Review article

Tuberculous meningitis

Introduction

Tuberculous meningitis is a devastating disease ofcentral nervous system. It primarily affects themeninges of brain and spinal cord along withadjacent brain parenchyma. Human immunodefi-ciency virus-infected patients have a high incidenceof tuberculous meningitis. Bacterial and host�sgenetic factors play a crucial role in its pathogen-esis. Early diagnosis is important for the success ofthe treatment (1). Diagnosis often remains prob-lematic despite many significant advances in diag-nostic techniques. The mortality and morbidity oftuberculous meningitis are exceptionally high.Corticosteroids reduce the number of deaths andincrease the survival in adult patients (2). Genepolymorphisms, which appear to influence out-come in patients with tuberculous meningitis, havebeen identified (3). Multidrug-resistant tuberculous

meningitis, which has been reported worldwide, isdifficult to diagnose and treat. This review focuseson the various aspects of tuberculous meningitis.Special emphasis is given to recent developments inthe early detection and treatment of this dreadeddisease. An extensive review of the literature,published in English, was carried out using thePubMed and Google Scholar databases. Thesearch terms those were used included tuberculosis,tuberculous meningitis, meningeal tuberculosis andcentral nervous system tuberculosis.

Epidemiology

Globally, there were an estimated 13.7 millionprevalent cases of tuberculosis in 2007 (206 per100 000 population). During this period, estimated9.27 million new cases of tuberculosis were regis-tered worldwide. Of these 9.27 million new cases of

Acta Neurol Scand 2010: 122: 75–90 DOI: 10.1111/j.1600-0404.2009.01316.x Copyright � 2009 The AuthorJournal compilation � 2009 Blackwell Munksgaard

ACTA NEUROLOGICASCANDINAVICA

Garg RK. Tuberculous meningitis.Acta Neurol Scand: 2010: 122: 75–90.� 2009 The Author Journal compilation � 2009 Blackwell Munksgaard.

Tuberculous meningitis is a severe form of extrapulmonarytuberculosis. The exact incidence and prevalence are not known. Incountries with high burden of pulmonary tuberculosis, the incidence isexpected to be proportionately high. Children are much morevulnerable. Human immunodeficiency virus-infected patients have ahigh incidence of tuberculous meningitis. The hallmark pathologicalprocesses are meningeal inflammation, basal exudates, vasculitis andhydrocephalus. Headache, vomiting, meningeal signs, focal deficits,vision loss, cranial nerve palsies and raised intracranial pressure aredominant clinical features. Diagnosis is based on the characteristicclinical picture, neuroimaging abnormalities and cerebrospinal fluidchanges (increased protein, low glucose and mononuclear cellpleocytosis). Cerebrospinal fluid smear examination, mycobacterialculture or polymerase chain reaction is mandatory for bacteriologicalconfirmation. The mortality and morbidity of tuberculous meningitisare exceptionally high. Prompt diagnosis and early treatment arecrucial. Decision to start antituberculous treatment is often empirical.WHO guidelines recommend a 6 months course of antituberculoustreatment; however, other guidelines recommend a prolongedtreatment extended to 9 or 12 months. Corticosteroids reduce thenumber of deaths. Resistance to antituberculous drugs is associatedwith a high mortality. Patients with hydrocephalus may needventriculo-peritoneal shunting. Bacillus Calmette-Guerin vaccinationprotects to some degree against tuberculous meningitis in children.

R. K. GargDepartment of Neurology, Chhatrapati Shahuji MaharajMedical University, Uttar Pradesh, Lucknow, India

Key words: Bacillus Calmette-Gu�rin vaccination;extrapulmonary tuberculosis; human immunodeficiencyvirus; dexamethasone; Mycobacterium tuberculosis

Dr Ravindra Kumar Garg, Department of Neurology,Chhatrapati Shahuji Maharaj Medical University,Uttar Pradesh, Lucknow – 226003, IndiaTel.: 91 522-4003496Fax: 91 522-2258852e-mail: garg50@yahoo.com

Accepted for publication December 1, 2009

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tuberculosis, an estimated 1.37 million (14%) werehuman immunodeficiency virus-positive. In 2007,approximately 1.3 million deaths (20 per 100 000population) occurred in patients with tuberculosis.The five countries, that have highest number oftuberculosis cases, are India, China, Indonesia,Nigeria and South Africa (4).The exact incidence and prevalence of tubercu-

lous meningitis in the most parts of the world arenot exactly known. Some epidemiological detailsof extra-pulmonary tuberculosis are available fromdeveloped countries. In developed countries,despite an overall decrease in numbers of tubercu-losis cases, the proportion of extra-pulmonarytuberculosis and tuberculous meningitis cases hasincreased. In Germany, 26 302 tuberculosis caseswere registered during 1996–2000. The proportionof patients with extrapulmonary tuberculosis(including tuberculous meningitis) was 21.6%.Extrapulmonary tuberculosis was frequent amongfemales, children aged less than 15 years andpersons migrated from Africa and Asia (5) Theincidence of tuberculous meningitis in France (inthe year 2000) was estimated as 1.55 cases permillion. The incidence rate was 0.7 cases permillion when only culture-positive cases werecounted. Among 143 tuberculous meningitis casesreported to two agencies of France �the Tuber-culosis Mandatory Notification System� and the�National Reference Centre� total number of con-firmed tuberculous meningitis cases were 91. Thenumber of culture-positive meningitis cases wasestimated to be 41 and the number of culture-negative meningitis cases was 50 (6). In UnitedStates, at a large inner-city medical center, duringan 11.5-year period, 34 patients were found to havepositive cerebrospinal fluid cultures for Myco-bacterium tuberculosis, accounting for 1.5% ofculture-confirmed tuberculosis cases. All patientswere born in the United States, 31 (91%) wereblack people and 16 (47%) were human immuno-deficiency virus-infected patients (7). In poor anddeveloping countries with very high burden ofpulmonary tuberculosis, the incidence of tuber-culous meningitis is expected to be proportionatelyhigh.The natural history and clinical manifestations

of tuberculosis in children are different as com-pared with that of adults. Neonates have thehighest risk of progression to severe forms oftuberculosis. Mortality is highest in early child-hood because of a high incidence of disseminatedforms of tuberculosis in this population (8). In astudy from South Africa, the incidence rate oftuberculous meningitis, in children, was observedto be age specific. The incidence in neonates was

31.5 per 100 000 as compared with 0.7 per 100 000among older children (10–14 years) (9). Anotherstudy from South Africa observed that in humanimmunodeficiency virus-infected children dissemi-nated tuberculosis was significantly more common(6 ⁄25) as compared with human immunodeficiencyvirus-negative children (12 ⁄414). In children with-out human immunodeficiency virus infectiondisseminated (miliary) disease (9 ⁄11) and tubercu-lous meningitis (10 ⁄13) were predominantly seen inthose who were less than 3 years of age (10).Tuberculosis, in human immunodeficiency virus-

infected patients, progresses to severe forms oftuberculosis at a rate five times greater than thatfor people not infected with human immuno-deficiency virus (11). In a study, of 2205 patientswith all types of tuberculosis, 455 (21%) patientswere human immunodeficiency virus-infected. Inthis study, 45 patients had culture-positive tuber-culous meningitis. It was observed that of the 1750patients without human immunodeficiency virusinfection only 2% had tuberculous meningitis, ascompared with 10% of the human immuno-deficiency virus-infected patients. The majority ofhuman immunodeficiency virus-infected patientswith culture-positive tuberculous meningitis hadclinical or radiologic evidence of extra-meningealtuberculosis as well (12).

