acute viral infections

Neurovirology

• Acute viral infections– Rabies, Enteroviridae, Mumps, Arenaviridae,

Arboviruses• Herpes viral infections

– HSV, VZV, CMV• Chronic viral infections

– JC-virus (PML), Measles (SSPE)

Acute viral infections• Forms of acute neurological disease

– Meningitis, Panencephalitis, Leukoencephalitis and Poliomyelitis

– Uncommon complications of common systemic infections

• Clinical Features: Depend on which cells are infected – Meningitis

• headache, fever, stiff neck, CSF pleocytosis• Most common cause of viral meningitis: enteroviruses,

HSV2, mumps, HIV LCMV

Acute viral infections: Clinical features

• Encephalitis– Increased intracranial pressure common– Altered consciousness, focal neurological

signs, accentuated tendon reflexes, seizures, tremors,

– Involvement of hypothalamus can lead to hypothermia diabetes insipidus, SIADH

– Spinal cord involvement - flaccid paralysis, bowel and bladder symptoms.

– With the exception of HSV, the topography of lesions is of little help in diagnosis

Encephalitis: Histopathology / Etiology

• Panencephalitis (involving both gray and white matter)– Necrotizing

• HSV-1 or -2, VZV, Arbo– Non-necrotizing

• HIV, CMV, HTLV-1, measles • Polioencephalitis (predominantly involving gray

matter)– Polys followed by lymphs, neuronophagia and microglial

nodules– Enteroviruses, rabies, arboviruses

• Leukoencephalitis (predominantly involving white matter)– PML, HIV, Post-infectious

Rabies: Virus

• One of the rhabdoviruses, a group of negative-single-strand RNA viruses with a distinct bullet shape

• Receptor: NCAM (CD56), Acetylcholine receptor• Can grow in a wide variety of cell cultures

• generally noncytopathic, in curious contrast to the fatal outcome of infection in vivo in virtually all warm blooded animals.

• Susceptibility is variable as are periods of latency and infectivity and salivary excretion

Rabies: Epidemiology• Virus is sustained in wild carnivores and

insectivorous bats– Sylvatic reservoirs: foxes, skunks raccoons

and bats – Skunk now the commonest reservoir of

wildlife rabies in US. – Airborne transmission in bat caves– Transmission from man to man has not

been documented (except for corneal transplants)

Rabies: Epidemiology• 50% of dogs with proven rabies do not

have virus in saliva. – Overall transmission through bite is 15%.– Dog excretes virus up to 5 to 7 days prior to

clinical symptoms• other carnivores viral secretion not known,

therefore quarantine and observation of no use except for dogs (e.g. bats frequently without clinical symptoms).

Rabies: Clinical• Incubation period in man 15 days to 1

year (?) • Half of patients in US with no history of

bite. • Half develop hydrophobia. • Ascending paralysis with pleocytosis in

25% and elevation of protein

Rabies: Pathology• Bland pathologic findings - • Grossly normal

– diagnosis in dogs used to be made by examining stomachs

• Microscopic– Perivascular inflammation– Without tissue necrosis – Neuronophagia uncommon– Pathognomonic feature is Negri body

• 1 to 7 micron inclusions mostly in neurons• Found in ammon's horn and Purkinje cells of cerebellum

Rabies

From: Neuropathology Illustrated 1.0

Negri Body

Rabies• H&E stained section of

cerebellum showing purkinje cell with eosinophilic cytoplasmic inclusion (Negri body)

• Electron micrograph of myelinated axon showing viral inclusions (between arrows) with axoplasm

From C.A. Wiley

From C.A. Wiley

Rabies: Pathogenesis• Saliva inoculation through bite

– Local infection of individual muscle cells • Incubation period determined by persistent

infection of muscle fibers prior to ascension of nerves

• Replicates in parikaryon and dendritic processes of neuron– Localized to limbic system with relative sparing of

the cortex• Later transmitted centrifugally to many

organs including hair follicles

Enteroviruses: Virus

• Nonenveloped positive single-stranded RNA viruses– 70 human enteroviruses are known– Replication is species-specific

