今日の臨床サポート

日本脳炎

著者: 加島雅之 熊本赤十字病院 内科

監修: 上原由紀 藤田医科大学医学部感染症科

著者校正/監修レビュー済:2022/11/24
患者向け説明資料

概要・推奨   

  1. 日本の夏場または海外渡航歴のある患者の脳炎・髄膜炎症状を呈する患者には日本脳炎を考慮して対応する必要がある(推奨度1)
  1. 日本脳炎では視床病変が特徴とされるが、視床病変が画像検査で見つからなくても否定はできない(推奨度4)
  1. 日本脳炎を疑う患者では、海外渡航歴を詳細に聴取し、デング熱や西ナイルウイルスなどの他のフラビウイルス属の曝露の確認を行うべきである(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
加島雅之 : 未申告[2022年]
監修:上原由紀 : 特に申告事項無し[2022年]

改訂のポイント:
  1.  定期レビューを行い、診断方針、治療方針/治療の項目に若干の変更を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 日本脳炎は、蚊によって媒介されるフラビウイルス属の日本脳炎ウイルスに感染することで発症する。
  1. 感染してもほとんどは無症状または発熱のみで、一部の感染者が脳炎症状を呈する。
  1. 4類感染症に定められており、診断した医師はただちに最寄りの保健所に届け出る。
  1. 日本脳炎ワクチン未接種者または不完全接種者で、夏季や、海外渡航歴がある者の脳炎患者では必ず日本脳炎を考慮する。
  1. 発症者のほとんどは、小児と高齢者である。
  1. 現在有効な治療法はなく、脳炎を発症した者の死亡率は20~40%であり、また、生存者の45~70%で精神神経学的後遺症が認められる(国立感染症研究所ウイルス第一部)。
 
  1. 日本の夏場または海外渡航歴のある患者の脳炎・髄膜炎症状を呈する患者には日本脳炎を考慮して対応する必要がある(推奨度 1o)
  1. まとめ:日本脳炎は頻度は少ないとはいえ、脳炎を発症した者は死亡率20~40%、精神神経学的後遺症は生存者の45~70%で認められる重篤な感染症である[1]。4類感染症に指定されており、医師は診断した場合にはただちに保健所に届け出なくてはならない。
  1. 追記:けいれんは小児では多いが、成人では少なく[2]、また指や眉のみの焦点発作や気分障害などの高次機能障害が前面に立つこともあり、注意を要する[3]
問診・診察のポイント  
  1. 日本脳炎ワクチンの接種歴を確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

A F LINCOLN, S E SIVERTSON
Acute phase of Japanese B encephalitis; two hundred and one cases in American soldiers, Korea, 1950.
J Am Med Assoc. 1952 Sep 27;150(4):268-73.
Abstract/Text
PMID 14955436
Penny Lewthwaite, M Veera Shankar, Phaik-Hooi Tio, Janet Daly, Anna Last, R Ravikumar, Anita Desai, V Ravi, Jane M Cardosa, Tom Solomon
Evaluation of two commercially available ELISAs for the diagnosis of Japanese encephalitis applied to field samples.
Trop Med Int Health. 2010 Jul;15(7):811-8. doi: 10.1111/j.1365-3156.2010.02537.x. Epub 2010 May 11.
Abstract/Text OBJECTIVE: To compare two commercially available kits, Japanese Encephalitis-Dengue IgM Combo ELISA (Panbio Diagnostics) and JEV-CheX IgM capture ELISA (XCyton Diagnostics Limited), to a reference standard (Universiti Malaysia Sarawak - Venture Technologies VT ELISA).
METHODS: Samples were obtained from 172/192 children presenting to a site in rural India with acute encephalitis syndrome.
RESULTS: Using the reference VT ELISA, infection with Japanese encephalitis virus (JEV) was confirmed in 44 (26%) patients, with central nervous system infection confirmed in 27 of these; seven patients were dengue seropositive. Of the 121 remaining patients, 37 (31%) were JEV negative and 84 (69%) were JEV unknown because timing of the last sample tested was <10 day of illness or unknown. For patient classification with XCyton, using cerebrospinal fluid alone (the recommended sample), sensitivity was 77.8% (59.2-89.4) with specificity of 97.3% (90.6-99.2). For Panbio ELISA, using serum alone (the recommended sample), sensitivity was 72.5% (57.2-83.9) with specificity of 97.5% (92.8-99.1). Using all available samples for patient classification, sensitivity and specificity were 63.6% (95% CI: 48.9-76.2) and 98.4% (94.5-99.6), respectively, for XCyton ELISA and 75.0% (59.3-85.4) and 97.7% (93.3-99.2) for Panbio ELISA.
CONCLUSION: The two commercially available ELISAs had reasonable sensitivities and excellent specificities for diagnosing JEV.

