Eastern equine encephalitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anthony Gallo, B.S. [2]

Synonyms and Keywords: EEE; EEEV; East equine encephalitis; Triple E

Overview

Eastern equine encephalitis is a moderate to severe infection of the central nervous system. Eastern equine encephalitis belongs to the Group IV positive-sense ssRNA virus within the Togaviridae family of viruses, and the genus Alphavirus. Eastern equine encephalitis is closely related to western equine encephalitis and Venezuelan equine encephalitis. Eastern equine encephalitis virus is usually transmitted via mosquitos to the human host, primarily Culiseta melanura. Eastern equine encephalitis virus must be differentiated from other diseases that cause fever, headache, seizures, and altered mental status. There are approximately 8 human cases of eastern equine encephalitis annually in the United States, most commonly affecting children under the age of 15 and adults over the age of 50. Prognosis for eastern equine encephalitis is generally poor. Approximately 33% of patients progress to mortality, and approximately 50% of surviving patients have mild to severe neurodegenerative losses and seizures. The diagnostic method of choice for eastern equine encephalitis virus is laboratory testing. There is no treatment for eastern equine encephalitis virus; the mainstay of therapy is supportive care. There are currently no human vaccines available for eastern equine encephalitis.

Historical Perspective

In 1831, eastern equine encephalitis virus was first reported in Massachusetts, USA following the sudden death of 75 horses, which died mysteriously of viral encephalitis. In 1938, the earliest evidence of eastern equine encephalitis virus activity in Canada was reported in the Ontario cities of St. George and St. Catharines.[1][2]

Classification

Eastern equine encephalitis may be classified according to location of the disease into 2 subtypes: systemic or encephalitic. Eastern equine encephalitis may also be classified according to neuroinvasiveness of the disease into 2 subtypes: neuroinvasive and non-neuroinvasive. Eastern equine encephalitis belongs to the Group IV positive-sense ssRNA virus within the Togaviridae family of viruses, and the genus Alphavirus. Eastern equine encephalitis is closely related to western equine encephalitis virus and Venezuelan equine encephalitis virus. Eastern equine encephalitis is known as an arbovirus, or an arthropod-borne virus.

Pathophysiology

Eastern equine encephalitis virus is usually transmitted via mosquitos to the human host. Eastern equine encephalitis virus contains positive-sense viral RNA; this RNA has its genome directly utilized as if it were mRNA, producing a single protein which is modified by host and viral proteins to form the various proteins needed for replication. The following table is a summary of the eastern equine encephalitis virus:[3]

Characteristic Data
Nucleic acid RNA
Sense ssRNA(+)
Virion Enveloped
Capsid Spherical
Symmetry Yes; T=4 icosahedral
Capsid monomers 240
Monomer length (diameter) 65-70 nm
Additional envelope information 80 spikes; each spike is a trimer of E1/E2 proteins
Genome shape Linear
Genome length 11-12 kb
Nucleotide cap Yes
Polyadenylated tail Yes
Incubation period 4-10 days

Eastern equine encephalitis is contracted by the bite of an infected mosquito, primarily Culiseta melanura. The virus is maintained in a cycle between Culiseta melanura mosquitos and avian hosts in freshwater hardwood swamps. Culiseta melanura is not an important vector of eastern equine virus to humans because it feeds almost exclusively on birds. Transmission to humans requires mosquito species capable of creating a "bridge" between infected birds and uninfected mammals, such as some Aedes, Coquillettidia, and Culex species. The incubation period is 4-10 days.[4] Humans and horses are dead-end hosts for the virus, meaning there is an insufficient amount of eastern equine encephalitis virus in the blood stream to infect a mosquito. Many cases in horses are fatal. There is no known transmission between horses and humans.[5] Recent studies have demonstrated other equine, such as mules and donkeys, and other animals, such as pigs, reptiles, amphibians, and rodents, can be infected.