• Cell receptor for polio on chromosome #19– Approximately 3000 copies of

receptor on HeLa cells

Enteroviruses: Epidemiology/Clinical

• Cause 30 to 50% of viral meningitis and most cases of paralytic polio

• Transmission by fecal to oral contamination – "man's fecal veneer"

• High infectivity 76% of household contacts for coxsackie, – Epidemic Poliomyelitis

• 1916 9,000 cases in NYC, • 80% in children under 5• But primary infection of adults and adolescents 10

times more likely to progress to paralysis.

Enteroviruses: Diagnosis

• Coexistence of rash and meningitis may be helpful but confusion with meningococcemia

• Meningitis lasts days to weeks• CSF may contain a few polys

initially but progresses to lymphocytes by 24 hours.

Polio: Pathology• Gray matter hemorrhage

– Neuronophagia• Viral binding within CNS is greater than restricted

distribution of receptor.– Neuron phagocytosed by surrounding microglia


Dieing neuron

Mumps: Clinical / Epidemiology • Respiratory route during winter• Single most common cause of aseptic

meningitis and mild encephalitis– 15% of all cases of aseptic meningitis

• Half of all infections associated with CNS symptoms

• 50% of cases with CNS involvement without parotitis.– Most resolve without neurological complications

• CSF pleocytosis may extend for 1 year

Mumps: Pathogenesis• Excretion and viremia for 6 days prior to

clinical symptoms• Cleared with appearance of IgA and IgM

respectively.• Infection of CNS is secondary to choroid plexus

infection– CSF isolation within first 4-5 days(20-50%)

• Compression of facial nerve with parotitis, hearing loss due to cochlea infection.

• Occasionally associated with lower motor neuron disease

Adenoviruses: Virus / Epidemiology/Clinical

• Fecal to oral in families, respiratory in epidemics. – Can be transmitted by fomites– 50% of infections cause clinical disease.

• Respiratory infections, conjunctivitis, hemorrhagic cystitis and gastroenteritis.

• Encephalitis rather than aseptic meningitis occurs but rare– Very rare neurological complications

• almost exclusively in children

Arenaviruses: Epidemiology / Clinical

• Zoonotic infection in which man acquires virus from the mouse or hamster

• Biphasic course- pneumonitis followed by meningitis (and encephalitis in half of these)suggests that second phase may be immunologically mediated– Multisystem disease in which primary viral

attack of lymphoid and bone marrow cells leads to damage of cells, release of vascular permeability mediators, shock.

– Clinical CNS disease remains unexplained

Arenaviruses: Pathology/Pathogenesis

• Lassa fever more virulent - 10 reported autopsies– No consistent findings- no CNS lesions seen in 4

patients.– Lassa fever (Nigeria 1969) human to human spread

hospital outbreaks with 30 to 60% mortality among infected personnel

– Pathologist who preformed the first autopsy died of Lassa.

Arboviruses: Epidemiology

• Include majority of Togaviruses,Flaviviruses, Bunyaviruses, Reoviruses and Bunyaviruses.

• Obligatory cycle of multiplication in arthropod – In ticks and mosquitoes infection can be

transovarian.– Incubation in mosquitoes for 4 days to 2

weeks– Geographic and seasonal limitations

Arboviruses: Clinical

– 4 syndromes associated with arboviruses• Encephalitis• Yellow fever• Hemorrhagic fever• Undifferentiated tropical fevers.

– Pathology• nonspecific inflammation

Arbovirus Encephalitis

From: Charleen Chu MD/PhD

From: Charleen Chu MD/PhD

Viral Capsids

Viral Capsids

NeuronNeuron

Eastern Equine Encephalitis: Epidemiology

• Usual transmission between marsh birds and mosquitoes– Changes in marsh condition etc. lead to spill

over into mosquito hosts that feed on mammals.• Horse being important sentinel animal but

dead-end host for virus. – Ratio of inapparent infections to apparent

infections is low (20:1)• Pathology

– meningeal and perivascular inflammation, neuronophagia.

