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Gen Pathology (Dra.

Sionzon) CNS PART 1 : CNS PATHOLOGY 16 February 2008 CNS PATHOLOGY Review: Principal cells of the CNS • Neurons • Glial Cells – Astrocytes – Olidodendroglia – ependyma • Microglia • Meningothelial cells

Notes: negli bodies – in rabies cytopathic efeects – in CMV neurofibrillary bundles – in alzheimers 1. ASTROCYTES • star-shaped glial cells • functions include nutritional supply and insulation of neurons, contribution to blood brain barrier • play prominent role in response to injury • cytoplasm of “resting” astrocytes not readily evident

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Acute neuronal injury (red neurons): irreversible injury due to various causes including hypoxia/ischemia, infections, toxins

response to tissue injury: hypertrophy; astrogliosis



highlighted by immunostaining for GFAP (Glial fibrillary Astrocytic protein –for astrocytic process)

Chromatolysis: reaction w/in the neuronal cell body to axonal injury

(a) (b) (a) ASTROGLIOSIS (GLIOSIS) (b) GFAP STAINING OF REACTIVE ASTROCYTES 2. OLIGODENDROCYTES • Process wrap around axons of neurons to form myelin

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Oligodendrocyte injury is a feature of demyelinating diseases (e.g multiple sclerosis) Nuclei may harbor viral inclusions in progressive multifocal leukoencephalopathy Limited capacity for regeneration

brim, leu, virns

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Gen Pathology – CNS1: CNS Pathology by Dra Sionzon
• • Cerebral parenchymal compartment Intravntricular spaces

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Notes: egg shaped daw 3. EPENDYMAL CELLS • Line ventricular chambers, aqueduct, central canal of spinal cord • Modulate the transfer of fluid between CSF and parenchyma

Reaction to injury ; ependymal granulations (loss of ependyma plus subependymal astrogliosis)

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FEATURES UNIQUE TO CNS Enclosed in a rigid bony compartment Autoregulation of cerebral blood flow Dependent on glucose and high O2 supply CSF fills ventricles and spaces Lack a lymphatic circulation Cell have limited regenrative ability Immunologically secluded BBB and blood CSF barrier separates the brain from the rest of the body INTRACRANIAL COMPARTMENTS Epidural space Subdural space Subarachnoid space

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Gen Pathology – CNS1: CNS Pathology by Dra Sionzon
PATHOLOGIC REACTIONS • Selective vulnerability” • Pathologic reactions of neurons – Acute injury – Degeneration – Axonal reaction – Formation of neuronal inclusions – Vacuolization of cytoplasm and neurophil – Aggregation of abnormal proteins – Neuronophagia • Astrocytes - Gliosis – glial scar • Microglia - glial nodules – Phagocytosis of dying neurons (neuronophagia) COMMON PATHOPHYSIOLOGIC PHENOMENA • • •

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CEREBRAL EDEMA 1. Vasogenic Edema – blood brain barrier dysfunction, fluid accumulates between neurons and glial cells 2. Cytotoxic Edema – fluid accumulates inside the cells (ischemia, hypoxia) 3. Interstitial Edema – results from increase CSF (dysfunction of brain CSF barrier) – Complication of hydrocephalus Gross Appearance Of The Brain In Vasogenic Edema • Common autopsy findings – Flattened broad gyri – Narrowed slit-like sulci – Compressed lateral ventricles – Brain is heavier than normal, soft; fluid seeps from cut surfaces – Signs of herniation may be seen

Brain surrounded by rigid skull Rigid barriers divide the cranial cavity into subcompartments (falx cerebri, cerebellar tentorium) Intracranial volume is fixed (brain parenchyma, CSF, blood) Space occupying masses (tumor, hemorrhage, etc), brain edema, increased CSF lead to increased CSF intracranial pressure and may cause herniation Herniation is displacement of expanding brain to adjacent subcompartments or through formaen magnum


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Necrosis of herniated parenchyma Compression of vessels and consequent infarction (eg posterior cerebral artery infarction involving the visual cortex) Nerve compression (eg III cranial nerve in transtentorial herniation w/ consequent papillary dilation and impaired ocular movement) Death (eg brainstem compression in tonsillar herniation

