Continuing Education Activity

Japanese encephalitis is the most common preventable cause of mosquito-borne encephalitis in Asia, Australia, and the western Pacific. The Culex species of mosquitoes transmit the virus with their bite. Transmission occurs most commonly in agricultural areas such as farms and rice paddies but may occur in urban areas under certain conditions. While the vast majority of infections are asymptomatic, those who do develop symptoms of encephalitis suffer significant morbidity and mortality. This activity describes the clinical evaluation of Japanese encephalitis and explains the role of the health professional team in coordinating the care of this condition.

Objectives:

• Review how Japanese encephalitis is acquired.
• Describe the history and physical exam of a patient with japanese encephalitis.
• Summarize the treatment of japanese encephalitis.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by Japanese encephalitis.

Introduction

Japanese encephalitis is the most common preventable cause of mosquito-borne encephalitis in Asia, Australia, and the western Pacific.  The Culex species of mosquitoes transmit the virus with their bite. Transmission occurs most commonly in agricultural areas such as farms and rice paddies but may occur in urban areas under certain conditions. While the vast majority of infections are asymptomatic, those who do develop symptoms of encephalitis suffer significant morbidity and mortality. Symptomatic patients develop a high fever, headache, disorientation, coma, tremors and mental status changes due to cerebral inflammation. Movement disorders, neurologic deficits, and seizures are common, particularly in children. Approximately one in four symptomatic cases are fatal. Children are most commonly affected, and most people who reside in endemic areas will have immunity by adulthood. There is no specific therapy beyond supportive care, but there is an effective vaccine available to prevent infection. The vaccine is recommended for high-risk travelers to endemic areas. Many endemic areas have implemented childhood vaccination programs. The best protection is the prevention of mosquito bites.[1][2][3][4]

Etiology

Japanese encephalitis is a mosquito-borne illness caused by a single-stranded RNA virus, closely related to the West Nile flavivirus. Japanese encephalitis transmission is primarily due to the bite of Culex mosquito species, most commonly Culex tritaeniorhynchus. The virus is maintained and amplified in intermediate hosts, specifically pigs and wading birds. Humans are considered dead-end hosts in that they do not generally develop high enough levels of virus to transmit the infection to feeding mosquitoes. Because the amplifying hosts tend to be most abundant in agricultural areas such as farms and rice paddies where flooding irrigation attracts wading birds, most infections occur in rural areas. Recently, however, infections are being documented more commonly in suburban regions, particularly in South Korea, China, Singapore, and Taiwan. This suggests that the vaccine recommendations for travelers should be expanded to include some suburban regions. While mosquitoes transmit the vast majority of infections, there is some concern that exposure to infected pigs, which are amplifying hosts, may result in virus transmission from close contact without vector involvement.[5][6]

Epidemiology

There are between 30,000 and 50,000 global cases of Japanese encephalitis each year. Severe disease is estimated to occur in about one in 250 infections. Transmission is seasonal in temperate climates and peaks between May and October, but the risk persists year-round in more tropical climates. The time of greatest risk for infection is during the rainy season and the pre-harvest period in rice cultivating areas due to increased mosquito vector populations. Most mosquito bites occur between dawn and dusk. Twenty-four countries in South-East Asia and the Western Pacific have endemic Japanese encephalitis virus transmission placing more than three billion people at risk for infection. Major outbreaks occur every 2 to 15 years. Between 1965 and 1975 more than one million cases were reported in China alone. The introduction of routine childhood vaccination programs in Japan, Korea, and Taiwan has nearly eliminated the risk in vaccinated patients despite ongoing infection in endemic animals and birds. Most cases in these areas are now reported in unvaccinated visitors.

Pathophysiology

The Japanese encephalitis virus attaches to host cell membranes, initially propagating at the site of the bite and nearby lymph nodes. Subsequent viremia develops but most cases are cleared before the virus enters the central nervous system, resulting in subclinical disease. If the virus is transmitted to the brain hematogenously with the invasion of the blood-brain barrier, neuroinvasive disease develops. Japanese encephalitis virus has both direct neurotoxic effects and the capacity to alter neuro stem cell development.

