今日の臨床サポート

結核性髄膜炎

著者: 森野英里子 国際医療研究センター病院 呼吸器内科

監修: 具芳明 東京医科歯科大学大学院医歯学総合研究科 統合臨床感染症学分野

著者校正/監修レビュー済:2017/08/31
患者向け説明資料

概要・推奨   

疾患(疫学・病態)のまとめ:
  1. 結核性髄膜炎とは、結核菌によって生じる髄膜炎である。亜急性の無菌性髄膜炎として認識されることが多い。
  1. 髄膜炎のほか脳結核腫、脊髄結核なども中枢神経結核に含まれる。中枢神経結核の中で最も頻度が高いのが髄膜炎である。
 
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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:
森野英里子 : 特に申告事項無し[2021年]
監修:具芳明 : 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. 結核性髄膜炎とは、結核菌によって生じる髄膜炎である。亜急性の無菌性髄膜炎として認識されることが多い。
  1. 髄膜炎のほか脳結核腫、脊髄結核なども中枢神経結核に含まれる。中枢神経結核の中で最も頻度が高いのが髄膜炎である。
  1. 髄液の抗酸菌塗抹検査、結核菌PCR検査、培養検査の感度が低いため確定診断は難しいことが多い。
  1. 診断においては髄液所見、臨床像、画像、インターフェロンγ放出試験(IGRA)の結果による総合的判断を要する。
  1. 治療は速やかに開始されるべきである。標準治療薬のほか、髄液移行性のよいレボフロキサシンなどが追加されることも多い。ステロイドの併用が推奨される。
  1. 適切な治療が行われても死亡や後遺症が多く認められる。結核性髄膜炎は結核の病型の中で最も重篤な病態である。
  1. 診断時はただちに保健所への届け出が必要である。治療にあたっては公費申請が可能である。
問診・診察のポイント  
問診:
  1. 症状とその出現時期、経過を確認する(発熱、倦怠感、体重減少、寝汗などの全身症状のほか、不機嫌、注意力低下、無気力、性格変化、頭痛、嘔気・嘔吐、複視、意識障害などの髄膜炎に伴う症状)。

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文献 

著者: Kameshwar Prasad, Mamta B Singh, Hannah Ryan
雑誌名: Cochrane Database Syst Rev. 2016 Apr 28;4:CD002244. doi: 10.1002/14651858.CD002244.pub4. Epub 2016 Apr 28.
Abstract/Text BACKGROUND: Tuberculous meningitis is a serious form of tuberculosis (TB) that affects the meninges that cover a person's brain and spinal cord. It is associated with high death rates and with disability in people who survive. Corticosteroids have been used as an adjunct to antituberculous drugs to treat people with tuberculous meningitis, but their role has been controversial.
OBJECTIVES: To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis.
SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register up to the 18 March 2016; CENTRAL; MEDLINE; EMBASE; LILACS; and Current Controlled Trials. We also contacted researchers and organizations working in the field, and checked reference lists.
SELECTION CRITERIA: Randomized controlled trials that compared corticosteroid plus antituberculous treatment with antituberculous treatment alone in people with clinically diagnosed tuberculous meningitis and included death or disability as outcome measures.
DATA COLLECTION AND ANALYSIS: We independently assessed search results and methodological quality, and extracted data from the included trials. We analysed the data using risk ratios (RR) with 95% confidence intervals (CIs) and used a fixed-effect model. We performed an intention-to-treat analysis, where we included all participants randomized to treatment in the denominator. This analysis assumes that all participants who were lost to follow-up have good outcomes. We carried out a sensitivity analysis to explore the impact of the missing data.
MAIN RESULTS: Nine trials that included 1337 participants (with 469 deaths) met the inclusion criteria.At follow-up from three to 18 months, steroids reduce deaths by almost one quarter (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337 participants, high quality evidence). Disabling neurological deficit is not common in survivors, and steroids may have little or no effect on this outcome (RR 0.92, 95% CI 0.71 to 1.20; eight trials, 1314 participants, low quality evidence). There was no difference between groups in the incidence of adverse events, which included gastrointestinal bleeding, invasive bacterial infections, hyperglycaemia, and liver dysfunction.One trial followed up participants for five years. The effect on death was no longer apparent at this time-point (RR 0.93, 95% CI 0.78 to 1.12; one trial, 545 participants, moderate quality evidence); and there was no difference in disabling neurological deficit detected (RR 0.91, 95% CI 0.49 to 1.69; one trial, 545 participants, low quality evidence).One trial included human immunodeficiency virus (HIV)-positive people. The stratified analysis by HIV status in this trial showed no heterogeneity, with point estimates for death (RR 0.90, 95% CI 0.67 to 1.20; one trial, 98 participants) and disability (RR 1.23, 95% CI 0.08 to 19.07; one trial, 98 participants) similar to HIV-negative participants in the same trial.
AUTHORS' CONCLUSIONS: Corticosteroids reduce mortality from tuberculous meningitis, at least in the short term.Corticosteroids may have no effect on the number of people who survive tuberculous meningitis with disabling neurological deficit, but this outcome is less common than death, and the CI for the relative effect includes possible harm. However, this small possible harm is unlikely to be quantitatively important when compared to the reduction in mortality.The number of HIV-positive people included in the review is small, so we are not sure if the benefits in terms of reduced mortality are preserved in this group of patients.

