今日の臨床サポート

単純ヘルペス脳炎

著者: 早野聡史 亀田総合病院 感染症科

監修: 大曲貴夫 国立国際医療研究センター

著者校正/監修レビュー済:2019/02/07
患者向け説明資料

概要・推奨   

疾患のポイント:
  1. 単純ヘルペス脳炎とは、単純ヘルペスウイルス(HSV-1、HSV-2)による脳炎で、ウイルス性脳炎の中で最も多く、全体の10%を占める。
  1. 季節性はなく、通年で生じ、すべての年代に認めるが、5~30歳と50歳以上の2峰性に多く、男女差はない。
  1. 無治療では70%が死亡し、適切な治療を行っていても神経学的後遺症や治療後の再発の可能性がある。
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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。
※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、実際の保険適用の査定において保険適用及び保険適用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用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:
早野聡史  : 未申告[2021年]
監修:大曲貴夫 : 特に申告事項無し[2021年]

病態・疫学・診察

疾患(疫学・病態)のまとめ  
  1. 単純ヘルペス脳炎とは、単純ヘルペスウイルス(HSV-1、HSV-2)による脳炎で、ウイルス性脳炎の中で最も多く、全体の10%を占める[1]
  1. 単純ヘルペス脳炎の90%以上がHSV-1による感染であり、HSV-2による感染は少ない[2]
  1. 単純ヘルペス脳炎は、症状だけでは脳炎・脳症との鑑別は困難であり、その他の感染性(ウイルス性、細菌性、真菌性)脳炎や非感染性脳症との鑑別が必要である。
  1. 季節性はなく、通年で生じ、すべての年代に認めるが、5~30歳と50歳以上の2峰性に多く、男女差はない[2][3]
  1. 無治療では70%が死亡し、適切な治療を行っていても神経学的後遺症や治療後の再発の可能性がある[4]
問診・診察のポイント  
  1. 症状は、発熱(90~100%)・頭痛(74~81%)に加えて、意識障害(97~100%)、人格変化(85~87%)などの症状が特徴的である[4]

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文献 

著者: Richard J Whitley, David W Kimberlin
雑誌名: Semin Pediatr Infect Dis. 2005 Jan;16(1):17-23. doi: 10.1053/j.spid.2004.09.007.
Abstract/Text Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the central nervous system despite available antiviral therapy. Children and adolescents account for approximately one third of all cases of HSE. Clinical diagnosis is suggested in the encephalopathic, febrile patient with focal neurologic signs. However, these clinical findings are not pathognomonic because numerous other infections in the central nervous system can mimic HSE. Support for the diagnosis from a neurodiagnostic perspective is aided by the demonstration of disease of the temporal lobe by magnetic resonance image scan and spike and slow-wave activity on electroencephalogram. In the current era, the gold standard for establishing diagnosis is the detection of herpes simplex virus DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Although PCR is an excellent test and far more desirable than brain biopsy, false negatives can occur early after disease onset. Current therapeutic management calls for the administration of acyclovir at 10 mg/kg every 8 hours for 21 days. Even with early administration of therapy after the onset of disease, nearly two thirds of survivors will have significant residual neurologic deficits. Recent investigative efforts are assessing the value of PCR detection of viral DNA at the completion of therapy and the value of prolonged antiviral therapy.