Western Encephalitis• Mosquito and birds in cycle but

mosquito does feed on large vertebrates– Ratio of unapparent to apparent

infections is very high • 1000:1 sequelae rare but fatal

St. Louis Encephalitis• Commonest cause of human

arbovirus encephalitis • Paradoxically urban epidemics

occur in drought years – Poor drainage, rural outbreaks with

high rainfall• Man can become active

intermediate host

Other arboviruses• Venezuelan Equine Encephalitis• California Encephalitis• Japanese Encephalitis• Colorado Tick Fever virus• Tick-borne Encephalitis• Undefined virus

– Recapitulate epidemiological patterns of virus dissemination

Differential Diagnosis of Acute Viral Infections

• Infections masquerading as viral CNS infections– TB, brucellosis, fungi, Syphilis, Lyme

disease, Rickettsial Diseases, Leptospirosis, Mycoplasma

– Noninfectious disease – carcinomatosis meningitis, gliomatosis

cerebri, glaucomatous angitis, sarcoidosis, SLE, rheumatoid meningitis, ruptured cysts in subarachnoid

Post-Infectious Encephalomyelitis



Perivascular inflammatory cuff

Diffuse inflammatory infiltrate

General consideration of herpes viral infections

• Most herpesviruses are restricted to their natural host, only herpes simiae of macaque causes significant disease in man.

• Host never clears infection • To have endemic acute disease virus you need:

– a population of 200,000– or zoonotic infection– or LATENCY

Latency

• Property of all herpes viruses• Term used in two ways:

– Continuous shedding of small amounts– or more usually implies persistent without

production of recoverable virus

HSV Latency• virus particles and antigen not present during

quiescent periods– may involve integration of viral DNA into chromosomal,

• but since integration usually occurs during cellular DNA synthesis for latency in neurons must postulate that integration occurs during DNA repair or that episomal form of virus is sequestered.

• Latency in either neural cells or hematopoetic cells– Transport up sensory nerve fiber during primary infection

leading to establishment of latency

8 Human Herpesviruses• Alpha- (HSV1 & 2, VZV)

– variable host range– short reproductive cycle– latency usually in ganglia– have viral encoded thymidine kinase

• Beta- (CMV, HHV6 & 7)– resticted host range– long reproductive cycle– latent in secretory glands & lymphoreticular tissue

• Gamma - (EBV, HHV8)– limited host range– frequently arrested replication pre-viral production

Herpes Replication

• Very similar to adenovirus with some splicing• Cascade - Immediate early, early, late

– Immediate early proteins peak at 2-4 hours• required to synthesize early proteins

– Early proteins peak 5-7 hours• TK and other DNA synthesis related proteins

– Late proteins require DNA synthesis • capsid proteins

HSV1: Epidemiology• 90% of adults have antibody, despite rare

involvement of the CNS it is the commonest cause of nonepidemic fatal encephalitis in US – 1000 to 2000 cases per year with death in over half of

untreated• Spread by salivary or respiratory contact, primary

infection is asymptomatic or gingivostomatitis – herpes gladiatorum from inoculation with saliva

• Most patients who develop CNS complications in good health with cold sore of similar incidence to rest of population

HSV: Clinical presentation• Initial infection (e.g. gingivostomatitis)

– Half of the cases first infection does not produce clinically apparent disease

– In immunosuppressed spreads rapidly and is lethal – Otherwise primary infection terminated with appearance of

immune response• Significant neurological disease

– Insidious or fulminant onset, fever and headache, – Local lesion in one or both fronto-temporal lobes giving

personality changes – Seizures and coma late

MRI of HSV Encephalitis

• T-2 weighted MRI showing increased signal in frontal lobe (orbital gyrus on right) and bilaterally in temporal lobe