Multidrug-resistant tuberculous meningitis

In 2007, there were an estimated 0.5 million casesof multidrug-resistant tuberculosis worldwide (4).Drug resistance is more common in human immu-nodeficiency virus-positive patients. Under optimaltreatment conditions, the cure rate of multidrug-resistant pulmonary tuberculosis is approximately70–90%, but the cure rate averages to 50% indiverse clinical conditions (13). The problem ofmultidrug-resistant tuberculosis has also beenidentified in patients with tuberculous meningitis.Multidrug-resistant tuberculous meningitis is oftenassociated with poor prognosis (13). In a center ofSouth Africa, during the period of 1999–2002, 350patients with tuberculous meningitis were identi-fied by cerebrospinal fluid culture. In this group, 30patients (8.6%) had tuberculous meningitis thatwas resistant to at least isoniazid and rifampicin.The majority of multidrug-resistant tuberculousmeningitis cases either died or experienced signif-icant morbidity. Eighteen of multidrug-resistanttuberculous meningitis patients were human immu-nodeficiency virus-positive (14). In a Vietnamesestudy, Mycobacterium tuberculosis isolates fromthe cerebrospinal fluid of 198 adults were com-pared with 237 isolates from patients with pulmo-

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nary tuberculosis. It was observed that drugresistance rates were lower in the isolates fromcerebrospinal fluid (2.5% multidrug resistance)than pulmonary isolates (5.9% multidrug resis-tance) (15). Fortunately, multidrug-resistant tuber-culous meningitis is still not a serious problem insome of the endemic countries. In a study fromIndia, a total of 366 isolates were analyzed formultidrug-resistant tuberculous meningitis. Amongthese, 301 (82.2%) were sensitive to all fourprimary drugs tested, whereas 65 (17.8%) showedresistance. There were 46 (12.5%) isolates resistantto isoniazid, whereas only nine isolates (2.4%)demonstrated multidrug resistance (16).

Etiology

Tuberculous meningitis is caused by bacteriaMycobacterium tuberculosis. Mycobacterium tuber-culosis is a gram-positive, aerobic, non-spore-forming, non-motile, pleomorphic rod that isdistantly related to the Actinomycetes. Myco-bacterium tuberculosis is an acid-fast bacterium.One of the most widely used acid-fast stainingmethod for Mycobacterium tuberculosis is theZiehl-Neelsen stain. Lowenstein-Jensen medium ismost popular and widely available culture mediumto grow Mycobacterium tuberculosis.

Pathogenesis

Predisposing factors for the development of tuber-culous meningitis, like for any other forms oftuberculosis, include poverty, overcrowding, illit-eracy, malnutrition, alcoholism, substance abuse,diabetes mellitus, immunosuppressive treatment,malignancy, head trauma and human immunode-ficiency virus infection (17). Transmission of bac-teria Mycobacterium tuberculosis to a healthyperson is primarily by airborne droplet nuclei. Inthe lungs, Mycobacterium tuberculosis bacteriamultiply in alveolar macrophages. Within 2–4weeks, through blood circulation, bacilli spread toextrapulmonary sites and produce small granulo-mas in the meninges and adjacent brain paren-chyma. These small granulomas are known as �Richfocus�. These lesions are usually present in themeninges and on the subpial or subependymalsurface of the brain. Rich foci remain dormant foryears. Tuberculous meningitis develops when acaseating Rich focus discharges its contents intothe subarachnoid space. Decreased immunity isbelieved to play a role, however, the exact trigger forthe rupture of Rich foci is not known (17–19).Several reports suggest that, in children, miliarytuberculosis is directly involved in the pathogenesis

of tuberculous meningitis. The bacillaemia thataccompanies miliary dissemination increase thelikelihood that a meningeal or sub-cortical tubercu-lous focus will be formed, which may eventuallycaseate and give rise to tuberculous meningitis (19,20). The bacilli enter the central nervous system bytraversing the blood–brain barrier.

Pathogen factors

Some strains of Mycobacterium tuberculosis areconsidered more virulent and capable of causingdisseminated and meningeal forms of tuberculosisthan others. For example, Beijing strain of Myco-bacterium tuberculosis (highly prevalent in Asiaand in the countries of the former Soviet Union) isstrongly associated with tuberculous meningitis;however, the tuberculosis caused by the Euro-American strain (the most prevalent strain inEurope and the Americas) is more likely to bepulmonary rather meningeal (21). In addition,these two different genotypes of Mycobacteriumtuberculosis may manifest with variable clinicalmanifestations in the host. For example, meningitiscaused by the East Asian ⁄Beijing genotype wasassociated with a shorter duration of illness andpresence of lesser number of leukocytes in cere-brospinal fluid. The East Asian ⁄Beijing genotypewas strongly associated with drug-resistant tuber-culosis and a high incidence of human immuno-deficiency virus co-infection. It was suggested thatthe association between the East Asian ⁄Beijingstrain and disease progression and cerebrospinalfluid leukocyte count might influence protectiveinflammatory responses of the brain (22, 23).