Eastern equine encephalitis virus is transmitted in the following pattern:[3]

  1. Attachment of the viral E glycoprotein to host receptors mediates clathrin-mediated endocytosis of virus into the host cell.
  2. Fusion of virus membrane with the host cell membrane. RNA genome is released into the cytoplasm.
  3. The positive-sense ssRNA virus is translated into a polyprotein, which is cleaved into non-structural proteins necessary for RNA synthesis (replication and transcription).
  4. Replication takes place in cytoplasmic viral factories at the surface of endosomes. A dsRNA genome is synthesized from the genomic ssRNA(+).
  5. The dsRNA genome is transcribed thereby providing viral mRNAs (new ssRNA(+) genomes).
  6. Expression of the subgenomic RNA (sgRNA) gives rise to the structural proteins.
  7. Virus assembly occurs at the endoplasmic reticulum.
  8. Virions bud at the endoplasmic reticulum, are transported to the Golgi apparatus, and then exit the cell via the secretory pathway.

Causes

Eastern equine encephalitis may be caused by eastern equine encephalitis virus.

Differentiating Eastern equine encephalitis from Other Diseases

Eastern equine encephalitis virus must be differentiated from other diseases that cause fever, headache, seizures, and altered mental status, such as:[6][7][8][9][10]

Disease Similarities Differentials
Meningitis Classic triad of fever, nuchal rigidity, and altered mental status Photophobia, phonophobia, rash associated with meningococcemia, concomitant sinusitis or otitis, swelling of the fontanelle in infants (0-6 months)
Brain abscess Fever, headache, hemiparesis Varies depending on the location of the abscess; clinically, visual disturbance including papilledema, decreased sensation; on imaging, a lesion demonstrates both ring enhancement and central restricted diffusion
Demyelinating diseases Ataxia, lethargy Multiple sclerosis: clinically, nystagmus, internuclear ophthalmoplegia, Lhermitte's sign; on imaging, well-demarcated ovoid lesions with possible T1 hypointensities (“black holes”)

Acute disseminated encephalomyelitis: clinically, somnolence, myoclonic movements, and hemiparesis; on imaging, diffuse or multi-lesion enhancement, with indistinct lesion borders

Substance abuse Tremor, headache, altered mental status Varies depending on type of substance: prior history, drug-seeking behavior, attention-seeking behavior, paranoia, sudden panic, anxiety, hallucinations
Electrolyte disturbance Fatigue, headache, nausea Varies depending on deficient ions; clinically, edema, constipation, hallucinations; on EKG, abnormalities in T wave, P wave, QRS complex; possible presentations include arrhythmia, dehydration, renal failure
Stroke Ataxia, aphasia, dizziness Varies depending on classification of stroke; presents with positional vertigo, high blood pressure, extremity weakness
Intracranial hemorrhage Headache, coma, dizziness Lobar hemorrhage, numbness, tingling, hypertension, hemorrhagic diathesis
Trauma Headache, altered mental status Amnesia, loss of consciousness, dizziness, concussion, contusion

Epidemiology and Demographics

Incidence

There are approximately 8 human cases of eastern equine encephalitis annually in the United States.[4]

Age

Eastern equine encephalitis commonly affects individuals younger than 15 and older than 50 years of age.[4]

Seasonal

Eastern equine encephalitis outbreaks have occurred when there is relatively higher rainfall in the late summer and early fall of the previous year and during the current summer of an outbreak.[11] Specifically, the risk of contracting eastern equine encephalitis is highest from late July through September, when more mosquitos are present and active.[12]

Geographic Location

The majority of eastern equine encephalitis cases are reported on the East Coast of the United States, specifically in Massachusetts, Florida, and New Jersey. Eastern equine encephalitis virus transmission is most common in and around freshwater hardwood swamps in the Atlantic and Gulf Coast states and the Great Lakes region.[4]

Maps regarding geographic distribution of eastern equine encephalitis cases can be found here.

