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・臨床研究センター

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:2022/09/14
参考ガイドライン:
  1. 日本結核・非結核性抗酸菌症学会(旧日本結核病学会):結核診療ガイドライン 改訂第3版 2015
  1. 日本結核・非結核性抗酸菌症学会(旧日本結核病学会)「結核医療の基準」の改訂―2018年
  1. 厚生労働省:令和3(2021)年10月18日付厚生労働省健康局結核感染症課長通知(健感発1018第1号)「結核医療の基準」の一部改正について
  1. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. 2016
  1. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. 2017
  1. World Health Organization:WHO consolidated guidelines on tuberculosis: Module 4: Treatment - Drug-susceptible tuberculosis treatment. 2022.
患者向け説明資料

概要・推奨   

  1. 結核性髄膜炎の治療として標準治療薬による4剤治療が推奨される(推奨度1 JG)
  1. 結核性髄膜炎の治療時にはステロイドの併用が推奨される(推奨度1 S/CSJG)
  1. 結核性髄膜炎に併用するステロイドは一般的に、デキサメサゾンもしくはプレドニゾロンが4~8週間使用される(推奨度2 JG)
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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:
森野英里子 : 特に申告事項無し[2022年]
監修:具芳明 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行った。
  1. 推奨度にガイドラインへの記載の有無を追記した。

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. 結核の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 

Bharat Kumar Gupta, Anchit Bharat, Bandyopadhyay Debapriya, Haren Baruah
Adenosine Deaminase Levels in CSF of Tuberculous Meningitis Patients.
J Clin Med Res. 2010 Oct 11;2(5):220-4. doi: 10.4021/jocmr429w.
Abstract/Text BACKGROUND: Tuberculosis kills five lakh patients in India every year, out of which 7-12 % are with meningeal involvement. Delay in its diagnosis and in initiation of treatment results in poor prognosis and sequlae in up to 25% of cases. The aim of the present study is to look for a simple, rapid, cost effective, non-invasive and fairly specific test in differentiating tubercular etiology from other causes.
METHODS: Forty patients between the age of 6 - 24 months attending hospital with symptoms and signs of meningitis were selected and divided into two groups: tubercular and non-tubercular, depending upon the accepted criteria. CSF was drawn and ADA estimated.
RESULTS: Out of 19 tubercular patients, 18 had CSF ADA at or above the cutoff value while one had below. Out of 21 non-tuberculous patients, two had ADA levels at or above the cutoff value while 19 had below this value. Results of our study indicate that ADA level estimation in CSF is not only of considerable value in the diagnosis of TBM, CSF ADA level 10 U/L as a cutoff value exhibited 94.73% sensitivity and 90.47% specificity in differentiating tuberculous from non-tuberculous meningitis; it also has 90.00% positive predictive value and 95.00% negative predictive value.
CONCLUSIONS: It can be concluded that ADA estimation in CSF is not only simple, inexpensive and rapid but also fairly specific method for making a diagnosis of tuberculous etiology in TBM, especially when there is a dilemma of differentiating the tuberculous etiology from non-tuberculous ones. For this reason ADA estimation in TBM may find a place as a routine investigation.
KEYWORDS: Cerebrospinal fluid; Adenosine deaminase; Tuberculous meningitis.

PMID 21629544
I Corral, C Quereda, E Navas, P Martín-Dávila, M-J Pérez-Elías, J-L Casado, V Pintado, J Cobo, E Pallarés, J Rubí, S Moreno
Adenosine deaminase activity in cerebrospinal fluid of HIV-infected patients: limited value for diagnosis of tuberculous meningitis.
Eur J Clin Microbiol Infect Dis. 2004 Jun;23(6):471-6. doi: 10.1007/s10096-004-1110-z. Epub 2004 May 13.
Abstract/Text Adenosine deaminase activity (ADA) determination in cerebrospinal fluid (CSF) is considered a specific test for the diagnosis of tuberculous meningitis. In order to study the variability of this marker in patients with different neurological disorders associated with HIV infection, and its utility for the diagnosis of tuberculous meningitis in these patients, the ADA levels in 417 CSF samples from HIV-infected patients with neurological symptoms were reviewed. HIV infection, HIV-associated neurological disorders, and progressive multifocal leukoencephalopathy were not associated with elevated ADA in CSF. Among patients with meningitis, receiver operating characteristic curve analysis gave an optimal ADA cut-off point of 8.5 IU/l for the diagnosis of tuberculous meningitis, with 57% sensitivity, 87% specificity, and an area under the curve of 0.747 (similar to that for CSF glucose concentration). False-positive results were found in patients with neurological CMV disease and cryptococcal, lymphomatous, and probable candidal meningitis. The results of this study indicate that ADA determination in CSF has limited utility for the diagnosis of tuberculous meningitis in HIV-infected patients.

