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Viral Encephalitis. Dan Karlin, Jenny Richmond, Chiemi Suzuki BIO 4158: Microbiology and Bioterrorism Dr. Zubay April 20, 2004. Roadmap. Introduction History and epidemiology Molecular biology Weaponization Clinical manifestations Preparednes and continued surveillance. Introduction.

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Viral encephalitis

Viral Encephalitis

Dan Karlin, Jenny Richmond, Chiemi Suzuki

BIO 4158: Microbiology and Bioterrorism

Dr. Zubay

April 20, 2004


Roadmap
Roadmap

  • Introduction

  • History and epidemiology

  • Molecular biology

  • Weaponization

  • Clinical manifestations

  • Preparednes and continued surveillance


Introduction
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


Causes of viral encephalitis
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


What is an arbovirus
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



Major arboviruses that cause encephalitis
Major Arboviruses That Cause Encephalitis

  • Flaviviridae

    • Japanese encephalitis

    • St. Louis encephalitis

    • West Nile

  • Togaviridae

    • Eastern equine encephalitis

    • Western equine encephalitis

  • Bunyaviridae

    • La Crosse encephalitis




West nile virus1
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
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
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
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 virus 2004 breaking news
West Nile Virus 2004: of March 24, 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.


St louis encephalitis

St. Louis Encephalitis of March 24, 2004


St louis encephalitis1
St. Louis Encephalitis of March 24, 2004

  • Flavivirus

  • Most common mosquito-transmitted human pathogen in the US

  • Leading cause of epidemic flaviviral encephalitis


History of st louis encephalitis
History of St. Louis Encephalitis of March 24, 2004

  • 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 encephalitis2
St. Louis Encephalitis of March 24, 2004


Japanese encephalitis

Japanese Encephalitis of March 24, 2004


Japanese encephalitis1
Japanese Encephalitis of March 24, 2004

  • 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
History of Japanese Encephalitis of March 24, 2004

  • 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.



Eastern equine encephalitis

Eastern Equine Encephalitis of March 24, 2004


Eastern equine encephalitis1
Eastern Equine Encephalitis of March 24, 2004

  • 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
History of Eastern Equine Encephalitis of March 24, 2004

  • 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 of March 24, 2004


Western equine encephalitis1
Western Equine Encephalitis of March 24, 2004

  • 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
History of Western Equine Encephalitis of March 24, 2004

  • 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 of March 24, 2004


La crosse encephalitis1
La Crosse Encephalitis of March 24, 2004

  • 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



Molecular biology of viruses that can cause viral encephalitis

Molecular Biology of Viruses that can Cause Viral Encephalitis

Flaviviridae: West Nile Virus

Togaviridae: Eastern and Western Equine Encephalitis

Bunyaviridae: La Crosse Virus


Flavivirus

Flavivirus Encephalitis

Japanese Encephalitis Virus

St. Louis encephalitis virus

West Nile Virus


Flavivirus virus classification
Flavivirus: Virus Classification Encephalitis

  • Family Flaviviridae

  • 3 Genera

    • Flavivirus, Pestivirus, Hepacivirus

  • Flavivirus - 12 Serogroups

    • Japanese encephalitis virus serogroup

      • Includes West Nile Virus (WNV), St. Louis Encephalitis, and others



Viral replication cycle
Viral Replication Cycle from a crow found in New York.


Genome structure
Genome Structure from a crow found in New York.


Viral genome
Viral Genome from a crow found in New York.

  • 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


Secondary structure loops
Secondary structure loops from a crow found in New York.


3 stem loop of plus strand
3’ Stem Loop of Plus Strand from a crow found in New York.

  • 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-1α, and p84


Conserved secondary and tertiary terminal rna structures in minus strand
Conserved Secondary from a crow found in New York. 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.


Viral proteins structural and non structural
Viral Proteins: Structural and Non-Structural from a crow found in New York.

  • 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 the membrane

  • 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
Viral Non-Structural Proteins from a crow found in New York.

  • 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



Togavirus

Togavirus from a crow found in New York.

Eastern Equine Encephalitis Virus

Western Equine Encephalitis Virus

Venezuelan Equine Encephalitis Virus


Togavirus1
Togavirus from a crow found in New York.

  • 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


Alphavirus structure
Alphavirus Structure from a crow found in New York.

http://www.cdc.gov/ncidod/dvbid/arbor/alphavir.htm


Alphaviruses protein function
Alphaviruses: Protein Function from a crow found in New York.

  • 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
Replication Cycle from a crow found in New York.

  • 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

Bunyaviridae from a crow found in New York.

La Crosse Virus


La crosse virus
La Crosse Virus from a crow found in New York.

http://www.virology.net/Big_Virology/BVRNAbunya.html


Bunyaviruses
Bunyaviruses from a crow found in New York.

  • 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


Bioweaponization
Bioweaponization from a crow found in New York.

http://www.cdc.gov/ncidod/dvbid/arbor/index.htm


Viral encephalitis

Transmission Cycle is Key to Weaponization from a crow found in New York.