Risk Factors

Common risk factors in the development of eastern equine encephalitis include:

  • Age (<15 years; >50 years)
  • Immunosuppression
  • Residing or visiting woodland areas
  • Mosquito contact
  • Bird contact
  • Horse contact
  • Summer season
  • Outdoor recreational activities

Natural History, Complications, and Prognosis

Natural History

If left untreated, eastern equine encephalitis may cause uncontrolled fever, increased intracranial pressure, and seizures.[13] Eastern equine encephalitis usually clears within 1-2 weeks and rarely recurs; the recovery period is significantly longer.

Complications

Common complications of eastern equine encephalitis include:[14]

Prognosis

Prognosis for eastern equine encephalitis is generally poor. Approximately 33% of patients progress to mortality.[4] Approximately 50% of surviving patients have mild to severe neurodegenerative losses and seizures.[15]

Diagnosis

Diagnostic criteria

Neuroinvasive vs non-neuroinvasive eastern equine encephalitis can be differentiated based on both clinical and laboratory findings. These include:[16][17]

Eastern Equine Encephalitis Subtype Clinical Presentation Laboratory Findings
Neuroinvasive
Meningitis, encephalitis, acute flaccid paralysis, or other acute signs of central or peripheral neurologic dysfunction, as documented by a physician AND
Absence of a more likely clinical explanation
Isolation of virus from, or demonstration of specific viral antigen or nucleic acid in, tissue, blood, cerebrospinal fluid (CSF) OR
Four-fold or greater change in virus-specific quantitative antibody titers in paired sera OR
Virus-specific IgM antibodies in serum with confirmatory virus-specific neutralizing antibodies in the same or a later specimen OR
Virus-specific IgM antibodies in cerebrospinal fluid, with or without a reported pleocytosis, and a negative result for other IgM antibodies in cerebrospinal fluid for arboviruses endemic to the region where exposure occurred
Non-neuroinvasive
Fever and chills as reported by the patient or a health care provider AND
Absence of neuroinvasive disease AND
Absence of a more likely clinical explanation
Isolation of virus from, or demonstration of specific viral antigen or nucleic acid in, tissue, blood, or other body fluid, excluding cerebrospinal fluid OR
Four-fold or greater change in virus-specific quantitative antibody titers in paired sera OR
Virus-specific IgM antibodies in serum with confirmatory virus-specific neutralizing antibodies in the same or a later specimen

History and Symptoms

If possible, a detailed and thorough history from the patient is necessary. Common symptoms of eastern equine encephalitis include:[4][6]

Physical Examination

Common physical examination findings of eastern equine encephalitis include:[12]

Laboratory Findings

The diagnostic method of choice for eastern equine encephalitis is laboratory testing. Laboratory findings consistent with the diagnosis of eastern equine encephalitis include:[6]

CT

On CT scan, eastern equine encephalitis is characterized by diffuse cerebral edema in 40% of patients.

MRI

On MRI, eastern equine encephalitis is characterized by abnormalities in the thalamus, basal ganglia, and brainstem.

EEG

On EEG, eastern equine encephalitis is typically diffusely slow with some patients having burst suppression, or diffuse high-voltage delta wave slowing.

Treatment

Medical Therapy

There is no treatment for eastern equine encephalitis; the mainstay of therapy is supportive care. Because supportive care is the only treatment for eastern equine encephalitis, physicians often do not request the tests required to specifically identify the eastern equine encephalitis virus.

Surgery

Surgical intervention is not recommended for the management of eastern equine encephalitis.

Prevention

There is no human vaccine for eastern equine encephalitis. There is an eastern equine encephalitis vaccine available for horses. In consultation with a veterinarian, vaccinate your horse(s) against the virus. Primary prevention strategies for eastern equine encephalitis include:[12]

  • Removal of standing water
  • Screens on doors and windows
  • When outdoors, wearing:
    • Insect repellent containing DEET
    • Long sleeves, pants; tucking in pants into high socks

