Viral Encephalitis

1
Viral Encephalitis

• Dan Karlin, Jenny Richmond, Chiemi Suzuki
• BIO 4158 Microbiology and Bioterrorism
• Dr. Zubay
• April 20, 2004

2
Roadmap

• Introduction
• History and epidemiology
• Molecular biology
• Weaponization
• Clinical manifestations
• Preparednes and continued surveillance

3
Introduction

• Encephalitis is an acute inflammatory process
  affecting the brain
• Viral infection is the most common and important
  cause, with over 100 viruses implicated worldwide
• Symptoms
• Fever
• Headache
• Behavioral changes
• Altered level of consciousness
• Focal neurologic deficits
• Seizures
• Incidence of 3.5-7.4 per 100,000 persons per year

4
Causes of Viral Encephalitis

• Herpes viruses HSV-1, HSV-2, varicella zoster
  virus, cytomegalovirus, Epstein-Barr virus, human
  herpes virus 6
• Adenoviruses
• Influenza A
• Enteroviruses, poliovirus
• Measles, mumps, and rubella viruses
• Rabies
• Arboviruses examples Japanese encephalitis
  St. Louis encephalitis virus West Nile
  encephalitis virus Eastern, Western and
  Venzuelan equine encephalitis virus tick borne
  encephalitis virus
• Bunyaviruses examples La Crosse strain of
  California virus
• Reoviruses example Colorado tick fever virus
• Arenaviruses example lymphocytic
  choriomeningitis virus

5
What Is An Arbovirus?

• Arboviruses arthropod-borne viruses
• Arboviruses are maintained in nature through
  biological transmission between susceptible
  vertebrate hosts by blood-feeding arthropods
• Vertebrate infection occurs when the infected
  arthropod takes a blood meal

6
http//www.cdc.gov/ncidod/dvbid/arbor/schemat.pdf
7
Major Arboviruses That Cause Encephalitis

• Flaviviridae
• Japanese encephalitis
• St. Louis encephalitis
• West Nile
• Togaviridae
• Eastern equine encephalitis
• Western equine encephalitis
• Bunyaviridae
• La Crosse encephalitis

8
http//www.cdc.gov/ncidod/dvbid/arbor/worldist.pdf
9
West Nile Virus
10
West Nile Virus

• Flavivirus
• Primary host wild birds
• Principal arthropod vector mosquitoes
• Geographic distribution - Africa, Middle East,
  Western Asia, Europe, Australia, North America,
  Central America

http//www.walgreens.com/images/library/healthtips
/july02/westnilea.jpg
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History of West Nile Virus

• 1937 - West Nile virus isolated from woman in
  Uganda
• 1950s First recorded epidemics in Israel
  (1951-1954, 1957)
• 1962 Epidemic in France
• 1974 Epidemic in South Africa. Largest ever
  West Nile epidemic.
• 1996 Romanian epidemic with features similar to
  those of the North American outbreak. 500 cases
  and 50 deaths.
• 1999 Russian outbreak. 40 deaths.

12
West Nile Virus 1999 New York Outbreak

• Crows dying in and around Queens in late summer
• 27 deaths among captive birds in the Queens and
  Bronx zoos
• Concomitant human infection of apparent
  encephalitis in the same area
• Outbreak was first attributed to St. Louis
  encephalitis, but tissue samples from dead crows
  confirmed that it was West Nile virus
• 59 human cases requiring hospitalization,
  including 7 deaths

13
Spread of West Nile Virus in the US

• 2000 spread throughout New England and
  Mid-Atlantic regions.
• 18 new human cases reported
• 2001 spread throughout the entire eastern half
  of the US
• 64 cases reported, with NY, FL and NJ accounting
  for 60
• 2002 spread westward across Great Plains into
  Western US. Reached California by Labor Day.
• By end of 2002 cumulative human cases gt 3900,
  with gt 250 deaths
• 2003 US, Canada, Mexico
• 9,858 cases reported to CDC, including 262 deaths
  in 45 states and D.C.

