Gen Pathology (Dra. Sionzon) CNS PART 1 : CNS PATHOLOGY 16 February 2008
CNS PATHOLOGY Review: Principal cells of the CNS CNS Neurons Glial Cells – Astrocytes – Olidodendroglia – ependyma Microglia Meningothelial Meningothelial cells • • • •
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negli bodies – in rabies cytopathic efeects – in CMV neurofibrillary neurofibrillary bundles – in alzheimers 1.
ASTROCYTES star-shaped glial cells function functions s include include nutrition nutritional al supply supply and insulatio insulation n 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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resp respo onse nse to tiss is s ue inj injury: ry: issu sue hypertrophy; astrogliosis
hype yperpla rplasi sia a
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highlighted by immunostaining for GFAP (Glial fibrillary Astrocytic protein –for astrocytic process)
Acute neuronal injury (red neurons): irreversible injury due to various causes including hypoxia/ischemia, hypoxia/ischemia, hypoxia/ische mia, infections, toxins
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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Oligodend Oligodendrocyt rocyte e injury injury is a feature feature of demyelina demy elinating ting demyelin dem yelinatin ating g diseases (e.g multiple sclerosis)
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Nucle Nucleii may harbor har borr viral viral inclus inclusion ions s in progre progressi ssive ve harbo ha rbor multifocal leukoencephalopathy leukoenc ephalopathy leukoence phalopathy Limited capacity for regeneration regeneration regeneratio n
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brim, leu, virns
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Gen Pathology – CNS1: CNS Pathology by Pathology by Dra Dra Sionzon
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egg shaped daw
EPENDYMAL CELLS Line ventricular chambers, aqueduct, central canal of spinal cord Modula Modulate te the transf transfer er of fluid fluid betwee between n CSF and and parenchyma
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Reaction to injury ; ependymal granulations (loss of ependyma plus subependymal astrogliosis)
FEATURES UNIQUE TO CNS Enclosed in a rigid bony compartment Autoregulation Autoregulation of cerebral blood flow Dependent 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 separates the brain from the rest of the body INTRACRANIAL COMPARTMENTS Epidural space Subdural space Subarachnoid Subarachnoid space
Cerebral parenchymal compartment Intravntricular spaces
Gen Pathology – CNS1: CNS Pathology by Pathology by Dra Dra Sionzon
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PATHOLOGIC REACTIONS Selective vulnerability” Pathologic reactions of neurons – Acute injury – Degeneration – Axonal reaction – Formation of neuronal inclusions – Vacuolization Vacuo lization of cytoplasm and neurophil Vacuolization – Aggregation of abnormal proteins Neuronophagia – Astrocytes - Gliosis – glial scar Microglia - glial nodules – Phagocytosis of dying neurons (neuronophagia) • • • •
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COMMON PATHOPHYSIOLOGIC PHENOMENA • •
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CEREBRAL EDEMA 1. Vasogenic Edema – blood brain barrier dysfunction, fluid accumulates accumulates between neurons and g lial 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 hydrocephalus
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Brain surrounded by rigid skull Rigid barriers divide the cranial cavity into subcompartments subcompartments (falx cerebri, cerebellar tentorium) Intracranial volume is fixed (brain parenchyma, CSF, blood) Space occupying masses (tumor, hemorrhage, etc), brain increased CSF lead to increased brain edema, edema, increased intracranial pressure and may cause herniation Herniation is displacement of expanding brain to adjacent subcompartments subcompartments or through formaen magnum
COMPLICATIONS OF BRAIN HERNIATION
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 • •
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Necrosis of herniated parenchyma
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Compression of vessels and consequent infarction (eg posterior cerebral artery infarction involving the visual cortex)
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Nerve compression (eg III cranial nerve in transtentorial transtentorial herniation w/ consequent papillary dilation and impaired ocular movement)
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Death (eg brainstem compression in tonsillar herniation
MALFORMATIONS AND DEVELOPMENTAL DEFECTS A.
B.