Mosquito vector

Incidental infections

West Nile virus

Bird reservoir hosts

Incidental infections

http://www.cdc.gov/ncidod/dvbid/westnile/conf/February_2003.htm


Bioweaponization1
Bioweaponization from a crow found in New York.

  • 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 Iraq Connection from a crow found in New York.

  • 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
WNV as a low-tech Bioweapon: from a crow found in New York.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

Clinical Considerations from a crow found in New York.


Case study
Case Study from a crow found in New York.

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.


Clinical considerations1

Clinical Considerations from a crow found in New York.

Diagnosis


Patient history
Patient History from a crow found in New York.

  • 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.


History cont
History cont. from a crow found in New York.

  • 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


Initial signs
Initial Signs from a crow found in New York.

  • Headache

  • Malaise

  • Anorexia

  • Nausea and Vomiting

  • Abdominal pain


Developing signs
Developing Signs from a crow found in New York.

  • 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 >50% severe cases.

  • Severe focused neurologic deficits.


Neurologic signs
Neurologic Signs from a crow found in New York.

  • 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)


Other causes of encephalopathy
Other Causes of Encephalopathy from a crow found in New York.

  • Anoxic/Ischemic conditions

  • Metabolic disorders

  • Nutritional deficiency

  • Toxic (Accidental & Intentional)

  • Systemic infections

  • Critical illness

  • Malignant hypertension

  • Mitochondrial cytopathy (Reye’s and MELAS syndromes)

  • Hashimoto’s encephalopathy

  • Traumatic brain injury

  • Epileptic (non-convulsive status)

  • CJD (Mad Cow)


Differential diagnosis
Differential Diagnosis from a crow found in New York.

  • 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


Differential diagnosis cont
Differential Diagnosis cont. from a crow found in New York.

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.


Clinical considerations2

Clinical Considerations from a crow found in New York.

Radiology


Viral encephalitis
MRI from a crow found in New York.


Viral encephalitis
MRI from a crow found in New York.


Clinical considerations3

Clinical Considerations from a crow found in New York.

Laboratory Diagnosis


Laboratory diagnosis
Laboratory Diagnosis from a crow found in New York.

  • 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


Nysdoh pcr
NYSDOH PCR from a crow found in New York.

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


Clinical considerations4

Clinical Considerations from a crow found in New York.

Disease Progression


Disease progression
Disease Progression from a crow found in New York.

  • 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 considerations5

Clinical Considerations from a crow found in New York.

Treatment


Treatment
Treatment from a crow found in New York.

  • 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
Suspected HSE Treatment Plan from a crow found in New York.


Acyclovir
Acyclovir from a crow found in New York.

  • 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
Acyclovir Action from a crow found in New York.

  • 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
Supportive Therapy from a crow found in New York.

  • 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
Dexamethasone from a crow found in New York.

  • 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 considerations6

Clinical Considerations from a crow found in New York.

Patient Prognosis


Prognosis
Prognosis from a crow found in New York.

  • 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
Prognosis w/ Treatment from a crow found in New York.

  • 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
Glasgow Coma Scale from a crow found in New York.

  • 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 considerations7

Clinical Considerations from a crow found in New York.

Vaccination


Vaccination
Vaccination from a crow found in New York.

  • 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

Public Health Considerations from a crow found in New York.

Endemic Prevention


Infection control
Infection Control from a crow found in New York.

  • CDC’s “Three Ways to Reduce your West Nile Virus Risk”

    • Avoid mosquito bites

    • Mosquito-proof your home

    • Help your community


Avoid mosquito bites
Avoid Mosquito Bites from a crow found in New York.

  • 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.


Mosquito proof home
Mosquito-Proof Home from a crow found in New York.

  • Drain Standing Water

  • Install or Repair Screens


Community wide efforts
Community-Wide Efforts from a crow found in New York.

  • Clean Up Breeding Grounds

  • Ensure Safe Blood Supply

  • Mosquito Control Programs

    • Controversial

  • Surveillance


Blood supply
Blood Supply from a crow found in New York.

  • 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.”


Mosquito control programs
Mosquito Control Programs from a crow found in New York.

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.”


Mosquito control
Mosquito Control from a crow found in New York.

  • But wait, there’s more:

  • Same Memo:

    Confirmed or suspected cases of pesticide poisoning must be reported to the New York State Department of Health’s Pesticide Poisoning Registry at (800)-322-6850, and to the New York City Poison Control Center at (212)-764-7667.


What s being sprayed
What’s Being Sprayed from a crow found in New York.

  • 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.


Crop dusting nyc
Crop-Dusting NYC? from a crow found in New York.

  • Aerosolized liquids sprayed over large areas of the city.

  • Terrorism concern?

  • New vector for urban area.


Public health considerations1

Public Health Considerations from a crow found in New York.

Surveillance


Surveillance
Surveillance from a crow found in New York.

“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.”


Standing water reporting
Standing Water Reporting from a crow found in New York.

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.


Dead bird reporting
Dead-Bird Reporting from a crow found in New York.

  • 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.


  • Mosquito testing
    Mosquito Testing from a crow found in New York.

    “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”


    Disease reporting
    Disease Reporting from a crow found in New York.

    “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.”