From C.A. Wiley

HSVE Gross

From Neuropathology Illustrated 1.0

Swollen Hemorrhagic Temporal lobe

HSV: Pathology• Adults: HSV I localization to orbital-frontotemporal

lobes - often unilateral• Children: diffuse encephalitis caused by type 1 or 2 • Immunofluorescence shows virus in ipsilateral

olfactory nerve, but not in all patients.• Not usually found in CNS with primary infection

except in immunosuppressed, rather reactivation of trigeminal latency

HSV Encephalitis H&E



Microscopic hemorrhages

Perivascular and parenchymal inflammation

HSV Immunohistochemistry

Low power of needle biopsy immunostained (red) for HSV antigens

From C.A. Wiley

HSV Encephalitis



Cowdry A Inclusions

Intranuclear Viral capsids

HSV: Diagnosis

• Earliest change EEG slowing sometimes focal, similar to SSPE.

• MRI abnormalities early• CT abnormalities are late• CSF shows increased pressure early few

cells or polys, but late usually mononuclear cells. – Protein up and glucose normal. – CSF PCR usually positive during encephalitis

HSV: Treatment • Prophylactic Acyclovir to bonemarrow transplant patients• Age and level of consciousness at time of initiation of

treatment is critical in prognosis• Half of patients suspected of HSV encephalitis turn out not

to have it– 20% of these have a different, treatable disease– Therefore diagnosis is critical part of care

• Acyclovir - acyclic nucleotide that is selective substrate for herpesvirus thymidine kinase. – Cellular thymidine kinase in uninfected cells does not use acyclovir.

• Therefore drug is phosphorylated only in infected cells.

HSV 2: Epidemiology

• Primary infection can occur in utero or during parturition.– Majority of infections between 14 and 35 years of age (when

20 to 30% develop antibody).

• 250,000 genital infections / year in US – Shedding can occur without disease

• 80% recovery from second or fourth sacral ganglia of routine autopsies.

HSV 2: Clinical• Infected at birth develop disseminated herpetic infections. • Adults primary infection is complicated by acute benign

meningitis– With exacerbations of genital lesions, meningitis or radiculitis may

recur in contrast to the lack of correlation of mucocutaneous lesions with HSV I.

• Immundeficiency disease can lead to fatal dissemination• Recurrences more often in type 2 (74/123) than type 1

(2/14).• Pathology

– Infants hepatitis and adrenal necrosis and diffuse encephalitis.

Varicella-Zoster: virus

• Varicella= diminutive form of variola-smallpox– Cell associated- inoculation with infected

cells necessary even though virus is stabled in cell-free form in vesicular fluid.

– ganglionic latency

VZV: Clinical / Epidemiology

• Two distinct clinical diseases (chickenpox and shingles)

• Shingles (herpes zoster= Greek to girdle) less common endemic disease of older or immunocomrpomised individuals– First suggestion that both diseases were

manifestations of the same infection in 1888.

Varicella: ClinicalHighly contagious generalized exanthematous disease with

marked seasonality (winter and spring)Occurs at a rate of 5 per 1000 population per year

Spread by respiratory routeMajority of infections are clinically obvious

less than 4% escape detection. Rare pulmonary infection and acute neurological complications

Including encephalomyelitis, localized myelitis, acute ataxia, GBS or Reye's syndrome.

CNS involvement in 1:1000 acute cerebellar ataxia - transient

Neonatal varicella in utero infection with cicatricial scarring during first trimester

Zoster: Clinical• Half of people by age of 85 suffer at least one attack of

shingles.– Proposed decline in immunity with age – Activation with or without rash

• Dysesthesia usually precede rash for 4 to 5 days• Persistent pain for months to years• Ophthalmic division of trigeminal account for 10-15% of all cases of

Zoster• Immune suppression does lead to reactivation

– Life-threatening encephalitis in immunosuppressed, acute transverse myelitis and fatal ascending myelitis