14
West Nile Activity in the US Reports as of
April 7, 2004
15
West Nile Activity in the US Counties Reporting
Cases as of March 24, 2004
16
West Nile Virus 2004BREAKING NEWS

• April 13, 2004 Ohio may have first 2004 West
  Nile Case
• 79 year old man from Scioto County, OH was
  admitted April 1 with viral meningitis and
  encephalitis which rapidly progressed to coma
  over 2 days.
• Initial IgM antibody titers were positive for
  West Nile virus and he complained of itching from
  insect bites upon admission
• Has been treated with blood-pressure drugs to
  control over-response by the immune system to
  West Nile virus, causing brain inflammation.
• Previously unresponsive and paralyzed.
• Can now open his eyes and shake his head in
  response to questions, but still cannot talk.

17
St. Louis Encephalitis
18
St. Louis Encephalitis

• Flavivirus
• Most common mosquito-transmitted human pathogen
  in the US
• Leading cause of epidemic flaviviral encephalitis

19
History of St. Louis Encephalitis

• 1933 virus isolated during St. Louis and Kansas
  City, MO epidemic
• 1940s virus spread to Pacific Coast
• 1959-1971 virus spread to Southern Florida
• 1974-1977 last major epidemic. Over 2,500
  cases in 35 states.
• 1990-1991 South Florida epidemic. 226 cases
  and 11 deaths.
• 1999 New Orleans outbreak. 20 reported cases.

20
St. Louis Encephalitis
21
Japanese Encephalitis
22
Japanese Encephalitis

• Flavivirus related to St. Louis encephalitis
• Most important cause of arboviral encephalitis
  worldwide, with over 45,000 cases reported
  annually
• Transmitted by culex mosquito, which breeds in
  rice fields
• Mosquitoes become infected by feeding on domestic
  pigs and wild birds infected with Japanese
  encephalitis virus. Infected mosquitoes transmit
  virus to humans and animals during the feeding
  process.

23
History of Japanese Encephalitis

• 1800s recognized in Japan
• 1924 Japan epidemic. 6125 cases, 3797 deaths
• 1935 virus isolated in brain of Japanese
  patient who died of encephalitis
• 1938 virus isolated from Culex mosquitoes in
  Japan
• 1948 Japan outbreak
• 1949 Korea outbreak
• 1966 China outbreak
• Today extremely prevalent in South East Asia.
  30,000-50,000 cases reported each year.

24
Distribution of Japanese Encephalitis in Asia,
1970-1998
25
Eastern Equine Encephalitis
26
Eastern Equine Encephalitis

• Togavirus
• Caused by a virus transmitted to humans and
  horses by the bite of an infected mosquito.
• 200 confirmed cases in the US 1964-present
• Average of 4 cases per year
• States with largest number of cases Florida,
  Georgia, Massachusetts, and New Jersey.
• Human cases occur relatively infrequently,
  largely because the primary transmission cycle
  takes place in swamp areas where populations tend
  to be limited.

27
History of Eastern Equine Encephalitis

• 1831 First recognized as a disease in horses.
  Over 75 horses died in 3 counties in
  Massachusetts.
• 1845-1912 epizootics in Northeast and
  Mid-Atlantic regions
• 1933 virus isolated from horse brains
• 1938 association of human disease with
  epizootics. 30 cases of fatal encephalitis in
  children living in same area as equine cases.
• 1947 largest recorded outbreak in Louisiana and
  Texas. 13,344 cases and 11,722 horse deaths

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29
Western Equine Encephalitis
30
Western Equine Encephalitis

• Togavirus
• Mosquito-borne
• 639 confirmed cases in the US since 1964
• Important cause of encephalitis in horses and
  humans in North America, mainly in the Western
  parts of the US and Canada

31
History of Western Equine Encephalitis

• Early 1900s epizootics of viral encephalitis
  in horses described in Argentina
• 1912 25,000 horses died in Central Plains of US
• 1930 San Joaquin Valley, CA outbreak. 6000
  cases in horses. Virus isolated from horse
  brains
• 1938 virus isolated from brain of a child

32
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33
La Crosse Encephalitis
34
La Crosse Encephalitis