HERNIATIONS 1. Cingulate Herniation/ Subfalcine – Cingulate gyrus compressed underneath the falx cerebri – Caused by unilateral hemispheric mass 2. Transtentorial Transtentorial Herniation/ Herniation/ Uncinate Uncus gyri herniate in the cerebellar – tentorium 3. Tonsillar Herniation Cerebellar tonsils are compressed in the – foramen magnum – Life threatening threatening
DEVELOPMENTAL DISORDERS 1. Cranial Dysraphism – Anencephaly – Encephalocele 2. Spinal Dysraphism – Spina bifida occulta Meningocele – – Meningimyelocele – Rachischisis
B. CNS MALFORMATIONS •
Congenital CNS Malformation : Morphological CNS defe defec ct prese resen nt at birt birth h due due to an abn abnorm ormal development process)
Causes: unknown in a majority of cases, genetic and chromo chromosom somal al abnorm abnormalit alities ies,, enviro environm nmen ental tal (eg infection, drugd, nutritional, multifactorial) Anatomic pattern of malformation reflects the stage of formation of the CNS at the time of injury injury Important types and examples: Tube Defects (eg (eg anen anence ceph phal aly y, 1. Neural myelomeningocele, myelomeningocele, spina bifida, encephalocele) •
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Gen Pathology – CNS1: CNS Pathology by Pathology by Dra Dra Sionzon Forebrai rain n 2. Foreb
anoma anomalie lies s (eg holoprosen holop rosenceph cephaly aly,, holoprose rosencep ncephaly haly, agenesis of the corpus callosum, neuronal migration defects, microencephaly) microencephaly) microenceph aly) 3. Posterior fossa defects (Arnold-Chiari and DandyWalker Walker malformation) 4. Hydromyelia, Hydromyelia, syringomyelia syringomyelia 1.
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2.
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 charac character terize ized d by abnorm abnormalit alities ies involv involving ing both both racte rized neural tissue and overlying one or soft tissues Most Most comm common on type type of CNS CNS malf malfor orma mati tion on,, wide wide geog geogra raph phic ic and and ethn ethnic ic varia variati tion on in freq freque uenc ncy y, recurrence rate: 4-5%
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Etio Etiolo logy gy:: unkn unknow own n, some association w/ chromosoma chromosomall disorders disorders (trisomy (trisomy 13), environme environmental ntal factors factors (eg folate folate deficien deficiency), cy), interact interaction ion of genetic genetic and enviro environm nment ental al etiolo etiology gy suspec sus pecte ted d based based on nmen tal suspe su specte cted research in mice.
Anenephaly Anenephaly with complete rachischisis (craniorachischisis) : Skull vault and vertebral arches are deficient, replacement of brain w/ vascular mass (area cerebrovasculosa) cerebrovasculosa)
Spinal neural tube tube defects: defects: Myelomeningocele: h erni errnia niat atio ion n of the spin spinal al cord cord hern he iati tion on meningeal tissue through a vertebral defect (picture) Meningocele: herniation of meningeal tissue only
and and
Gen Pathology – CNS1: CNS Pathology by Pathology by Dra Dra Sionzon Encephalocele Encepha locele Encephalocel e (occipital) (occipital (occi pital) ) through a skull defect 3. FOREBRAIN ANOMALY
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hern hernia iatio tion n
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of brain brain tiss tissue ue
FOREBRAIN ANOMALY
Forebrain anomaly: Holoprosencephaly Failure of separation of cerebral hemispheres • •
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May be ass associ ociate ated d with with facial facial abnorm abnormalit alities ies (eg cyclopia)
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Etiology associations: o trisomy 13, 18 o Sonic hedgehog gene mutations o o o Maternal diabetes mellitus o Toxoplasmosis, other infections o o
Agyria
POST ERIOR OR FOSSA FOSSA ABNORMAL ABNO RMALITY: ITY:: ArnoldArnold- Chiari Chiari 4. POSTERI POSTERIOR ABNORMA RMALITY LITY: Malformation (Chiari Type II Malformation) Small posterior fossa
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Forebrain Forebrain anomaly: anomaly: Agenesis Agenesis of of the corpus callosum callosum Absence of white matter bundles connecting cerebral hemispheres • •
Polymicrogyria
Downward extension of cerebellar vermis through foramen foramen magnum Caudally displaced medulla Often associated; Aqueductal stenosis o o Hydrocephalus Lumbar myelomeningocele o o hydromyelia
PERINATAL BRAIN INJURY • •
Important cause of childhood neurological disability
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Cerebra Cere bral clinical term): term): non-progr non-progressiv essive e Cerebral brall Palsy (a clinical neur neurol olog ogic ic moto motorr defic deficit it attr attrib ibut utab able le to insu insult lts s occurring during the prenatal and perinatal period
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Most common underlying pathology : hemorrhages and infarctions infarctions
Gen Pathology – CNS1: CNS Pathology by Pathology by Dra Dra Sionzon • •
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Prematur Premature e infants infants at increased increased risk germinal germinal matrix matrix hemorrha hemorrhage ge and perivent periventricula ricularr infarcts infarcts leading leading to periventricular leucomalacia In term term infant infants: s: choroi choroid d plexus plexus hemor hemorrha rhage ge and and infarcts infarcts involving involving cerebral cerebral cortex, corte x, basal ganglia and cortex, thalamus Common causes: maternal disease (eg hemorrhage, shock, shock, drugs, drugs, traum trauma), a), placen placental tal abnorm abnormalit alities ies,, neonatal disease (eg congenital heart disease)
Caseous mycobacterial 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 deceleration Laceration (tearing) Diffuse Axonal Injury Traumatic vascular injury Penetrating wounds
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Discharge of mycobacteria from tubercles into the subarachnoid subarachnoid space results in tuberculous tuberculous meningitis that typically affects the base of the brain.