Host factors

Mycobacterium tuberculosis is an intracellularpathogen that survives within the phagosome ofhost macrophages. Apoptosis of infected macro-phages is an effective host�s mechanism againsttuberculous bacilli. Virulent strains of Mycobacte-rium tuberculosis have evolved several geneticmechanisms to subvert host immune responses,leading to their prolonged survival and growth inthe host�s macrophages (24, 25). The mechanismsby which Mycobacterium tuberculosis manipulatesthe host immune system are attributed to lipoara-binomannans and their precursor lipomannans.These two are important glycolipids of Mycobac-terium tuberculosis cell wall. Lipoarabinomannan isinvolved in the inhibition of phagosome matura-tion, apoptosis, interferon-gamma signaling inmacrophages and interleukin-12 cytokine secretionof dendritic cells. It has been observed that lipid

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fractions from the virulent Beijing strain inducemacrophages to secrete large amounts of tumornecrosis factor-alpha and interleukin-10, butdownregulate toll-like receptor-2, toll-like recep-tor-4 and major histocompatibility complex class IIexpression. In contrast, lipids from Mycobacteriumtuberculosis Canetti (a less virulent strain) do notproduce these inflammatory changes (26).Several genetic abnormalities increase the host�s

susceptibility to Mycobacterium tuberculosis (27,28). A group of authors identified polymorphismsin the P2X7 receptor (an ATP-gated Ca2+ chan-nel) gene. Normally, activation of the P2X7receptor leads to the induction of apoptosis anddeath of the infecting mycobacteria. Macrophagesfrom subjects who have these polymorphisms failto undergo macrophage apoptosis and show defectin mycobacterial killing (27). Another recentinvestigation revealed that single nucleotide poly-morphisms in toll-interleukin-1 receptor domaincontaining adaptor protein gene were morestrongly associated with the risk of meningealtuberculosis (29). Presence of toll-like receptor-2gene polymorphisms has been shown to increasethe host�s susceptibility to severe forms of tuber-culosis like miliary tuberculosis and tuberculousmeningitis (30). Single nucleotide polymorphisms,located at these genes, are thought to influencecytokine levels and regulate resistance and suscep-tibility of an individual to tuberculosis (21). Poly-morphisms in interferon-gamma gene have alsobeen associated to individual�s susceptibility totuberculous infection (31).

Immunopathogenesis

Once mycobacteria enter in the central nervoussystem, macrophages recognize them and appro-priate innate and adaptive immune responses areinitiated. Subsequent immunopathogenesis mayresult in impairment of the blood–brain barrier,development of cerebral edema and increasedintracranial pressure. The elevated level of tumornecrosis factor-alpha produced during mycobacte-rial infection is an important element in theimmunopathogenesis (32). Microglial cells (theresident macrophages of the brain) are the princi-pal cells producing immunological chemicalsagainst tubercle bacilli. Several studies haveshown that microglia produce a variety of chemo-kines that act to initiate or promote inflammatoryresponses in the central nervous system throughfacilitating the recruitment of peripheral immunecells into the brain parenchyma (33, 34). Theelevated levels of serum and cerebrospinal fluidtumor necrosis factor-alpha and interferon-gamma

have a positive correlation with the severity of thetuberculous meningitis (35). Human immunodefi-ciency virus co-infection with tuberculous menin-gitis has been shown to attenuate cerebrospinalfluid inflammatory changes. Low cerebrospinalfluid interferon-gamma concentration was inde-pendently associated with death, suggesting thatinterferon-gamma contributes to host�s immunityand survival (36).

Animal models

Animal models have played an important role inthe understanding of pathogenesis of tuberculousmeningitis. Currently, the rabbit is being used as amodel of human tuberculosis because of its closeresemblance to human tuberculosis. In 1998,the rabbit model of tuberculous meningitis wasprepared by introducing a virulent strain ofMycobacterium bovis by intracranial route.Authors observed acute inflammatory changes inthe cerebrospinal fluid. Histologically, severe men-ingitis with thickening of the leptomeninges, prom-inent vasculitis and encephalitis was apparent byday 8 (37). Recently, a murine model has beendeveloped to study the pathogenesis of tuberculousmeningitis. Mice were intracerebrally injected withMycobacterium tuberculosis. Later on bacilli couldbe cultured from brain homogenates (38). In themurine model, authors identified central nervoussystem-specific Mycobacterium tuberculosis genesthat play an important role in the pathogenesis ofcentral nervous system tuberculosis (39).

Pathology

The tuberculous meningitis has a strong propensityto affect the basal parts of the brain. Pathologicchanges diffusely affect the arachnoid membraneand subarachnoid space. The hallmark pathologicfeatures are meningeal inflammation, fibrogelati-nous basal exudates, vasculitis of the arteriestraversing the exudates and obstruction of flow ofcerebrospinal fluid resulting in hydrocephalus. Thebrain tissue underlying the tuberculous exudatesshows varied degrees of edema, perivascular infil-tration and a microglial reaction collectivelytermed as ‘border zone encephalitis�. Microscopicpathological feature of tuberculous meningitis isformation of epithelioid cell granulomas withLanghans giant cells, lymphocytic infiltrates andcaseous necrosis. Exudates are prominently presentaround sylvian fissure, basal cisterns, brainstemand cerebellum. The optic chiasma and the roots ofother cranial nerves arising from the ventral aspectof the brainstem are usually entrapped in thick

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exudates. Exudates can be seen surrounding thelower part of spinal cord and cauda equinaresulting in tuberculous rediculomyelopathy.Changes in cerebral vessels are characterized byinflammation, spasms, constriction and eventuallythrombosis of cerebral vessels. Occlusion of cere-bral arteries leads to infarction of the underlyingtissue. The meningeal veins passing through theinflammatory exudate show varying degree ofphlebitis. Obstruction to the flow of cerebrospinalfluid occurs in the posterior fossa, as thick exudateblocks the openings of fourth ventricles, at sylvianaqueduct or at the opening of the tentorium. As aconsequence, hydrocephalus develops. Infre-quently, tuberculous meningitis may results information of tuberculoma consisting of caseousnecrotic material, epithelioid cell granuloma andmononuclear cell infiltration (17, 40).

Clinical features

Typically, tuberculous meningitis is preceded bya variable period of non-specific symptoms.Common non-specific symptoms include malaise,anorexia, fatigue, weight loss, fever, myalgia andheadache. At first consultation, most of thepatients are already in the advanced stages of thedisease (41). Fever, headache, vomiting, alterationin sensorium and nuchal rigidity are the mostfrequent presenting manifestations. Cranial nervepalsies, vision loss, focal neurological deficits andsigns of raised intracranial pressure are common inadvanced stages. In a series of 101 adult patients,frequent presenting neurologic features includedheadache (96.0%), fever (91.1%), nuchal rigidity(91.1%), vomiting (81.2%), meningism (79.2%)and abnormal mental state (72.3%). In this series,the mean duration of the symptoms before admis-sion was 12 days (42). Atypical clinical features inelderly often lead to a delayed diagnosis. In elderly,meningeal signs are less frequently present. In astudy conducted on 53 adults patients (over of50 years), the major clinical presentations were:fever (81%), headache (47%), vomiting (34%),neck rigidity (51%), altered sensorium (64%),seizures (28%) and focal neurological deficits(24%) (43). Tuberculous meningitis in elderlypatients may present as a subacute dementia withmemory deficits and personality changes typical offrontal lobe-like disease. In pediatric patientscoma, raised intracranial pressure, seizures andfocal neurological deficits dominate the clinicalmanifestations. Generalized tonic and clonic sei-zures are the commonest type of seizures followedby focal seizures and tonic spasms (44). Hyponat-remia in patients with tuberculous meningitis is a

common metabolic abnormality. Hyponatremia isoften caused by repeated vomiting and cerebral saltwasting syndrome. The advanced stages of tuber-culous meningitis are marked by deep coma,hemiplegia or paraplegia, decerebrate posturing,deterioration in vital signs, and, eventually, death.Cranial nerve palsies are seen in approximately

