Approach Considerations
The most important factor in the appropriate management of intracranial pressure is to identify and initiate appropriate therapeutic interventions.
Patients with Japanese encephalitis should be monitored closely for complications, including bacterial infections (eg, pneumonia, urinary tract infections), decubitus ulcers, Guillain-Barré syndrome, and acute obstructive hydrocephalus.
Be cautious of coinfection with other tropical diseases (eg, tuberculosis, malaria, neurocysticercosis).
Supportive care
No clearly effective antiviral agent exists. Therapy for symptomatic Japanese encephalitis virus (JEV) infection is supportive. Patients often require feeding, airway management, and anticonvulsants for seizure control.
Management of intracranial pressure
Mannitol is used to decrease intracranial pressure, when needed. In the intensive care unit (ICU) setting, cerebral perfusion pressure (ie, mean arterial pressure minus intracranial pressure) must be maintained through appropriate modulation of systemic blood pressure.
Steroid therapy
Steroids (eg, dexamethasone) have not been shown to offer benefit. [30]
Experimental therapies
One small study demonstrated some benefit from interferon alfa. [31] However, a randomized trial of interferon alfa-2a in children demonstrated no benefit in overall outcome at discharge or at 3 months after discharge. [32]
One preliminary randomized trial of intravenous immunoglobulin (IVIG) in children showed no difference in outcome in those who received IVIG or placebo. [33]
Suramin, [34] a drug used to treat trypanosomal disease, and diethyldithiocarbamate [35] have shown reasonably good antiviral efficacy against Japanese encephalitis virus in vitro.
A novel intervention using a plant lignan called arctigenin has been shown to yield complete protection against experimental Japanese encephalitis in a mouse model. It appears to provide a newer mechanism of action by decreasing CNS viral replication, decreasing neuronal death, and reducing inflammation and oxidative stress. [36]
Minocycline was investigated for its role in protecting against encephalitis and neurodegeneration. Proposed protective effects may result from direct inhibition of viral replication and its anti-inflammatory and immunomodulatory properties. [37] It conferred complete protection in an experimental mouse model following Japanese encephalitis virus infection. [38] A 2016 study in Uttar Pradesh, India, where Japanese encephalitis virus is an important cause of encephalitis, found a trend toward a better outcome among patients presenting with acute encephalitis who received minocycline. [39]
Several studies have shown that tetracyclines and aminoglycoside-derivative compounds have been beneficial against reovirus, West Nile virus, and dengue virus. An in vitro study showed that doxycycline and kanamycin administered in a dose-dependent manner decreased Japanese encephalitis viral RNA replication. [40]
Invasive monitoring
Patients with evidence of elevated intracranial pressure may require invasive monitoring.
Further care
In rare cases, relapses of Japanese encephalitis have been reported several months after recovery.
Patients may require long-term care and rehabilitation for residual neurologic deficits, including seizures and movement disorders.
Prevention: Vaccination
Vaccines
Japanese encephalitis vaccines used worldwide fall into 4 classes. They are based on Japanese encephalitis virus genotype III but are cross-protective against the other genotypes. The 4 vaccine classes include inactivated mouse brain vaccines, inactivated Vero cell-derived vaccines, live attenuated vaccines, and live recombinant (chimeric) vaccine, which is derived from yellow fever virus strain.
In the United States, 2 vaccines have been available for use: an inactivated mouse brain–derived vaccine (JE-VAX) and an inactivated Vero cell culture–derived vaccine (JE-VC; Ixiaro). JE-VAX is derived from the Nakayama Japanese encephalitis virus strain. It was licensed for use in the United States in 1992 but discontinued in 2006 because of safety issues. It has not been used since 2011. The only available Japanese encephalitis vaccine for use in the United States is Ixiaro, an inactivated vaccine prepared by propagating Japanese encephalitis virus strain SA14-14-2 in Vero cells. Ixiaro is indicated for adults and children aged 2 months or older. Primary immunization consists of a 2-dose series administered IM 28 days apart. Adults aged 18-65 years may receive an accelerated regimen 7 days apart. A single booster dose (third dose) may be given at least 11 months after completing the primary immunization series if ongoing exposure or reexposure to JEV is expected. [41, 42]
Several other vaccines are available in Asian countries but are not available in the United States.
