Tuberculosis 92 (2012) 377e383 Contents lists available at SciVerse ScienceDirect Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube REVIEW Diagnosis and therapy of tuberculous meningitis in children Nicola Principi*, Susanna Esposito Department of Maternal and Pediatric Sciences, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milan, Italy a r t i c l e i n f o s u m m a r y Article history: Received 31 March 2012 Received in revised form 22 May 2012 Accepted 29 May 2012 Children are among the subjects most frequently affected by tuberculous meningitis (TBM) due to their relative inability to contain primary Mycobacterium tuberculosis infection in the lung. TBM is a devastating disease with about 30% mortality among the most severe cases; moreover, 50% of survivors have neurological sequelae despite an apparently adequate administration of antibiotics. Early diagnosis and prompt treatment are crucial for reducing the risk of a poor outcome. However, especially in children, the best and most rapid way to conﬁrm the diagnosis is controversial; the optimal choice, dose, and treatment duration of anti-tuberculosis drugs are not precisely deﬁned, and the actual importance of adjunctive therapies with steroids and neurosurgery has not been adequately demonstrated. This review is an effort to discuss present knowledge of the diagnosis and treatment of pediatric TBM in order to offer the best solution to address this dramatic disease. In conclusion, we stress that new studies in children are urgently needed because data in the early years of life are more debatable than those collected in adults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude to diagnosis and therapy is necessary, because TBM is a devastating disease. Ó 2012 Elsevier Ltd. All rights reserved. Keywords: Children Meningitis Mycobacterium tuberculosis Tuberculosis Tuberculous meningitis 1. Introduction Tuberculous meningitis (TBM) occurs mainly in developing countries where tuberculosis (TB) is more common and the wider incidence of the human immunodeﬁciency virus (HIV) favors the onset of a great number of cases. However, TBM is also encountered in industrialized countries, particularly in recent years, as a consequence of the large immigration of infected people1 and the frequent use of biological agents that favor TB development.2,3 Children are among the subjects who most frequently suffer from TBM due to their relative inability to contain primary Mycobacterium tuberculosis infection in the lung.1,3 TBM is a devastating disease with about 30% mortality in the most severe forms; moreover, 50% of survivors have neurological sequelae despite apparently adequate administration of antibiotics.4,5 Early diagnosis and prompt treatment are crucial for reducing the risk of a negative evolution. However, especially in children, the best and most rapid way to diagnose the disease is controversial; the optimal choice, dose, and treatment duration of anti-tuberculosis drugs are not precisely deﬁned, and the actual importance of adjunctive therapies with steroids and neurosurgery have not been adequately demonstrated. Consequently, the approach to pediatric TBM is frequently inadequate. This review is aimed at discussing * Corresponding author. Tel.: þ39 02 55032203; fax: þ39 02 50320206. E-mail address: [email protected] (N. Principi). 1472-9792/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tube.2012.05.011 present knowledge on the diagnosis and treatment of pediatric TBM in order to offer the best solution to address this dramatic disease. 2. Diagnosis Although early and rapid identiﬁcation of TBM is crucial for successful disease management, in most of the cases, diagnosis is signiﬁcantly delayed. Initial signs and symptoms of disease are non-speciﬁc and the suspicion of TBM usually arises only some days or weeks after the disease’s onset and is not different in children who have or have not been vaccinated with Bacille Calmette-Guerin.6 Fever, headache, anorexia, and vomiting characterize the prodrome of disease in older children, whereas failure to thrive, poor appetite, vomiting, and sleep disturbances are more common in younger ones.7 TBM is more easily suspected when these symptoms are associated with a history of recent contact with a case of documented TB or when, after the ﬁrst days of disease, relevant