Clinical Features in Children Hospitalized during the 2005 Epidemic of Japanese Encephalitis in Uttar Pradesh, India

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1 MAJOR ARTICLE Clinical Features in Children Hospitalized during the 2005 Epidemic of Japanese Encephalitis in Uttar Pradesh, India Rashmi Kumar, 1 Piyush Tripathi, 1 Sudhakar Singh, 1 and Gopa Bannerji 2 Departments of 1 Pediatrics and 2 Microbiology, King George s Medical University, Lucknow, Uttar Pradesh, India Background. Japanese encephalitis is a disease that affects the rural poor in Asia. In August September 2005, a severe epidemic of Japanese encephalitis occurred in Uttar Pradesh, one of India s poorest states. Methods. Children admitted to the King George Medical University hospital (Lucknow, Uttar Pradesh, India) with acute febrile encephalopathy (defined as fever plus encephalopathy of 2 weeks duration) from July to October 2005 underwent ELISA for Japanese encephalitis virus immunoglobulin M in cerebrospinal fluid or serum on hospital admission. Clinicolaboratory features of patients with positive test results were recorded. Results. Of the 223 children tested, 77 had positive results for Japanese encephalitis immunoglobulin M. Patients were from 18 districts of Uttar Pradesh. All but 1 were from rural areas, and none were!2 years of age. The prodromal period was very short ( mean standard deviation, days). Convulsions were present in 76 patients (98.7%). The mean ( standard deviation) Glasgow Coma Scale score was Generalized hypertonia was found in 39 patients (50.6%), and focal deficits were found in 35 patients (45.4%), including 19 cases of monoparesis and 16 cases of hemiparesis. Gastric hemorrhage was found in 42 patients (54.5%). Extrapyramidal features were found in 24 (31.1%), a hyperepneic breathing pattern was found in 20 (26%), and thrombocytopenia was found in 5 (15.6%) of 32 patients. The mean cerebrospinal fluid cell count was 48.3 cells/ mm 3. The serum bilirubin level was normal in all patients, but the aspartate aminotransferase level was elevated in all 21 patients (100%) tested and the alanine aminotranferase level was elevated in 25 (47.2%) of 53 patients. In-hospital mortality was 34%. Conclusions. Clinical features of Japanese encephalitis were severe. Derangements in liver function and thrombocytopenia were found in a significant proportion of patients. These findings were not highlighted during earlier epidemics of the illness and could suggest a possible mutation of the virus towards other flaviviruses. The Japanese encephalitis (JE) virus is the single largest cause of viral encephalitis in the world today. Although it originally was the cause of summer epidemics in Japan in the 19th century and the early part of the 20th century, the virus has been almost eradicated from that country. Presently, there are JE outbreaks and epidemics in large parts of southeast Asia [1]. In India, the first cases were reported from the southern state of Tamil Nadu in the 1950s [2]. However, the first major epidemic occurred in the state of West Bengal in 1973 [3]. Received 17 February 2006; accepted 4 April 2006; electronically published 9 June Reprints or correspondence: Prof. Rashmi Kumar, Dept. of Pediatrics, King George Medical University, Lucknow, UP, India (rashmik2005@gmail.com). Clinical Infectious Diseases 2006; 43: by the Infectious Diseases Society of America. All rights reserved /2006/ $15.00 After this, there were annual monsoon and postmonsoon outbreaks of the disease in most of the southern and eastern states. The disease is also making inroads in the western part of the state, with outbreaks reported from more western states [4 6]. India s northern state, Uttar Pradesh (figure 1) saw its first epidemic in 1978 [7]; since then, there have been annual outbreaks of disease affecting the northern and eastern districts of the state. Since 1978, it is estimated that JE has been the cause of 8000 deaths in the state. In 2005, there was a severe epidemic of encephalitis in the eastern Uttar Pradesh, as well as in the adjoining areas of the neighboring state of Bihar and in Nepal, during the monsoon and postmonsoon seasons of August and September [8]. We describe the clinical and demographic features of pediatric patients admitted to King George Medical University (Lucknow, Uttar Pradesh, India) during the epidemic. Japanese Encephalitis Epidemic in India CID 2006:43 (15 July) 123