High seroprotection rates have been found in patients receiving the inactivated Vero cell–derived vaccines, ranging from 93-99%. [19]
Novel nonparenteral vaccination approaches such as intranasal inoculation using mouse brain–derived inactivated Japanese encephalitis virus appear to have some potential for inducing immunogenicity but will likely require more effective adjuvant products. [43]
Vaccination Candidates
Vaccination is recommended for travelers who plan to spend a month or longer in endemic areas during the Japanese encephalitis virus season, especially those who will visit rural and agricultural areas. Vaccination should be considered for short-term (< 1 month) travelers to endemic areas during the Japanese encephalitis virus season if they expect unprotected nighttime outdoor exposure. Persons visiting areas with active epidemic Japanese encephalitis should be considered for vaccination even if their projected stay is less than 30 days. The vaccine is not recommended for short-term travelers who visit only urban areas.
Worldwide, Japanese encephalitis vaccine is recommended for persons living in endemic and epidemic areas.
Laboratory workers who could have potential exposure to Japanese encephalitis virus likely would benefit from vaccination.
Vaccination Dosing and Administration
The primary immunization schedule for the currently available Japanese encephalitis vaccine in the United States, Ixiaro, is 2 doses administered intramuscularly 28 days apart ( Adults aged 18-65 years may receive an accelerated regimen 7 days apart.). For children aged 2 months to 2 years, each dose is 0.25 mL. For children older than 3 years and adults, each dose is 0.5 mL. The last dose should be given at least 1 week before travel or expected exposure. [41, 42]
A booster dose is recommended for adults or children whose primary series of Ixiaro was given more than 1 year previously prior to reexposure or if there is continued risk for Japanese encephalitis virus infection. For those who have received the JE-VAX vaccine, booster with Ixiaro is not recommended, but they should receive the 2-dose series of Ixiaro before potential exposure. [41, 42]
Dosing schedule for other vaccines vary by country.
Vaccination adverse effects
Mild adverse reactions are reported in as many as 20% of vaccine recipients; adverse reactions include local pain and redness, fever, gastrointestinal symptoms, headache, and myalgia. The incidence of reactions usually decreases with each subsequent dose. Hypersensitivity, including angioedema or urticaria, occurs in 0.6% of patients, with 2.6 per 100,000 vaccinees requiring hospitalization, and represents the main contraindication to the use of the vaccine. The hypersensitivity reaction may occur as late as 10-14 days after the last dose. To prepare for a possible delayed hypersensitivity reaction, patients should have access to medical care for 10 days after the last dose. Patients with a history of allergies or urticaria may be at higher risk for adverse reactions. Use caution when vaccinating patients with a history of multiple allergies, urticaria, or angioedema, because they may be at higher risk for adverse reactions.
Pregnant women should be vaccinated only if they are at high risk for exposure to Japanese encephalitis virus and must travel to areas during active viral transmission.
Cases of encephalitis and other potentially vaccine-related neurologic symptoms have been reported. A study in Japan in the 1960s and 1970s found a rate of severe neurologic reactions to be 1-2.3 cases per million persons vaccinated. This association has not yet been definitively established. Passive surveillance in the United States in the 1990s of more than 800,000 doses revealed no reported neurologic sequelae.
Other Modes of Prevention
The most important deterrent for people visiting endemic areas is avoidance of mosquito exposure, particularly at night. Persons living in or traveling to endemic areas should strongly consider the use of bed nets while sleeping and mosquito repellents with diethyltoluamide (DEET) during times when risk for contact with infected mosquitos exists. Use of long-sleeved shirts and pants in endemic areas also is important to prevent mosquito bites.
Measures to decrease mosquito populations and control viral spread, including the use of insecticides and larva-killing agents, juxtapositioning of larvivorous fish in rice paddies, and draining rice paddies, may be used.
Although used in the past, vaccination of swine has not demonstrated consistent effectiveness in reducing mosquito and/or human infections. Pigs can be relocated away from humans to potentially decrease viral spread.
Veterinary surveillance efforts could be expanded to include epidemiologic monitoring of potentially infected goats as sentinel animals. [44]
Consultations
Consider consultation with an infectious disease specialist trained in tropical and travel medicine for all returning travelers with encephalitis.
Consultation with a neurologist may be required for assistance with management of neurologic sequelae.
Critical care specialists may be required for help with managing severely symptomatic patients in an intensive care setting.
Consultation with a neurosurgeon may be required to assist in managing elevated intracranial pressure.
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Japanese encephalitis, 2006. Courtesy of WHO.
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Geographic distribution of Japanese encephalitis virus. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/japaneseencephalitis/maps/index.html].
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Transmission of Japanese encephalitis virus. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/japaneseencephalitis/transmission/index.html].
