{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:34:48Z","timestamp":1787009688705,"version":"build-2736575974"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T00:00:00Z","timestamp":1606262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To compare the safety and efficacy of sequential anti-tubercular treatment (ATT) regimen with the standard regimen in tuberculous meningitis (TBM).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-centre, open-label, parallel group randomized controlled trial was conducted from May 2017 to June 2019 in India. Treatment-na\u00efve patients with TBM fulfilling the inclusion criteria were randomized to four drug ATT regimens (rifampicin, isoniazid, ethambutol and pyrazinamide) administered either simultaneously (standard arm) or one after another (sequential arm) in a 1\u2009:\u20091 ratio. The primary endpoint was drug-induced hepatitis (DIH) and the secondary endpoints were in-hospital death and disability at 3 and 6\u00a0months using a modified Rankin Scale.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 97 patients with TBM were recruited; 15 did not meet the inclusion criteria and 2 refused to participate. The median age of the patients was 26\u00a0y (range 15\u201375) and 37 (46.2%) were males. The patients in the sequential arm had fewer cases of DIH (20% vs 42.5%; p=0.03). The patients in the sequential arm had lower in-hospital mortality (2.5% vs 17.5%; p=0.025) and better 6-month outcomes (25.0% vs 50.0%; p=0.02) compared with the standard arm.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Sequential ATT was associated with a lower frequency of DIH, lower in-hospital mortality and better 6-month outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>Clinical Trials Registry of India (ctri.nic.in) identifier: REF\/2016\/09\/012214\/CTRI\/2017\/10\/010072.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/trstmh\/traa144","type":"journal-article","created":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T07:15:11Z","timestamp":1604646911000},"page":"94-102","source":"Crossref","is-referenced-by-count":12,"title":["Standard versus sequential anti-tubercular treatment in patients with tuberculous meningitis: a randomized controlled trial"],"prefix":"10.1093","volume":"115","author":[{"given":"Usha Kant","family":"Misra","sequence":"first","affiliation":[{"name":"Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India"},{"name":"Apollomedics Super Speciality Hospital,31, Kanpur Rd, Sector I, Sector B, Bargawan, LDA Colony, Lucknow, Uttar Pradesh 226004, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mritunjai","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India"},{"name":"Department of Neurology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayantee","family":"Kalita","sequence":"additional","affiliation":[{"name":"Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,25]]},"reference":[{"issue":"17","key":"2021010701305684000_bib1","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1097\/QAD.0b013e3283320de8","article-title":"The effect of HIV infection on adult meningitis in Indonesia: a prospective cohort study","volume":"23","author":"Ganiem","year":"2009","journal-title":"AIDS."},{"issue":"12","key":"2021010701305684000_bib2","doi-asserted-by":"crossref","first-page":"e27821","DOI":"10.1371\/journal.pone.0027821","article-title":"Dexamethasone and long-term outcome of tuberculous meningitis in Vietnamese adults and adolescents","volume":"6","author":"T\u00f6r\u00f6k","year":"2011","journal-title":"PLoS One."},{"issue":"2","key":"2021010701305684000_bib3","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1084\/jem.56.2.203","article-title":"The role of hypersensitivity in the production of experimental meningitis: I. Experimental meningitis in tuberculous animals","volume":"56","author":"Burn","year":"1932","journal-title":"J Exp Med."},{"issue":"5","key":"2021010701305684000_bib4","first-page":"677","article-title":"Inflammasome activation underlying central nervous system deterioration in HIV-associated tuberculosis","volume":"215","author":"Marais","year":"2017","journal-title":"J Infect Dis."},{"issue":"1","key":"2021010701305684000_bib5","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.neulet.2010.07.029","article-title":"A study of cytokines in tuberculous meningitis: clinical and MRI correlation","volume":"483","author":"Misra","year":"2010","journal-title":"Neurosci Lett."},{"issue":"4","key":"2021010701305684000_bib6","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1128\/IAI.63.4.1598-1602.1995","article-title":"CD14 receptor-mediated uptake of nonopsonized Mycobacterium tuberculosis by human microglia","volume":"63","author":"Peterson","year":"1995","journal-title":"Infect Immun."},{"issue":"10","key":"2021010701305684000_bib7","doi-asserted-by":"crossref","first-page":"5657","DOI":"10.1073\/pnas.96.10.5657","article-title":"Tumor necrosis factor \u03b1 is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system","volume":"96","author":"Tsenova","year":"1999","journal-title":"Proc Natl Acad Sci USA."},{"issue":"8","key":"2021010701305684000_bib8","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1177\/088307380001500801","article-title":"Adjunctive thalidomide therapy of childhood tuberculous meningitis: possible anti-inflammatory role","volume":"15","author":"Schoeman","year":"2000","journal-title":"J Child Neurol."},{"issue":"2","key":"2021010701305684000_bib9","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1056\/NEJMoa1507062","article-title":"Intensified antituberculosis therapy in adults with tuberculous meningitis","volume":"374","author":"Heemskerk","year":"2016","journal-title":"N Engl J Med."},{"issue":"1","key":"2021010701305684000_bib10","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S1473-3099(12)70264-5","article-title":"Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial","volume":"13","author":"Ruslami","year":"2013","journal-title":"Lancet Infect Dis."},{"issue":"6","key":"2021010701305684000_bib11","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.tube.2010.07.003","article-title":"The chemotherapy of tuberculous meningitis in children and adults","volume":"90","author":"Donald","year":"2010","journal-title":"Tuberculosis (Edinb)"},{"issue":"6 Pt 1","key":"2021010701305684000_bib12","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1164\/ajrccm.157.6.9711039","article-title":"Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus","volume":"157","author":"Ungo","year":"1998","journal-title":"Am J Respir Crit Care Med."},{"issue":"8","key":"2021010701305684000_bib13","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1164\/rccm.200510-1666ST","article-title":"An official ATS statement: hepatotoxicity of antituberculosis therapy","volume":"174","author":"Saukkonen","year":"2006","journal-title":"Am J Respir Crit Care Med."},{"issue":"2","key":"2021010701305684000_bib14","first-page":"1000146","article-title":"Predictors of drug induced hepatotoxicity in tuberculous meningitis","volume":"5","author":"Misra","year":"2014","journal-title":"J Neuroinfect Dis."},{"issue":"2","key":"2021010701305684000_bib15","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0041-3879(86)90003-6","article-title":"Hepatic toxicity in South Indian patients during treatment of tuberculosis with shortcourse regimens containing isoniazid, rifampicin and pyrazinamide","volume":"67","author":"Parthasarathy","year":"1986","journal-title":"Tubercle."},{"issue":"3\u20134","key":"2021010701305684000_bib16","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1159\/000457640","article-title":"Malnutrition and drugs: clinical implications","volume":"15","author":"Mehta","year":"1990","journal-title":"Dev Pharmacol Ther."},{"issue":"11","key":"2021010701305684000_bib17","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1093\/trstmh\/try006","article-title":"Is drug-induced hepatitis related to the severity of tuberculous meningitis?","volume":"111","author":"Kumar","year":"2017","journal-title":"Trans R Soc Trop Med Hyg."},{"key":"2021010701305684000_bib18","doi-asserted-by":"crossref","first-page":"116825","DOI":"10.1016\/j.jns.2020.116825","article-title":"Oxidative stress and ER stress may contribute to drug-induced hepatitis in tuberculous meningitis","volume":"414","author":"Misra","year":"2020","journal-title":"J Neurol Sci"},{"issue":"17","key":"2021010701305684000_bib19","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1056\/NEJMoa040573","article-title":"Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults","volume":"351","author":"Thwaites","year":"2004","journal-title":"N Engl J Med."},{"issue":"11","key":"2021010701305684000_bib20","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S1473-3099(10)70138-9","article-title":"Tuberculous meningitis: a uniform case definition for use in clinical research","volume":"10","author":"Marais","year":"2010","journal-title":"Lancet Infect Dis."},{"issue":"6503","key":"2021010701305684000_bib21","first-page":"582","article-title":"Streptomycin treatment of tuberculous meningitis","volume":"251","author":"British Medical Research Council","year":"1948","journal-title":"Lancet."},{"issue":"7","key":"2021010701305684000_bib22","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1136\/thx.53.7.536","article-title":"Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998","volume":"53","author":"Joint Tuberculosis Committee of the British Thoracic Society","year":"1998","journal-title":"Thorax"},{"issue":"6","key":"2021010701305684000_bib23","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1086\/650576","article-title":"Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity","volume":"50","author":"Sharma","year":"2010","journal-title":"Clin Infect Dis."},{"key":"2021010701305684000_bib24","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1136\/thx.51.2.132","article-title":"Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study","volume":"51","author":"Pande","year":"1996","journal-title":"Thorax."},{"key":"2021010701305684000_bib25","doi-asserted-by":"crossref","DOI":"10.1002\/0471445428","volume-title":"Statistical Methods for Rates and Proportions","author":"Fleiss","year":"2003"},{"issue":"1","key":"2021010701305684000_bib26","first-page":"65","article-title":"The management of anti-tuberculosis drug induced hepatotoxicity","volume":"5","author":"Tahaoglu","year":"2001","journal-title":"Int J Tuberc Lung Dis."},{"issue":"7","key":"2021010701305684000_bib27","doi-asserted-by":"crossref","first-page":"3244","DOI":"10.1128\/AAC.00064-11","article-title":"Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis","volume":"55","author":"Thwaites","year":"2011","journal-title":"Antimicrob Agents Chemother."},{"issue":"1","key":"2021010701305684000_bib28","first-page":"23","article-title":"Chemotherapy induced hepatitis intuberculous meningitis: a prospective study of 54 cases","volume":"3","author":"Tripathi","year":"2000","journal-title":"Ann Indian Acad Neurol."},{"issue":"11","key":"2021010701305684000_bib29","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.5588\/ijtld.20.0036","article-title":"Complications of tuberculous meningitis and their effect on outcome in a tertiary care cohort","volume":"24","author":"Misra","year":"2020","journal-title":"Int J Tuberc Lung Dis."},{"key":"2021010701305684000_bib30","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.eplepsyres.2018.10.005","article-title":"Seizures in tuberculous meningitis","volume":"148","author":"Misra","year":"2018","journal-title":"Epilepsy Res"},{"issue":"4","key":"2021010701305684000_bib31","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.tmaid.2013.04.001","article-title":"The Jarisch-Herxheimer reaction: revisited","volume":"11","author":"Belum","year":"2013","journal-title":"Travel Med Infect Dis."},{"issue":"1","key":"2021010701305684000_bib32","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3109\/00365549509018969","article-title":"Treatment of louse-borne relapsing fever with low dose penicillin or tetracycline: a clinical trial","volume":"27","author":"Seboxa","year":"1995","journal-title":"Scand J Infect Dis."},{"issue":"6","key":"2021010701305684000_bib33","doi-asserted-by":"crossref","first-page":"447","DOI":"10.7326\/0003-4819-133-6-200009190-00013","article-title":"Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy","volume":"133","author":"DeSimone","year":"2000","journal-title":"Ann Intern Med."},{"issue":"4","key":"2021010701305684000_bib34","doi-asserted-by":"crossref","first-page":"486","DOI":"10.5588\/ijtld.13.0556","article-title":"Predictors of paradoxical tuberculoma in tuberculous meningitis","volume":"18","author":"Kalita","year":"2014","journal-title":"Int J Tuberc Lung Dis."}],"container-title":["Transactions of The Royal Society of Tropical Medicine and Hygiene"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/trstmh\/article-pdf\/115\/1\/94\/35483329\/traa144.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/trstmh\/article-pdf\/115\/1\/94\/35483329\/traa144.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T19:42:07Z","timestamp":1610480527000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/trstmh\/article\/115\/1\/94\/6006355"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,25]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,11,25]]},"published-print":{"date-parts":[[2021,1,7]]}},"URL":"https:\/\/doi.org\/10.1093\/trstmh\/traa144","relation":{},"ISSN":["0035-9203","1878-3503"],"issn-type":[{"value":"0035-9203","type":"print"},{"value":"1878-3503","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,1]]},"published":{"date-parts":[[2020,11,25]]}}}