PMID 20487425
T Solomon, R Kneen, N M Dung, V C Khanh, T T Thuy, D Q Ha, N P Day, A Nisalak, D W Vaughn, N J White
Poliomyelitis-like illness due to Japanese encephalitis virus.
Lancet. 1998 Apr 11;351(9109):1094-7. doi: 10.1016/S0140-6736(97)07509-0.
Abstract/Text BACKGROUND: Acute flaccid paralysis remains common among Vietnamese children despite a pronounced fall in the incidence of poliomyelitis.
METHODS: During 1995, all 22 children presenting with acute flaccid paralysis to a referral centre in Ho Chi Minh City, Vietnam, had virological cultures and antibody measurements done on serum, cerebrospinal fluid, and faeces. A year later the children were reassessed and electrophysiological studies were done.
FINDINGS: Wild poliovirus type 1 was isolated from the faeces of only one patient, and non-polio enteroviruses from three patients. 12 (55%) of the 22 children with acute flaccid paralysis had evidence of acute Japanese encephalitis virus (JEV) infection, compared with only one (1%) of 88 age-matched hospital controls (children with diphtheria; p<0.0001). Compared with JEV-negative patients, weakness in JEV-infected children was more rapid in onset, tended to be asymmetrical, but was less likely to involve the arms. All 12 children with JEV infection were febrile at the onset of weakness, seven had acute retention of urine, and ten had CSF pleiocytosis. Seven of eight JEV-negative patients met the case-definition of Guillain-Barré syndrome, compared with only one of 12 JEV-positive children. At follow-up, patients with JEV infection had greater disability and were more likely to have muscle wasting than were JEV-negative children. Nerve conduction and electromyographic studies indicated damage to the anterior horn cells.
INTERPRETATION: JEV causes an acute flaccid paralysis in children that has similar clinical and pathological features to poliomyelitis. In endemic areas, children with acute flaccid paralysis should be investigated for evidence of JEV infection.

PMID 9660579
Tom Solomon, Nguyen Minh Dung, Rachel Kneen, Le Thi Thu Thao, Mary Gainsborough, Ananda Nisalak, Nicholas P J Day, Fenella J Kirkham, David W Vaughn, Shelagh Smith, Nicholas J White
Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis.
Brain. 2002 May;125(Pt 5):1084-93.
Abstract/Text Japanese encephalitis (JE) causes at least 10 000 deaths each year. Death is presumed to result from infection, dysfunction and destruction of neurons. There is no antiviral treatment. Seizures and raised intracranial pressure (ICP) are potentially treatable complications, but their importance in the pathophysiology of JE is unknown. Between 1994 and 1997 we prospectively studied patients with suspected CNS infections referred to an infectious disease referral hospital in Ho Chi Minh City, Vietnam. We diagnosed Japanese encephalitis virus (JEV), using antibody detection, culture of serum and CSF, and immunohistochemistry of autopsy material. We observed patients for seizures and clinical signs of brainstem herniation, measured CSF opening pressures (OP) and, on a subset of patients, performed EEGs. Of 555 patients with suspected CNS infections, 144 (26%) were infected with JEV (134 children and 10 adults). Seventeen (12%) patients died and 33 (23%) had severe sequelae. Of the 40 patients with witnessed seizures, 24 (62%) died or had severe sequelae, compared with 26 (14%) of 104 with no witnessed seizures [odds ratio (OR) 4.50, 95% confidence interval (CI) 1.94-10.52, P < 0.0001]. Patients in status epilepticus (n = 25), including 15 with subtle motor seizures, were more likely to die than those with other seizures (P = 0.003). Patients with seizures were more likely to have an elevated CSF OP (P = 0.033) and to develop brainstem signs compatible with herniation syndromes (P < 0.0001). Of 11 patients with CSF OP > or =25 cm, five (46%) died, compared with seven (9%) of 80 patients with lower pressures [OR 8.69, 95% CI 1.73-45.39, P = 0.005). Of the 50 patients with a poor outcome, 35 (70%) had signs compatible with herniation syndromes (including 19 with signs of rostro-caudal progression), compared with nine (10%) of those with better outcomes (P < 0.0001). Of 11 patients with CSF OP > or =25 cm, five (46%) died, compared with seven (9%) of 80 patients with lower pressures (OR 8.69, 95% CI 1.73-45.39, P = 0.005). The combination of coma, multiple seizures, brainstem signs and illness for 7 or more days was an accurate predictor of outcome, correctly identifying 42 (84%) of 50 patients with a poor outcome and 82 (87%) of 94 with a better outcome. These findings suggest that in JE, seizures and raised ICP may be important causes of death. The outcome may be improved by measures aimed at controlling these secondary complications.

