒ Encephalitis

ƒ Any age group: children/young adult*

ƒ Alterating mood, memory, behavior

ƒ Orbital gyri of frontal lobe Herpes simplex virus type 2 ƒ Medial regions of temporal lobe

ƒ Necrotizing and hemorrhagic ƒ Meningitis-Adult

ƒ Perivascular cuffing ƒ Encephalitis-vaginal delivered neonate

ƒ Cowdry type A in neurons/glia ƒ AIDS-acute hemorrhagic necrotizing encephalitis 27/10/51 Jantima Tanboon, MD 163 27/10/51 Jantima Tanboon, MD 164

Varicellar-zoster virus (Herpes zoster) Cytomegalovirus

ƒ Immunosuppressed – herpes zoster encephalitis Immunosuppressed – herpes zoster encephalitis ƒ Virus: paraventricular subependymal region ƒ Inclusion bodies in in glia and neuron ƒ Severe hemorrhagic necrotizing Cytomegalovirus ventriculoencephalitis

ƒ Choroid plexitis ƒ Immunosuppressed-subacute encephalitis ƒ Fetus - In utero -> periventricular necrosis + severe brain destruction -> microcephaly + periventricular calcification

27/10/51 Jantima Tanboon, MD 165 27/10/51 Jantima Tanboon, MD 166

Poliomyelitis Rabies

ƒ Anterior horn cell motor neuron of spinal cord Anterior horn cell motor neuron of spinal cord Neuronal degeneration + inflammation ƒ Perivascular cuff, neuronophagia th ƒ Posterior horn/ motor cranial nuclei ƒ Midbrain, floor of 4 ventricle, medulla

ƒ Long term: neuronal loss, gliosis, atrophy ƒ Basal ganglia, spinal cord, dorsal root ganglia

Negri body – inflammation:

ƒ Pyramidal neuron – hippocampus

ƒ Purkinje cell - medulla

27/10/51 Jantima Tanboon, MD 167 27/10/51 Jantima Tanboon, MD 168

28 HIV HIV

ƒ Direct effect/ opportunistic infection/ tumors HIV-1 meningoencephalitis (subacute encephalitis) ƒ AIDS dementia complex: mental slowing, Aseptic HIV-1 meningitis memory loss mood disterbance ƒ 10%: 1-2 wks after seroconversion ƒ Chronic inflammatory cell infiltration

ƒ mild lymphocytic meningitis ƒ Microglial nodule + multinucleated giant cells

ƒ perivascular cuffing Vacuolar myelopathy ƒ Tracts of spinal cord ƒ myelin loss

27/10/51 Jantima Tanboon, MD 169 27/10/51 Jantima Tanboon, MD 170

Progressive multifocal leukoencephalopathy

ƒ PML: JC polyomavirus

ƒ Immunosuppressed: CML, chemoRX, AIDS

ƒ 65% of normal people: exposure by 14 yr

ƒ Reactivation

ƒ Oligodendrocyte-> demyelination CT:

ƒ extensive multifocal ring enhancing lesion in hemispheric/ cerebellar white matter

27/10/51 Jantima Tanboon, MD 171 27/10/51 Jantima Tanboon, MD 172

Fungal encephalitis

ƒ Granulomas, abscesses, meningitis Candida albicans Multiple microabscesses w/wo granuloma Mucor Aspergillus fumigatus Septic hemorrhagic infarction Cryptococcus neoformans Histoplasma capsulatum

27/10/51 Jantima Tanboon, MD 173 27/10/51 Jantima Tanboon, MD 174

29 Cerebral toxoplasmosis

ƒ Toxoplasma gondii

ƒ AIDS CT/MR: multiple ring enhancing lesion Gross:

ƒ Abscesses, Gray-white junction, deep gray nuclei Micro:

ƒ Central necrosis, petichiae hemorrhage, tachyzoite, bradyzoite 27/10/51tachyzoite, bradyzoiteJantima Tanboon, MD 175 27/10/51 Jantima Tanboon, MD 176

Cysticercosis

Tenia solium

27/10/51 Jantima Tanboon, MD 177 27/10/51 Jantima Tanboon, MD 178

Amebic meningoencephalitis

Naegleria spp

ƒ Swimming in nonflowing fresh water

ƒ Fatal encephalitis

Acanthamoeba spp

ƒ Chronic granulomatous meningoencephalitis

27/10/51 Jantima Tanboon, MD 179 27/10/51 Jantima Tanboon, MD www.fujita-hu.ac.jp180

30 Thank27/10/51 you for your attentionJantima Tanboon, MD 181

31