PMID 27121755  Cochrane Database Syst Rev. 2016 Apr 28;4:CD002244. doi・・・
著者: Payam Nahid, Susan E Dorman, Narges Alipanah, Pennan M Barry, Jan L Brozek, Adithya Cattamanchi, Lelia H Chaisson, Richard E Chaisson, Charles L Daley, Malgosia Grzemska, Julie M Higashi, Christine S Ho, Philip C Hopewell, Salmaan A Keshavjee, Christian Lienhardt, Richard Menzies, Cynthia Merrifield, Masahiro Narita, Rick O'Brien, Charles A Peloquin, Ann Raftery, Jussi Saukkonen, H Simon Schaaf, Giovanni Sotgiu, Jeffrey R Starke, Giovanni Battista Migliori, Andrew Vernon
雑誌名: Clin Infect Dis. 2016 Oct 1;63(7):e147-e195. doi: 10.1093/cid/ciw376. Epub 2016 Aug 10.
Abstract/Text The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
PMID 27516382  Clin Infect Dis. 2016 Oct 1;63(7):e147-e195. doi: 10.10・・・
著者: A Dorothee Heemskerk, Nguyen D Bang, Nguyen T H Mai, Tran T H Chau, Nguyen H Phu, Pham P Loc, Nguyen V V Chau, Tran T Hien, Nguyen H Dung, Nguyen T N Lan, Nguyen H Lan, Nguyen N Lan, Le T Phong, Nguyen N Vien, Nguyen Q Hien, Nguyen T B Yen, Dang T M Ha, Jeremy N Day, Maxine Caws, Laura Merson, Tran T V Thinh, Marcel Wolbers, Guy E Thwaites, Jeremy J Farrar
雑誌名: N Engl J Med. 2016 Jan 14;374(2):124-34. doi: 10.1056/NEJMoa1507062.
Abstract/Text BACKGROUND: Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients.
METHODS: We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization.
RESULTS: A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08).
CONCLUSIONS: Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.).