PMID 11960897
N M Dung, Lance Turtle, W K Chong, N T Mai, T T Thao, T T Thuy, R Kneen, N H Phu, B Wills, J Farrar, K Das, Tom Solomon
An evaluation of the usefulness of neuroimaging for the diagnosis of Japanese encephalitis.
J Neurol. 2009 Dec;256(12):2052-60. doi: 10.1007/s00415-009-5249-5.
Abstract/Text Japanese encephalitis virus (JEV) is estimated to cause 30–50,000 cases of encephalitis every year. The disease occurs mainly in rural Asia and is transmitted to humans from birds and pigs by mosquitoes of the genus Culex. JE is diagnosed with antibody testing of the serum and CSF, but this is not available in many hospitals. Neuroimaging abnormalities, particularly thalamic hypodensity on computed tomography (CT) and hyperintensity on T2 weighted magnetic resonance imaging (MRI) have been described in case studies, but their usefulness for diagnosing JE is not known. We have therefore evaluated the usefulness of neuroimaging (CT and MRI) for the diagnosis of JE. The findings of thalamic lesions were compared with the final serological diagnosis in a cohort of 75 patients (children and adults) with suspected CNS infections in Southern Vietnam, a JEV endemic area. Thalamic lesions on CT and/or MRI combined had sensitivity 23% (95% confidence interval 12.9–33.1%), specificity 100%, positive predictive value 100% and negative predictive value 42.1% (95% confidence interval 30.2–53.8%) for a diagnosis of JE in this cohort. Over time, the thalamic lesions resolved in some patients. One patient showed disappearance of lesions on CT followed by reappearance of the lesions some time later, known as the fogging effect. In this setting, the presence of thalamic abnormalities suggested the diagnosis of JE, but their absence did not exclude it.

PMID 19633907
Sumalee Chanama, Walailuk Sukprasert, Areerat Sa-ngasang, Atchareeya A-nuegoonpipat, Somchai Sangkitporn, Ichiro Kurane, Surapee Anantapreecha
Detection of Japanese encephalitis (JE) virus-specific IgM in cerebrospinal fluid and serum samples from JE patients.
Jpn J Infect Dis. 2005 Oct;58(5):294-6.
Abstract/Text Detection of Japanese encephalitis virus (JEV)-specific IgM by IgM-capture enzymed-linked immunosorbent assay (IgM-capture ELISA) has been accepted as the standard for serological diagnosis. In the present study, we analyzed the time course of the positive rate of JEV-specific IgM in serum and cerebrospinal fluid (CSF) specimens from confirmed JE patients. Serum and CSF samples were obtained from 155 JE cases for diagnostic purposes at hospitals in Thailand from 2002 to 2004. The levels of specific IgM were assessed by IgM-capture ELISA in the 171 serum and 156 CSF samples. Anti-JEV IgM was detected in 26 of 44 serum samples collected on days 1-4 of the disease period, in 31 of 44 samples collected on days 5-8, in 23 of 26 samples collected on days 9-12, and in all the samples collected on day 13 or later. Specific IgM was detected in 60 of 66 CSF samples collected on days 1-4 of illness, and in all the CSF samples but one collected on day 7 or later. The results indicate that the detection of JEV-specific IgM in CSF by IgM-capture ELISA is a reliable laboratory diagnostic method for confirmation of JE throughout the disease period, while the detection of IgM in serum samples is a reliable method on day 9 or later.