25% of cases. The sixth cranial nerve is mostcommonly affected cranial nerve. Third and fourthcranial nerves are less frequently involved. Cranialnerves are affected either because of entrapment ofnerve trunk in thick basilar exudates or because ofincreased intracranial pressure (45, 46). Vision lossis a devastating complication of tuberculous men-ingitis. There several possible reasons for opticnerve involvement like optochiasmatic arachnoid-itis, third ventricular compression of optic chiasmain patients with a large hydrocephalus, optic nervegranulomas or ethambutol toxicity (47). Opto-chiasmatic tuberculoma is a rare cause of progres-sive visual failure in tuberculous meningitis.Magnetic resonance imaging in optochiasmatictuberculoma demonstrates ring enhancing lesionsin optic chiasma and brainstem (48). Papilledema isan unusual feature of tuberculous meningitis.In tuberculous meningitis, several types of

movement disorders like chorea, hemiballismus,athetosis, generalized tremors, myoclonic jerks andataxia have been described. Movement disordersare more common in children than in adults. Onimaging, deep periventricular vascular lesions arefrequently present (49).Paraplegia frequently complicates tuberculous

meningitis. Paraplegia is either caused by tubercu-lous radiculomyelitis or intramedullary tuberculo-mas. Tuberculous radiculomyelopathy is characterized by the subacute paraparesis. Other mani-festations of tuberculous radiculomyelopathyincluderootpain,paraesthesias,bladderdisturbanceand muscle wasting. Muscle wasting is a late mani-festation. In the lower limbs, there is hypotonia anddeeptendonreflexesareusuallyabsent.Theremaybeextensor plantar response. In most of the patients,cerebrospinal fluid examination often reveals a veryhigh protein content (probably as a consequence ofspinal block) (50, 51). Other possible causes ofparaplegia are an intradural, extramedullary spinalcord tuberculoma or intramedullary spinal syringo-myelic cavities.Infarcts are common in patients with tubercu-

lous meningitis (52). Infarcts are frequently locatedat internal capsule, basal ganglion and thalamicregions. Infarcts are much more common in theareas supplied by medial striate and thalamoper-forating arteries. The regions supplied by lateralstriate, anterior choroidal and thalamogeniculate

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arteries are less frequently affected. Infracts caneither be asymptomatic or symptomatic. Symp-tomatic strokes in tuberculous meningitis presentwith dense hemiplegia (53, 54). In children, infarctsof basal ganglia and internal capsule were associ-ated with a poor outcome. Purely hemisphericinfarcts were associated with good prognosis (55).Choroidal tubercles are infrequent fundoscopic

finding in patients with tuberculous meningitis.These lesions are considered virtually pathogno-monic of tuberculous meningitis. Choroidal tuber-cles are often associated with miliary tuberculosis(56). On fundoscopic examination, choroidaltubercles are white, gray or yellow lesions andhave indistinct borders with surrounding edema.Their size varies from about 0.5 to 3 mm indiameter (57) (Fig. S1). Histopathologically, cho-roidal tubercles represent caseating granulomas.Tubercle bacilli have also been demonstratedwithin the choroidal tubercles (58).

Diagnosis

Cerebrospinal fluid examination

Cerebrospinal fluid examination is crucial for theconfirmation of the diagnosis. Characteristic cere-brospinal fluid changes help in differentiating fromother causes of chronic meningitis. Typical cere-brospinal fluid changes are mononuclear cellpleocytosis, low glucose levels and elevated proteinlevels (Table 1). However, the �gold standard� fordiagnosis is demonstration of Mycobacteriumtuberculosis bacilli in the cerebrospinal fluid(Table 2). Unfortunately, smear for acid-fast bacil-lus is positive only in 5–30% of patients. Culture ofMycobacterium tuberculosis from cerebrospinalfluid is also not always positive and it takes severalweeks for a positive result. Conventional cerebro-spinal fluid culture on Lowenstein-Jensen mediumis positive in approximately 45–90% of cases. Inhuman immunodeficiency virus-associated tuber-culous meningitis 69% positivity for smear and

87.9% positivity for bacterial culture have beendemonstrated (59). To increase the yield of smearexamination at least 6 ml of cerebrospinal fluid iscollected and smear is examined for at least 30 min(60). Cerebrospinal fluid sediments should alwaysbe subjected for smear examination.Several liquid culture systems have been evalu-

ated extensively in tuberculous meningitis andseem to provide comparable results to the solidmedia-based tests with the advantage of rapidresults. MB ⁄BacTMycobacterium detection systemis a fully automated and non-radiometric systemthat utilizes a bottle containing a colorimetricsensor embedded in its bottom. Carbon dioxideproduced by microbial metabolism causes reduc-tion in pH of medium and changes the sensor colorfrom dark green to yellow. The color change iscontinuously monitored and promptly reported bythe instrument (61). Microscopic observation drugsusceptibility assay is an also newer technique forthe cheap, rapid identification of drug-resistantMycobacterium tuberculosis in patients with tuber-culous meningitis (62).The detection of Mycobacterium tuberculosis

DNA in cerebrospinal fluid samples using poly-merase chain reaction is widely used diagnosticmethod (63, 64). A meta-analysis found the sensi-tivity of commercial nucleic acid amplification teststo be only 56%; however, the specificity was ashigh as 98%. Sensitivity of polymerase chainreaction testing is higher in culture-positivepatients (65). A proper selection of Mycobacteriumtuberculosis-specific DNA and a caution againstcontamination of cerebrospinal fluid specimens areimportant for obtaining high specificity. A recentstudy observed that cerebrospinal fluid �filtrates�contain a substantial amount of Mycobacteriumtuberculosis DNA. Authors suggests that the�filtrates� and not �sediments� are likely to reliablyprovide a polymerase chain reaction-based diag-nosis (66). A current review suggests that nucleic

Table 1 Cerebrospinal fluid diagnostic tests

Cerebrospinal fluid studies

Color Clear or xanthochromic*Cerebrospinal fluid pressure ElevatedGlucose levels <400 mg ⁄ l (<2.22 mmol ⁄ l)�

Protein levels 0.8–5 g ⁄ lCell contents 100–500 cells ⁄ ll (0.10 to 0.50 · 109 ⁄ l)

Predominance of lymphocytes

*In the presence of subarachnoid block.�Cerebrospinal fluid and blood glucose ratio < 0.5.