PMID 26760084  N Engl J Med. 2016 Jan 14;374(2):124-34. doi: 10.1056/N・・・
著者: N I Girgis, Z Farid, M E Kilpatrick, Y Sultan, I A Mikhail
雑誌名: Pediatr Infect Dis J. 1991 Mar;10(3):179-83.
Abstract/Text During a 5-year period, 280 of 2010 patients admitted to the meningitis ward of a referral hospital in Cairo, Egypt, were clinically diagnosed as having tuberculous meningitis and were treated with either antituberculous chemotherapy and dexamethasone or antituberculous chemotherapy alone. Fatality rates and neurologic sequelae were compared for the 2 treatment groups in the 160 patients who had cerebrospinal fluid cultures positive for Mycobacterium tuberculosis. The overall mortality rate of 51% reflects the delay in receiving appropriate therapy (79% with symptoms for more than 2 weeks) and the severity of illness on admission (56% in coma, 39% drowsy). The fatality rate was significantly lower in the group receiving dexamethasone (43% vs. 59%, P less than 0.05), particularly in the drowsy patients (15% vs. 40% P less than 0.04), and in patients surviving long enough to receive at least 10 days of treatment (14% vs. 33%, P less than 0.02). Development of neurologic complications after initiation of therapy (4 vs. 10) and permanent sequelae (6 vs. 13) were significantly lower in the dexamethasone-treated group (P less than 0.02).

PMID 2041662  Pediatr Infect Dis J. 1991 Mar;10(3):179-83.
著者: Henry M Blumberg, William J Burman, Richard E Chaisson, Charles L Daley, Sue C Etkind, Lloyd N Friedman, Paula Fujiwara, Malgosia Grzemska, Philip C Hopewell, Michael D Iseman, Robert M Jasmer, Venkatarama Koppaka, Richard I Menzies, Richard J O'Brien, Randall R Reves, Lee B Reichman, Patricia M Simone, Jeffrey R Starke, Andrew A Vernon, American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society
雑誌名: Am J Respir Crit Care Med. 2003 Feb 15;167(4):603-62. doi: 10.1164/rccm.167.4.603.
Abstract/Text
PMID 12588714  Am J Respir Crit Care Med. 2003 Feb 15;167(4):603-62. d・・・
著者: Guy E Thwaites, Duc Bang Nguyen, Huy Dung Nguyen, Thi Quy Hoang, Thi Tuong Oanh Do, Thi Cam Thoa Nguyen, Quang Hien Nguyen, Tri Thuc Nguyen, Ngoc Hai Nguyen, Thi Ngoc Lan Nguyen, Ngoc Lan Nguyen, Hong Duc Nguyen, Ngoc Tuan Vu, Huu Hiep Cao, Thi Hong Chau Tran, Phuong Mai Pham, Thi Dung Nguyen, Kasia Stepniewska, Nicholas J White, Tinh Hien Tran, Jeremy J Farrar
雑誌名: N Engl J Med. 2004 Oct 21;351(17):1741-51. doi: 10.1056/NEJMoa040573.
Abstract/Text BACKGROUND: Tuberculous meningitis kills or disables more than half of those affected with the disease. Previous studies have been too small to determine whether adjunctive treatment with corticosteroids can reduce the risk of disability or death among adults with tuberculous meningitis, and the effect of coinfection with the human immunodeficiency virus (HIV) is unclear.
METHODS: We performed a randomized, double-blind, placebo-controlled trial in Vietnam in patients over 14 years of age who had tuberculous meningitis, with or without HIV infection, to determine whether adjunctive treatment with dexamethasone reduced the risk of death or severe disability after nine months of follow-up. We conducted prespecified subgroup analyses and intention-to-treat analyses.
RESULTS: A total of 545 patients were randomly assigned to groups that received either dexamethasone (274 patients) or placebo (271 patients). Only 10 patients (1.8 percent) had been lost to follow-up at nine months of treatment. Treatment with dexamethasone was associated with a reduced risk of death (relative risk, 0.69; 95 percent confidence interval, 0.52 to 0.92; P=0.01). It was not associated with a significant reduction in the proportion of severely disabled patients (34 of 187 patients [18.2 percent] among survivors in the dexamethasone group vs. 22 of 159 patients [13.8 percent] in the placebo group, P=0.27) or in the proportion of patients who had either died or were severely disabled after nine months (odds ratio, 0.81; 95 percent confidence interval, 0.58 to 1.13; P=0.22). The treatment effect was consistent across subgroups that were defined by disease-severity grade (stratified relative risk of death, 0.68; 95 percent confidence interval, 0.52 to 0.91; P=0.007) and by HIV status (stratified relative risk of death, 0.78; 95 percent confidence interval, 0.59 to 1.04; P=0.08). Significantly fewer serious adverse events occurred in the dexamethasone group than in the placebo group (26 of 274 patients vs. 45 of 271 patients, P=0.02).
CONCLUSIONS: Adjunctive treatment with dexamethasone improves survival in patients over 14 years of age with tuberculous meningitis but probably does not prevent severe disability.