PMID 16249624
Akanksha Roberts, Sonu Gandhi
Japanese encephalitis virus: a review on emerging diagnostic techniques.
Front Biosci (Landmark Ed). 2020 Jun 1;25(10):1875-1893. doi: 10.2741/4882. Epub 2020 Jun 1.
Abstract/Text Japanese Encephalitis Virus (JEV) is the most common Flavivirus based mosquito borne viral encephalitis in the world, especially in countries of South-East Asia. The conventional methods such as Enzyme-Linked Immunosorbent Assays (ELISA), Reverse Transcriptase Polymerase Chain Reaction (RT-PCR), Plaque Reduction Neutralization Test and virus isolation are still in use today but new advances are being made to develop more efficient, inexpensive, quicker, sensitive and time-saving techniques to detect JEV. Some of these include the use of immunosensors, both lateral flow based assays and electrochemical, as well as the incorporation of nanotechnology into biosensors to develop highly sensitive detection tools. This review focuses on the recent advances that have been made to diagnose Japanese Encephalitis Virus which are critical in breaking the link to zoonotic transmission into the human population where humans are dead-end hosts.

PMID 32472762
Vasanthapuram Ravi, Jaimie S Robinson, Brandy J Russell, Anita Desai, Nalini Ramamurty, David Featherstone, Barbara W Johnson
Evaluation of IgM antibody capture enzyme-linked immunosorbent assay kits for detection of IgM against Japanese encephalitis virus in cerebrospinal fluid samples.
Am J Trop Med Hyg. 2009 Dec;81(6):1144-50. doi: 10.4269/ajtmh.2009.09-0144.
Abstract/Text Infection with Japanese encephalitis virus (JEV) is a major public health problem in Asia. Detection of JEV-specific IgM in serum and cerebrospinal fluid (CSF) by the IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) is currently the most widely used diagnostic method to detect JEV infection. Because of the possible presence of IgM cross-reactivity with other flaviviruses in serum and the high ratio of inapparent-to-apparent JEV infections, a positive result in serum only suggests a recent infection and not necessarily an encephalitic illness caused by JEV. Consequently, detection of JEV-specific IgM in CSF assumes great diagnostic relevance. We evaluated two commercial JEV MAC-ELISA kits using 60 CSF samples obtained from patients with acute encephalitis syndrome. The Panbio and XCyton kits had sensitivities of 65-80% and 95% and specificities of 90% and 97.5%, respectively. Performance information on these commercial JEV MAC-ELISA kits for CSF should assist in laboratory-based JE surveillance programs.

PMID 19996450
Reena Swami, Radha Kanta Ratho, Baijayantimala Mishra, Mini P Singh
Usefulness of RT-PCR for the diagnosis of Japanese encephalitis in clinical samples.
Scand J Infect Dis. 2008;40(10):815-20. doi: 10.1080/00365540802227102.
Abstract/Text The present study was carried out between July 2003 and December 2005 in PGIMER, Chandigarh, India and aimed to compare IgM capture ELISA and nested RT-PCR for the diagnosis of Japanese encephalitis (JE). The samples collected were cerebrospinal fluid and blood from 40 febrile patients with encephalitis (n=40, group I) and blood samples from febrile patients without encephalitis residing in JE endemic areas (n=45, group II). Overall, in CSF samples JE specific RNA was detected in 9/40 (22.5%), while 7/28 (25%) patients showed the presence of specific IgM antibodies. Only 28 CSF samples could be subjected to both RT-PCR and IgM and, among these, 13 cases were found to be confirmed JE based on IgM and/or RT-PCR positivity. Among the confirmed cases, 6 (6/13, 46.5%) could be detected by RT-PCR alone, 4 (4/13, 30.7%) by IgM capture ELISA and 3 (3/13, 23.1%) patients were positive by both the methods. All the RT-PCR positive cases had presented within 5 d of onset of illness. The serum samples of only 16 patients in group I could be tested for IgM antibodies and 5 (31.25%) were found to be positive, while in group II, 11.1% (5/45) positivity was observed. JE specific RNA could not be detected in serum samples of either group of patients. This study highlights the need for carrying out RT-PCR in CSF samples, compared to IgM antibody detection, for the early detection of JEV.