MALFORMATIONS AND DEVELOPMENTAL DEFECTS A. DEVELOPMENTAL DISORDERS 1. Cranial Dysraphism – Anencephaly – Encephalocele 2. Spinal Dysraphism – Spina bifida occulta – Meningocele – Meningimyelocele – Rachischisis CNS MALFORMATIONS


HERNIATIONS 1. Cingulate Herniation/ Subfalcine – Cingulate gyrus compressed underneath the falx cerebri – Caused by unilateral hemispheric mass 2. Transtentorial Herniation/ Uncinate – Uncus gyri herniate in the cerebellar tentorium 3. Tonsillar Herniation – Cerebellar tonsils are compressed in the foramen magnum – Life threatening


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Congenital CNS Malformation : Morphological CNS defect present at birth due to an abnormal development process)

Causes: unknown in a majority of cases, genetic and chromosomal abnormalities, environmental (eg infection, drugd, nutritional, multifactorial) • Anatomic pattern of malformation reflects the stage of formation of the CNS at the time of injury Important types and examples: 1. Neural Tube Defects (eg anencephaly, myelomeningocele, spina bifida, encephalocele)

Gen Pathology – CNS1: CNS Pathology by Dra Sionzon

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2. 3.
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Forebrain anomalies (eg holoprosencephaly, agenesis of the corpus callosum, neuronal migration defects, microencephaly) Posterior fossa defects (Arnold-Chiari and DandyWalker malformation) Hydromyelia, syringomyelia


NEURAL TUBE DEFECTS • Transformation of the neural plate into the neural tube occurs at 22-28 days of gestation • Neural tube defects are due to failure of a portion of the neural tube to close or reopening of a region after successful closure • All characterized by abnormalities involving both neural tissue and overlying one or soft tissues • Most common type of CNS malformation, wide geographic and ethnic variation in frequency, recurrence rate: 4-5%

Etiology: unknown, some association w/ unknown, chromosomal disorders (trisomy 13), environmental factors (eg folate deficiency), interaction of genetic and environmental etiology suspected based on research in mice.

Anenephaly with complete rachischisis (craniorachischisis) : Skull vault and vertebral arches are deficient, replacement of brain w/ vascular mass (area cerebrovasculosa)

Spinal neural tube defects: Myelomeningocele: herniation of the spinal cord meningeal tissue through a vertebral defect (picture) Meningocele: herniation of meningeal tissue only


Gen Pathology – CNS1: CNS Pathology by Dra Sionzon
Encephalocele (occipital) through a skull defect 3. FOREBRAIN ANOMALY : herniation of brain tissue

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Forebrain anomaly: Holoprosencephaly • Failure of separation of cerebral hemispheres

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May be associated with facial abnormalities (eg cyclopia) Etiology o o o o associations: trisomy 13, 18 Sonic hedgehog gene mutations Maternal diabetes mellitus Toxoplasmosis, other infections




POSTERIOR FOSSA ABNORMALITY: Arnold- Chiari Malformation (Chiari Type II Malformation) • Small posterior fossa

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Downward extension of cerebellar vermis through foramen magnum Caudally displaced medulla Often associated; o Aqueductal stenosis o Hydrocephalus o Lumbar myelomeningocele o hydromyelia

Forebrain anomaly: Agenesis of the corpus callosum • Absence of white matter bundles connecting cerebral hemispheres

PERINATAL BRAIN INJURY • Important cause of childhood neurological disability Cerebral Palsy (a clinical term): non-progressive neurologic motor deficit attributable to insults occurring during the prenatal and perinatal period Most common underlying pathology : hemorrhages and infarctions

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Gen Pathology – CNS1: CNS Pathology by Dra Sionzon
• • • Premature infants at increased risk germinal matrix hemorrhage and periventricular infarcts leading to periventricular leucomalacia In term infants: choroid plexus hemorrhage and infarcts involving cerebral cortex, basal ganglia and thalamus Common causes: maternal disease (eg hemorrhage, shock, drugs, trauma), placental abnormalities, neonatal disease (eg congenital heart disease)

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Caseous mycobacterial tubercles in the subarachnois space