Table 2 Other diagnostic tests used for the diagnosis of tuberculous meningitis

Currently available diagnostic testsCerebrospinal fluid smear examinationCulture of Mycobacterium tuberculosisPolymerase chain reactionEnzyme-linked immunosorbent assayMicroscopic observation drug susceptibility assayMycobacterial growth indicator tubeDot enzyme-linked immunosorbent method

Newly devised methodsEx vivo Mycobacterium tuberculosis-specific enzyme-linked immunospot assay(ELISpot assay)Anti-Bacillus Calmette-Gu�rin antibody-secreting cell detectionAdenosine deaminase assaysGen-Probe amplified Mycobacterium tuberculosis direct test

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acid amplification tests cannot replace conven-tional tests such as microscopy, culture and biopsy.Results of nucleic acid amplification tests should beinterpreted in conjunction with conventional testsand clinical data (67).In several studies, the results of smear, culture

and polymerase chain reaction were compared (63,68, 69). In one such study, 105 cerebrospinal fluidspecimens (from clinically suspected cases oftuberculous meningitis) were subjected to variousdiagnostic tests. Polymerase chain reaction test waspositive in 31.42% of specimens, whereas byconventional culture 3.8% specimens providedbacteriological confirmation. Only 2% specimenswere smear-positive by the fluorochrome stainingmethod. None was positive by the Ziehl-Neelsenstaining method (68). In the similar study (in 57samples) from India, the sensitivity of cerebrospi-nal fluid microscopy, culture, computed tomogra-phy and polymerase chain reaction was only 3.3%,26.7%, 60.0% and 66.7%, respectively (63). It wasobserved that the yields of all these diagnostic testswere much better when a combination of tests wereperformed on serial samples (69).Demonstration of tuberculous bacilli in cerebro-

spinal fluid still remains a great diagnostic chal-lenge. In response to this challenge, several newerdiagnostic tests have been devised. Among newlydevised methods, the ex vivo Mycobacterium tuber-culosis-specific enzyme-linked immunospot assay(ELISpot assay) is a novel assay for the rapiddetection of Mycobacterium tuberculosis-specificT-lymphocytes. In an initial study, the ELISpotassay detectedMycobacterium tuberculosis antigen-specific interferon-gamma secreting T-cells in

cerebrospinal fluid from nine of 10 prospectivelyrecruited patients with tuberculous meningitis (70).Later on, the sensitivity of ELISpot assay wasfound to vary in patients with different forms oftuberculosis, with highest sensitivity in patientswith sputum positive pulmonary tuberculosis(89.89%) and lowest in tuberculous meningitis(62.5%) (71). Anti-Bacillus Calmette-Guerin anti-body-secreting cell detection in cerebrospinal fluidby an enzyme-linked immunospot assay was foundvaluable because of its high degree of sensitivity.The number of cerebrospinal fluid anti-BacillusCalmette-Guerin antibody-secreting cells washigher in the early phase of tuberculous meningitisand then gradually declined, suggesting that thisassay was particularly effective for the early diag-nosis of tuberculous meningitis (72). At present,these immunological tests are not recommended forroutine diagnosis of tuberculous meningitis becauseno proper evaluation of these tests exists.

Neuroimaging

Both computed tomography and magnetic reso-nance are valuable in tuberculous meningitis forthe diagnosis and evaluation of complications. Thecharacteristic computed tomographic changesinclude basal enhancement, presence of exudates,hydrocephalus and periventricular infarcts (Fig. 1).Basal meningeal enhancement and hydrocephalusare the most frequent imaging abnormalities.Hyperdensity in the basal cisterns on non-contrastcomputed tomography has been considered asensitive and specific imaging sign (73). A reviewof computed tomographic findings of 289 patients

A B

Figure 1. Contrast enhanced computed tomography showing (A, B) thick basal exudates, meningeal enhancement and ventriculardilatation in adult patients with tuberculous meningitis.

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revealed that in 35 patients computed tomographywas normal. Remaining 254 patients had someabnormality. Common abnormalities were hydro-cephalus (204 patients), parenchymal enhancement(62 patients), contrast enhancement of basal cis-terns (49 patients), cerebral infarct and focal ordiffuse brain edema (39 patients), and tuberculoma(14 patients) (74). Presence of hydrocephalus wasshown to be associated with a higher risk of strokeand poor prognosis (75). Follow-up imaging maybe valuable as it may demonstrate some newfeature that is not initially present (like hydro-cephalus and infarcts) (76).Magnetic resonance imaging is considered more

sensitive imaging modality in tuberculous menin-gitis (77). A gadolinium-enhanced study can detectmeningeal enhancement early in course of illness.On magnetic resonance imaging focal meningealenhancement is much more frequently encounteredthan diffuse meningeal enhancement. Basal pialareas, particularly the interpeduncular fossa, werenoted as the most preferred site of focal meningealenhancement (78) (Fig. 2).Chest radiography may be abnormal in substan-

tial number of patients with tuberculous menin-gitis. In one study, chest roentgenography demonstrated abnormal findings in 43% (32 ⁄74) cases.Hilar adenopathy, miliary pattern, bronchopneu-monic infiltrate were most frequent abnormalities.Chest computed tomography was more sensitive(68 ⁄74) in detecting chest abnormalities. Mediasti-nal and hilar lymphadenopathy, miliary patternand bronchopneumonic infiltrate were the most

frequent computed tomographic findings (79).Presence of tuberculosis elsewhere often helps inmaking diagnosis of tuberculous meningitis.

Differential diagnosis

A variety of infective, inflammatory, neoplasticand vascular diseases need to be considered in thedifferential diagnosis of tuberculous meningitis.Differential diagnosis from partially treated bacte-rial meningitis is frequently difficult (80). Sixfeatures (duration of illness more than 5 days,presence of headache and cerebrospinal fluid whiteblood cell count of <1000 per mm3, clear appear-ance, lymphocyte count >30% and protein con-tent of >100 mg ⁄dl) favor tuberculous meningitis(81). Several inflammatory or autoimmune diseases(like Wegener granulomatosis, sarcoidosis, Behcetdisease, Vogt-Koyanagi-Harada syndrome andacute posterior multifocal placoid pigment epithe-liopathy), in addition to meningeal inflammation,often cause inflammation of several other bodyorgans.In human immunodeficiency virus-infected

patients, cryptococcal meningitis is the mostimportant differential diagnosis of tuberculousmeningitis. In cryptococcal meningitis, headacheis often the most dominant and sometimes may bethe sole manifestation. In cryptococcal meningitis,meningeal signs may not be demonstrable. Neuro-imaging studies are often normal. India ink prepa-ration of cerebrospinal fluid is diagnostic. This testdemonstrates presence of fungal elements in the

A B C

Figure 2. (A) Gadolinium-enhanced cranial magnetic resonance imaging showing thick basilar exudates in pontine region,multiple small tuberculoma ventricular dilatation; (B) T2-weighted magnetic resonance image showing in right basal ganglion andthalamus; (C) gadolinium-enhanced cranial magnetic resonance imaging showing multiple tuberculoma in a patient with tuberculousmeningitis.