PMID 18618334
Usha Kant Misra, Jayantee Kalita
Overview: Japanese encephalitis.
Prog Neurobiol. 2010 Jun;91(2):108-20. doi: 10.1016/j.pneurobio.2010.01.008. Epub 2010 Feb 2.
Abstract/Text Japanese encephalitis (JE) is one of the most important endemic encephalitis in the world especially in Eastern and Southeastern Asia. JE affects over 50,000 patients and results in 15,000 deaths annually. JE virus is a single stranded positive sense RNA virus belonging to family flaviviridae. JE virus is transmitted through a zoonotic cycle between mosquitoes, pigs and water birds. Humans are accidentally infected and are a dead end host because of low level and transient viremia. In the northern region, large epidemics occur during summers whereas in the southern region JE tends to be endemic: cases occur throughout the year with a peak in the rainy season. Occurrence of JE is more closely related to temperature than to humidity. JE is regarded as a disease of children in the endemic areas but in the newly invaded areas, it affects both the adults and children because of the absence of protective antibodies. For every patient of JE, there are large numbers of subclinical cases (25-1000). Symptomatic JEV infection manifests with nonspecific febrile illness, aseptic meningitis or encephalitis. Encephalitis manifests with altered sensorium, seizures and focal neurological deficit. Acute flaccid paralysis may occur due to anterior horn cell involvement. A wide variety of movement disorders especially transient Parkinsonian features and dystonia (limb, axial, orofacial) are reported in 20-60% patients. JE mainly affects thalamus, corpus striatum, brainstem and spinal cord as revealed by MRI and on autopsy studies. Coinfection of JE and cysticercosis occurs because of the important role of pigs in the life cycle of both JEV and cysticercosis. Laboratory diagnosis of JE is by IgM capture ELISA, which has high sensitivity and specificity. In the absence of specific antiviral therapy, JE is managed by symptomatic and supportive therapies and preventive measures. Purified formalin inactivated mouse brain derived vaccine and live attenuated vaccine (SA 14-14-2) are available; the latter is reported to be safe, effective and cheap. The role of Chimeric recombinant attenuated JE vaccine is under investigation. Control of JE is related to the wider issues of hygiene, environment, education and economy.

(c) 2010 Elsevier Ltd. All rights reserved.
PMID 20132860
S K Handique, R R Das, B Saharia, P Das, R Buragohain, P Saikia
Coinfection of Japanese encephalitis with neurocysticercosis: an imaging study.
AJNR Am J Neuroradiol. 2008 Jan;29(1):170-5. doi: 10.3174/ajnr.A0769. Epub 2007 Oct 10.
Abstract/Text BACKGROUND AND PURPOSE: Coinfection of neurocysticercosis (NCC) and Japanese encephalitis (JE) has been advocated as more than a chance occurrence resulting in poor outcome. We undertook this study to determine whether the association of the 2 infections is more than a chance occurrence, to define the imaging characteristics of coinfections, and to explore the synergistic effect of NCC in JE.
MATERIALS AND METHODS: Sixty-two patients with JE were studied by MR imaging and CT. CT was done in 53 and MR imaging in 53 patients. The diagnosis of JE was established by CSF JE virus immunoglobulin M capture (MAC) enzyme-linked immunosorbent assay (ELISA). NCC was diagnosed from imaging. A control group of 385 patients was evaluated by imaging for prevalence of NCC in the general population.
RESULTS: A significantly high association of NCC with JE (19.3%) was observed in comparison with prevalence of NCC in control subjects (1.04%; P = .0003). JE lesions in coinfection were significantly asymmetric with lateralization to the side of the brain having the maximum NCC or a cyst with edema. The JE lesions in coinfections were more florid, with a significantly higher proportion of abnormal CT scans and more abnormal MR imaging. Coinfections were significantly more common in children. Significantly lower CSF MAC-ELISA units in patients with coinfection reflected low CSF IgM levels, suggesting altered immune status.
CONCLUSION: In our series, there was a strong association between JE and NCC, and, thus, this coinfection was more than a chance occurrence.