2 Figure 1. Map of India showing Uttar Pradesh and its capital, Lucknow. DESCRIPTION OF THE EPIDEMIC AREA Uttar Pradesh is India s most populous state (population, 160 million; approximately one-sixth of the country s population) and also one of its poorest, with the lowest human development indices. It is divided into 70 districts or administrative units. It is located in the Gangetic Plain of northern India. The state s population density is 689 people per square kilometer, and children!12 years of age account for 40% of the population [9]. Approximately 79% of the people live in rural areas. The eastern parts of the state are poorer, less developed, and largely rice growing. The countryside is sprinkled with villages; the population range is per village. There are 3 seasons: summer (March June), rainy or monsoon season (July October) and winter (November February). Temperatures may soar up to 45 C in summer and fall as low as 3 C in winter. During and after the monsoon season, the rice fields, as well as large areas around the villages, are waterlogged. Pigs are reared by certain sects for their meat. There are 2 parallel systems of health care: the government system (i.e., state-run services) and the private sector system. The government network consists of community health workers, subcenters, primary health centers, district hospitals, and tertiary care medical college hospitals. The private system also has a hierarchy of individual private medical practitioners, private polyclinics and nursing homes, and tertiary care corporate hospitals. As is the case throughout the country, there is no tight referral system in Uttar Pradesh. The private system is preferred for outpatient consultations, and the government system is used more for serious illnesses and preventive services. Lucknow is the capital city of Uttar Pradesh and has a population of 4 million people. King George Medical University Hospital is a tertiary care teaching hospital that caters mostly 124 CID 2006:43 (15 July) Kumar et al.

3 Figure 2. Map of Uttar Pradesh showing the districts that our patients came from: Barabanki (16 patients), Lucknow (9), Gonda (8), Bahraich (6), Ambedkar Nagar (5), Faizabad (5), Balrampur (4), Sitapur (4), Rae Bareli (3), Sultanpur (3), Basti (3), Unnao (3), Siddharth Nagar (2), Lakhimpur (2), Sultanpur (1), Ballia (1), Barreilly (1), Fatehpur (1), and Nepal (1). to the poor and severely ill. The catchment area of the hospital includes both the city and district of Lucknow and most of the eastern districts, extending to Nepal. The pediatric department of this hospital, which caters to medical problems for patients from birth to 12 years of age, admits patients with cases of encephalitis annually, mostly during the monsoon and postmonsoon seasons. Because facilities for viral diagnosis are not regularly available or are too expensive, most patients do not receive virological examination; rather, their illnesses are presumed to be JE, which is known to be endemic in the eastern regions of the state. We have been involved in research on JE for many years, and in 2005, we launched a randomized, controlled trial of ribavirin in this illness. As part of the study, all patients admitted to the hospital with possible encephalitis were investigated for JE with an IgM capture ELISA on CSF or serum performed within 24 h after admission. Ethical approval for the study was obtained from the ethics committee of King George Medical University (Lucknow, Uttar Pradesh, India). It is against this background that a severe epidemic of encephalitis occurred in The epicenter of the epidemic was in Kushinagar, 250 km east of Lucknow. According to the Uttar Pradesh Department of Health, a total of 5477 cases of suspected JE, including 1330 deaths, were reported by the state from August 2005 through November Serum or CSF samples from a total of 1207 patients were tested in 4 different laboratories for JE virus IgM by ELISA; samples from 438 patients were positive. The most affected districts were Kushinagar (1087 cases), Gorakhpur (1006 cases), Maharajganj (609 cases), and Deoria (485 cases). Most of the patients from Gorakhpur and the surrounding districts were admitted to the Baba Raghav Das Medical College Hospital (Gorakhpur, Uttar Pradesh, India). However, many patients from other districts filtered into the King George Medical University Hospital. Patients 12 years of age were admitted to the childrens wards, and those 112 years of age were admitted to the adult medicine departments. METHODS Children were enrolled for the study if they were 6 months to 12 years of age and presented with acute febrile encephalopathy Japanese Encephalitis Epidemic in India CID 2006:43 (15 July) 125