neurological manifestations, such as cranial nerve palsy, occur.6,7 2.1. Probable or possible TBM Diagnosis of probable or possible TBM requires signs and symptoms of meningitis in association with clinical, CSF and cerebral imaging ﬁndings suggestive of M. tuberculosis infection. The 378 N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383 evidence of TB outside the CNS can further contribute to probable or possible diagnosis. A score that includes the most common ﬁndings in children with TBM and in which single ﬁndings are assigned a point according to the frequency with which they are usually demonstrated has been created by Marais et al.8 According to these authors, probable TBM is deﬁned by a score between 10 and 12, whereas possible TBM is deﬁned by a score higher than 6 (Table 1). 2.1.1. Clinical ﬁndings The low sensitivity and speciﬁcity of most of the relevant neurologic symptoms has been largely demonstrated by several clinical trials. Prodromal stage 7 days, optic atrophy on fundal examination, focal deﬁcit and abnormal movements were found to be independently predictive of TBM (p < 0.007) in a group of children aged 1 months to 12 years,9 but optic atrophy is usually a late occurrence and abnormal movements are rare. 2.1.2. Laboratory ﬁndings CSF modiﬁcations are common in children with TBM. In these cases, CSF shows a clear appearance, moderate pleocytosis with Table 1 Diagnostic criteria for classiﬁcation of deﬁnite, probable or possible tuberculous meningitis. Criteria Clinical criteria Symptom duration of more than 5 days Systemic symptoms suggestive of TB (one or more of the following): weight loss or poor weight gain, night swabs or persistent cough for more than 2 weeks History of recent (within the past year) close contact with an individual with pulmonary TB or a positive tuberculin skin test or interferon-g release assay Focal neurologic deﬁcit (excluding facial nerve palsies) Cranial nerve palsy Altered consciousness CSF criteria Clear appearance Cells 10e500 per mL Lymphocytic predominance (>50%) Protein concentration >1 g/L CSF to plasma glucose ratio of less than 50% or an absolute CSF glucose concentration <2.2 mmol/L Cerebral imaging criteria Hydrocephalus Basal meningeal enhancement Tuberculoma Infarct Pre-contrast basal hyperdensity Evidence of tuberculosis elsewhere Chest X-ray suggestive of active TB: signs of TB ¼ 2; miliary TB ¼ 4 CT/MR/ultrasound evidence for TB outside the CNS M. tuberculosis cultured from another source (i.e., sputum, lymph node, gastric lavage, urine, blood culture) Positive commercial M. tuberculosis NAAT from extra-neural specimen Maximum category score ¼ 6 4 2 2 1 1 1 Maximum category score ¼ 4 1 1 1 1 1 Maximum category score ¼ 6 1 2 2 1 2 Maximum category score ¼ 4 2/4 2 4 4 CNS, central nervous system; CT, computed tomography; MR, magnetic resonance; NAAT, nucleic acid ampliﬁcation test; TB, tuberculosis. From Marais et al.,8 modiﬁed. a predominance of lymphocytes, an increase in protein content and a very low glucose concentration. These ﬁndings are different from those usually reported for typical bacterial meningitis in which CSF is opaque, pleocytosis is very high, and neutrophils are predominant. Reduction in glucose content is usually less marked in comparison to purulent bacterial meningitis, where CSF glucose values below 5 mg/dL will often be found. Clear appearance, white blood cell count between 50 and 500 per mL with 50% or more lymphocytes, protein content greater than 1 g/L and a glucose content less than 2.2 mmol/L are considered to be indicative of TBM. However, atypical CSF ﬁndings have been repeatedly described in children with TBM.7 To improve diagnosis of probable or possible TBM, other CSF tests have been recently studied. Among them, the evaluation of adenosine deaminase activity (ADA), the measurement of interferon-gamma (IFN-g) release by lymphocytes, the detection of M. tuberculosis antigens and antibodies, and the immunocytochemical staining of mycobacterial antigens (ISMA) in the cytoplasm of CSF macrophages are those for which the greatest amount of data is available. However, none of these seems to have elevated sensitivity and speciﬁcity, although they can be useful in some cases to support the diagnosis. The ADA activity test is a rapid test that represents the proliferation and differentiation