PMID 17928378
Mong How Ooi, Penny Lewthwaite, Boon Foo Lai, Anand Mohan, Daniela Clear, Lina Lim, Shekhar Krishnan, Teresa Preston, Chae Hee Chieng, Phaik Hooi Tio, See Chang Wong, Jane Cardosa, Tom Solomon
The epidemiology, clinical features, and long-term prognosis of Japanese encephalitis in central sarawak, malaysia, 1997-2005.
Clin Infect Dis. 2008 Aug 15;47(4):458-68. doi: 10.1086/590008.
Abstract/Text BACKGROUND: Japanese encephalitis is a major public health problem in Asia. However, there is little data on the long-term outcome of Japanese encephalitis survivors.
METHODS: We prospectively evaluated children with serologically confirmed Japanese encephalitis over an 8.3-year period. The patients were assessed and their outcomes were graded with a functional outcome score at hospital discharge and at follow-up appointments. We examined how patient outcome at hospital discharge compared with that at long-term follow-up visits, when changes in outcome occurred, and the prognostic indicators of the eventual outcome.
RESULTS: One hundred and eighteen patients were recruited into the study, and 10 (8%) died during the acute phase of illness. At hospital discharge, 44 (41%) of the 108 patients who survived had apparent full recovery; 3 (3%) had mild, 28 (26%) had moderate, and 33 (31%) had severe neurological sequelae. Eighty six of the 108 patients were followed up for a median duration of 52.9 months (range, 0.9-114.9 months). During follow-up, 31 patients experienced improvement, but 15 patients experienced deterioration in their outcome grade. In most cases, assessment during the first 3-6 months after hospital discharge was predictive of the long-term outcome. More than one-half of the patients continued to experience neuropsychological sequelae and behavioral disorders. A combination of poor perfusion, Glasgow coma score < or =8, and > or =2 witnessed seizures predicted a poor long-term outcome with 65% sensitivity and 92% specificity.
CONCLUSIONS: Neurological assessment of Japanese encephalitis survivors at hospital discharge does not predict long-term outcome. Seizures and shock are treatable risk factors for a poor outcome at hospital discharge and at long-term follow-up visits.

PMID 18616397
A Desai, V Ravi, S C Guru, S K Shankar, V G Kaliaperumal, A Chandramuki, M Gourie-Devi
Detection of autoantibodies to neural antigens in the CSF of Japanese encephalitis patients and correlation of findings with the outcome.
J Neurol Sci. 1994 Mar;122(1):109-16.
Abstract/Text This study reports the detection of autoantibodies to myelin basic protein (MBP) and neurofilament proteins (NFP) in serum and cerebrospinal fluid (CSF) of Japanese encephalitis patients. The diagnosis of Japanese encephalitis was confirmed in 72 patients by the presence of virus specific antibodies to JEV in the CSF (28/72), viral antigen in the CSF (19/72) and simultaneous presence of both antigen and JEV antibodies in the CSF in 25/72 patients. Autoantibodies to either purified NFP (10) or MBP (8) or both (17) were detected in the CSF of 35 patients by ELISA in contrast with the control CSF samples. Amongst them 20 had similar antibodies in the serum as well. Correlation of immunological findings with the clinical outcome revealed that the presence of autoantibodies in the CSF especially to NFP was associated with a fatal outcome (P < 0.05).

PMID 7515105
R Kumar, A Mathur, K B Singh, P Sitholey, M Prasad, R Shukla, S P Agarwal, J Arockiasamy
Clinical sequelae of Japanese encephalitis in children.
Indian J Med Res. 1993 Jan;97:9-13.
Abstract/Text Over a five and a half year period, virological investigations for Japanese encephalitis (JE) were conducted in children admitted with acute encephalitis like illness to a large city hospital. The diagnosis of Japanese encephalitis was made by viral isolation from cerebrospinal fluid and/or a four-fold or higher rise in haemagglutination inhibiting antibodies in paired sera followed by demonstration of specific IgM antibodies by HI test after treatment with 2-mercapto ethanol. All children surviving the illness were contacted by post and followed up for sequelae. A total of 55 children could be followed up after 12-18 months and 22 of these even after 2 yr. A high rate of major sequelae (45.5%) in the form of frank motor deficits (32.7%), mental retardation (21.8%) and/or convulsions (18.2%) was observed. Neurological deficits were of diverse types and improved even after 2 yr of the illness. Fourteen patients (25.4%) had only minor deficits in the form of scholastic backwardness, behavioural problems and/or subtle neurological signs. Only 16 (29.2%) patients were completely normal on follow up. JE may therefore be an important cause of neurological handicap in this area. Sequelae of the disease were more severe if the initial illness was prolonged (P < 0.001, CI 2.45, 12.64), or associated with focal neurological deficits (P < 0.001, CI 1.97, 7.02).