4 RESULTS Figure 3. Number of patients, by period, admitted to the hospital with acute febrile encephalopathy (AFE) or whose test results were positive for IgM antibodies to Japanese encephalitis virus (JE+ve). (AFE) (i.e., they had fever with altered sensorium of up to 14 days in duration at the time of hospital admission). Written informed consent was obtained from the patients guardians. CSF or blood samples were obtained from enrolled children, and IgM ELISAs were performed with the JE Chex ELISA kit (Excyton). The kit uses the IgM capture ELISA technique and was developed at the National Institute of Mental Health and Neurosciences (Bangalore, Karnataka, India) [10]. If the results were positive, patients were examined according to a predesigned protocol that incorporated demographic information, clinical history, complete clinical and neurological examination, and investigations. The investigations include blood counts, peripheral blood smear examination, CSF examination for appearance, cell count (total and differential), measurement of protein and glucose, Gram stain and bacterial culture, liver function tests, and rapid test for malaria, blood urea, creatinine, and serum electrolyte levels. Daily follow-up was done during hospital stay. Patients were managed on supportive care with intravenous fluids, nasogastric tubes, antibiotics, antipyretics, anticonvulsants, and intracranial tension lowering agents (injection mannitol, nasogastric glycerol, and tab acetazolamide) as needed. Nursing was done mostly by family members of the patient. CSF and blood samples were stored at 20 C. Ten CSF samples that were tested for West Nile neutralizing antibodies had negative results. Over a period of 3.5 months, from mid-july to the end of October 2005, a total of 278 patients with AFE were admitted to the pediatric wards. The adult medicine wards also admitted 86 patients during the same period. A total of 223 children were tested for JE virus IgM antibodies, of whom 77 had results positive for JE virus. Figure 1 shows the location of Uttar Pradesh and Lucknow in India. Figure 2 shows the number of cases from various districts, and figure 3 shows hospital admission, by time period, of patients with AFE and patients whose test results were positive for IgM antibodies to JE virus. The socioeconomic and demographic profile of the patients is as follows. A total of 76 of the 77 patients with proven JE had illness that was of pure rural origin, and the single remaining patient s illness was of periurban origin. Of these 77 patients, 61 (79.2%) were children of farmers or farm labourers. Thirty-eight (49.4%) of the family heads of patients were either illiterate or had only attended primary school. Only 34 family heads (44.2%) admitted to the presence of pigs in their neighborhood. Table 1 shows the age and sex distribution of patients who were not tested, those who were tested, those whose results were JE virus IgM positive, and those whose results were JE virus IgM negative. Table 2 describes the clinical features of the patients. Fever was usually high or moderate, but it was seldom measured before admission to the hospital. Convulsions were present in almost all cases (98.7%) and was the first neurological manifestation of illness, usually followed by altered mentation. More than one-half of the patients had generalized hypertonia, and the very deeply comatose children had flaccidity. Extrapyramidal features were prominent in the form of rigidity and posturing, and abnormal movements were observed in 7 patients (9.1%), usually in the convalescent stage. Intracranial tension could not be measured in our patients, but 22 (28.6%) had breathing abnormalities, and 3 patients (3.9%) had bradycardia with hypertension suggestive of raised intracranial tension. Table 3 shows the laboratory features of the patients. Thrombocytopenia was observed in 5 (15.6%) of 32 patients tested. Serum electrolyte and serum bilirubin levels were within normal limits in all the patients. However, liver enzyme levels were commonly elevated, and serum protein levels were low with reversal of albumen; globulin ratio and prothrombin time were prolonged, compared with control subjects. Renal function was also deranged, as evidenced by the elevated blood urea level in 3 patients. Bacterial culture was routinely done for all CSF samples and was positive for Streptococcus pneumoniae in 2 patients with results negative for JE virus IgM. Peripheral smears were examined for malarial parasites in all patients, but the smears were positive in only 3 patients with test results negative for JE virus IgM. Of the 278 patients with AFE, 105 (37.7%) died in the hospital. Of the 77 patients whose test results were positive for IgM antibodies to JE virus, 26 (34%) died. 126 CID 2006:43 (15 July) Kumar et al.