– Multifocal demyelinating lesions of brain• Resembles PML

Zoster: Pathology/pathogenesis

– Primary skin infection presumably originates from blood • Transported along sensory nerves to ganglia where it becomes

latent– Acute ganglionitis with intense inflammation and cell

necrosis and occasional hemorrhage.• Virus can not be recovered from ganglia at autopsy - only found

within ganglia during acute disease• Motor paralysis in 5% in same region as dermatomal rash

– Mild lymphocytic meningitis frequently occurs• Unilateral poliomyelitis can occur• Necrotizing encephalitis and transverse myelitis can occur

VZV Encephalitis

From:Francoise Gray MD From:Francoise Gray MD

Nuclear Viral capsidsConfluent regions of demyelination

VZV Ganglionitis



Ganglion cells

Ganglion cell surrounded by inflammatory cells

VZV Leukoencephalitis

From C.A. WileyFrom C.A. Wiley

Cytomegalovirus (CMV): Epidemiology

• Ancient virus - (salivary gland virus)– Genome 50% larger than HSV– Replication- similar to HSV

• 1 to 2% of all newborns have evidence of intrauterine infection– 30,000 infections per year in U.S.– 12% of autopsied infants

• Another 50% infected in first 5 months– breast milk is major source

• 50-90% of adults with steady rate of antibody acquistion throughout life.

CMV: Clinical

• Primary infection usually subclinical (even in utero )

• Congential Infection – 1% of all live births – 5% with CID, 5% with atypical infection, 90% with

subclinical• 10% of these go on to deafness

– CMV transmitted in utero with primary and secondary infections of mother, but CID seen only in primary infections

CMV: Pathology

• Numerous scattered glial nodules in gray matter

• Infrequent cytomegalic cells• Extensive necrosis and calcifications

seen in the fetal infections are not encountered in adult

CMV Ventriculitis


Periventircular erosions

CMVHigh Power H&E of

microglial nodule with central cytomegalic cell (arrow)

Electron micrograph of nucleus containing numerous round to hexagonal nucleocapsids

From C.A. Wiley

From C.A. Wiley

CMV VentriculitisH&E of lateral ventricle (V) showing

mostly denuded ependyma with occasional cytomegalic cell (arrow)

Immunostain for CMV antigens

(red) shows numerous infected ependymal and underlying glial cells

V

V

From C.A. Wiley

From C.A. Wiley

CMV: In immunosuppressed

• Often asymptomatic involvement of CNS in immuno-suppressed patients– Cardiac transplant patients retrospectively

had confusion, tremor spastic quad• Numerous scattered glial nodules in

gray matter with infrequent cytomegalic cells

Fetal CMV Encephalitis



Periventricular mineralization

Centrifugal inflammation

EBV: Clinical• Neurological complications - pleocytosis and protein

elevation probably less than 1% of patients• Reported complications aseptic, meningitis, encephalitis,

GBS, Bell's Palsy and transverse myelitis, acute cerebellar syndrome

• Virus is difficult to recover and has never been recovered from CSF or brain seizures and coma late tissue(?)

• Occasionally with CNS symptoms of cranial nerve involvementLymphomas that arise in EBV positive immune compromised

individuals

General considerations of chronic viral infection

• Differentiate between chronic infection and chronic disease – e.g. paralysis of polio

• Some symptoms develop late in life suggesting a progressive disease, but independent of chronic infection. – e.g. delayed onset of paralysis after childhood infection

with polio.• Frequently fetal and neonatal acute self-limited

infections suggest a progressive deterioration as the animal matures.– Chronic diseases as sequel of acute fetal infection.

Chronic inflammatory and demyelinating diseases

• Definitions of chronic infections– Lingers on and has an irregular unpredictable course– Continually demonstrable virus

• Definitions of slow infections– Long period of latency

• Latent implies potential to be reactivated– Regular course after clinical signs

Visna prototype of slow infections

• Long incubation periods, insidious onset, afebrile, progressive neurological disease leads to death.

• 1957 Sigurdsson described "visna"(Icelandic for wasting) inflammatory demyelinating disease of sheep

• CNS appears to be favored site of persistence

Mechanisms of virus persistence• Tolerance

– Ineffective antibody response (poor affinity, high antigen concentration).