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SPINAL CORD INJURIES Hyperextension injury – Cervical spinal – Sudden posterior displacement of the head – Rupture of anterior spinal ligament ligament Hyperflexion injury Impact Impact force drivin driving g the the head head down down and – forward – Anterior contusion of the cervical spine
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INTRACRANIAL BLEEDING Epidural hematoma Subdural hematoma Subarachnoid hematoma Intracerebral hemorrhage Intraven Intraventricu tricular lar hemorrh hemorrhage age internus”
Tuberculous meningitis – microscopic findings: granulomatous granulomatous inflammation w/ multinucleated multinucleated giant cells, epithelioid cells, macrophages and lymphocytes.
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“hydroce “hydrocepha phalus lus
INFECTIONS
A. CHRONIC BACTERIAL INFECTIONS - TUBERCULOSIS •
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Manifest Manifestatio ations: ns: chronic chronic mengitis men gitis circumscribed ed meng itis and circumscrib abscess: TUBERCULOMA Typically ypically due to hematoge hematogenous nous spread spread of bacteria 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 Pathology by Dra Dra Sionzon
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CHRONIC BACTERIAL INFECTIONS -NEUROSYPHILIS •
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Neurosyphylis is a terti tertiary ary stage of syphil syphilis is and and occurs in about 10% of patients w/ untreated infection Manifestations: meningeal- meningovascular syphilis, paretic neurosyphilis, tabes dorsalis
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Impaired joint position sense, ataxia Loss of pain sensation- skin and joint damage Lightning pains Loss of deep tendon reflexes
C. VIR AL INFECTIONS ; VIRAL ASEPTIC MENINGITIS • •
MeningealMeningeal- Meningovascular Meningovascular Syphilis : chroni chronic c mengi mengitis tis w/ nume numerou rous s plasma plasma cellS that that may may be associated w/ obliterative obliterative endarteritis
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Paretic Neurosyphilis Neurosyphilis ; invasi invasion on of the the brain brain by Treponema pallidum inflammatory meningeal lesions are assoc as sociat iated ed par enchy chymal mal damage : loss loss of associ ass ociate ated d w/ paren parenc enchym hymal al damage cortical neurons, striking proliferation of microglia (rod cells)
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Most common viral infection of the CNS Common causative agents : enteroviruses, enteroviruses, herpes simplex virus type 2, mumps virus Pathology : mild to moderate lymphocytic infiltration of the leptomeninges leptomeninges Clinical Clinical symptoms symptoms:: headach headache, e, fever fever, usually usua lly short, short, usually benign course
VIRAL ENCEPHALITIS, MYELITIS, ENCEPHALOMYELITIS •
Viral infections of the brain (encephalitis), spinal cord (myelitis) or both (encephalomyelitis)
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Clinically Clinically most important important infection infections s caused caused by HIV, Herpe Herpes s Simple Simplex x Virus, Virus, Human Human Cytome Cytomegal galovi ovirus rus,, Poliov Polioviru irus, s, Rabie Rabies s Virus, Virus, Measle Measles s Virus. Vir us. JC Virus, Vir us, Virus. Arboviruses Localization of the infection within the CNS is often characteristic for specific viruses Micr Micros osco copi pic c path pathol olog ogy y simi simila larr for fo r almo almost st all: all: for perivascu perivascular lar cuffs cuffs of the lymphocyt lymphocytes, es, astroglios astrogliosis, is, micr microg ogli lial al nodu nodule les, s, if neur neuron ons s are are infe infect cted ed:: neuronophagia
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Viral inclusions in some cases may be characteristic
Neurosyphilis Neurosyphilis : leptomeningeal leptomeningeal thickening, spirochetes and rod cells. Patients show progressive loss of mental functions, often delusions of grandeur terminating in severe dementia : general paresis paresis of the insane
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HIV ENCEPHALITIS As many many as 60% 60% of pati patie ents nts w/ AIDS IDS deve develo lop p neurological dysfunction HIV infection can cause CNS damage by infecting the CNS and by leading to opportunistic CNS infections
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Tabes dorsalis. Degeneration Degeneration of the posterior columns of the spinal cord w/ loss of both axons and myelin Symptoms:
Main target cells of HIV in CNS : microglial cells and macrophages Cytokines Cytokines and reactive reactive reac tive oxygen oxygen oxyg en and and nitrogen nitrogen nitro gen species species spec ies released released from infected infected cells may cause cause secondary secondary neuron damage and lead to HIV dementia
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Typical ypically ly affec affects ts deep deep gray gray struc structur tures es and white white matter
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Multinucleated Multinucleated cells, microglial nodules, demyelination
Gen Pathology – CNS1: CNS Pathology by Pathology by Dra Dra Sionzon •
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Most common opportuni opportunistic stic CNS infections infections in AIDS: AIDS: CMV Encephalit Encephalitis, is, Toxoplasm oxoplasma a Abscess, Abscess, JC Virus – Induced Progressive Multifocal Leukoencephalopathy Leukoencephalopathy