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cerebrospinal fluid. Patients with toxoplasmosis canalso present with diffuse meningoencephalitis.If the cerebrospinal fluid glucose concentration

is very low, then possibility of neoplastic meningitis(metastasis, lymphoma, leukemia) should alwaysbe considered. Neoplastic meningitis occurs inapproximately 5% of all patients with cancer.Primary diffuse leptomeningeal gliomatosis is arare condition whereby a glioma arises fromheterotopic cell nests in the leptomeninges andproduces a clinical picture similar to chronicinfective meningitis. A meticulous cytologic anal-ysis of cerebrospinal fluid, neuroimaging of brainand spine, and an appropriate clinical setting arethe key factors which help in the diagnosis ofneoplastic meningitis (82, 83).

Tuberculous meningitis and human immunodeficiencyvirus

There is an increased incidence of tuberculousmeningitis in human immunodeficiency virus-infected persons. In several studies, it has beendocumented that human immunodeficiency virusdoes not significantly alter the clinical manifesta-tions, laboratory, or radiographic findings or theresponse to therapy (12, 84). However, somestudies, on the contrary, suggest that differencesexist between immunodeficiency virus-infected andimmunodeficiency virus-negative patients of tuber-culous meningitis. For example, it was observedthat a higher number of immunodeficiency virus-infected patients had evidence of active tuberculo-sis on chest radiography. The classic computedtomographic signs of tuberculous meningitis(obstructive hydrocephalus and basal enhance-ment) were significantly less prominent (85). Intra-cerebral mass lesions were more common (60% vs14% in the non-immunodeficiency virus-infectedgroup) (86). A high frequency of non-inflammatorycerebrospinal fluid (absence of pleocytosis) and ofinfection by multidrug-resistant strains of Myco-bacterium tuberculosis have been reported (87). Inan earlier study, authors observed neutrophilpredominance, high smear and culture positivity,and high antituberculous drug resistance in cere-brospinal fluid of human immunodeficiency virus-infected patients of tuberculous meningtis (59).These patients have a higher mortality rate (88).

Treatment

In patients with tuberculous meningitis antituber-culous treatment should be started as quickly aspossible. Antimicrobial therapy often needs to beinstituted empirically, much before a bacteriological

diagnosis is established. Treatment is started withfirst-line antituberculous drugs which include isoni-azid, rifampicin, pyrazinamide, streptomycin andethambutol. The second-line antituberculous drugs(ethionamide, cycloserine, para-aminosalicylic acid,aminoglycosides, capreomycin and thiacetazone)are kept in reserve. Fluoroquinolones (levofloxacin,gatifloxacin and moxifloxacin) are antimicrobialagents which are used for the treatment of drug-resistant tuberculosis. Substitution of older fluoro-quinolones, especially ciprofloxacin, into a regimenmeant for treating drug-resistant tuberculosisresulted in a higher rate of relapse (89, 90).Most of the first-line antituberculous drugs

(except ethambutol) penetrate satisfactorily in tothe cerebrospinal fluid. In a study, the cerebrospi-nal fluid concentrations of isoniazid and pyrazin-amide were well above the minimum inhibitoryconcentrations. Concentrations of rifampin andstreptomycin, 3 h after administration, were abovethe minimal inhibitory concentration but declinedlater. Corticosteroids had no effect on cerebrospi-nal fluid penetration of antituberculous drugs (91).

Antituberculous treatment regimens

World Health Organization recommends a cate-gory-based treatment for tuberculosis.Tuberculous meningitis falls under category-1 of

World Health Organization treatment category.For the patients of category-I, antituberculosistreatment regimen is divided into two phases: anintensive (initial) phase and a continuation phase.In intensive phase, antituberculous therapy regi-men includes a combination of four-first-linedrugs: isoniazid, rifampicin, streptomycin andpyrazinamide. The intensive phase continues for2 months. In continuation phase, two drug regi-men (isoniazid and rifampicin) is given at least for4 months. In patients with tuberculous meningitis,the continuation phase is usually extended to 7or 10 months (92). American Thoracic Societyguideline also recommends a longer duration(9–12 months) of antituberculous therapy fortuberculous meningitis. Optimal length of therapyfor tuberculous meningitis is not yet established(93). (Table 3) Antituberculous therapy in humanimmunodeficiency virus-infected patients remainsthe same as for human immunodeficiency virus-uninfected patients (93).Multidrug-resistant tuberculous meningitis

should be considered if there is a history of contactwith a patient of multidrug-resistant pulmonarytuberculosis or a poor clinical response to anti-microbial therapydespiteadequatetreatment.Avail-able guidelines recommend that antituberculous

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treatment regimen for these patients should includeat least fivedrugs.Treatment regimen should includedrugs that the patient has not received before and towhich the patient�s organism is susceptible. Theregimen should also include an injectable medica-tion. In fivedrug regimen, one of the antituberculousdrugs should be fluroquinolone. Second-line bacte-riostaticagentsasneededtobringthetotalnumberofdrugs in the regimen up to five. The initial phase of6 months should be followed by the continuationphase of 12–18 months (13). With emergence ofextensively drug-resistant tuberculosis (a form ofmultidrug-resistant tuberculosiswith resistance to atleast isoniazid and rifampicin, any fluoroquinolone,and at least one of the injectable drugs like amikacin,kanamycinandcapreomycin), in future, treatmentoftuberculous meningitis may become much moredifficult.Immune reconstitution inflammatory syndrome

is a potentially life-threatening condition which isseen in human immunodeficiency virus-infectedpatients of tuberculosis. This complication may beseen within 3 months after starting highly activeantiretroviral therapy. Immune reconstitutioninflammatory syndrome is characterized byimprovement in CD4 cell counts. Differentialdiagnoses of immune reconstitution inflammatorysyndrome include failure of antituberculous treat-ment, drug reactions and alternative opportunisticconditions. Infective forms of immune reconstitu-tion inflammatory syndromes may manifest aseither an inflammatory �unmasking� of previously