• Bunyavirus
• On average 75 cases per year reported to the CDC
• Most cases occur in children under 16 years old
• Zoonotic pathogen that cycles between the daytime
  biting treehole mosquito, and vertebrate
  amplifier hosts (chipmunk, tree squirrel) in
  deciduous forest habitats
• Most cases occur in the upper Midwestern state,
  but recently cases have been reported in the
  Mid-Atlantic region and the Southeast
• 1963 isolated in La Crosse, WI from the brain
  of a child who died from encephalitis

35
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36
Summary Confirmed and Probable Human Cases in
the US
Virus Years Total cases
Eastern Equine 1964-2000 182
Western Equine 1964-2000 649
La Crosse 1964-2000 2,776
St. Louis 1964-2000 4,482
West Nile 1999-present gt 9,800
37
Molecular Biology of Viruses that can Cause Viral
Encephalitis

• Flaviviridae West Nile Virus
• Togaviridae Eastern and Western
  Equine Encephalitis
• Bunyaviridae La Crosse Virus

38
Flavivirus

• Japanese Encephalitis Virus
• St. Louis encephalitis virus
• West Nile Virus

39
Flavivirus Virus Classification

• Family Flaviviridae
• 3 Genera
• Flavivirus, Pestivirus, Hepacivirus
• Flavivirus - 12 Serogroups
• Japanese encephalitis virus serogroup
• Includes West Nile Virus (WNV), St. Louis
  Encephalitis, and others

40
Scanned images of West Nile virus isolated from
brain tissue from a crow found in New York.
41
Viral Replication Cycle

42
Genome Structure

43
Viral Genome

• Positive Strand RNA Genome
• 1 ORF Genome encodes single polyprotein which
  is subsequently cleaved
• 5 portion
• 3 structural proteins
• 3 portion
• 7 non-structural proteins
• Genome also includes 5 and 3 noncoding regions
  which have functional importance

44
Secondary structure loops

45
3 Stem Loop of Plus Strand

• Tertiary interactions of 3 non-coding region
  serve to stabilize and compact the 3 region of
  the genome and may also create binding sites for
  cellular and/or viral proteins
• Pseudoknots Formed by interactions between 3
  stem loop and adjacent nucleotides
• PK1 May be important for minus strand replication
• Interacts with cellular proteins
• P104, EF-1a, and p84

46
Conserved Secondary and Tertiary Terminal RNA
Structures in Minus Strand

• Stem loop structures at 5 and 3 ends are
  conserved across flavivirus species suggesting a
  functional importance for these groups.
• Minus strand stem loops may play a role in
  facilitating the formation of replication
  complexes and in releasing newly synthesized
  minus strands from plus strands.
• In addition, its interaction with cellular
  proteins is important for replication.

47
Viral Proteins Structural and Non-Structural

• Structural Proteins
• Capsid (C), Membrane (M), Envelope (E)
• The envelope - receptor binding
• Dimers of E protein arrange their ß sheets in a
  head to tail formation which lie flat on top of
  the lipid bilayer. The distal portions of these
  proteins are anchored in the membrane
• Non-Structural Multifunctional Proteins
• NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5
• Many functions of non-structural proteins have
  yet to be determined

48
Viral Non-Structural Proteins

• NS1- may play a role in flavivirus RNA synthesis
  it has been shown to be essential for negative
  strand synthesis
• NS2A, NS2B, NS4A, NS4B - may facilitate the
  assembly of viral replication complexes by an
  unknown mechanism
• NS3 Multifunctional
• Proteolytic function upon association with NS2B
• RNA triphosphatase function thought to be
  important for the synthesis of the 5 cap
  structure
• Helicase and NTPase activity
• Its activity may be upregulated through
  interaction with phosphorylated NS5
• NS5
• RNA dependent RNA polymerase
• Methyltransferase domain thought to be required
  for formation of the 5 cap

49
Model for Closed-Loop Complex Formation in
Flaviviruses
50
Togavirus

• Eastern Equine Encephalitis Virus
• Western Equine Encephalitis Virus
• Venezuelan Equine Encephalitis Virus

