Japanese Encephalitis outbreaks have been reported from almost all the states and union territories in India through the years with the highest risk in the monsoon and post-monsoon period.

 

 

 

 

 

 

 

Japanese Encephalitis can be considered one of the major public health problems in India and throughout Asia due to the vulnerability of the pediatric population. It is a mosquito-borne flaviviral disease that is transmitted by infective bites of female mosquitoes. Many species of mosquitoes play a role in its transmission but mainly the responsible mosquitoes belong to the family of Culex tritaeniorhynchus, Culex vishnui and Culex pseudovishnui. The virus is neurotropic and arbovirus and primarily affects central nervous system. It is estimated that of those who contract the disease, approximately 70% either die or are left with a long-term neurological disability. 

Signs and symptoms of Japanese Encephalitis

Japanese encephalitis virus infection results in different disease manifestations in the host from mild subclinical febrile illness to clinical infections leading to encephalitis. It can be asymptomatic in some cases, while others show classical symptoms of any other virus causing encephalitis. That is why clinically it is difficult to differentiate between Japanese Encephalitis and other viral encephalitis.

However, JE is mostly associated with following signs and symptoms

• Fever of variable severity associated with neurological illness ranging from headache to meningitis or encephalitis. Neurological symptoms include a headache, meningeal signs, stupor, disorientation, coma, tremors, generalized paralysis, hypertonia, loss of coordination etc.
• Parkinsonian syndrome with masklike facies, tremor, cogwheel rigidity, and choreoathetoid movements.
• The prodromal stage may be abrupt (1-6 hours), acute (6-24 hours) or more commonly subacute (2-5 days). The acute stage of encephalitis shows symptoms like convulsions, alteration of sensorium, behavioural changes, motor paralysis, and involuntary movement supervene, focal neurological deficit etc. in prodromal phase. This stage usually lasts for a week but may prolong due to complications.
• The Convalescent phase is prolonged and varies from a few weeks to several months. The surviving patients may lead to full recovery through steady improvement or some may suffer from stabilization of neurologic, cognitive, or psychiatric deficit. 

A study conducted by Kumar R on clinical features in children with Japanese encephalitis concluded that the clinical features of Japanese encephalitis were severe with derangements in liver function and thrombocytopenia in a significant proportion of patients. These new findings suggest a possible mutation of the virus towards other flaviviruses. 

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Diagnosis of Japanese Encephalitis

The suspected cases of Japanese Encephalitis need laboratory tests for confirmation of diagnosis. Following laboratory tests are available for detection of virus of Japanese Encephalitis:

Antibody detection

• IgM ELISA is the method of choice provided samples are collected 3-5 days after the infection
• Heamagglutination Inhibition Test (HI)
• Compliment Fixation Test (CF)
• Enzyme Linked Immuno-Sorbant Assay (ELISA) for IgG (paired) and IgM (MAC) antibodies

Antigen Detection

• RPHA
• IFA
• Immunoperoxidase

Genome Detection

• RTPCR 

Chanama S et al conducted a study for confirmation of Japanese encephalitis in 2005 and the results concluded that the detection of JEV-specific IgM in cerebrospinal fluid by IgM-capture ELISA is a reliable laboratory diagnostic method throughout the disease period while the detection of IgM in serum samples is a reliable method on day 9 or later. 

Another study was carried out by Swami R et al between July 2003 and December 2005 in PGIMER, Chandigarh, India to compare IgM capture ELISA and nested RT-PCR for the diagnosis of Japanese encephalitis (JE). This study concluded that for the early detection of Japanese encephalitis virus, RT-PCR needs to be performed in CSF samples, compared to IgM antibody detection.