PMID 15141333
Felipe Francisco Tuon, Hermes Ryoiti Higashino, Max Igor Banks Ferreira Lopes, Marcelo Nóbrega Litvoc, Angela Naomi Atomiya, Leila Antonangelo, Olavo Munhoz Leite
Adenosine deaminase and tuberculous meningitis--a systematic review with meta-analysis.
Scand J Infect Dis. 2010 Mar;42(3):198-207. doi: 10.3109/00365540903428158.
Abstract/Text Tuberculous meningitis (TBM) is a severe infection of the central nervous system, particularly in developing countries. Prompt diagnosis and treatment are necessary to decrease the high rates of disability and death associated with TBM. The diagnosis is often time and labour intensive; thus, a simple, accurate and rapid diagnostic test is needed. The adenosine deaminase (ADA) activity test is a rapid test that has been used for the diagnosis of the pleural, peritoneal and pericardial forms of tuberculosis. However, the usefulness of ADA in TBM is uncertain. The aim of this study was to evaluate ADA as a diagnostic test for TBM in a systematic review. A systematic search was performed of the medical literature (MEDLINE, LILACS, Web of Science and EMBASE). The ADA values from TBM cases and controls (diagnosed with other types of meningitis) were necessary to calculate the sensitivity and specificity. Out of a total of 522 studies, 13 were included in the meta-analysis (380 patients with TBM). The sensitivity, specificity and diagnostic odds ratios (DOR) were calculated based on arbitrary ADA cut-off values from 1 to 10 U/l. ADA values from 1 to 4 U/l (sensitivity >93% and specificity <80%) helped to exclude TBM; values between 4 and 8 U/l were insufficient to confirm or exclude the diagnosis of TBM (p = 0.07), and values >8 U/l (sensitivity <59% and specificity >96%) improved the diagnosis of TBM (p < 0.001). None of the cut-off values could be used to discriminate between TBM and bacterial meningitis. In conclusion, ADA cannot distinguish between bacterial meningitis and TBM, but using ranges of ADA values could be important to improve TBM diagnosis, particularly after bacterial meningitis has been ruled out. The different methods used to measure ADA and the heterogeneity of data do not allow standardization of this test as a routine.

PMID 20001225
H-B Xu, R-H Jiang, L Li, W Sha, H-P Xiao
Diagnostic value of adenosine deaminase in cerebrospinal fluid for tuberculous meningitis: a meta-analysis.
Int J Tuberc Lung Dis. 2010 Nov;14(11):1382-7.
Abstract/Text OBJECTIVE: To determine the accuracy of adenosine deaminase (ADA) measurements in the diagnosis of tuberculous meningitis (TBM).
DESIGN: After a systematic review of English language studies, the sensitivity, specificity and accuracy of ADA concentrations in the diagnosis of cerebrospinal fluid (CSF) were evaluated using random effects models. Summary receiver operating characteristic curves were used to summarise overall test performance.
RESULTS: Ten studies met our inclusion criteria. The sensitivity of ADA in the diagnosis of TBM was 0.79 (95%CI 0.75-0.83), specificity 0.91 (95%CI 0.89-0.93), positive likelihood ratio 6.85 (95%CI 4.11-11.41), negative likelihood ratio 0.29 (95%CI 0.19-0.44) and diagnostic odds ratio 26.93 (95%CI 12.73-56.97).
CONCLUSION: Our data suggest that ADA in the CSF can be a sensitive and specific target and a critical criteria for the diagnosis of TBM.

PMID 20937176
D H Kennedy, R J Fallon
Tuberculous meningitis.
JAMA. 1979 Jan 19;241(3):264-8.
Abstract/Text To evaluate modern treatment and identify important factors influencing the outcome of tuberculous meningitis, clinical and laboratory findings in 52 patients aged from 9 months to 68 years have been reviewed. Patients were classified by clinical criterions at admission and at the start of treatment. Delay in commencing treatment was associated with deterioration and consequently poorer prognosis, but some severely ill patients made a good recovery. Forty-four survivors (85%) recovered, and only two patients (4%) had severe residual disability; eight (15%) of the patients died. Treatment should commence as soon as possible on clinical grounds without necessarily waiting for demonstration of Mycobacterium tuberculosis, as the organism can often be demonstrated in CSF withdrawn after the start of drug therapy.