51
Togavirus

• Family Togaviridae
• Genus Alphavirus
• 49S Single Stranded Genome
• 11700 Nucleotides
• 3 end Five potential structural proteins
• C, E3, E2, 6K, and E1
• 5 end Unknown number of non-structural proteins
  probably involved in replication
• Genome has an opposite orientation from the
  Flaviviruses

52
Alphavirus Structure
http//www.cdc.gov/ncidod/dvbid/arbor/alphavir.htm
53
Alphaviruses Protein Function

• E1and E2 glycoprotein heterodimers form trimers
  that appear as knobs on the surface of the virion
• E1 transmembrane glycoprotein with 2 to 3
  N-linked glycosylation sites
• E2 - glycoprotein with 1 to 2 N-linked
  glycosylation sites, contains short
  intracytoplasmic tail and hydrophobic stretch of
  amino acids that serves as the fusion peptide for
  viral entry
• Capsid protein has a conserved N-terminal region
  which binds RNA and a C-terminal region which
  interacts with the cytoplasmic tail of E2 as well
  as capsid proteins
• E3 and 6K proteins are signal sequences for E2
  and E1, respectively, and are largely cleaved off
  from the mature virion

54
Replication Cycle

• Proposed Model E1 glycoprotein interacts with
  proteins on the cell surface. E2 binds to
  cellular proteins and receptor-mediated
  endocytosis takes place.
• In acidified endosomal compartment, glycoproteins
  fuse with membrane and the nucleocapsid is
  released.
• Virion RNA serves as mRNA, translation of
  non-structural proteins begins
• Structural proteins are transcribed as
  polyprotein
• E2 and E1 travel from ER to the Golgi
• At cellular membrane regions containing E1 and E2
  heterodimers interact with nucleocapsids and
  viral particles bud from the cell surface

55
Bunyaviridae

• La Crosse Virus

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La Crosse Virus
http//www.virology.net/Big_Virology/BVRNAbunya.ht
ml
57
Bunyaviruses

• Genome - single strand of negative sense RNA
• Four structural proteins
• Two external proteins
• Two associated with RNA to form nucleocapsid
• Matrix proteins absent from Bunyaviruses,
  therefore capsid proteins and envelope
  glycoproteins directly interact prior to budding

58
Bioweaponization
http//www.cdc.gov/ncidod/dvbid/arbor/index.htm
59
Transmission Cycle is Key to Weaponization
Mosquito vector
Incidental infections
West Nile virus
Bird reservoir hosts
Incidental infections
http//www.cdc.gov/ncidod/dvbid/westnile/conf/Febr
uary_2003.htm
60
Bioweaponization

• Vector, Vector, Vector
• In areas around NYC mosquitoes are extremely
  ubiquitous during the summer months
• Mosquitoes are already virulent, further genetic
  engineering is unnecessary
• A fully effective cure is not available
• Diagnosis is difficult
• Widespread Panic would be generated as the
  outbreak progresses

61
The Iraq Connection

• The US shipped various pathogens, including WNV,
  to Iraq in the 1980s
• In 1999 following the West Nile Virus outbreak in
  NYC there were fears that Iraqi bioterrorism was
  involved
• Investigations by the CDC and the CIA found no
  evidence of bioterrorism in the 1999 outbreak

62
WNV as a low-tech BioweaponPossible Connection
to 1999 outbreak

• Gather mosquitoes in an endemic area
• Incubate mosquitoes with a food source
• Put them to sleep
• Place mosquitoes in a matchbox
• Board plane to US
• Take bus from airport Release mosquitoes from
  bus window
• Wait for outbreak

Source Dr. Ilya Trakht
63
Clinical Considerations

64
Case Study

• In August 2002, a 91 year old male from Northern
  Staten Island who presented initially with sudden
  onset of fever, left lower extremity weakness,
  inability to walk, and possibly some transient
  and mild AMS, was admitted to a Staten Island
  hospital.
• He was not considered to have aseptic meningitis
  or encephalitis and WN virus infection was not
  considered at that time. After being discharged,
  he was evaluated by a neurologist for persistent
  left leg weakness and inability to walk.
• In April 2003, the neurologist reported this
  case to the DOHMH as a possible polio case.
  Serological specimens were forwarded to the
  NYSDOH where they tested positive for WN virus.