References

  1. Schofield F, Labzoffsky N. Report on cases of suspected encephalomyelitis occurring in the vicinity of St. George. Rep Ont Dept Agric OVC. 193829:25-29.
  2. Carman PS, Artsob H, Emery S, Maxie MG, Pooley D, Barker IK; et al. (1995). "Eastern equine encephalitis in a horse from southwestern Ontario.". Can Vet J. 36 (3): 170–2. PMC 1686920Freely accessible. PMID 7757923. 
  3. 3.0 3.1 Alphavirus. SIB Swiss Institute of Bioinformatics. http://viralzone.expasy.org/viralzone/all_by_species/625.html Accessed on March 15, 2016
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Eastern Equine Encephalitis. CDC. http://www.cdc.gov/EasternEquineEncephalitis/index.html Accessed on March 15, 2016
  5. Eastern Equine Encephalitis Virus (EEEV). Illinois Department of Public Health (2010) http://www.idph.state.il.us/public/hb/hb_eee.htm Accessed on March 15, 2016.
  6. 6.0 6.1 6.2 M.D. JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Expert Consult Premium Edition. Saunders; 2014.
  7. Kennedy PG (2004). "Viral encephalitis: causes, differential diagnosis, and management.". J Neurol Neurosurg Psychiatry. 75 Suppl 1: i10–5. PMC 1765650Freely accessible. PMID 14978145. 
  8. Arboviral Infections (arthropod-borne encephalitis, eastern equine encephalitis, St. Louis encephalitis, California encephalitis, Powassan encephalitis, West Nile encephalitis). New York State Department of Health (2006). https://www.health.ny.gov/diseases/communicable/arboviral/fact_sheet.htm Accessed on February 23, 2016
  9. Eckstein C, Saidha S, Levy M (2012). "A differential diagnosis of central nervous system demyelination: beyond multiple sclerosis.". J Neurol. 259 (5): 801–16. PMID 21932127. doi:10.1007/s00415-011-6240-5. 
  10. De Kruijk JR, Twijnstra A, Leffers P (2001). "Diagnostic criteria and differential diagnosis of mild traumatic brain injury.". Brain Inj. 15 (2): 99–106. PMID 11260760. doi:10.1080/026990501458335. 
  11. Ontario Agency for Health Protection and Promotion (Public Health Ontario). Eastern equine encephalitis: history and enhanced surveillance in Ontario. Toronto, ON: Queen's Printer for Ontario; 2014. Accessed on March 15, 2016
  12. 12.0 12.1 12.2 Eastern Equine Encephalitis (EEE). New York State Department of Public Health (2012). https://www.health.ny.gov/diseases/communicable/eastern_equine_encephalitis/fact_sheet.htm Accessed on March 15, 2016.
  13. Silverman MA, Misasi J, Smole S, Feldman HA, Cohen AB, Santagata S; et al. (2013). "Eastern equine encephalitis in children, Massachusetts and New Hampshire,USA, 1970-2010.". Emerg Infect Dis. 19 (2): 194–201; quiz 352. PMC 3559032Freely accessible. PMID 23343480. doi:10.3201/eid1902.120039. 
  14. Meningitis and Encephalitis Fact Sheet. National Institute of Neurological Disorders and Stroke. National Institutes of Health (2015). http://www.ninds.nih.gov/disorders/encephalitis_meningitis/detail_encephalitis_meningitis.htm Accessed on February 9, 2015
  15. Eastern Equine Encephalitis. Minnesota Department of Health (2010). http://www.health.state.mn.us/divs/idepc/diseases/eeencephalitis/eee.html Accessed on March 17, 2016.
  16. Arboviral Infection: Surveillance Protocol (2016) West Virginia Department of Health and Human Resources: Bureau of Public Health (2016). http://www.dhhr.wv.gov/oeps/disease/Zoonosis/Mosquito/Documents/arbovirus/arbovirus-protocol.pdf Accessed on March 3, 2016
  17. Arboviral diseases, neuroinvasive and non-neuroinvasive 2015 Case Definition. National Notifiable Diseases Surveillance System (NNDSS). Centers for Disease Control (2015). https://wwwn.cdc.gov/nndss/conditions/arboviral-diseases-neuroinvasive-and-non-neuroinvasive/case-definition/2015/ Accessed on March 31, 2016.



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