GERMINAL MATRIX HEMORRHAGE in premature infant TRAUMA A. PHYSICAL INJURIES • Contusions (bruising) – “Coup lesions” and “contre coup” contusion – Rapid accelaration/ deceleration • Laceration (tearing) • Diffuse Axonal Injury • Traumatic vascular injury • Penetrating wounds SPINAL CORD INJURIES • Hyperextension injury – Cervical spinal – Sudden posterior displacement of the head – Rupture of anterior spinal ligament • Hyperflexion injury – Impact force driving the head down and forward – Anterior contusion of the cervical spine INTRACRANIAL BLEEDING • Epidural hematoma • Subdural hematoma • Subarachnoid hematoma • Intracerebral hemorrhage • Intraventricular hemorrhage internus” Tuberculous meningitis – microscopic findings: granulomatous inflammation w/ multinucleated giant cells, epithelioid cells, macrophages and lymphocytes. “hydrocephalus

Discharge of mycobacteria from tubercles into the subarachnoid space results in tuberculous meningitis that typically affects the base of the brain.






Manifestations: chronic mengitis and circumscribed abscess: TUBERCULOMA Typically due to hematogenous spread of bacteria from pulmonary lesions or lymph nodes This leads to caseous tubercles in the subarachnoid space or brain parenchyma

Tuberculoma: Growth or coalescence of small parenchymal tubercles creates abscesses w/ a caseous center. May occur anywhere in the brain but show a predilection for the cerebellum

Gen Pathology – CNS1: CNS Pathology by Dra Sionzon
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Neurosyphylis is a tertiary stage of syphilis and occurs in about 10% of patients w/ untreated infection Manifestations: meningeal- meningovascular syphilis, paretic neurosyphilis, tabes dorsalis Meningeal- Meningovascular Syphilis : chronic mengitis w/ numerous plasma cellS that may be associated w/ obliterative endarteritis Paretic Neurosyphilis ; invasion of the brain by Treponema pallidum inflammatory meningeal lesions are associated w/ parenchymal damage : loss of cortical neurons, striking proliferation of microglia (rod cells)

Impaired joint position sense, ataxia Loss of pain sensation- skin and joint damage Lightning pains Loss of deep tendon reflexes



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Common causative agents : enteroviruses, herpes simplex virus type 2, mumps virus Pathology : mild to moderate lymphocytic infiltration of the leptomeninges Clinical symptoms: headache, fever, usually short, benign course



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Viral infections of the brain (encephalitis), spinal cord (myelitis) or both (encephalomyelitis) Clinically most important infections caused by HIV, Herpes Simplex Virus, Human Cytomegalovirus, Poliovirus, Rabies Virus, Measles Virus. JC Virus, Arboviruses Localization of the infection within the CNS is often characteristic for specific viruses Microscopic pathology similar for almost all: perivascular cuffs of the lymphocytes, astrogliosis, microglial nodules, if neurons are infected: neuronophagia Viral inclusions in some cases may be characteristic

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Neurosyphilis : leptomeningeal thickening, spirochetes and rod cells. Patients show progressive loss of mental functions, often delusions of grandeur terminating in severe dementia: general paresis of the insane dementia:


HIV ENCEPHALITIS • As many as 60% of patients w/ AIDS develop neurological dysfunction • HIV infection can cause CNS damage by infecting the CNS and by leading to opportunistic CNS infections

Tabes dorsalis. Degeneration of the posterior columns of the spinal cord w/ loss of both axons and myelin Symptoms:

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Main target cells of HIV in CNS : microglial cells and macrophages Cytokines and reactive oxygen and nitrogen species released from infected cells may cause secondary neuron damage and lead to HIV dementia Typically affects deep gray structures and white matter Multinucleated cells, microglial nodules, demyelination

Gen Pathology – CNS1: CNS Pathology by Dra Sionzon

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Most common opportunistic CNS infections in AIDS: CMV Encephalitis, Toxoplasma Abscess, JC Virus – Induced Progressive Multifocal Leukoencephalopathy