untreated tuberculosis or as the paradoxical clin-ical deterioration of tuberculous meningitis (92,94). Immune reconstitution inflammatory syn-drome may be severe enough to cause death (95).Concomitant administration of antituberculous

drugs and antiretroviral drugs may produce signif-icant drug interactions. For example, induction ofcytochrome P-450 enzymes and P-glycoprotein byrifampicin results in reduced concentrations ofnon-nucleoside reverse-transcriptase inhibitorsand, particularly, protease inhibitors. This poten-tially results in the loss of antiretroviral drugefficacy (96).Drug-induced hepatitis following antituber-

culous therapy often poses a great challenge tosuccessful treatment. No separate guidelines existto counter drug-induced hepatitis in patients withtuberculous meningitis. If a patient of pulmonarytuberculosis develops drug-induced hepatitis anti-tuberculous treatment should be withdrawntemporarily. After hepatitis has resolved, sameregimen may be reintroduced. In patients withtuberculous meningitis it is recommended that atleast two antituberculous drugs having least hep-atotoxic effect (like ethambutol and streptomycin)should always be continued (92, 97).

Role of corticosteroids

The recent Cochrane review recommends thatcorticosteroids should routinely be used in tuber-culous meningitis because it significantly reducesdeath and disabling residual neurological deficitamongst survivors (98). In fact, the actual evidenceof benefit of corticosteroids in tuberculous menin-gitis came from a well-designed, randomized,double-blind, placebo-controlled trial conductedin Vietnam. In this trial, a total of 545 patientswere randomly assigned to receive either dexa-methasone or placebo. Patients with grade-II orgrade-III tuberculous meningitis received intra-venous dexamethasone for 4 weeks and then oraldexamethasone for 4 weeks. Patients with grade-Idisease received 2 weeks of intravenous dexameth-asone and then 4 weeks of oral therapy. After9 months of follow-up, treatment with dexametha-sone was associated with a significantly improvedsurvival. However, treatment with corticosteroidsdid not alter the combined outcome of death andsevere disability. However, subgroup analysisrevealed that for the patients in stage-I there was aslightstatisticallysignificantbenefitforthecombinedoutcome. This observation suggested that earlytreatment is important. As additional benefit, thedexamethasone group experienced significantlyfewer number adverse effects of antituberculous

Table 3 Antituberculous treatment regimen for tuberculous meningitis (92, 93)(dosage of antituberculous drugs is given in mg ⁄ kg for children along with max-imum adult dose)

Tuberculous meningitis by drug-susceptible organisms (adult, children and humanimmunodeficiency virus-infected patients)

Initiation phase: 2 monthsIsoniazid (4–6 mg ⁄ kg, 300 mg)Rifampicin (8–12 mg ⁄ kg, 600 mg)Pyrazinamide (20–30 mg ⁄ kg, 1600 mg)Streptomycin (12–18 mg ⁄ kg, 1000 mg)

Continuation phase: 4–7 monthsIsoniazid (4–6 mg ⁄ kg, 300 mg)Rifampicin (8–12 mg ⁄ kg, 600 mg)

Multidrug-resistant tuberculous meningitisInitiation phase: 4 months

Amikacin or Kanamycin (intravenous or intramuscular 15–30 mg ⁄ kg,1000 mg)

Ethionamide (15–20 mg ⁄ kg, 1000 mg)Pyrazinamide (20–30 mg ⁄ kg, 1600 mg)Ofloxacin (7.5–15 mg ⁄ kg, 800 mg)Ethambutol or cycloserine (15–25 mg ⁄ kg, 1200 mg; 10–20 mg ⁄ kg, 1000 mg)

Continuation phase: 12–18 monthsEthionamide (5–10 mg ⁄ kg, 750 mg)Ofloxacin (7.5–15 mg ⁄ kg, 800 mg)Ethambutol or cycloserine (15–25 mg ⁄ kg, 1200 mg; 10–20 mg ⁄ kg, 1000 mg)

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drugs than in the placebo group (99). Later, insame group of patients, same group of authorsdemonstrated that dexamethasone affected theoutcome of tuberculous meningitis, possibly, byreducingtheincidenceofhydrocephalusandcerebralinfarctions (100).The mechanism of action of corticosteroids in

tuberculous meningitis is not exactly known. Corti-costeroids are supposed to reduce cerebral andmeningeal inflammatory changes, cerebral edemaand increased intracranial pressure. Corticosteroidsare thought to operate via modulation of theproduction of cytokines and chemokines by macro-phages (33, 34).However, contrary topopularbelief,Simmons and coworkers demonstrated thatimproved survival following corticosteroid treat-mentwaspossiblynotmediatedbyfavorablechangesin the immunological mediators of inflammation incerebrospinal fluid or by suppression of peripheral Tcell responses against mycobacteria (101). Matrixmetalloproteinases are mediators of extracellularmatrix degradation and are implicated in the path-ogenesis of several inflammatory diseases of thecentralnervous system.Arecent studydemonstratedthat dexamethasone decreased cerebrospinal fluidmatrix metalloproteinases-9 concentrations early incourse of the treatment. Authors suggested that thismight be one of the mechanisms by which corticos-teroids improve outcome in tuberculous meningitis(102).

Paradoxical response

Expansion of an existing tuberculoma or devel-opment of multiple new brain lesions duringantimicrobial treatment of tuberculous meningitishas been recognized as a paradoxical response.Sometimes, paradoxical reaction manifests as anincrease in cerebrospinal fluid lymphocytic pleo-cytosis or initial lymphocytic response maychange transiently in the direction of polymor-phonuclear predominance (103, 104). However,the exact timing and frequency of paradoxicalresponse are not known. A paradoxical responseis often interpreted as a clinical deterioration.Citing an example of paradoxical response, apatient having pulmonary tuberculosis, tubercu-lous meningitis and brain tuberculoma serialmagnetic resonance imaging revealed a paradox-ical enlargement of existing cerebral tuberculo-mas along with an aggravation of anteriorcerebral artery vasculitis, despite the appropriatetreatment (105). There was some evidence thatcorticosteroid treatment might have a beneficialeffect in patients having paradoxical reaction(106).