History and Physical

Most infected individuals will provide a history of mosquito exposure in an endemic area. The incubation period averages 6 to 8 days but ranges from 4 to 15 days. There is often a prodromal period of nonspecific symptoms of fever, headache, nausea, vomiting, diarrhea, and myalgias which may last for several days. Symptoms then progress to encephalitis, which is the most common neurologic manifestation.  Symptoms may include altered mental status, agitation, confusion, and psychosis. A headache and meningismus are frequently reported in adults while children often develop seizures. More unusual presentations include mutism and flaccid paralysis. As the disease progresses, patients may develop dystonia, choreoathetoid movements that mimic extrapyramidal symptoms of Parkinson disease.

Evaluation

Patients with symptoms consistent with encephalitis are initially evaluated with neuroimaging and lumbar puncture. MRI or CT may show bilateral thalamic edema, lesions, or hemorrhage. A lumbar puncture may be significant for elevated opening pressure, elevated protein, and normal glucose. Blood work may reveal leukocytosis or hyponatremia. These findings are common in many forms of encephalitis or viral meningitis. If clinically suspected based on travel history, Japanese encephalitis virus immunoglobulin M (IgM) may be detected using an enzyme-linked immunoassay (ELISA) on serum or cerebrospinal fluid. Humans are dead-end hosts with low, transient viral loads making virus isolation difficult.[7][8]

Treatment / Management

There is no effective antiviral therapy for Japanese encephalitis. Management is limited to supportive care with intravenous (IV) fluids and antipyretics. Anticonvulsants may be required for seizure control. Survivors often have poor neurologic outcomes requiring long-term care due to neurologic devastation and ongoing psychiatric symptoms. Up to 30% will suffer permanent intellectual, behavioral or neurologic issues ranging from paralysis, recurrent seizures or inability to speak or perform independent activities of daily living.[9][10]

Since there is no effective treatment prevention is critical. This is best accomplished by avoiding mosquito bites entirely. Even very short periods of outdoor exposure can result in bites, so proper protective clothing that includes long sleeves, long pants, socks, and closed-toe shoes should be worn.  Pant legs can be tucked into socks to prevent bites to exposed ankles. Transmission is common during the warmer months and mosquitoes may bite through very thin clothing so treating clothing with repellents containing permethrin, DEET or other EPA-registered insect repellants will reduce this risk. Transmission is most frequent when mosquitoes feed, between dawn and dusk, so outdoor activities during this period should be avoided. Travelers should sleep in air-conditioned spaces or use mosquito nets or screens to prevent bites during sleep.

A safe, effective vaccine exists and may be administered in a short-course regimen. The vaccine is quite underutilized. The current Center for Disease Control and Prevention (CDC) recommendations for the use of the Japanese encephalitis vaccine are as follows:

1. The vaccine is recommended for travelers who plan to spend one month or more in endemic areas during the transmission season. This includes travelers who will be based primarily in urban areas.
2. The vaccine should be considered for short-term travelers (less than one month) who are planning to spend substantial amounts of time outdoors in rural or agricultural areas, those who plan to participate in outdoor activities and those staying in areas without air conditioning, screens or bed nets. It should also be considered in travelers to an area with a known outbreak and those with uncertain destinations, activities, and duration of travel.
3. The vaccine is not currently recommended for travelers with short-term travel plans to urban areas only.

Differential Diagnosis

There are many differential diagnoses of Japanese encephalitis; therefore, a careful travel history important. It includes:

• Murray Valley encephalitis
• West Nile virus encephalitis
• St. Louis encephalitis
• Herpes simplex encephalitis
• Western and Eastern equine encephalitis
• Venezuelan Equine encephalitis
• Ehrlichiosis
• Enterovirus meningitis
• Mycoplasma meningitis
• Cytomegalovirus infection in the immunocompromised host
• Typhoid fever
• Dengue fever
• Malaria
• Brain abscess
• Tuberculous meningitis
• Nipah virus infection
• Rocky Mountain spotted fever
• Fungal meningitis
• Leptospirosis
• Neurocysticercosis
• Amebic meningoencephalitis
• Lupus with central nervous system involvement
• Central nervous system (CNS) tumor
• Cerebrovascular accident

Prognosis

Only 1% of patients infected with the virus will progress to encephalitis. Unfortunately, mortality for patients who do develop encephalitis is 20% to 30%. While most cases will improve in 6 to 12 months, many patients who survive will have significant neurologic and psychiatric sequelae (30% to 50% of cases).