Vaccination for Japanese Encephalitis

Vaccination for Japanese encephalitis is licensed in India and is produced in limited quantities at the Central Research Institute, Kasauli, India. However, due to cost and unstable supply, they have not been able to meet the needs of developing country health systems. 2 Moreover there is no national vaccination program in India, but the Ministry of Health has recently drawn up a plan to immunize children between 1–12 years of age. In Tamil Nadu and Uttar Pradesh, immunization programs are already running. The Cell Culture Derived Live SA-14-14-2 Vaccine is based on a stable neuro-attenuated strain of JE virus (SA-14-14-2). Vaccination is available in 5-dose vials as a lyophilized powder that looks like a milky-white crisp cake and needs to be rehydrated with 2.5 mL diluent. The dose for vaccine is 0.5 mL administered subcutaneously for all ages and contains not less than 5.4 log PFU of live JE virus (JEV).

But this vaccine is not recommended as an outbreak control measure as it takes at least one month after the second dose to develop antibodies at protective levels and the outbreaks are usually short lived.

Therapeutic approach

A lot of research is going on to develop an effective therapeutic countermeasure to tackle Japanese encephalitis. The main treatment for Japanese encephalitis remains supportive, with occasional use of intravenous ceftriaxone and empirical acyclovir. New therapeutics for Japanese encephalitis are on the way of development like use of minocycline, short interfering RNA, arctigenin, rosmarinic acid, DNAzymes etc. Recently three clinical trials with two different drugs i.e. minocycline & Intravenous immunoglobulin (IVIG) have shown promising results for further investigations.

Minocycline: Minocycline is a semisynthetic tetracycline having excellent penetration into cerebrospinal fluid, established neuroprotective and antiviral properties. Following two clinical trials observed better outcomes in patients with Japanese encephalitis and acute encephalitis syndrome (AES). 

• A first randomized placebo-controlled clinical trial of nasogastric/oral minocycline administration in patients with Japanese encephalitis was conducted in the pediatrics department of King George’s Medical University, in Lucknow (UP), by Kumar R, Basu A, Sinha S, et al. Minocycline (or placebo) was administered as suspension through a nasogastric tube for 7 days at a loading dose of 5 mg/kg per day followed by 2.5 mg/kg every 12 hours in children up to 12 years old and a 200 mg loading dose followed by 100 mg every 12 hours in older patients. 281 patients were enrolled, 140 received drug and 141 placebo. Though there was no statistically significant difference in survival between the drug and placebo groups there was a clear significant improvement with minocycline. Also on excluding the data from patients who succumbed within 24 hours of hospitalization, a significantly better overall outcome was observed at 3 months with minocycline along with a trend toward lower cumulative mortality.
• Another trial was conducted in the Baba Raghav Das Medical College, in Gorakhpur (UP), by Singh AK, Mehta A, Kushwaha KP, et al. on smaller population of only 44 patients of confirmed cases of Japanese encephalitis. Minocycline was administered at 5 to 6 mg/kg in two divided doses for 10 days through a feeding tube starting from the day of hospitalization. The study concluded that minocycline was effective in reducing the duration of symptoms like fever and unconsciousness and the mean duration of hospitalization.

Intravenous immunoglobulin (IVIG): IVIG containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. It's anti-inflammatory properties may also be beneficial.9

• A feasibility study was conducted in Nepal by Rayamajhi A, Nightingale S, Bhatta NK, et al, involving administration of intravenous immunoglobulin (IVIG) to a small group of children (11 per group; ages between 1 and 14 years) manifesting symptoms of acute encephalitis syndrome.  There was no significant difference between the two groups when analyzed by intention-to-treat for complete recovery either at hospital discharge or at follow-up. JEV neutralizing antibody titers were expectedly higher in patients who received IVIG compared with placebo. The level of interleukin-4 (IL-4) was found to be significantly elevated in IVIG-treated patients. Its higher levels have been detected in survivors of JE as compared with non-survivors.

These advances in therapeutics do provide hope for the future ability to counter Japanese encephalitis. Also , t can be controlled, with effective surveillance systems, changing agricultural practices, pig vaccination, and vaccines playing key roles.