65
Clinical Considerations

• Diagnosis

66
Patient History

• Detailed history critical to determine the likely
  cause of encephalitis.
• Prodromal illness, recent vaccination,
  development of few days ? Acute Disseminated
  Encephalomyelitis (ADEM) .
• Biphasic onset systemic illness then CNS disease
  ? Enterovirus encephalitis.
• Abrupt onset, rapid progression over few days ?
  HSE.
• Recent travel and the geographical context
• Africa ? Cerebral malaria
• Asia ? Japanese encephalitis
• High risk regions of Europe and USA ? Lyme
  disease
• Recent animal bites ? Tick borne encephalitis or
  Rabies.
• Occupation
• Forest worker, exposed to tick bites
• Medical personnel, possible exposure to
  infectious diseases.

67
History cont.

• Season
• Japanese encephalitis is more common during the
  rainy season.
• Arbovirus infections are more frequent during
  summer and fall.
• Predisposing factors
• Immunosuppression caused by disease and/or drug
  treatment.
• Organ transplant ? Opportunistic infections
• HIV ? CNS infections
• HSV-2 encephalitis and Cytomegalovirus infection
  (CMV)
• Drug ingestion and/or abuse
• Trauma

68
Initial Signs

• Headache
• Malaise
• Anorexia
• Nausea and Vomiting
• Abdominal pain

69
Developing Signs

• Altered LOC mild lethargy to deep coma.
• AMS confused, delirious, disoriented.
• Mental aberrations
• hallucinations
• agitation
• personality change
• behavioral disorders
• occasionally frank psychosis
• Focal or general seizures in gt50 severe cases.
• Severe focused neurologic deficits.

70
Neurologic Signs

• Virtually every possible focal neurological
  disturbance has been reported.
• Most Common
• Aphasia
• Ataxia
• Hemiparesis with hyperactive tendon reflexes
• Involuntary movements
• Cranial nerve deficits (ocular palsies, facial
  weakness)

71
Other Causes of Encephalopathy

• Anoxic/Ischemic conditions
• Metabolic disorders
• Nutritional deficiency
• Toxic (Accidental Intentional)
• Systemic infections
• Critical illness
• Malignant hypertension
• Mitochondrial cytopathy (Reyes and MELAS
  syndromes)
• Hashimotos encephalopathy
• Traumatic brain injury
• Epileptic (non-convulsive status)
• CJD (Mad Cow)

72
Differential Diagnosis

• Distinguish Etiology
• (1) Bacterial infection and other infectious
  conditions
• (2) Parameningeal infections or partially treated
  bacterial meningitis
• (3) Nonviral infectious meningitides where
  cultures may be negative (e.g., fungal,
  tuberculous, parasitic, or syphilitic disease)
• (5) Meningitis secondary to noninfectious
  inflammatory diseases
• MRI
• Can exclude subdural bleeds, tumor, and sinus
  thrombosis
• Biopsy
• Reserved for patients who are worsening, have an
  undiagnosed lesion after scan, or a poor response
  to acyclovir.
• Clinical signs cannot distinguish different viral
  encephalitides

73
Differential Diagnosis cont.

• Encephalopathy Encephalitis
• Fever Uncommon Common
• Headache Uncommon Common
• AMS Steady deterioration May fluctuate
• Focal Neurologic Signs Uncommon Common
• Types of seizures Generalized Both
• Blood Leukocytosis Uncommon Common
• CSF Pleocytosis Uncommon Common
• EEG Diffuse slowing Common Focal
• MRI Often normal Focal Abn.