5 Table 1. Age and sex distribution among 4 groups of patients admitted to the hospital during the 2005 Japanese encephalitis (JE) epidemic, by test status. Not tested Tested JE-negative results JE-positive results Patients Male Female All Male Female All Male Female Total Male Female All Age, months (16.9) (49.4) (33.8) Total no. (%) of patients 33 (60) a 22 (40) (69.5) a 68 (30.5) (67.1) a 48 (32.9) (75.3) a 19 (24.7) 77 Age, mean months SD NOTE. Data are no. (%) of patients, unless otherwise indicated. Comparison of the mean SD age of patients in months (by independent samples t test) for the groups are as follows: tested versus untested patients, P p.225 ; untested patients versus those with positive test results for JE, P p.010; those with negative test results for JE versus those with positive test results, P p.005. a Proportion of males in each group were compared by x 2 test: proportion of male patients who were tested versus patients who were not tested, P p.177; proportion of male patients with negative test results versus male patients with positive test results, P p.204. DISCUSSION The epidemic of 2005 was superimposed on baseline endemicity of JE in this part of the country. The high ambient temperature and waterlogged rice fields, coupled with the local practice of pig rearing by the poor, illiterate rural population, create a perfect combination of factors for epidemics of this kind to occur. The epicenter of this epidemic was Kushinagar and its neighboring districts, but 30 eastern districts were affected. Because there is no tight referral system and private practitioners attend to both outpatients and inpatients, it is likely that the incidences of disease and mortality were much higher than reported. The number of patients admitted to our hospital most likely reflects the distance to Lucknow from rural areas, the severity of illness, and the type of facilities available locally, as well as other factors. Most of the descriptions of the clinical features of JE have come from studies conducted during epidemics. One of the strengths of the present study is the prospective enrollment of patients. The IgM ELISA results were available within 24 h after hospital admission, and this gave us the opportunity to study the patients prospectively. The starting point for entry into our study was an acute febrile encephalopathic illness. An attempt was made to perform an IgM ELISA for JE for all children presenting with fever and altered mentation of 2 weeks in duration. However, of the 278 patients with AFE who were admitted to the hospital during this period, only 223 could be tested for JE virus IgM. This was partly because many patients were very sick and died soon after their arrival and partly because of a shortage of ELISA kits. Although the treatment trial allowed us to purchase the expensive kits, the sudden rush of cases did not give us time to procure enough kits, which were in short supply. Of the patients tested, only 77 had positive results for JE virus IgM. Again, the high negative rate could be because the samples were obtained very early in the illness in many instances or because of the characteristics of the kit itself. Although only a fraction of patients had positive results for JE virus, we believe that the large majority of patients with suspected encephalitis who were admitted to the hospital around that time had JE. This is because of the close temporal relationship and their area of residence, as well the very similar demographic and clinical picture observed among patients. Admittedly, a few patients may have had illness due to other causes of AFE, including bacterial meningitis, cerebral malaria, or even dengue. Lucknow is an area of endemicity for dengue virus, but not for Plasmodium falciparum infection. We used the IgM capture ELISA for CSF and serum to diagnose JE. This test is known to reliably differentiate JE virus from related flaviviruses [11]. It is still possible that some degree of cross-reactivity does exist, even with this test. Again, the extremely homogenous nature of the cases makes it unlikely that there was more than a single agent involved. Some patients from Gorakhpur had positive results by RT-PCR for JE virus when their samples were tested at the National Institute of Virology (Pune, India; M. Gore, personal communication). Figure 3 shows the sudden rush of cases in early August 2005 continuing until mid-september 2005 and decreasing thereafter. The epidemic was intense but brief. The age and