PMID 15685145  Semin Pediatr Infect Dis. 2005 Jan;16(1):17-23. doi: 10・・・
著者: Kenneth L Tyler
雑誌名: Herpes. 2004 Jun;11 Suppl 2:57A-64A.
Abstract/Text Herpes simplex encephalitis (HSE) is a life-threatening consequence of herpes simplex virus (HSV) infection of the central nervous system (CNS). Although HSE is rare, mortality rates reach 70% in the absence of therapy and only a minority of individuals return to normal function. Antiviral therapy is most effective when started early, necessitating prompt diagnosis. The International Herpes Management Forum (IHMF) has issued guidelines to aid the diagnosis and treatment of HSE. Polymerase chain reaction (PCR) of the cerebrospinal fluid (CSF) is the diagnostic method of choice for HSE, but negative results need to be interpreted in the context of the patient's clinical presentation and the timing of the CSF sampling. CSF virus culture is of little value in all but patients under the age of 6 months. CSF (intrathecal) antibody measurements are not recommended for acute diagnostic purposes. However, demonstration of an intrathecal HSV antibody response may be helpful in retrospective diagnosis or in cases in which CSF is sampled only late after onset of infection and PCR is negative. Serum HSV antibody measurements are not of utility in the diagnosis of HSV encephalitis in adults. In children and young adults, HSV serology may help define whether HSE is part of a primary or a reactivated HSV infection, although the clinical features, therapy, and prognosis of these two forms of HSV encephalitis are similar. The IHMF recommends that all patients with HSE receive intravenous aciclovir 10 mg/kg every 8 h for 14-21 days. Owing to the life-threatening nature of the disease, if there is a delay in diagnostic test results therapy should not be withheld until they become available. After completion of therapy, PCR of the CSF can confirm the elimination of replicating virus, aiding further management of the patient. Clinical trials of other antiviral agents (i.e. adjunctive oral valaciclovir after intravenous aciclovir) for the treatment of HSE are underway. Herpes infection of the CNS, especially with HSV-2, can also cause both monophasic and recurrent aseptic meningitis, as well as myelitis or radiculitis. Limited evidence suggests that aciclovir may be effective in its treatment. Recurrent aseptic meningitis is predominantly caused by HSV-2 infection, and is characterized by self-limited episodes of fever, meningismus and severe headache. Many cases are indistinguishable from cases previously classified as "Mollaret's meningitis", a term that should now be reserved for idiopathic cases of recurrent aseptic meningitis.

PMID 15319091  Herpes. 2004 Jun;11 Suppl 2:57A-64A.
著者: Kenneth L Tyler
雑誌名: Rev Neurol Dis. 2004 Fall;1(4):169-78.
Abstract/Text Herpes simplex encephalitis is the most common identified cause of sporadic viral encephalitis in the United States. Early diagnosis is critical because treatment with the antiviral drug acyclovir dramatically decreases morbidity and mortality. The use of polymerase chain reaction (PCR) techniques to amplify the genome of herpes simplex virus (HSV) from cerebrospinal fluid (CSF) has become the diagnostic procedure of choice. False-positive CSF HSV PCR results are rare when testing is performed in experienced laboratories. Negative CSF HSV PCR results should always be interpreted in the context of the timing of specimen collection and the likelihood of disease. Negative CSF HSV PCR tests can occur within the first 72 hours of illness, with subsequent tests becoming positive. Patients with HSV encephalitis will typically have a negative CSF HSV PCR after 14 days of acyclovir treatment, and a persisting positive PCR should prompt consideration of additional or revised antiviral therapy. Quantitative PCR testing provides information about HSV viral load in CSF, but the potential correlation of viral load with prognosis or other clinical features of disease remains uncertain. Although the neuroimaging abnormalities seen in HSV encephalitis are not unique, more than 90% of patients with proven HSV encephalitis will have magnetic resonance imaging (MRI) abnormalities involving the temporal lobes. Special MRI techniques, including fluid-attenuated inversion recovery and diffusion-weighted imaging, might reveal abnormalities not seen with conventional imaging sequences. Neuroimaging patterns in infants and children differ significantly from those seen in adults and include a higher frequency of extratemporal lesions.

PMID 16400278  Rev Neurol Dis. 2004 Fall;1(4):169-78.
著者: R J Whitley, S J Soong, C Linneman, C Liu, G Pazin, C A Alford
雑誌名: JAMA. 1982 Jan 15;247(3):317-20.
Abstract/Text Continuing evaluations of antiviral agents for treatment of herpes simplex encephalitis (HSE) provided an opportunity to collect clinical data from 113 patients in whom the diagnosis was proved by viral isolation. Occurrence of HSE was in all ages and in both sexes and was nonseasonal. Characteristically, patients had behavioral changes, fever, confusion, speech disturbances, and, less frequently, seizures. The EEG was the most useful neurodiagnostic aid followed by technetium and computed axial tomographic scans. Employing a logistic regression model for variable selection, the diagnosis could be predicted by clinical findings and neurodiagnostic tests in 83% of the proved cases, but the evidence in 25% was falsely positive. There was evidence of localization by either clinical or neurodiagnostic assessment in all patients with proved disease. Among patients wtih negative findings for HSE, similar focal findings predominated in all but a few. The CSF and brain scans were normal in many patients with proved HSE. This extensive clinical experience in patients wtih diagnosis proved by viral isolation shows that diagnosis cna be confirmed only by brain biopsy.

