Transcript Acute viral infections - Division of Neuropathology

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
Negri Body
From: Neuropathology Illustrated 1.0
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
From: Neuropathology Illustrated 1.0
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
Neuron
Neuron
From: Charleen Chu MD/PhD
Viral Capsids
From: Charleen Chu MD/PhD
Viral Capsids
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
Diffuse inflammatory infiltrate
Perivascular inflammatory cuff
From: Neuropathology Illustrated 1.0
From: Neuropathology Illustrated 1.0
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
Swollen
Hemorrhagic
Temporal lobe
From Neuropathology Illustrated 1.0
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
From Neuropathology Illustrated 1.0
From Neuropathology Illustrated 1.0
HSV Immunohistochemistry
Low power of
needle biopsy
immunostained
(red) for HSV
antigens
From C.A. Wiley
HSV Encephalitis
Cowdry A Inclusions
From Neuropathology Illustrated 1.0
Intranuclear Viral capsids
From Neuropathology Illustrated 1.0
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 variolasmallpox
– 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: Clinical
Highly contagious generalized exanthematous disease with
marked seasonality (winter and spring)
Occurs at a rate of 5 per 1000 population per year
Spread by respiratory route
Majority 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
Confluent regions of demyelination
From:Francoise Gray MD
Nuclear Viral capsids
From:Francoise Gray MD
Ganglion cells
VZV Ganglionitis
Ganglion cell surrounded
by inflammatory cells
From Neuropathology Illustrated 1.0
From Neuropathology Illustrated 1.0
VZV Leukoencephalitis
From C.A. Wiley
From 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
From Neuropathology Illustrated 1.0
CMV
High 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 Ventriculitis
H&E of lateral ventricle (V) showing mostly
denuded ependyma with occasional
cytomegalic cell (arrow)
V
From C.A. Wiley
Immunostain for CMV antigens (red)
shows numerous infected ependymal
and underlying glial cells
V
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
From Neuropathology Illustrated 1.0
From Neuropathology Illustrated 1.0
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
involvement
Lymphomas 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
Multifocal white matter discoloration
PML
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
Nuclear inclusions
In Situ Hybridization for JC virus
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
Perivascular Inflammation
From: Neuropathology Illustrated 1.0
From: Neuropathology Illustrated 1.0
EM
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?