sex distribution brings out some interesting facts. Notably, not a single proven case occurred in a person!2 years of age. JE is known to occur in older children, because they play outdoors. Passive transfer of maternal antibodies may also protect young children and infants. Adults living in areas of endemicity may be relatively protected because of prior subclinical infection, but nonimmune adults (such as travelers visiting areas of endemicity) are susceptible [12]. Sex distribution shows a male preponderance in all 4 groups without significant differences between untested and tested patients and those with positive and negative test results, implying either that the illness more commonly affected boys or that boys were more likely to be brought to hospital. Almost all proven cases (98.7%) were of Japanese Encephalitis Epidemic in India CID 2006:43 (15 July) 127

6 Table 2. Clinical features of patients with Japanese encephalitis IgM positive test results. Table 2. (Continued.) Feature No. (%) of patients (n p 77) Mean SD First symptom Fever 62 (80.5) Headache 10 (13.0) Vomiting 5 (6.5) Headache 55 (71.4) Vomiting 47 (61.0) Diarrhea 6 (7.8) Convulsions Any 76 (98.7) Generalized tonic 39 (50.6) Generalized tonic-clonic 34 (44.1) Focal 3 (3.9) No. of convulsions per day (31.1) a (68.9) a Prodromal stage !2 days 28 (36.4) 2 5 days 38 (49.3) 6 10 days 10 (13.0) 110 days 1 (1.3) Weight-for-age percentage b !50 1 (1.3) (6.5) (22.0) (39.0) (19.5) (11.7) Meningeal signs 27 (35.1) Glasgow Coma Scale score !7 34 (44.1) (44.1) (11.7) Hepatomegaly 17 (22.1) Splenomegaly 4 (5.2) Muscle tone Normal 19 (24.7) Increased 39 (50.6) Decreased 19 (24.7) Gastric hemorrhage 42 (54.5) Fundus blurring/papilledema 8 (14.0) c Focal deficit Any 35 (45.4) Monoparesis 19 (24.7) Hemiparesis 16 (20.8) Cranial nerve palsy 5 (6.5) Extrapyramidal features Any 24 (31.1) Rigidity 20 (26.0) Posturing 12 (15.6) Movements 7 (9.1) (continued) Feature No. (%) of patients (n p 77) Mean SD Decerebrate posturing 12 (15.6) Breathing pattern Normal 53 (68.8) Hyperventilation 20 (26.0) Cheyne stoke 2 (2.6) Gasping 1 (1.3) a n p 45. b Weight of the child is expressed as a percentage of the 50th percentile for that age by National Center for Health Statistics standards. c n p 57. purely rural origin. JE virus transmission, therefore, appears to have been restricted to rural areas, a finding that is in agreement with the known epidemiology of the disease. Almost four-fifths of patients were children of farmers or farm laborers. Interestingly, family members of less than one-half of the patients said that there were pigs in their village, suggesting that alternative hosts, such as wild birds, may be involved [13]. Humans are ordinarily dead-end hosts, because they do not produce high enough virus titres to infect mosquitoes [13]. A study of clinical features revealed some striking findings, most of which bear out the severity of illness. The severe pattern of illness observed by us may also have been caused by the referral pattern. Patients with milder illness may have been filtered out and not presented to the hospital. In the majority of patients, the illness was of very acute onset with a very short prodromal stage. Seizures were almost universal, with the most common type of seizure in our patients being multiple, recurrent, generalized tonic spasms. Misra and Kalita [14] presented an analysis of 65 patients aged 2 57 years with JE seen from 1991 to Thirty (46.1%) patients had seizures within 1 week of onset of illness; seizures were generalized tonic-clonic in 17 and partial motor with secondary generalization in 13. These authors did not describe generalized tonic seizures in their patients [14]. In a different comparative study between 37 adults and 30 children with JE described by Kalita et al. [15], seizures were present in a comparable proportion of adults (62.2%) and children (56.7%). Solomon et al. [16] described 144 Vietnamese patients with JE (134 children and 10 adults), of whom 59 (41%) had seizures. Forty patients had observed seizures, of whom 18 had generalized tonic-clonic seizures, 15 had subtle seizures, and 7 had partial motor seizures. Multiple seizures correlated with a poor outcome (OR, 2.78; 95% CI, ; P p.015). In our own series of children seen in the late 1980s, 85% of patients had seizures [17]. Such a high prevalence of frequent seizures reflects the severity of illness in our patients. The Glasgow Coma Scale score of!7 in almost 128 CID 2006:43 (15 July) Kumar et al.