HERPES SIMPLEX ENCEPHALITIS •
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Most common sporadic encephalitis in the US, affects immunoco immunocompet mpetent ent people, people, most commonly commonly due to HSV-1 Initial Initial infection infection of mucocuta mucocutaneou neous s surfaces surfaces of oral cavity, nose, eye Virus infects infects nerve nerve endings, endings, reaches reaches ganglia ganglia in the periphera peripherall nervous nervous system and the CNS by axonal axonal transport = in most cases causes latent infection in neurons Initial Initial infection infection and reactiva reactivation tion from neurons neurons may cause encephalitis HSV encephalitis typically involves the temporal lobe
CYTOMEGALOVIRUS INFECTION OF THE CNS
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CMV infecti infection on of the CNS CNS occ occurs urs in two two groups groups of of the individuals : fetuses and the immunocompressed Congenit Congenital al CMV infection infection l: the commonest commonest of the known intrauterine viral infections affecting 0.2-2.2% of live births
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Acute infection: Necrotzing Encephalitis
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Residu Residual al lesion lesions s : microc microceph ephaly aly,, polymi polymicro crogyr gyria, ia, hydrocephalus hydrocephalus and periventricular periventricular calcifications
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CMV Ventriculoencephalitis Ventriculoencephalitis in AIDS: AIDS: Virus targets ependyma and subependymal brain parenchyma. Note cytomegalic cells w/ intranuclear intranuclear inclusions FUNGAL INFECTIONS OF THE CNS •
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Affect Affect prima primaril rily y immuno immunocom compro promis mised ed patie pa tient nts s in patien pat ients ts industrialized countries Ofte Often n pres presen ents ts as a comp compon onen entt of wide widesp spre read ad hematogenous hematogenous dissemination of fungus Thre Three e basi basic c pat patterns rns : Vascul Vasculiti itis, s, Chron Chronic ic Meningi ingiti tis, s, And And Pare arenchy chymal Invasio asion n (granulomas or abscesses) Vasculitis Vasculitis commonly caused by Aspergillus and Mucor, Mucor, occasionally Candida
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 Pathology by Dra Dra Sionzon
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ASPERGILLOSIS
Candida Albicans Infection most often associated with microabscesses but may also cause vasculitis leading to multiple hemorrhagic infarcts
TOXOPLASMOSIS
FUNGAL INFECTIONS •
Fungi causing chronic mengitis: Histoplasma capsulatum, Coccidioides immitis, Blastomyces Blastomyces dermatitidis, Cryptococcus neoformans
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Cryptococcal mengitis : observed in increased frequency in AIDS patients
DISEASE OF MYELIN • •
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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 Simila Similarly rly to CMV, import importan ant t cause cause of congen congenita itall ortant ant infe infect ctio ions ns and and necr necrot otizi izing ng ence enceph phal alit itis is in the the immunocompromised
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LEUKODYSTROPHIES : inherited diseases, typical onset in infancy to adolescence, diffuse white matter involvement, involvement, relentless progressive course
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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
MULTIPLE SCLEROSIS •
Clinical : distinct episodes of neurological deficits attributable to white matter lesions “ separated in time and space space “, “, waxing waxing and and waning course
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Common symptoms : impaired vision, motor weakness, paresthesias, paresthesias, ataxia, etc. etc.
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Gross pathology; pathology; multiple, well delineated, firm, gray lesions (plaques) in white matter, may focally extend into gray matter
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Microscopic pathology : well defined area of myelin loss with relative preservation of axons, lymphocytic infiltrate, loss of ol igodendrocytes, igodendrocytes, foamy macrophages, astrogliosis
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Shadow plaque : only partial loss of myelin
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Congenital toxoplasma infection infection is responsib responsible le for the the clas classi sic c tria triad d of : Chorioretinitis, Cerebral Calcifications And Hydrocephalus Hydrocephalus In immunocompromised patients toxoplasma causes solitary or multifocal abscesses Up to 30% of AIDS patients affected
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 normal myelin myelin :: Demyelinating Demyelinating diseases most common : multiple clerosis
Gen Pathology – CNS1: CNS Pathology by Pathology by Dra Dra Sionzon
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 namang masisipag masisipag kayo e. may medstud medstudent ent bang tamad?! tamad?! Kung tamad ka edi sna wla ka na ditto.. diba?!.. in short, read your books.. books.. haha! haha! ;) –brim
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