• Immunosuppression– measles general immune suppression– invasion of lymphoid tissue with elimination of

responsive clones.• No antigen produced• Antigenic variation

– e.g. Rhinoviruses Equine infectious anemia virus• Inaccessible to immune system

– Absence of complement in CNS• Decreased interferon induction or responsiveness

Mechanisms of virus persistence: Structural and immunologic factors

• CNS unique lack of vascular permeability and tightly packed parenchyma deters infection and clearance.

• Devoid of lymphatics or immuno-competent cells.• Low levels of immunoglobulin and complement

leading to failure to neutralize or lyse virus.• Static nature of CNS cells encourages persistence

– e.g. rubella chronic noncytopathic infection leads to slowed cell growth rapidly overgrown by normal replacement populations in most organs.

Progressive multifocal leukoencephalopathy (PML)

• Virus– Identified in 1907 as capable of

transmitting diseases from human to human by inoculation of cell-free wart extract

– Papovavirus family• Papilloma (wart), polyoma and

vacuolating virus (SV-40)

PML: Replication– Initial site in GI or respiratory tract then

disseminate to internal organs• Tissue culture - BKV grows in epithelial cells and

fibroblasts, while JC virus grows only in primary human fetal glial cells (can be adapted to grow in other cells)

• may undergo nonpermissive infection and transform cells in tissue culture

• cytocidal for oligos in culture and “transforms” astrocytes

– ?site of persistence Kidney versus bone marrow

PML: Epidemiology– Ubiquitous virus– Mostly species specific

• Human viruses not recovered from animals, but SV40 has been found in monkeys with PML

– Majority of persons develop antibody by 14 years of age

• 50% of children + by age of 10, 75% by adult– Role of viruria

• Virus shed from urine and throat.

PML: Clinical • First chronic demyelinating disease for

which viral cause firmly established– Develops in background of lymphoproliferative

disease malignancy or immunosuppression• Therefore disease is due to a reactivation

– Afebrile death in 3 to 6 months.– CSF normal,

• antibodies against virus are ubiquitous• antibody not found in CSF

– CT shows multiple radiolucent lesions in white matter

PMLMultifocal white matter discoloration

White matter necrosis

PML: Pathology

• Sparing of axons, loss of myelin and oligos around lesion with large intranuclear inclusions.

• Astrocytes are enlarged with bizarre mitotic figures

• Little inflammatory response except for macrophages

• Viral DNA in lymph node, spleen, liver, lung kidney, brain

PML

Gliosis and bizarre astrocytes

Sea of Macrophages

CD68

In Situ Hybridization for JC virus

Nuclear inclusions

PML: Pathogenesis• Not recoverable from normal brain.

– 1010 particles per gram of PML brain.– With immunosupression virus appears in CNS and renal

tubules.• ? reinfection versus reactivation versus spread to CNS

• Usually explainable on the basis of virus-induced cytopathology and destruction of the infected cell– In vivo primarily leads to lysis but some surviving

astrocytes proliferate rapidly and contain T antigen.– Why it evolves slowly is not known given its rapid in vitro

cycle.

PML: Immune Response / Treatment

• Serology worthless – Ig does not increase with disease

• Lymphocytes of PML patients do not respond to JCV antigens

• Restoration of immunocompetence, if possible otherwise relentless progression

• Because papovaviruses utilize host-cell polymerase to replicate DNA cytosine arabinoside does not work.

Measles: Clinical• Rash on forehead spreads within 24 to 48

hours• Catarrhal (inflammation of mucous

membranes) 2 - 4 days before Koplik's spots on buccal mucosa

• Acute appendicitis prior to rash in some cases secondary to lymphoid inflammatory changes

• Enteropathic changes are a particular problem in developing countries

Measles: Clinical• Involvement of CNS is common

– 5 - 7 days post rash presumed autoimmune etiology• 10% with pleocytosis • 50% of children with EEG changes

– 1:1,000 cases with symptomatic encephalitis • Virus usually not recoverable

Measles: Clinical• SSPE in 1/300,000

– normal humoral and cellular immune response? – viral clearance? – 60% of people with detectable nucleic acids in CNS?