7 Table 3. Investigation results of patients with Japanese encephalitis positive test results. Finding No. (%) of patients Mean value SD Hemoglobin, g per 100 ml /76 (25.0) /76 (75.0) Total leukocyte count, a cells/mm ,000 62/76 (81.6) 10,001 15,000 13/76 (17.1) 115,000 1/76 (1) Neutrophils in blood, % /74 (22.9) /74 (64.8) 180 9/74 (12.1) Platelet count b platelets/mm 3 5/32 (15.6) CSF cell count, c cells/mm /73 (50.6) /73 (26.0) /73 (10.9) /73 (12.3) Polymorphonuclear leukocytes in CSF, % /43 (46.5) /43 (13.9) /43 (11.6) /43 (27.9) CSF protein concentration, d mg per 100 ml /70 (62.8) /70 (18.6) /70 (8.6) /70 (1.4) (8.6) CSF glucose level, mg per 100 ml CSF/blood glucose ratio e Serum bilirubin level, f mg per 100 ml Serum aspartate aminotransferase level, g U/L /21 (33.3) /21 (47.6) /21 (14.2) /21 (4.8) Serum alanine aminotransferase level, h U/L /53 (52.8) /53 (33.9) /53 (7.5) /53 (5.6) Serum protein concentration, i g per 100 ml /53 (15.1) /53 (56.6) /53 (28.3) Serum albumen concentration, j g per 100 ml /53 (22.6) /53 (52.8) /53 (24.5) Albumen : globulin ratio k!1.0 12/53 (22.6) (continued)

8 Table 3. (Continued.) Finding Prothrombin concentration, l % No. (%) of patients Mean value SD!25 6/14 (42.8) /14 (7.1) /14 (14.2) /14 (35.7) Blood urea concentration, m mg per 100 ml !40 50/63 (79.3) /63 (17.4) /63 (3.2) Collapse on chest radiograph 2/61 (3.2) Positive rapid dipstick test result for Plasmodium falciparum 0/23 (0) NOTE. Normal value is defined as the values that are normal for children in Uttar Pradesh, India. Prothrombin concentration is calculated as the prothrombin time in the control subject, divided by the test result, then multiplied by 100. CSF glucose level was examined in 70 patients, CSF/blood glucose ratio was examined in 69 patients, and serum bilirubin level was examined in 53 patients. a Normal value, ,000 cells/mm 3. b Normal value, platelets/mm 3. c Normal value,!5 cells/mm 3. d Normal value, mg per 100 ml. e Normal value, 66%. f Normal value,!1 mg per 100 ml. g Normal value,!15 40 U/L. h Normal value,!15 40 U/L. i Normal value, g per 100 ml. j Normal value, g per 100 ml. k Normal value, l Normal value, 90% 100%. m Normal value, mg per 100 ml. 45% of our patients again reflects the very severe illness. Gastric hemorrhage was found in a larger proportion of patients during this epidemic, compared with our previous series [17], but it has not been described by other authors. Focal deficits again were observed much more frequently in this epidemic than what has been reported in the past. Significantly, monoparesis was the commonest type of deficit, usually without corresponding changes on CT imaging. Extrapyramidal features are believed to be one of the characteristic findings in persons with JE. Hyperventilation was found in a similar proportion of patients during this epidemic as that observed in our earlier study [17]. In our own analysis of clinical differentiating features of JE in children, hyperventilation and extrapyramidal features stood out in the logistic regression model as significant independent predictors of the diagnosis of JE [18]. In their comparative study between adults and children, Kalita et al. [15] found that children were more likely to have dystonia (66.7% of children), compared with adults (18.9% of adults), though radiological findings were not significantly different between adults and children. Investigative findings revealed low platelet counts in a significant proportion of those tested. In a study from Thailand, Watt and Jongsakul [19] reported thrombocytopenia in 8 patients with JE that manifested as acute undifferentiated febrile illness (median platelet count, 119,000 platelets/mm 3 ; range, 44, ,000 platelets/mm 3 ). This is the only other report in the literature of thrombocytopenia in patients with JE that we could find. Another striking finding was the abnormality in liver function test results. Abnormalities in liver and renal function were not reported in the early reports of epidemics of JE [3 7, 20 22] and may have been missed. However, in our own study of cases of acute encephalopathy in children admitted year-round in the late 1980s, liver function tests were done in patients with unexplained encephalopathy to look for Reye syndrome, and results were normal for all. These patients then underwent virological investigation, and 92 (23%) of 394 had evidence of JE virus infection [23]. On a detailed literature search, we did find a recent study by Misra et al. [24], also conducted in Lucknow, in which abnormal liver and renal functions are described in patients with JE. These authors report 14 patients with laboratory-confirmed JE, 11 of whom had elevated serum transaminase levels and 4 of whom had elevated serum bilirubin levels. Significant proteinuria (urinary protein, 1300 mg per day) was found in 10 patients, and 2 had overt renal failure. None of our patients had proteinuria, and elevated blood urea levels could be attributed to dehydration and poor 130 CID 2006:43 (15 July) Kumar et al.