PMID 8387460
Rashmi Kumar, Piyush Tripathi, Madan Baranwal, Sudhakar Singh, Sanjeev Tripathi, Gopa Banerjee
Randomized, controlled trial of oral ribavirin for Japanese encephalitis in children in Uttar Pradesh, India.
Clin Infect Dis. 2009 Feb 15;48(4):400-6. doi: 10.1086/596309.
Abstract/Text BACKGROUND: Japanese encephalitis is associated with high rates of mortality and disabling sequelae. To date, no specific antiviral has proven to be of benefit for this condition. We attempted to determine the efficacy of oral ribavirin treatment for reducing early mortality among children with Japanese encephalitis in Uttar Pradesh, India.
METHODS: Children (age, 6 months to 15 years) who had been hospitalized with acute febrile encephalopathy (a < or =2-week history of fever plus altered sensorium) were tested for the presence of immunoglobulin M antibodies to Japanese encephalitis virus with commercial immunoglobulin M capture enzyme-linked immunosorbent assay. Children with positive results were randomized to receive either ribavirin (10 mg/kg per day in 4 divided doses for 7 days) or placebo syrup through nasogastric tube or by mouth. The primary outcome was early mortality; secondary outcome measures were early (at hospital discharge; normal or nearly normal, independent functioning, dependent, vegetative state, or death) outcome, time to resolution of fever, time to resumption of oral feeding, duration of hospitalization, and late outcome (> or =3 months after hospital discharge). The study was double-blind, and analysis was by intention to treat.
RESULTS: A total of 153 patients were enrolled during a 3-year period; 70 patients received ribavirin, and 83 received placebo. There was no statistically significant difference between the 2 groups in the early mortality rate: 19 (27.1%) of 70 ribavirin recipients and 21 (25.3%) of 83 placebo recipients died (odds ratio, 1.10; 95% confidence interval, 0.5-2.4). No statistically significant differences in secondary outcome measures were found.
CONCLUSIONS: For the dosage schedule used in our study, oral ribavirin has no effect in reducing early mortality associated with Japanese encephalitis.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00216268 .

PMID 19143532
Tom Solomon, Nguyen Minh Dung, Bridget Wills, Rachel Kneen, Mary Gainsborough, Tran Vinh Diet, Tran Thi Nhu Thuy, Ha Thi Loan, Vo Cong Khanh, David W Vaughn, Nicholas J White, Jeremy J Farrar
Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial.
Lancet. 2003 Mar 8;361(9360):821-6.
Abstract/Text BACKGROUND: Japanese encephalitis virus (JEV), although confined to Asia, causes about 35000-50000 cases and 10000 deaths every year, and is the most important cause of encephalitis worldwide. There is no known antiviral treatment for any flavivirus. Results from in-vitro studies and work in animals have shown inteferon alfa has antiviral activity on Japanese encephalitis and other flaviviruses; therefore, we aimed to assess the efficacy of inteferon alfa-2a in Japanese encephalitis.
METHODS: We did a randomised double-blind placebo-controlled trial of interferon alfa-2a (10 million units/m2, daily for 7 days) in 112 Vietnamese children with suspected Japanese encephalitis, 87 of whom had serologically confirmed infections. Our primary endpoints were hospital death or severe sequelae at discharge. Analysis was by intention to treat.
FINDINGS: Overall, 21 children (19%) died, and 17 (15%) had severe sequelae. Outcome at discharge and 3 months did not differ between the two treatment groups; 20 children in the interferon group had a poor outcome (death or severe sequelae), compared with 18 in the placebo group (p=0.85, difference 0.1%, 95% CI -17.5 to 17.6%), there were no long-term side effects of interferon.
INTERPRETATION: The doses of interferon alfa-2a given in this regimen did not improve the outcome of patients with Japanese encephalitis.

