Neurovirology

1
Neurovirology

• Acute viral infections
• Rabies, Enteroviridae, Mumps, Arenaviridae,
  Arboviruses
• Herpes viral infections
• HSV, VZV, CMV
• Chronic viral infections
• JC-virus (PML), Measles (SSPE)

2
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

3
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

4
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

5
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

6
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)

7
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).

8
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

9
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

10
Rabies
Negri Body
From Neuropathology Illustrated 1.0
11
Rabies

• HE 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
12
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

13
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

14
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.

15
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.

16
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
17
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

18
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

19
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

20
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

21
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.

22
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

23
Arboviruses Clinical

• 4 syndromes associated with arboviruses
• Encephalitis
• Yellow fever
• Hemorrhagic fever
• Undifferentiated tropical fevers.
• Pathology
• nonspecific inflammation

24
Arbovirus Encephalitis
Neuron
Neuron
From Charleen Chu MD/PhD
Viral Capsids
Viral Capsids
From Charleen Chu MD/PhD
25
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 (201)
• Pathology
• meningeal and perivascular inflammation,
  neuronophagia.

26
Western Encephalitis

• Mosquito and birds in cycle but mosquito does
  feed on large vertebrates
• Ratio of unapparent to apparent infections is
  very high
• 10001 sequelae rare but fatal

27
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

28
Other arboviruses

• Venezuelan Equine Encephalitis
• California Encephalitis
• Japanese Encephalitis
• Colorado Tick Fever virus
• Tick-borne Encephalitis
• Undefined virus
• Recapitulate epidemiological patterns of virus
  dissemination

29
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

30
Post-Infectious Encephalomyelitis
Diffuse inflammatory infiltrate
Perivascular inflammatory cuff
From Neuropathology Illustrated 1.0
From Neuropathology Illustrated 1.0
31
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

32
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

33
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

34
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

35
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

36
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

37
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

38
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
39
HSVE Gross
Swollen Hemorrhagic Temporal lobe
From Neuropathology Illustrated 1.0
40
HSV Pathology

• Adults HSV I localization to orbital-frontotempor
  al 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

41
HSV Encephalitis HE
Microscopic hemorrhages
Perivascular and parenchymal inflammation

• From Neuropathology Illustrated 1.0

From Neuropathology Illustrated 1.0
42
HSV Immunohistochemistry

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

From C.A. Wiley
43
HSV Encephalitis
Cowdry A Inclusions
From Neuropathology Illustrated 1.0
Intranuclear Viral capsids
From Neuropathology Illustrated 1.0
44
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

45
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.

46
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.

47
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.

48
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

49
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.

50
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 11000 acute cerebellar ataxia
  - transient
• Neonatal varicella
• in utero infection with cicatricial scarring
  during first trimester

51
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

52
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

53
VZV Encephalitis
Confluent regions of demyelination
Nuclear Viral capsids
FromFrancoise Gray MD
FromFrancoise Gray MD
54
VZV Ganglionitis
Ganglion cells
Ganglion cell surrounded by inflammatory cells
From Neuropathology Illustrated 1.0
From Neuropathology Illustrated 1.0
55
VZV Leukoencephalitis
From C.A. Wiley
From C.A. Wiley
56
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.

57
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

58
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

59
CMV Ventriculitis
Periventircular erosions
From Neuropathology Illustrated 1.0
60
CMV

• High Power HE 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
61
CMV Ventriculitis

• HE 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
From C.A. Wiley
V
From C.A. Wiley
62
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

63
Fetal CMV Encephalitis
Periventricular mineralization
Centrifugal inflammation
From Neuropathology Illustrated 1.0
From Neuropathology Illustrated 1.0
64
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

65
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.

66
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

67
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

68
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

69
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.

70
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)

71
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

72
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.

73
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

74
PML
Multifocal white matter discoloration
White matter necrosis
75
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

76
PML
Sea of Macrophages
CD68
Gliosis and bizarre astrocytes
Nuclear inclusions
In Situ Hybridization for JC virus
77
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.

78
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.

79
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

80
Measles Clinical

• Involvement of CNS is common
• 5 - 7 days post rash presumed autoimmune etiology
• 10 with pleocytosis
• 50 of children with EEG changes
• 11,000 cases with symptomatic encephalitis
• Virus usually not recoverable

81
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

82
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

83
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

84
Measles Diagnosis

• virus isolation difficult
• IF of skin biopsies
• SSPE patients have 10 to 100 times antibody with
  oligoclonal CSF bands

85
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
• 1106 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

86
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

87
SSPE
Cowdry A Inclusions
Perivascular Inflammation
From Neuropathology Illustrated 1.0
EM
From Neuropathology Illustrated 1.0
88
Measles SSPE Pathology

• Mild meningitis
• Gray and white matter involved
• Mostly posterior hemispheres
• Microglial reaction
• Eosinophilic inclusions most commonly in oligos
• EM tubular structures

89
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

90
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

91
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

92
HIV Encephalitis

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