74
Clinical Considerations

• Radiology

75
MRI
76
MRI
77
Clinical Considerations

• Laboratory Diagnosis

78
Laboratory Diagnosis

• Diagnosis is usually based on CSF
• Normal glucose
• Absence of bacteria on culture.
• Viruses occasionally isolated directly from CSF
• Less than half are identified
• Polymerase Chain Reaction techniques
• Detect specific viral DNA in CSF

79
NYSDOH PCR

• NEW YORK STATE DEPARTMENT OF HEALTH (NYSDOH)
• Viral Encephalitis Letter of Agreement for
• Physician Ordered Testing by Polymerase Chain
  Reaction (PCR)
• NYSDOH's Wadsworth Center offers the following
  tests on CSF for viral encephalitis
• PCR testing for a panel of viruses, including
  herpes simplex, varicella zoster,
  cytomegalovirus, Epstein-Barr virus,
  enteroviruses, St. Louis encephalitis (SLE),
  eastern equine encephalitis (EEE), California
  encephalitis (including LaCrosse and Jamestown
  Canyon viruses), Powassan and West Nile (WN)
  viruses, and
• Enzyme-linked immunoassay (ELISA) for WN virus.
• If there is insufficient quantity of CSF (less
  than 1.0 ml) to conduct both ELISA and PCR for WN
  virus, please consider the following in
  determining which test is most appropriate for
  your patient
• ELISA is more sensitive than PCR for WN viral
  testing and should be considered when there is
  stronger suspicion of WN virus than other
  viruses.
• PCR is less sensitive for WN virus, but tests
  for a wide range of viruses. PCR should be
  considered if viruses other than WN virus are
  suspected.
• Please note your testing priority below or on the
  viral encephalitis/meningitis case report form.
  If PCR testing is desired, the agreement below
  must be completed.
• ? Viral Encephalitis PCR Panel? West Nile Virus
  ELISA Antibody Testing

80
Clinical Considerations

• Disease Progression

81
Disease Progression

• Worsening neurologic symptoms
• Vascular collapse and shock
• May be due to adrenal insufficiency.
• Loss of tissue fluid may be equally important.
• Homeostatic failure
• Decreased respiratory drive

82
Clinical Considerations

• Treatment

83
Treatment

• When HSE cannot be ruled out, Acyclovir must be
  started promptly (before the patient lapses into
  coma) and continued at least 10 days for maximal
  therapeutic benefit.
• Rocky Mountain spotted fever should also be
  considered, and empiric treatment with
  Doxycycline is indicated.

84
Suspected HSE Treatment Plan
85
Acyclovir

• Acyclovir is a synthetic purine nucleoside
  analogue with inhibitory activity against HSV-1
  and HSV-2, varicella-zoster virus (VZV),
  Epstein-Barr virus (EBV) and cytomegalovirus
  (CMV)
• In order of decreasing effectiveness
• Highly selective

86
Acyclovir Action

• Thymidine Kinase (TK) of uninfected cells does
  not use acyclovir as a substrate.
• TK encoded by HSV, VZV and EBV2 converts
  acyclovir into acyclovir monophosphate.
• The monophosphate is further converted into
  diphosphate by cellular guanylate kinase and into
  triphosphate by a number of cellular enzymes.
• Acyclovir triphosphate interferes with Herpes
  simplex virus DNA polymerase and inhibits viral
  DNA replication.
• Acyclovir triphosphate incorporated into growing
  chains of DNA by viral DNA polymerase.
• When incorporation occurs, the DNA chain is
  terminated.
• Acyclovir is preferentially taken up and
  selectively converted to the active triphosphate
  form by HSV-infected cells.
• Thus, acyclovir is much less toxic in vitro for
  normal uninfected cells because 1) less is taken
  up 2) less is converted to the active form.

87
Supportive Therapy

• Fever, dehydration, electrolyte imbalances, and
  convulsions require treatment.
• For cerebral edema severe enough to produce
  herniation, controlled hyperventilation,
  mannitol, and dexamethasone.
• Patients with cerebral edema must not be
  overhydrated.
• If these measures are used, monitoring ICP should
  be considered.
• If there is evidence of ventricular enlargement,
  intracranial pressure may be monitored in
  conjunction with CSF drainage.
• Outcome is usually poor.
• For infants with subdural effusion, repeated
  daily subdural taps through the sutures usually
  helps.
• No more than 20 mL/day of CSF should be removed
  from one side to prevent sudden shifts in
  intracranial contents.
• If the effusion persists after 3 to 4 weeks of
  taps, surgical exploration for possible excision
  of a subdural membrane is indicated.