PMID 6275134  JAMA. 1982 Jan 15;247(3):317-20.
著者: 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
雑誌名: 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  Clin Infect Dis. 2008 Aug 1;47(3):303-27. doi: 10.1086/・・・
著者: F J deCastro, R Biesbroeck, C Erikson, P Farrell, W Leong, D Murphy, R Green
雑誌名: Clin Pediatr (Phila). 1976 Jan;15(1):24-6.
Abstract/Text
PMID 1245078  Clin Pediatr (Phila). 1976 Jan;15(1):24-6.
著者: R B Domingues, A M Tsanaclis, C S Pannuti, M S Mayo, F D Lakeman
雑誌名: Clin Infect Dis. 1997 Jul;25(1):86-91.
Abstract/Text Detection of DNA from herpes simplex virus in cerebrospinal fluid (CSF) samples by polymerase chain reaction (PCR) analysis has been shown to be more sensitive and specific for the diagnosis of herpes simplex encephalitis than isolation of herpes simplex virus from biopsy specimens of brain tissue. Because of the invasiveness of brain biopsy, it has been suggested that PCR analysis of CSF may reveal a wider spectrum of the disease than has been previously recognized by brain biopsy studies. In this study, PCR assay of CSF samples obtained from 29, 12, and 8 patients with focal, mild, and diffuse encephalitis, respectively, was performed. PCR assay was positive for 15 (51.7%) of 29 patients with focal encephalitis and three (25%) of 12 patients with mild encephalitis. The correlation between temporal abnormalities shown by electroencephalography, computed tomography of the brain, or cranial magnetic resonance imaging and a positive PCR assay was high. PCR analysis has revealed that atypical and less severe forms of encephalitis are caused by herpes simplex virus.

PMID 9243040  Clin Infect Dis. 1997 Jul;25(1):86-91.
著者: Franck Raschilas, Michel Wolff, Frédérique Delatour, Cendrine Chaffaut, Thomas De Broucker, Sylvie Chevret, Pierre Lebon, Philippe Canton, Flore Rozenberg
雑誌名: Clin Infect Dis. 2002 Aug 1;35(3):254-60. doi: 10.1086/341405. Epub 2002 Jul 10.
Abstract/Text Management of herpes simplex encephalitis (HSE) has been considerably improved by the availability of acyclovir therapy and rapid polymerase chain reaction (PCR)-based diagnostic assays. Prognostic factors for this rare affliction are, however, misestimated. We conducted a large retrospective multicenter study that included 93 adult patients in whom HSE was diagnosed by PCR from 1991 through 1998 and who were treated with intravenous acyclovir. Among the 85 patients assessed at 6 months, 30 (35%) had a poor outcome, which led to death in 13 patients (15%) and severe disability in 17 (20%). The outcome was favorable for 55 patients (65%). A multivariate analysis identified 2 factors that were found to be independently associated with poor outcome: a Simplified Acute Physiology Score II >/=27 at admission and a delay of >2 days between admission to the hospital and initiation of acyclovir therapy. Early administration of antiviral therapy is the only parameter that can be modified to improve the prognosis of patients with HSE.

PMID 12115090  Clin Infect Dis. 2002 Aug 1;35(3):254-60. doi: 10.1086/・・・
著者: Uluhan Sili, Abdurrahman Kaya, Ali Mert, HSV Encephalitis Study Group
雑誌名: J Clin Virol. 2014 Jun;60(2):112-8. doi: 10.1016/j.jcv.2014.03.010. Epub 2014 Mar 25.
Abstract/Text BACKGROUND: Herpes simplex virus (HSV) is one of the most common causes of sporadic encephalitis worldwide.
OBJECTIVE: We aimed to determine clinical characteristics and prognosis of HSV encephalitis (HSVE) cases reviewed retrospectively from several collaborating centers.
STUDY DESIGN: We searched hospital archives of the last 10 years for patients with HSVE diagnosis, i.e. clinical presentation compatible with encephalitis and brain involvement on magnetic resonance imaging (MRI) and/or detection of HSV DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Clinical characteristics were noted and patients were phone-interviewed. HSVE cases were grouped and analyzed as proven and probable, based on virological confirmation by PCR. Univariate and multivariate analyses were used to determine factors associated with prognosis.
RESULTS: A total of 106 patients (63 males and 43 females; mean age, 44 years; range, 18-83 years) were included. Most common symptoms were changes in mental status, fever, headache, and seizure. HSV PCR was positive in 69% of patients tested, while brain involvement was detected on MRI in 95%. Acyclovir was started mostly within five days of main symptom and continued for ≥14 days. Case fatality rate was 8%, while 69% of patients recovered with sequelae. Favorable prognosis was observed in 73% of patients. Multivariate analysis identified the duration of disease before hospital admission (odds ratio (OR)=1.24) and the extent of brain involvement on MRI at the time of admission (OR=37.22) as two independent risk factors associated with poor prognosis.
CONCLUSIONS: Although HSVE fatality regressed considerably with acyclovir treatment, many patients survive with sequelae. Our results emphasize the importance of early diagnosis and prompt treatment of HSVE.

