• Encephalitis is an acute inflammatory process affecting
• Viral infection is the most common and important cause,
with over 100 viruses implicated worldwide
• Behavioral changes
• Altered level of consciousness
• Focal neurologic deficits
• Incidence of 3.5-7.4 per 100,000 persons per year
Causes of Viral Encephalitis
• Herpes viruses – HSV-1, HSV-2, varicella zoster virus,
cytomegalovirus, Epstein-Barr virus, human herpes virus 6
• Influenza A
• Enteroviruses, poliovirus
• Measles, mumps, and rubella viruses
• Arboviruses – examples: Japanese encephalitis; St. Louis
encephalitis virus; West Nile encephalitis virus; Eastern, Western
and Venzuelan equine encephalitis virus; tick borne encephalitis
• Bunyaviruses – examples: La Crosse strain of California virus
• Reoviruses – example: Colorado tick fever virus
• Arenaviruses – example: lymphocytic choriomeningitis virus
What Is An Arbovirus?
• Arboviruses = arthropod-borne viruses
• Arboviruses are maintained in nature through biological
transmission between susceptible vertebrate hosts by blood-
• Vertebrate infection occurs when the infected arthropod takes
a blood meal
Major Arboviruses That Cause
• Japanese encephalitis
• St. Louis encephalitis
• West Nile
• Eastern equine encephalitis
• Western equine encephalitis
• La Crosse encephalitis
History of West Nile Virus
• 1937 - West Nile virus isolated from woman in
• 1950s – First recorded epidemics in Israel (1951-
• 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.
History of St. Louis
• 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
History of Japanese
• 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
• 1948 – Japan outbreak
• 1949 – Korea outbreak
• 1966 – China outbreak
• Today – extremely prevalent in South East Asia.
30,000-50,000 cases reported each year.
History of Western Equine
• 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
• Japanese Encephalitis Virus
• St. Louis encephalitis virus
• West Nile Virus
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
• 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
Viral Proteins: Structural and
• Structural Proteins
• Capsid (C), Membrane (M), Envelope (E)
• The envelope - receptor binding
• Dimers of E protein arrange their β 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
• Non-Structural Multifunctional Proteins
• NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5
• Many functions of non-structural proteins have
yet to be determined
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
• RNA dependent RNA polymerase
• Methyltransferase domain thought to be required for formation of the 5’
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
• 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
La Crosse Virus
• 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
• Distinguish Etiology
• (1) Bacterial infection and other infectious conditions
• (2) Parameningeal infections or partially treated bacterial
• (3) Nonviral infectious meningitides where cultures may be
negative (e.g., fungal, tuberculous, parasitic, or syphilitic disease)
• (5) Meningitis secondary to noninfectious inflammatory diseases
• Can exclude subdural bleeds, tumor, and sinus thrombosis
• Reserved for patients who are worsening, have an undiagnosed
lesion after scan, or a poor response to acyclovir.
• Clinical signs cannot distinguish different viral
• 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
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
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
• 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
• 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.
• 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
• In order of decreasing effectiveness
• Highly selective
• Thymidine Kinase (TK) of uninfected cells does not use acyclovir as a
• TK encoded by HSV, VZV and EBV2 converts acyclovir into acyclovir
• The monophosphate is further converted into diphosphate by
cellular guanylate kinase and into triphosphate by a number of
• 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.
• Fever, dehydration, electrolyte imbalances, and convulsions require
• 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.
• 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
• 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
• 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.
• None for most Encephalitides
• Appears to be 91% effective
• There is no JE-specific therapy other than supportive
• 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
• CDC’s “Three Ways to Reduce your West Nile Virus Risk”
• Avoid mosquito bites
• Mosquito-proof your home
• Help your community
• Make sure window and door screens are "bug tight"
• Replace your outdoor lights with yellow "bug" lights
• Bug zappers are not very effective
• ULV foggers for backyard use
• Keep vegetation and standing water in check around the