9 intake of fluids and food. The abnormalities in platelet count and liver function in patients during this epidemic and in recent reports could suggest a change in the virulence of the virus or strain variation over time, with the virus developing properties similar to denguelike flaviviruses. Host genetic characteristics and environmental factors could also play a role. Acknowledgments Financial support. Indian Council of Medical Research, New Delhi. Potential conflicts of interest. All authors: no conflicts. References 1. Umenai T, Kryzsko R, Bektimorov TA, et al. Japanese encephalitis: current worldwide status. Bull WHO 1985; 63: Webb JKG, Perriera S. Clinical diagnosis of an arthropod borne type virus encephalitis in children in north Arcot district, Madras state, India. Indian J Med Sci 1956; 10: Sengupta SN, Sen M, Das PK, et al. Epidemic of Japanese encephalitis in west Bengal: A clinical appraisal of the first 143 cases at Bankura. J Assoc Phys India 1974; 22: Dhanda V, Thenmozhi V, Kumar NP, et al. Virus isolation from wildcaught mosquitos during a Japanese encephalitis outbreak in Kerela in Indian J Med Res 1997;106: Mohanrao CVR, Prasad S, Rodrigues JJ, et al. The first laboratory proven outbreak of Japanese encephalitis in Goa. Indian J Med Res 1983; 78: Prasad SR, Kumar V, Marwaha RK, et al. An epidemic of encephalitis in Haryana: serological evidence of Japanese encephalitis in a few patients. Indian Pediatr 1993;30: Mathur A, Chaturvedi UC, Tandon HO, et al. Japanese encephalitis epidemic in Uttar Pradesh, India during Indian J Med Res 1982; 75: World Health Organization Regional Office for South-East Asia. Communicable Diseases Surveillance & Response. Available at: w3.whosea.org/en/section10/section392_10316.htm Accessed 21 September Economic Profile of Uttar Pradesh. Available at: Accessed9 December Ravi V, Vanajakshi S, Gowda A, Chandramuki A. Laboratory diagnosis of Japanese encephalitis using monoclonal antibodies and correlation of findings with outcome. J Med Virol 1989; 29: Gadkari DA, Shaikh BH. IgM antibody capture ELISA in the diagnosis of Japanese encephaitis, West Nile & Dengue virus infections. Indian J Med Res 1984; 80: Solomon T. Flavivirus encephalitis. New Engl J Med 2004; 351: Medappa N. Japanese encephalitis in India. ICMR Bulletin 1980; 10: Misra UK, Kalita J. Seizures in Japanese encephalitis. J Neurol Sci 2001; 190: Kalita J, Misra UK, Pandey S, Dhole TN. A comparison of clinical and radiological findings in adults and children with Japanese encephalitis. Arch Neurol 2003; 60: Solomon T, Dung NM, Kneen R, et al. Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis. Brain 2002; 125: Kumar R, Mathur A, Kumar A, Sharma S, Chakraborty S, Chaturvedi UC. Clinical features and prognostic indicators of Japanese encephalitis in children in Lucknow. Indian J Med Res 1990; 91: Kumar R, Senthilselvan A, Sharma S, et al. Clinical Predictors of Japanese encephalitis. Neuroepidemiology 1994; 13: Watt G, Jongsakul K. Acute undifferentiated fever caused by infection with Japanese encephalitis virus. Am J Trop Med Hyg 2003; 68: Rao CV, Risbud AR, Rodrigues FM, Pinto BD, Joshi GD. The 1981 epidemic of Japanese encephalitis in Tamil Nadu & Pondicherry. Indian J Med Res 1988; 88: Prasad SR, George S, Gupta NP. Studies on an outbreak of Japanese encephalitis in Kolar district, Karnataka state in Indian J Med Res 1982; 75: Rao GLN, Rodrigues FM, Nambiapan M, et al. Etiology of the 1978 outbreak of encephalitis in Tirunelveli and other districts of Tamil Nadu. Indian J Med Res 1982; 76: Kumar R, Mathur A, Sethi G, Sharma S, Chuturvedi UC. Virological investigations in acute encephalopathy in India. Arch Dis Child 1990; 65: Misra UK, Kalita J, Goel D, Mathur A. Clinical, radiological and neurophysiological spectrum of JEV encephalitis and other nonspecific encephalitis during post monsoon period in India. Neurol India 2003; 51: Japanese Encephalitis Epidemic in India CID 2006:43 (15 July) 131