• ATYPICAL measles– Acute measles in patients vaccinated with

inactivated vaccine• Inactivation destroy immunogenecity of F protein and

therefore does not confer long term immunity.• Sets up Arthus reaction

Measles: Epidemiology• Requires population of 2-300,000 to

support endemic disease– disease first appeared in 2500BC possibly associated

with domestic animals– noninmmunized populations have epidemics every 2

to 5 years each lasting 3 - 4 months – usually in late winter and early spring.– Subclinical infection is rare

Measles: Pathogenesis• First signs of disease 9-11 days PI

– shortened to 7 days if given parenterally• Local viral replication in epithelial membranes

followed by lymphatic spread and then viremia • Dissemination includes mucosal membranes,

small blood vessels, lymphatic system and CNS– difficult to isolate virus from patients usually from

lymphocytes– Intranuclear and intracytoplasmic inclusions

• Certain CNS cells permit only non-lytic infection

Measles: Diagnosis• virus isolation difficult• IF of skin biopsies• SSPE patients have 10 to 100

times antibody with oligoclonal CSF bands

Measles: Subacute Sclerosing Panencephalitis (SSPE)

• Defined by Dawson in 1930 postulated viral cause but took 35 years to relate measles

• Rubeola, same as wild measles strains

• Epidemiology• 1:106 children per year (immune intact)• Age range 2 to 32 with average 7 to 8.• Males three times more common. • 1 to 10 years after recovery from uncomplicated

measles

Measles: SSPE Clinical• Insidious onset, early dementia, disturbed motor

function, myoclonic jerks, seizures, focal retinitis with optic atrophy, cerebellar ataxia leading to stuporous rigid state progresses to death in 1 to 3 years

• No fever or headache– EEG high amplitude slow waves followed by flat wave

pattern• No CSF pleocytosis, and normal protein and sugar

– Relative increase in IgG– CSF IgG titers to measles high

• Intrathecal synthesis of IgG• Oligoclonal bands

SSPE



Cowdry A Inclusions

EM

Perivascular Inflammation

Measles: SSPE Pathology• Mild meningitis• Gray and white matter

involved– Mostly posterior hemispheres– Microglial reaction– Eosinophilic inclusions most

commonly in oligos– EM: tubular structures

Measles: SSPE Pathogenesis Theories

• Abnormal Host response – Immune responses not involved - virus

remains cell associated in vitro – More frequent in children with history of

measles prior to 2 years of age – M-protein defect

• Normally RNA is replicated in cytoplasm while still encapsulated in nucleocapsid protein

– Major glycoproteins; hemagglutin and fusion protein inserted into cytoplasmic membrane

– EM of SSPE show no virions

Subacute measles encephalitis

• seen in children and adults following immunosuppression, neurological disease follows systemic measles by 1 to 6 months– Course of days to weeks ending in death– Elevations of antibodies not found, inclusions seen in

neurons and glia and antigen and virus recovered from one patient

• Subacute encephalitis in immuncompromised adult is clearly different from acute postinfectious encephalomyelitis and SSPE seen in normal children

Other persistent RNA viruses • Both DNA and retroviruses capable of establishing

static latency by sequestration of viral or proviral DNA – Mechanism of persistence of other RNA viruses more complex– No DNA intermediates seen in these

• Picornavirus– Difficult to explain latency, since it is not enveloped defects of

maturation are not known • Infection may be limited to a small population of cells-

smoldering lytic infection• Temperature sensitive mutants • Defective interfering particles• May promote persistence - host deficit leads to failure

to clear virus

HIV Encephalitis• ~1/4 of terminally ill AIDS patients• Macrophage tropic virus• ?Mechanism of neurodegeneration• Reversibility with immune

reconstitution?

acute viral infections

Documents