88
Dexamethasone

• Synthetic adrenocortical steroid
• Potent anti-inflammatory effects
• Dexamethasone injection is generally administered
  initially via IV then IM
• Side effects convulsions increased ICP after
  treatment vertigo headache psychic
  disturbances

89
Clinical Considerations

• Patient Prognosis

90
Prognosis

• The mortality rate varies with etiology, and
  epidemics due to the same virus vary in severity
  in different years.
• Bad Eastern equine encephalitis virus infection,
  nearly 80 of survivors have severe neurological
  sequelae.
• Not so Bad EBV, California encephalitis virus,
  and Venezuelan equine encephalitis virus, severe
  sequelae are unusual.
• Approximately 5 to 15 of children infected with
  LaCrosse virus have a residual seizure disorder,
  and 1 have persistent hemiparesis.
• Permanent cerebral sequelae are more likely to
  occur in infants, but young children improve for
  a longer time than adults with similar
  infections.
• Intellectual impairment, learning disabilities,
  hearing loss, and other lasting sequelae have
  been reported in some studies.

91
Prognosis w/ Treatment

• Considerable variation in the incidence and
  severity of sequelae.
• Hard to assess effects of treatment.
• NIAID-CASG trials
• The incidence and severity of sequelae were
  directly related to the age of the patient and
  the level of consciousness at the time of
  initiation of therapy.
• Patients with severe neurological impairment
  (Glasgow coma score 6) at initiation of therapy
  either died or survived with severe sequelae.
• Young patients (lt30 years) with good neurological
  function at initiation of therapy did
  substantially better (100 survival, 62 with no
  or mild sequelae) compared with their older
  counterparts (gt30 years) (64 survival, 57 no
  or mild sequelae).
• Recent studies using quantitative CSF PCR tests
  for HSV indicate that clinical outcome following
  treatment also correlates with the amount of HSV
  DNA present in CSF at the time of presentation.

92
Glasgow Coma Scale

• Test Response ____Score
• Eye None 1
• Opening To pain 2
• To verbal stimuli 3
• Spontaneously 4
• Best None 1
• Verbal Incomprehensible words 2
• Response Inappropriate words 3
• Disoriented conversation 4
• Oriented conversation 5
• Best None 1
• Motor Abnormal extension 2
• Response Abnormal flexion 3
• Flexion withdrawal 4
• Localizes pain 5
• ______________Obeys commands _________6 _
• Total score 3-15

93
Clinical Considerations

• Vaccination

94
Vaccination

• None for most Encephalitides
• JE
• Appears to be 91 effective
• There is no JE-specific therapy other than
  supportive care
• Live-attenuated vaccine developed and tested in
  China
• Appears to be safe and effective
• Chinese immunization programs involving millions
  of children
• Vero cell-derived inactivated vaccines have been
  developed in China
• 2 millions doses are produced annually in China
  and Japan
• Several other JE vaccines under development

95
Public Health Considerations

• Endemic Prevention

96
Infection Control

• CDCs Three Ways to Reduce your West Nile Virus
  Risk
• Avoid mosquito bites
• Mosquito-proof your home
• Help your community

97
Avoid Mosquito Bites

• Apply Insect Repellent Containing DEET
• Clothing Can Help Reduce Mosquito Bites
• Cover up
• Be Aware of Peak Mosquito Hours
• Dusk to dawn are peak mosquito biting times for
  many species.

98
Mosquito-Proof Home

• Drain Standing Water
• Install or Repair Screens

99
Community-Wide Efforts

• Clean Up Breeding Grounds
• Ensure Safe Blood Supply
• Mosquito Control Programs
• Controversial
• Surveillance

100
Blood Supply

• NYC Policy Statement reflecting FDA policy
• To reduce WN transmission through blood
  components. Blood donations will be screened for
  WN virus RNA using nucleic acid amplification
  tests (NAT). In the event of a NAT-reactive
  donation, blood centers will remove and
  quarantine all blood components associated with
  the donation and notify the state or local health
  department. In addition, blood testing centers
  have added screening questions to identify and
  exclude persons with fever and headache in the
  week prior to donation.