Role of neurosurgery

Cerebrospinal fluid diversion procedures are oftenemployed in patients of tuberculous meningitiswith hydrocephalus. Shunt procedures are helpfulin reducing intracranial pressure. Ventriculoperi-toneal shunting is most frequently used surgicalprocedure for the drainage of cerebrospinal fluid.Cerebrospinal fluid shunting is usually needed ifmedical therapy does not produce desired resultand patient clinical condition deteriorated consid-erably. Shunting is often performed in the acutestage if the hydrocephalus is obstructive type. Inpatients with communicating hydrocephalus, shuntsurgery is recommended following failed medicaltherapy (107). In advanced stages of tuberculousmeningitis, shunt surgery should be considered ifexternal ventricular drainage causes an improve-ment in sensorium (108). Early shunt procedureshave been reported to reduce the morbidity andmortality in childhood tuberculous meningitis aswell (109). Shunt malfunction is a common com-plication and is possibly because of the highprotein content of cerebrospinal fluid. Unfortu-nately, no placebo-controlled trial, demonstratingefficacy of shunt surgery in tuberculous meningitis,is currently available.Endoscopic third ventriculostomy creates a

communication between third ventricle and sub-arachnoid space bypassing cerebral aqueduct. It isnow considered as a safe and long-lasting treat-ment option for hydrocephalus in patient withtuberculous meningitis. This procedure has mostfrequently been used in patients who experiencedmultiple episodes of shunt dysfunction. Endo-scopic third ventriculostomy is likely to fail in thepresence of advanced clinical grade, extra-centralnervous system tuberculosis, dense adhesions inprepontine cisterns and an unidentifiable thirdventricular floor anatomy (110).

Prognosis

In tuberculous meningitis, early diagnosis andtreatment is important for better prognosis. Unfor-tunately, antituberculous treatment prevents deathor disability in less than 50% of the patients (111,112). Administration of corticosteroids in adultpatients is associated with significant decrease inthe mortality (99). Medical Research Councilstaging is used to assess the severity of tuberculousmeningitis. In this system of staging, in stage 1patient is fully conscious and without focal neuro-logical deficit; in stage 2 patient may be in alteredsensorium or has minor focal deficits such ashemiparesis or cranial nerve palsy; and in stage 3

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patient is comatose or may have severe focaldeficits like multiple cranial nerve palsy, hemiplegiaand ⁄or paraplegia (113).Mortality is highest in patients younger than

5 years, those older than 50 years, and those inwhom illness has been present for longer than2 months (114). A pediatric study (123 patients)observed that following treatment only 20% chil-dren recovered completely, 80% of the patientseither died or survived with disability (115). In mostof the studies, the stage of disease emerged as thesingle most important factor associated with mor-tality (42, 116). In a large series of 434 adult patients,101 patients (23.3%) died and 67 (27%) of survivorshad neurological sequelae. Coma, seizures anddelayed or irregular treatment were adverse prog-nostic factors (117). In another series, five factorswere associated with death which included stage-IIIat presentation, low glucose levels, low cerebrospi-nal fluid ⁄blood glucose ratio, high protein levelsand computed tomographic abnormality (42). Inseries of 554 pediatric patients of tuberculousmeningitis, mortality after 6 months was 13%. Allof the patients diagnosed with stage-I tuberculousmeningitis had normal outcome. Ethnicity, stage ofdisease, headache, convulsions, motor function,brainstem dysfunction and cerebral infarctionswere independently associated with poor outcomein multivariate logistic regression analysis (41). Inhuman immunodeficiency virus-infected patients oftuberculous meningitis, the mortality is quite high(84). In a comparative study, among human immu-nodeficiency virus-infected patients, 63.3%(64 ⁄101) died while among human immunodefi-ciency virus-negative patients mortality was only17.5% (7 ⁄40) (87).Various neurological sequelae, like hemiplegia,

paraplegia, quadriplegia, aphasia and vision loss,are common among survivors. In a study, completeneurological recovery was observed only in 21.5%of the surviving patients. Common sequelae werecognitive impairment in 55%, motor deficit in40%, and optic atrophy in 37% and other cranialnerve palsies in 23% (117).

Prevention

Bacillus Calmette-Guerin (BCG) vaccination hasbeen shown to have a high efficacy in preventingchildhood tuberculous meningitis and miliarytuberculosis. It is universally accepted that protec-tive efficacy of BCG vaccination decreases withage and there is insufficient protection againsttuberculosis in adults. A group of authors esti-mated that 100.5 million BCG vaccinations givento infants in 2002 will have prevented 29 729 cases

of tuberculous meningitis in children during theirfirst 5 years of lives (118). There are enoughevidences to suggest that a second dose of BCGvaccine does not increase its efficacy.It was observed that vaccinated children with

tuberculous meningitis had significantly lower ratesof altered sensorium and focal neurological deficitsand cerebrospinal fluid cell count. Short-termoutcomes (death and sequelae) were significantlybetter in the vaccinated group (119). The mecha-nism of protection by BCG vaccination is notprecisely known (120). Protective benefits of BCGvaccine for human immunodeficiency virus-infected persons are not known.

Conclusion

Tuberculous meningitis is associated with excep-tionally high mortality and morbidity. Not muchhas changed despite significant advances in therecent years. Half of the patients either die duringtreatment or they survive with significant disability.The early diagnosis of tuberculous meningitis isoften difficult. In majority of patients, antitubercu-lous treatment remains empirical. Available anti-tuberculous drugs are moderately effective. Newerdrugs with better cerebrospinal fluid penetrationare urgently needed (Table 4). Effective vaccinationagainst tuberculosis seems to be the only hopeavailable today. Several new vaccines are showingpromising results in preclinical studies and a few ofthem have already entered clinical trials.

Table 4 Current research questions

Epidemiology of tuberculous meningitis in highly endemic countries is not knownEfforts should be made to estimate the magnitude of problemNot all persons exposed to tuberculosis develop tuberculous meningitis. There isneed to explore the factors (including genetic factors) which make a personsusceptible to tuberculous meningitisHost and bacterial factors determining the clinical variability (like variablefrequency of disabling complications) need to be exploredFor better understanding of pathogenesis, appropriate animal models should bedeveloped and immunological profile of disease should be studied

Risk factors of some of the devastating complications like stroke, paraplegia andblindness should be studiedCurrently available drugs are not universally effective. Newer drugs effective evenagainst resistant cases with better penetration in cerebrospinal fluid are neededNew low-cost techniques for bacteriological diagnosis are required. Polymerasechain reaction test is still unaffordableNew low-cost techniques to rapidly detect drug resistance are required to insureadequate treatment without delayOptimum duration and an optimum antituberculous regimen need to be worked outFactors responsible for failure of treatment need to be identifiedAn effective anti-tuberculosis vaccine to prevent tuberculous meningitis in adultsneed to be developedDo other immunosuppressives have a role in the management of tuberculousmeningitis need to be explored?Use of ventriculo-peritoneal shunts is still empirical. A randomized trial is needed

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Supporting Information

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Figure S1. Fundus photograph showing a choroid tubercle.

Please note: Wiley-Blackwell are not responsible for thecontent or functionality of any supporting materials suppliedby the authors. Any queries (other than missing material)should be directed to the corresponding author for the article.

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