of lymphocytes as a result of the activation of cell-mediated immunity after M. tuberculosis infection.10,11 It has given good results in the diagnosis of the pleural, peritoneal and pericardial forms of tuberculosis. When applied to patients with TBM, it was found that ADA activity could not distinguish between TBM and other types of bacterial meningitis, but that it could add useful information to suggest TBM once meningitis due to different pathogens has been ruled out. ADA values from 1 to 4 U/ L (sensitivity >93% and speciﬁcity <80%) can help to exclude TBM and values >8 U/L (sensitivity <59% and speciﬁcity >96%) can improve the diagnosis of TBM (p < 0.001). However, values between 4 and 8 U/L are insufﬁcient to conﬁrm or exclude the diagnosis of TBM (p ¼ 0.07).10 Moreover, false positive results can be found in HIV-infected patients.11 Measurement of IFN-g release by lymphocytes stimulated by M. tuberculosis antigens has been demonstrated to be more accurate than skin testing for the diagnosis of latent TB and to be useful in the diagnosis of extrapulmonary TB. However, sensitivity and speciﬁcity of the test varied markedly according to the disease site.12 When adapted to TBM, collected data vary sharply from study to study. Liao et al. found that the test was 100% sensitive and 100% speciﬁc,12 whereas other authors reported a very poor value of the test in diagnosing TBM.13 It has been suggested that the failure of the test in some studies could be ascribed to the fact that lymphocytes die rapidly when stimulated with M. tuberculosis antigens ex vivo so that the test can be negative even if TBM is actually present.14 Detection of various M. tuberculosis antigen markers, such as lipoarabinomannan, puriﬁed protein derivatives, heat shock protein of 62Kd and 14Kd, GroE, Ag 85 complex and 38Kd antigen, have been tried to conﬁrm TBM diagnosis.15e17 However, their presence remains questionable and many of these antigens are reported in blood only, but not in the CSF and this questions their veracity for the diagnosis of TBM. The same seems true for speciﬁc antibody detection.18 Use of ISMA in the cytoplasm of CSF macrophages is based on the assumption that, during the initial stage of infection, ingestion of the bacilli by macrophages takes place and that during the second stage bacilli grow logarithmically within newly recruited macrophages.19 Consequently, the positivity of the test indicates that viable M. tuberculosis isolates are present in CSF. A recent study in which this test was evaluated in 393 patients, among whom N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383 some with deﬁnite TBM, has demonstrated that it has a sensitivity of 73.5% and speciﬁcity of 90.7% with positive and negative predictive values of 52.9% and 96.0% respectively.20 This means that this test can be useful, in actual fact, to exclude TBM, but that its sensitivity is too low to diagnose deﬁnite TBM. 2.1.3. Imaging Similarly to clinical and laboratory ﬁndings, cerebral imaging can also contribute to diagnosing probable or possible TBM. However, discrimination between TBM and another cerebral disease is frequently very difﬁcult. The most common brain computed tomography (CT) or magnetic resonance (MR) features in children with TBM are hydrocephalus, which can be demonstrated in about 80% of cases,21 and basal meningeal enhancement, found in 75% of young patients.22 Infarction, as a result of ongoing vasculitis, particularly of the basal ganglia and of the areas of the medial striates and thalamoperforating arteries, and tuberculoma can be found in a smaller number of TBM pediatric cases.23,24 MR has a higher sensitivity than CT in the identiﬁcation of CNS modiﬁcation, although it does not seem to offer more help in distinguishing TBM from other CNS diseases such as viral encephalitis, cryptococcal meningitis or cerebral lymphomas that can have similar cerebral imaging.25 However, a combination of basal meningeal enhancement, infarction and hydrocephalus was found to have a high speciﬁcity for the diagnosis of TBM, whereas basal meningeal enhancement was reported as the most sensitive feature.22 Recently, it was reported that border zone necrosis (BZN) of the brain parenchyma in areas adjacent to meningeal inﬂammation can occur in 50% of children with TBM.26 Detection and conﬁrmation of cytotoxic edema associated with BZN using diffusion-weighted MR can offer further support to probable or possible TBM diagnosis. However, it has to be highlighted that in stage 1 TBM imaging ﬁndings may be normal, yet it is at that stage that treatment should be started in order to prevent brain damage. 