Copyright © 2014 Elsevier B.V. All rights reserved.
PMID 24768322  J Clin Virol. 2014 Jun;60(2):112-8. doi: 10.1016/j.jcv.・・・
著者: A J Nahmias, R J Whitley, A N Visintine, Y Takei, C A Alford
雑誌名: J Infect Dis. 1982 Jun;145(6):829-36.
Abstract/Text Laboratory procedures were compared with brain biopsy findings in 113 biopsy-proven patients with herpes simplex virus (HSV) encephalitis and 93 biopsy-negative individuals. Examinations of brain tissue by histopathology, immunofluorescence, and electron microscopy demonstrated evidence of HSV infection in 56%, 70%, and 45% of proven cases and apparently false-positive results in 14%, 9% and 2% of those biopsy-negative. Serologic assessments revealed that HSV encephalitis occurred as both a primary (30%) and recurrent (70%) infection. Among patients with HSV encephalitis, 28% failed to seroconvert or seroboost within one month of the onset of disease. Titers of passive hemagglutinating and IgG immunofluorescent antibodies increased fourfold in the cerebrospinal fluid in 74% and 94%, respectively, of patients with proven disease. Similar percentages of patients had antibody ratios in serum and cerebrospinal fluid of less than 20 over the same interval. These data indicate the need for development of noninvasive diagnostic procedures.

PMID 6282983  J Infect Dis. 1982 Jun;145(6):829-36.
著者: Guy Boivin
雑誌名: Herpes. 2004 Jun;11 Suppl 2:48A-56A.
Abstract/Text The International Herpes Management Forum (IHMF) has produced guidelines to promote improved diagnosis of herpesvirus infections of the central nervous system (CNS). Recommendations include using polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) to help diagnose herpes simplex virus (HSV), varicella zoster virus (VZV) and cytomegalovirus (CMV) infections of the CNS. Laboratories routinely using such tests should participate in a proficiency testing programme. For retrospective diagnosis of herpesvirus infections of the CNS, intrathecal antibody detection can be used as an adjunct to PCR, assuming all appropriate controls are utilized. For suspected cases of herpes simplex encephalitis (HSE), a sensitive HSV PCR test of the CSF should be used in preference to other methods. Cultures are not recommended for HSE except as an adjunctive test in suspected neonatal HSV infections. While research continues into the role of PCR with VZV infections of the CNS, studies demonstrate that the technique is useful for diagnosing varicella-associated CNS syndromes but further research is required for its role in zoster-associated syndromes. For CMV CNS infections, PCR represents the most sensitive diagnostic method and can be used in conjunction with virus culture to determine suspected cases of CMV myelitis. For CNS infections with lymphotropic herpesviruses, a positive PCR test is suggestive, but not definitive, evidence of virus encephalitis. PCR analysis of CSF for Epstein-Barr virus can be useful for diagnosing AIDS-associated primary CNS lymphoma. This article presents the current evidence for these and other guidelines for the diagnosis of herpesvirus infections of the CNS.

PMID 15319090  Herpes. 2004 Jun;11 Suppl 2:48A-56A.
著者: Ana A Weil, Carol A Glaser, Zahwa Amad, Bagher Forghani
雑誌名: Clin Infect Dis. 2002 Apr 15;34(8):1154-7. doi: 10.1086/339550. Epub 2002 Mar 21.
Abstract/Text A statewide encephalitis diagnostic project of the California State Department of Health Services found that herpes simplex virus 1 DNA may not be detectable by molecular methods early in the clinical course of herpes simplex encephalitis.