Pearls and Other Issues

Japanese encephalitis is a potentially devastating but preventable disease. Travelers to endemic areas should review the CDC vaccination guidelines regarding immunization available at www.cdc.gov.

Enhancing Healthcare Team Outcomes

The management of Japanese encephalitis is interprofessional. The infection has no cure and patients need support from a variety of specialists. The key role of the primary caregiver and nurse practitioner is patient education. Since there is no effective treatment prevention is critical. This is best accomplished by avoiding mosquito bites entirely. Even very short periods of outdoor exposure can result in bites, so proper protective clothing that includes long sleeves, long pants, socks, and closed-toe shoes should be worn.  Pant legs can be tucked into socks to prevent bites to the exposed ankles. Transmission is common during the warmer months and mosquitoes may bite through very thin clothing so treating clothing with repellents containing permethrin, DEET or other EPA-registered insect repellants will reduce this risk. Transmission is most frequent when mosquitoes feed, between dawn and dusk, so outdoor activities during this period should be avoided. Travelers should sleep in air-conditioned spaces or use mosquito nets or screens to prevent bites during sleep.

A safe, effective vaccine exists and may be administered in a short-course regimen. The vaccine is quite underutilized. 

The outcomes for patients with Japanese encephalitis are guarded. Recovery does occur but is often marked by residual neuropsychiatric deficits which may persist for months or even years.[11]

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References

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2.

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Chai C, Palinski R, Xu Y, Wang Q, Cao S, Geng Y, Zhao Q, Wen Y, Huang X, Yan Q, Ma X, Wen X, Huang Y, Han X, Ma W, Wu R. Aerosol and Contact Transmission Following Intranasal Infection of Mice with Japanese Encephalitis Virus. Viruses. 2019 Jan 21;11(1) [PMC free article: PMC6356382] [PubMed: 30669601]

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5.

Fang Y, Zhang Y, Zhou ZB, Xia S, Shi WQ, Xue JB, Li YY, Wu JT. New strains of Japanese encephalitis virus circulating in Shanghai, China after a ten-year hiatus in local mosquito surveillance. Parasit Vectors. 2019 Jan 09;12(1):22. [PMC free article: PMC6327439] [PubMed: 30626442]

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Tian M, Li J, Lei W, Shu X. Japanese Encephalitis Virus-Induced Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Case Report and Review of Literature. Neuropediatrics. 2019 Apr;50(2):111-115. [PubMed: 30620950]

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Allison JR, Hogue AL, Shafer CW, Huntington MK. Infectious Disease: Mosquito-Borne Viral Illnesses. FP Essent. 2019 Jan;476:11-17. [PubMed: 30615405]

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Tiwari RI, Bhullar SS, Chandak NH, Baheti NN, Daginawala HF, Singh LR, Kashyap RS. Diagnosis of viral central nervous system infections using antipeptide antibody against viral antigen by ELISA. Acta Virol. 2018;62(4):386-393. [PubMed: 30472868]

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O'Leary ST, Kimberlin DW. Update From the Advisory Committee on Immunization Practices. J Pediatric Infect Dis Soc. 2018 Aug 17;7(3):181-187. [PubMed: 29961833]

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Caldwell JP, Chen LH, Hamer DH. Evolving Epidemiology of Japanese Encephalitis: Implications for Vaccination. Curr Infect Dis Rep. 2018 Jun 29;20(9):30. [PubMed: 29959548]

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Reid S, Thompson H, Thakur KT. Nervous System Infections and the Global Traveler. Semin Neurol. 2018 Apr;38(2):247-262. [PubMed: 29791951]

Disclosure: Leslie Simon declares no relevant financial relationships with ineligible companies.

Disclosure: Divyajot Sandhu declares no relevant financial relationships with ineligible companies.

Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies.

Disclosure: Brian Kruse declares no relevant financial relationships with ineligible companies.