Copyright 2004 Massachusetts Medical Society.
PMID 15496623  N Engl J Med. 2004 Oct 21;351(17):1741-51. doi: 10.1056・・・
著者: J F Schoeman, L E Van Zyl, J A Laubscher, P R Donald
雑誌名: Pediatrics. 1997 Feb;99(2):226-31.
Abstract/Text OBJECTIVE: To study the effect of highdose prednisone on intracranial pressure (ICP), cranial computed tomographic (CT) findings, and clinical outcome in young children with moderate to severe tuberculous meningitis (TBM).
STUDY DESIGN: Prospective, controlled, randomized study.
METHODS: Continuous lumbar, cerebrospinal fluid pressure monitoring and contrasted CT scanning were performed in 141 consecutive children with TBM at admission. All children were then randomly allocated to a nonsteroid group (71 children) or a steroid group (70 children) who received prednisone (first 16 children, 2 mg/kg per day; next 54 children, 4 mg/kg per day) for the first month of treatment. ICP monitoring and CT scanning were repeated regularly, and clinical outcome was assessed after 6 months of antituberculosis treatment.
RESULTS: No statistically significant difference in ICP or the degree of hydrocephalus (as demonstrated by CT scan) was found between the steroid and nonsteroid groups after the first month of treatment. Basal ganglia infarcts developed in 16% of children in the steroid group and 24% in the nonsteroid group during the first month of treatment. Neither this incidence nor the eventual size of infarcts present at admission differed significantly between the two treatment groups. Single or multiple tuberculomas were seen on the first CT scans of 7 children (5%), whereas tuberculomas developed in 11 children (8%) at treatment. Both the response of the tuberculomas to treatment and the incidence of new tuberculomas were significantly improved by steroid therapy. Basal enhancement was also significantly less in the steroid group after 1 month of treatment. Steroids lowered mortality in stage III TBM significantly. Similarly, more surviving children in the steroid group had IQs of greater than 75 than did the those in the nonsteroid group. No significant difference was found in the incidence of motor deficit, blindness, or deafness.
CONCLUSIONS: Corticosteroids significantly improved the survival rate and intellectual outcome of children with TBM. Enhanced resolution of the basal exudate and tuberculomas by steroids was shown by serial CT scanning. Corticosteroids did not affect ICP or the incidence of basal ganglia infarction significantly.

PMID 9024451  Pediatrics. 1997 Feb;99(2):226-31.
著者: V Chotmongkol, S Jitpimolmard, Y Thavornpitak
雑誌名: J Med Assoc Thai. 1996 Feb;79(2):83-90.
Abstract/Text We assessed the benefit of prednisolone regimen in adult-patients with tuberculous meningitis by a randomised, double-blind trial. 59 patients were treated with combined antituberculous drugs and randomised to receive oral prednisolone regimen or a placebo. There were 29 and 30 patients in the treatment and placebo groups respectively. The results revealed that prednisolone was not beneficial in patients with severe brain lesions, increased intracranial pressure and cranial nerve palsies. The role of prednisolone in patients with paraparesis, visual impairment and newly developed neurological complications during treatment needs further study.

PMID 8868018  J Med Assoc Thai. 1996 Feb;79(2):83-90.

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以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから