Tuberculous Meningitis, diagnosis and treatment Ahmad RizalDepartment of NeurologyHasan Sadikin Hospital Bandung

TBM, introductionThe most severe extrapulmonary TBDiagnosis remains difficultEarly recognition is crucial for better outcomeHigh mortality rate; sequalae in survivorsOptimal treatment has not been establishedHIV increases, TBM increases

TBM, historical aspects1836: Six cases of acute hydrocephalus reported in Lancet1882: M. tuberculosis stained and cultured (Koch)1933: Pathological features (Rich & McCordock)2009: too many questions, too few answers, still

TBM, clinical featuresFever (60 95%)Anorexia (60 80%)Headache (50 80%)Nuchal rigidity (60 80%)Coma (30 60%)Vomiting (30 60%)Thwaites & Hien, TLID, 200592.5%

82.5%90%

E. Torok, ASNA Meeting, March 2007

TBM, clinical featuresCranial nerve palsies (30 50%)Hemiparesis (10 20%)Paraparesis (5 10%)Seizure (children 50%, adults 5%)Thwaites & Hien, TLID, 200535%21.6%2.5%7.5%

E. Torok, ASNA Meeting, March 2007

TBM, Clinical DiagnosisClinical features not specificTB exposureExtra-meningeal TB50% have abnormal CXR (67% in our study)Miliary TB is considered helpful

TBM, when to suspect (1)To overcome difficulty in making diagnosis:Diagnostic algorithmIndia study: childrenVietnam study: adultsClinical scoring systemDiagnostic categories (definite TBM or not)Using clinical patterns, presence of extraneural TB and CSF abnormalitiesOgawa: 2 categories (definite, probable)Thwaites: 3 categories (definite, probable, possible)

Clinical Scoring System

TBM, when to suspect (2)Diagnostic algorithmsIndia study, 110 children (Kumar et al, 1999)History of illness > 6 days, optic atrophy, focal neuro deficits, abnormal movements, CSF neutrophils < 50%Sensitivity 98%, specificity 98% (if > 3 criteria found)Vietnam study, 143 adults (Thwaites et al, 2002)Age < 36 years, blood WCC < 15,000, history > 6 days, CSF WCC < 760, CSF neutrophils < 75%Sensitivity 86%, specificity 79%Diagnostic categories

TBM, when to suspect (3)Diagnostic algorithms Diagnostic categoriesOgawa (1987)Definite: AFB in CSF (direct staining, culture), and/or AFB is found on autopsyProbable: pleocytosis in CSF, negative culture for bacteria and yeast with 1 of the followings:Positive tuberculin testEvidence of extra-CNS TB, or history of active PTB, or significant exposure to TBCSF glucose < 40 mg/dLCSF protein > 60 mg/dLThwaites (2005)

TBM, when to suspect (4)Diagnostic algorithms Diagnostic categoriesOgawa (1987)Thwaites (2005)Definite TBM: Clinical meningitisandAbnormal CSF parameters and Acid-fast bacilli in CSF (microscopy) and/or culture positive for M. tuberculosis

TBM, when to suspect (5)Diagnostic algorithms Diagnostic categoriesOgawa (1987)Thwaites (2005)Probable TBM: Clinical meningitisandAbnormal CSF parameters and At least 1 of the following: Suspected active pulmonary tuberculosis (chest radiography)AFB found in any sample other than from the CSF

TBM, when to suspect (6)Diagnostic algorithms Diagnostic categoriesThwaites (2005) Possible TBM: Clinical meningitisand Abnormal CSF parametersand At least 4 of the following: History of tuberculosisMN predominance in the CSFIllness of > 5 days in durationCSF:blood glucose ratio < 0.5Altered consciousnessYellow (xanthochromic) CSFFocal neurological signs

TBM, MRC ClassificationGrade IAlert and good orientation without focal neurological deficitGrade IIGCS 10 14 + focal neurological deficitORGCS 15 with focal neurological deficitGrade IIIGCS < 10 with or without focal neurological deficit

TBM, diagnosticsWhat is expectedReliableEasy accessEasy to be done

TBM, diagnostics (2)What we have nowWorldwide:Yield of several techniques: ZN, Ogawa, liquid cultureMeans to increase positivity rate of diagnostic modalitiesOngoing large studies:TBM immunology study (immunol. marker in blood and CSF)Host genetic susceptibility to TBRapid cultureMolecular drug resistance

Indonesia, particularly Bandung

TBM, diagnostics (3)What we have nowWorldwideIndonesia, particularly BandungEfforts to gain more positive result:Ongoing study on clinical, lab. and radiological features (Indonesian setting)Clinical pattern, bacteriological patternOutcome (HIV vs. non-HIV)

TBM, diagnostic pitfallsLow positivity rateVolume of LCS, among others, seems to be the most significant factor in AFB findingThwaites (Vietnam): > 5 mLZainuddin (Bandung): > 7 mL

THE MORE, THE BETTER

TBM, treatmentOptimal TBM treatment has not been established in clinical trialsSame drugDifferent pharmacokineticsVarious guidelinesIntensive phase of 4 drugs (RHZ+S or E or ethionamide)Continuation phase of 2 drugs (RH)Treatment duration 9 12 months

TBM, treatment pitfallsControversy about choice of drugsH and Z good penetrationCSF conc. of R ~ 10% plasma concentrationNeither E nor S penetrates uninflammed meningesIncreasing S resistanceOptimal duration : 6, 9, or 12 months?Drug resistanceMDR-TB

TBM, adjunctive steroidsSteroids reduce case fatality but not morbidityMeta-analysis in children: steroids probably improves survival (Prasad, 2000)Dexamethasone trial in Vietnam (Thwaites et al, 2004)Randomized, double blind, placebo-controlled trial (n=545)Outcome: death or severe neuro sequalae at 9 monthDexamethasone is associated with reduced risk, but not prevent severe neurological disabilityFewer adverse events in dexamethasone group

TBM, adjunctive steroidsLatest Cochrane Review (Prasad, 2008)Helps reduce the risk of death or disabling residual neurological deficitsALL HIV-negative cases of TBM should receive corticosteroidsStill need more trials in HIV-positive

HIV and TBMHIV ~ extrapulmonary TBIncreasing incidence of TBMHIV infection is 1 risk factor of developing TBMTwo chronic meningitis:TBMCryptococcal meningitis

Natural Course of HIV Infection

Co-administration of ART and OATHIV infection significantly complicates the treatment of TBHigh prevalence of drug side effectsHigh risk of drug-drug interactionReduced drug absorptionThe risk of developing IRISOverlap toxicityRecommendation: initiate one line of treatment at a time

Co-administration of ART and OATRecommended guidelineCD4 > 100:ART starts after 2 months of OATCD4 < 100 ART starts earlier (2 weeks is acceptable)

HIV-associated TBMThwaites et al (JID, 2005)96 HIV-infected and 432 HIV-uninfected patientsNo difference in clinical presentationHIV ~ more EPTBNo differences in relapses or adverse eventsHIV reduces survival rates

Survival in HIV-associated TBMThwaites et al, JID, 2005

Meningitis, HIV+ vs HIV-

Factors Associated with 1-month death** p

Factors Associated with 1-month death

Survival curve, HIV+ vs. HIV-daysHIV-positiveHIV-negative

ConclusionClinical meningitis with abnormal CSF pattern, and supporting evidence of extraneural TB significant for diagnosisDiagnostics: Lab! volume is important for positive CSF resultTreatment ~ other EPTB: different PKGive adjunctive corticosteroid

ConclusionInfluence of HIV in the development of TBM anticipated burden to health systemHIV dramatically decreases the survival rate of TBM patientsHigh prevalence of HIV HIV screening to any meningitis caseHigh mortality rate warrants further studies