101
Mosquito Control Programs

• NYC DOHMH Statement
• We hope that spraying of adulticides will not
  be required this summer. However, if there is a
  threat of an outbreak of human illness and
  spraying is deemed necessary, targeted adult
  mosquito control measures (via ground or aerial
  spraying of pesticides) may be required.

102
Mosquito Control

• But wait, theres more
• Same Memo
• Confirmed or suspected cases of pesticide
  poisoning must be reported to the New York State
  Department of Healths Pesticide Poisoning
  Registry at (800)-322-6850, and to the New York
  City Poison Control Center at (212)-764-7667.

103
Whats Being Sprayed

• The adulticides used during the last three
  seasons in New York City is Sumithrin, a
  pyrethroid.
• Although pyrethroids are among the least toxic
  insecticides, they are nerve poisons, and act
  upon the sodium ion channels in nerve cell
  membranes.
• Inhaling pyrethroid insecticides can cause
  coughing, wheezing, shortness of breath, runny or
  stuffy nose, chest pain, or difficulty breathing.
  
• Skin contact can cause a rash, itching, or
  blisters.
• Sumithrin is not very toxic to mammals, but it is
  highly toxic to bees and fish.

104
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105
Crop-Dusting NYC?

• Aerosolized liquids sprayed over large areas of
  the city.
• Terrorism concern?
• New vector for urban area.

106
Public Health Considerations

• Surveillance

107
Surveillance

• Since 2000, the NYC DOHMH has conducted
  comprehensive arthropod-borne disease
  surveillance and control. In 2003, efforts will
  again focus on mosquito control through reduction
  of breeding sites and application of larvicides.
  In addition, comprehensive mosquito, avian and
  human data collected during the 2000-2002 seasons
  have allowed NYC DOHMH to develop more sensitive
  surveillance criteria for determining the level
  of WN viral activity in birds and mosquitoes that
  may indicate a significant risk for a human
  outbreak. These indicators will be monitored
  citywide to identify areas at risk for human
  transmission.

108
Standing Water Reporting

• The Department of Health Mental Hygiene is now
  accepting reports of standing water. However, we
  will not be able to visit and treat all reported
  nuisances. Therefore we are encouraging City
  residents and business owners to take immediate
  action to eliminate standing water on their
  property.

109
Dead-Bird Reporting

• Online form
• http//www.nyc.gov/html/doh/html/wnv/wnvbird.html
• The Department of Health Mental Hygiene is now
  accepting reports of dead birds. Only a sample of
  dead birds that meet specific criteria will be
  picked up and tested for the West Nile virus.
  However, your report of a dead bird is extremely
  important to us because dead bird reports may
  indicate the presence of West Nile virus. If you
  do not receive a call back from the Department of
  Health within two business days of making your
  report, please dispose of the bird.

110
Mosquito Testing

• Five pools of mosquitoes collected in New York
  City have tested positive for West Nile (WN)
  virus. These include a pool of Culex salinarius,
  a human biting mosquito, collected on July 15, in
  the Willowbrook Park area of Staten Island, a
  pool of Culex restuans, primarily a bird-biting
  mosquito, collected from Brookville Park, Queens
  on July 17, a pool of Culex pipiens, a mosquito
  that bites both birds and humans, collected from
  the Hunts Point area of the Bronx on July 18, a
  pool of Culex species collected from Jamaica Bay,
  Queens on July 16, and a pool of Culex salinarius
  collected from Greenwood Cemetery, Brooklyn on
  July 21. These positive pools are the first
  evidence of West Nile (WN) virus in New York City
  in 2003

111
Disease Reporting

• The New York City Department of Health and
  Mental Hygiene (NYC DOHMH) is again requesting
  that during the peak adult mosquito season, from
  June 1 October 31, 2003, all suspected cases of
  viral encephalitis (all ages) and viral
  meningitis (adults only) be reported immediately
  by telephone or facsimile and that appropriate
  laboratory specimens (cerebrospinal fluid and
  sera) be submitted promptly for testing for West
  Nile (WN) virus.