PMID 12642049
C H Hoke, D W Vaughn, A Nisalak, P Intralawan, S Poolsuppasit, V Jongsawas, U Titsyakorn, R T Johnson
Effect of high-dose dexamethasone on the outcome of acute encephalitis due to Japanese encephalitis virus.
J Infect Dis. 1992 Apr;165(4):631-7.
Abstract/Text Death due to Japanese encephalitis usually occurs in the first 5 days of hospitalization as a result of deepening coma with respiratory arrest. Death may result from edema-induced increases in intracranial pressure that might be reduced by the administration of steroids. Sixty-five patients presenting in Thailand to four hospitals with a diagnosis of acute Japanese encephalitis were randomized in a double-masked fashion and stratified by initial mental status into a placebo group (saline) or a treatment group (dexamethasone 0.6 mg/kg intravenously as a loading dose followed by 0.2 mg/kg every 6 h for 5 days). Fifty-five of the 65 had confirmed Japanese encephalitis as demonstrated by detection of virus or by Japanese encephalitis virus-specific IgM antibody. Important outcome measures included mortality (24%, treatment group; 27%, control group), days to alert mental status (3.9 vs. 6.2), and neurologic status 3 months after discharge (45% abnormal in each group). No statistically significant benefit of high-dose dexamethasone could be detected.

PMID 1313068
Pietro Caramello, Francesca Canta, Rosanna Balbiano, Filippo Lipani, Silvia Ariaudo, Maura De Agostini, Guido Calleri, Lucio Boglione, Antonino Di Caro
Role of intravenous immunoglobulin administration in Japanese encephalitis.
Clin Infect Dis. 2006 Dec 15;43(12):1620-1. doi: 10.1086/509644.
Abstract/Text
PMID 17109300
Allan R Tunkel, Carol A Glaser, Karen C Bloch, James J Sejvar, Christina M Marra, Karen L Roos, Barry J Hartman, Sheldon L Kaplan, W Michael Scheld, Richard J Whitley, Infectious Diseases Society of America
The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.
Clin Infect Dis. 2008 Aug 1;47(3):303-27. doi: 10.1086/589747.
Abstract/Text Guidelines for the diagnosis and treatment of patients with encephalitis were prepared by an Expert Panel of the Infectious Diseases Society of America. The guidelines are intended for use by health care providers who care for patients with encephalitis. The guideline includes data on the epidemiology, clinical features, diagnosis, and treatment of many viral, bacterial, fungal, protozoal, and helminthic etiologies of encephalitis and provides information on when specific etiologic agents should be considered in individual patients with encephalitis.

PMID 18582201
Abimbola O Ajibowo, Juan Fernando Ortiz, Ammar Alli, Taras Halan, Olasunkanmi A Kolawole
Management of Japanese Encephalitis: A Current Update.
Cureus. 2021 Apr 20;13(4):e14579. doi: 10.7759/cureus.14579. Epub 2021 Apr 20.
Abstract/Text Japanese encephalitis (JE) continues to be one of the world's most serious infections with no definitive treatment or guidelines. The high morbidity and mortality rate among symptomatic patients warrant the need for further investigation in this regard. Our review focuses on the recent updates on Japanese encephalitis treatment. For that reason, we used an advanced PubMed search with JE and drugs like minocycline, interferon, ribavirin, immunoglobulin, dexamethasone, and acyclovir. All research was done in full papers written in the English language and conducted in humans. This review aims to compare and analyze recent papers regarding JE treatment to guide healthcare providers with the latest information and make evidence-based decisions when presented with this infection. Overall, only minocycline had promising results because one of the two studies showed statistically significant results. The second study showed positive trends in children over 12 years and patients who survived on the first day of hospitalization. The study with intravenous immunoglobulin (IVIG) did not improve the outcomes; however, it increased the levels of neutralizing antibodies. Further study with higher doses may change the outcomes in patients with JE. The other drugs failed to show promising results.

Copyright © 2021, Ajibowo et al.
PMID 34036000

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