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Viral Encephalitis
Viral Encephalitis
Viral Encephalitis
Togaviridae
Eastern equine encephalitis
Western equine encephalitis
Bunyaviridae
La Crosse encephalitis
West Nile Virus
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
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.
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
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 > 3900, with > 250 deaths
2003 – US, Canada, Mexico
9,858 cases reported to CDC,
including 262 deaths in 45 states
and D.C.
West Nile Activity in the US –
Reports as of April 7, 2004
West Nile Activity in the US –
Counties Reporting Cases as of
March 24, 2004
West Nile Virus 2004:
BREAKING 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.
St. Louis Encephalitis
St. Louis Encephalitis
Flavivirus
Most common
mosquito-transmitted
human pathogen in the
US
Leading cause of
epidemic flaviviral
encephalitis
History of St. Louis Encephalitis
1933 – virus isolated during St. Louis and Kansas City,
MO epidemic
1940’s – 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.
St. Louis Encephalitis
Japanese Encephalitis
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.
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.
Distribution of Japanese
Encephalitis in Asia, 1970-1998
Eastern Equine
Encephalitis
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.
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
Western Equine
Encephalitis
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
History of Western Equine
Encephalitis
Early 1900’s – 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
La Crosse Encephalitis
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
Summary – Confirmed and Probable
Human Cases in the US
Virus Years Total cases
http://www.cdc.gov/ncidod/dvbid/arbor/alphavir.htm
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
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
Bunyaviridae
La Crosse Virus
La Crosse Virus
http://www.virology.net/Big_Virology/BVRNAbunya.html
Bunyaviruses
Genome - single strand of negative sense RNA
Four structural proteins
Two external proteins
http://www.cdc.gov/ncidod/dvbid/arbor/index.htm
Transmission Cycle is Key to
Weaponization
Mosquito vector
Incidental infections
http://www.cdc.gov/ncidod/dvbid/westnile/conf/February_2003.htm
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
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
WNV as a low-tech Bioweapon:
Possible 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
Clinical Considerations
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.
Involuntary movements
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
Clinical Considerations
Disease Progression
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
Clinical Considerations
Treatment
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.
Suspected HSE Treatment Plan
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
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.
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.
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
Clinical Considerations
Patient Prognosis
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.
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 (<30 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 (>30 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.
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
Clinical Considerations
Vaccination
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
Public Health
Considerations
Endemic Prevention
Infection Control
CDC’s “Three Ways to Reduce your West
Nile Virus Risk”
Avoid mosquito bites
Mosquito-proof your home