PMID 11915008  Clin Infect Dis. 2002 Apr 15;34(8):1154-7. doi: 10.1086・・・
著者: E Aurelius, B Johansson, B Sköldenberg, A Staland, M Forsgren
雑誌名: Lancet. 1991 Jan 26;337(8735):189-92.
Abstract/Text With the aim of improving early diagnosis of herpes simplex encephalitis a polymerase chain reaction (PCR) assay with two "nested" primer pairs was developed for the amplification of herpes simplex virus DNA in cerebrospinal fluid (CSF). Southern blotting was used to confirm the specificity of the amplification. The assay was applied to 151 CSF samples from 43 consecutive patients with herpes simplex encephalitis verified by the finding of herpes simplex virus/viral antigen in a brain biopsy sample or at necropsy (13) and/or intrathecal production of IgG antibody to the virus (40). As controls, 87 CSF samples from 60 patients with acute febrile focal encephalopathy (initially suspected to be herpes simplex encephalitis but excluded by the absence of intrathecal antibody synthesis) were tested. PCR detected herpes simplex virus DNA in 42 of the 43 patients with proven herpes simplex encephalitis; all but 1 were positive in the first CSF sample taken. The 1 PCR-negative patient had been treated with acyclovir from 20 h after the onset of symptoms. All the control subjects were PCR negative, as were 270 internal contamination controls. The PCR result remained positive in samples drawn up to 27 days after the onset of neurological symptoms. This method is a rapid and non-invasive means to diagnose herpes simplex encephalitis; it is highly sensitive and specific.

PMID 1670839  Lancet. 1991 Jan 26;337(8735):189-92.
著者: R E Levitz
雑誌名: Heart Lung. 1998 May-Jun;27(3):209-12.
Abstract/Text Patients with herpes simplex encephalitis generally have altered mental function and are rarely able to provide a good medical history. Failure to diagnose this serious disease may result in permanent neurologic damage or death of the patient. Rapid institution of newer diagnostic tests such as polymerase chain reaction for herpes simplex virus is essential for proper diagnosis. Parenteral acyclovir therapy is efficacious but, clearly, improvements in prevention and therapy are still important research goals. This review is meant to inform physicians and nurses concerning the current diagnosis and management of this treatable but potentially fatal illness.

PMID 9622408  Heart Lung. 1998 May-Jun;27(3):209-12.
著者: James F Bale
雑誌名: Pediatr Neurol. 2015 Jul;53(1):3-12. doi: 10.1016/j.pediatrneurol.2015.03.013. Epub 2015 Mar 19.
Abstract/Text Virus encephalitis remains a major cause of acute neurological dysfunction and permanent disability among children worldwide. Although some disorders, such as measles encephalomyelitis, subacute sclerosing panencephalitis, and varicella-zoster virus-associated neurological conditions, have largely disappeared in resource-rich regions because of widespread immunization programs, other disorders, such as herpes simplex virus encephalitis, West Nile virus-associated neuroinvasive disease, and nonpolio enterovirus-induced disorders of the nervous system, cannot be prevented. Moreover, emerging viral disorders pose new, potential threats to the child's nervous system. This review summarizes current information regarding the epidemiology of virus encephalitis, the diagnostic methods available to detect central nervous system infection and identify viral pathogens, and the available treatments. The review also describes immune-mediated disorders, including acute disseminated encephalomyelitis and N-methyl-D-aspartate receptor antibody encephalitis, conditions that mimic virus encephalitis and account for a substantial proportion of childhood encephalitis.

Copyright © 2015 Elsevier Inc. All rights reserved.
PMID 25957806  Pediatr Neurol. 2015 Jul;53(1):3-12. doi: 10.1016/j.ped・・・
著者: R J Whitley, C A Alford, M S Hirsch, R T Schooley, J P Luby, F Y Aoki, D Hanley, A J Nahmias, S J Soong
雑誌名: N Engl J Med. 1986 Jan 16;314(3):144-9. doi: 10.1056/NEJM198601163140303.
Abstract/Text We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis.

PMID 3001520  N Engl J Med. 1986 Jan 16;314(3):144-9. doi: 10.1056/NE・・・

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