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Most common sporadic encephalitis in the US, affects immunocompetent people, most commonly due to HSV-1 Initial infection of mucocutaneous surfaces of oral cavity, nose, eye Virus infects nerve endings, reaches ganglia in the peripheral nervous system and the CNS by axonal transport = in most cases causes latent infection in neurons Initial infection and reactivation from neurons may cause encephalitis HSV encephalitis typically involves the temporal lobe


CMV Ventriculoencephalitis in AIDS: Virus targets AIDS: ependyma and subependymal brain parenchyma. Note cytomegalic cells w/ intranuclear inclusions FUNGAL INFECTIONS OF THE CNS

Affect primarily immunocompromised patients in industrialized countries Often presents as a component of widespread hematogenous dissemination of fungus Three basic patterns : Vasculitis, Chronic Meningitis, And Parenchymal Invasion (granulomas or abscesses) Vasculitis commonly caused by Aspergillus and Mucor, occasionally Candida


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CMV infection of the CNS occurs in two groups of individuals : fetuses and the immunocompressed Congenital CMV infection l: the commonest of the known intrauterine viral infections affecting 0.2-2.2% of live births Acute infection: Necrotzing Encephalitis Residual lesions : microcephaly, polymicrogyria, hydrocephalus and periventricular calcifications

Mucormycosis: CNS vasculitis following local brain invasion from a paranasal sinus in a diabetic patient w/ ketoacidosis.

Residual lesions of congenital CMV infection: periventricular calcifications and hydrocephalus

Gen Pathology – CNS1: CNS Pathology by Dra Sionzon

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Candida Albicans Infection most often associated with microabscesses but may also cause vasculitis leading to multiple hemorrhagic infarcts FUNGAL INFECTIONS

TOXOPLASMOSIS DISEASE OF MYELIN • • Diseases in w/c myelin is lost selectively w/ relative preservation of other neural structures including axons Two main categories: VIII 1. associated w/ abnormal myelin metabolism: Leukodystrophies VIII 2. associated w/ loss of normal myelin : Demyelinating diseases most common : multiple clerosis LEUKODYSTROPHIES : inherited diseases, typical onset in infancy to adolescence, diffuse white matter involvement, relentless progressive course MULTIPLE SCLEROSIS sporadic incidence, typical onset in 20’s and 30’s, multiple demyelinating foci at different times during disease course, waxing and waning course

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Fungi causing chronic mengitis: Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Cryptococcus neoformans Cryptococcal mengitis : observed in increased frequency in AIDS patients

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Cryptococcus Meningitis: multiple small cysts in the basal ganglia corresponding to aggregates of fungi within expanded perivascular (Virchow-robin) spaces with minimal associated inflammation I. PROTOZOAL CNS INFECTION: TOXOPLASMOSIS • Similarly to CMV, important cause of congenital infections and necrotizing encephalitis in the immunocompromised


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Clinical : distinct episodes of neurological deficits attributable to white matter lesions “ separated in time and space “, waxing and waning course Common symptoms : impaired vision, motor weakness, paresthesias, ataxia, etc. Gross pathology; multiple, well delineated, firm, pathology; gray lesions (plaques) in white matter, may focally extend into gray matter Microscopic pathology : well defined area of myelin loss with relative preservation of axons, lymphocytic infiltrate, loss of oligodendrocytes, foamy macrophages, astrogliosis Shadow plaque : only partial loss of myelin

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Congenital toxoplasma infection is responsible for the classic triad of : Chorioretinitis, Cerebral Calcifications And Hydrocephalus In immunocompromised patients toxoplasma causes solitary or multifocal abscesses Up to 30% of AIDS patients affected

Gen Pathology – CNS1: CNS Pathology by Dra Sionzon

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guys, di na ko gumawa ng low ink version ha. kasi sabi ni doc kelngan daw yung pictures.. so ayan. magsayang na tayo ng ink! wohoo!!!!... eto pla e yung ppt lang. I checked the buk, dami pla niang di diniscuss.. Mga impt notes lang to.. so kahit mganda tong trans pagkagawa ko, don’t rely on this..lam ko namang masisipag kayo e. may medstudent bang tamad?! Kung tamad ka edi sna wla ka na ditto.. diba?!.. in short, read your books.. haha! ;) –brim