PMID 102806
Kameshwar Prasad, Mamta B Singh, Hannah Ryan
Corticosteroids for managing tuberculous meningitis.
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
Debra Benator, Mondira Bhattacharya, Lorna Bozeman, William Burman, Antonino Cantazaro, Richard Chaisson, Fred Gordin, C Robert Horsburgh, James Horton, Awal Khan, Christopher Lahart, Beverly Metchock, Constance Pachucki, Llewellyn Stanton, Andrew Vernon, M Elsa Villarino, Yong Chen Wang, Marc Weiner, Stephen Weis, Tuberculosis Trials Consortium
Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial.
Lancet. 2002 Aug 17;360(9332):528-34.
Abstract/Text BACKGROUND: Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week.
METHODS: We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat.
FINDINGS: 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups.
INTERPRETATION: Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

PMID 12241657
Awal Khan, Timothy R Sterling, Randall Reves, Andrew Vernon, C Robert Horsburgh
Lack of weight gain and relapse risk in a large tuberculosis treatment trial.
Am J Respir Crit Care Med. 2006 Aug 1;174(3):344-8. doi: 10.1164/rccm.200511-1834OC. Epub 2006 May 18.
Abstract/Text BACKGROUND: Readily identified markers of tuberculosis relapse risk are needed, particularly in resource-limited settings. The association between weight gain or loss during antituberculosis therapy and relapse has not been well studied.
METHODS: Subjects in the Tuberculosis Trials Consortium Study 22 were studied. Underweight was defined as 10% or more below ideal body weight at diagnosis. Weight change was assessed between (1) diagnosis and completion of induction phase therapy, (2) diagnosis and end of continuation phase therapy, and (3) completion of induction to completion of continuation phase therapy.
RESULTS: A total of 857 subjects were monitored for 2 yr, and 61 of 857 (7.1%) relapsed. Relapse risk was high among persons who were underweight at diagnosis (19.1 vs. 4.8%; p < 0.001) or who had a body mass index of less than 18.5 kg/m(2) (19.5 vs. 5.8%; p < 0.001). Among persons who were underweight at diagnosis, weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy was moderately associated with an increased relapse risk (18.4 vs. 10.3%; relative risk, 1.79, 95% confidence interval, 0.96-3.32; p = 0.06). In a multivariate logistic regression model that was adjusted for other risk factors, a weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy among persons underweight at diagnosis was significantly associated with relapse risk (odds ratio, 2.4; p = 0.03).
CONCLUSIONS: Among persons underweight at diagnosis, weight gain of 5% or less during the first 2 mo of treatment is associated with an increased relapse risk. Such high-risk patients can be easily identified, even in resource-poor settings. Additional studies are warranted to identify interventions to decrease risk of relapse in such patients.

PMID 16709935
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
Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.
Clin Infect Dis. 2016 Oct 1;63(7):e147-95. 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
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
Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis.
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
Rovina Ruslami, A Rizal Ganiem, Sofiati Dian, Lika Apriani, Tri Hanggono Achmad, Andre J van der Ven, George Borm, Rob E Aarnoutse, Reinout van Crevel
Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial.
Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.
Abstract/Text BACKGROUND: Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting.
METHODS: In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755.
FINDINGS: 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03).
INTERPRETATION: These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease.
FUNDING: Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23103177
Grace E Marx, Edward D Chan
Tuberculous meningitis: diagnosis and treatment overview.
Tuberc Res Treat. 2011;2011:798764. doi: 10.1155/2011/798764. Epub 2011 Dec 21.
Abstract/Text Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis (TB) and has very high morbidity and mortality. TBM is typically a subacute disease with symptoms that may persist for weeks before diagnosis. Characteristic cerebrospinal fluid (CSF) findings of TBM include a lymphocytic-predominant pleiocytosis, elevated protein, and low glucose. CSF acid-fast smear and culture have relatively low sensitivity but yield is increased with multiple, large volume samples. Nucleic acid amplification of the CSF by PCR is highly specific but suboptimal sensitivity precludes ruling out TBM with a negative test. Treatment for TBM should be initiated as soon as clinical suspicion is supported by initial CSF studies. Empiric treatment should include at least four first-line drugs, preferably isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol; the role of fluoroquinolones remains to be determined. Adjunctive treatment with corticosteroids has been shown to improve mortality with TBM. In HIV-positive individuals with TBM, important treatment considerations include drug interactions, development of immune reconstitution inflammatory syndrome, unclear benefit of adjunctive corticosteroids, and higher rates of drug-resistant TB. Testing the efficacy of second-line and new anti-TB drugs in animal models of experimental TBM is needed to help determine the optimal regimen for drug-resistant TB.

PMID 22567269
N I Girgis, Z Farid, M E Kilpatrick, Y Sultan, I A Mikhail
Dexamethasone adjunctive treatment for tuberculous meningitis.
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
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
American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis.
Am J Respir Crit Care Med. 2003 Feb 15;167(4):603-62. doi: 10.1164/rccm.167.4.603.
Abstract/Text
PMID 12588714
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
Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults.
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
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
V Chotmongkol, S Jitpimolmard, Y Thavornpitak
Corticosteroid in tuberculous meningitis.
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

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