2.2. Evidence of TB outside the CNS The evidence of TB infection or disease outside the CNS can signiﬁcantly increase the probability or possibility that a child with cerebral signs and symptoms can have TBM. However, a great number of patients, especially when HIV negative, will present with normal chest radiography or negative tuberculin skin testing.27 Moreover, particularly in high TB prevalence areas, a positive skin test with an unrelated illness has been frequently documented. Taking samples from sites of frequent TB infection such as lymph nodes, lung and gastric ﬂuid can increase the likelihood of a positive culture. Gastric aspiration was positive in 68% of children with TBM.28 In conclusion, considering the need for a rapid diagnosis of TBM, all possible efforts to demonstrate the probable or possible presence of this disease must be pursued using all available laboratory tests and imaging techniques. Moreover, the potential severity of TBM calls for the immediate treatment of all the doubtful cases. 2.3. Conﬁrmed diagnosis of TBM Independently from the characteristics and duration of the prodromal stage, a deﬁnite diagnosis of TBM can be made only when, after a lumbar puncture (LP) in a patient with signs and symptoms of central nervous system (CNS) disease, acid-fast bacilli (AFB) are seen and/or M. tuberculosis is detected by molecular methods and/or cultured in cerebrospinal ﬂuid (CSF). The same conclusion can be drawn from autopsy when M. tuberculosis is identiﬁed in histological lesions of the CNS. This is in line with what has been deﬁned by most of the authors who have made the 379 attempt to standardize clinical case deﬁnition of TBM for use in clinical research.5, 29e34 However, all the methods for the conﬁrmation of the diagnosis of TBM risk further delay in diagnosis and initiation of therapy.35e37 Culture requires >2e3 weeks to give results. Moreover, both microscopic AFB detection and culture isolation have low sensitivity, particularly in children in whom these allow for identiﬁcation of only about 20% of cases. Finally, modern molecular methods can have, at the same time, both low sensitivity and low speciﬁcity. Sensitivity of traditional microbiological tests seems to be strictly dependent on the amount of CSF that is sampled, the frequency of LPs, the time devoted to the microscopic search for the organism, and the moment in which the CSF is drawn. The minimum volume of CSF to obtain reliable results seems to be 6 mL,35 an amount difﬁcult to be safely obtained in younger children that have a low total volume of CSF.36 In comparison with a single LP, four LPs can increase sensitivity of microscopy examination and culture from 37% and 52% to 87% and 83%, respectively.37 However, in pediatrics several lumbar punctures are not easily performed, mainly because of the aversion of parents to let their children undergo repeated invasive procedures. Thirty minutes are considered the minimum time needed for a correct evaluation of CSF by microscopy36 and in a busy laboratory this may not be possible. Finally, antibiotic administration rapidly reduces the number of pathogens in the CSF. Anti-tuberculosis drugs are usually started immediately after TBM is suspected and consequently LPs are negative even in children actually suffering from the disease. Accuracy of nucleic acid-based ampliﬁcation (NAA) tests, though better than that of conventional microscopic methods,38 was not considered completely satisfactory for many years because their sensitivity and speciﬁcity in identifying M. tuberculosis, in comparison with culture, ranged from 2% to 100% and from 75% to 100%, respectively.39 The most important reason for the low sensitivity of some of the ﬁrst polymerase chain reaction (PCR)-based methods was the use of a single target for ampliﬁcation. Most studies have used the IS6110 gene of M. tuberculosis that is usually present in multiple copies in the bacterial genome assuring high sensitivity. Unfortunately, this gene is absent in a signiﬁcant number of isolates, so that a false negative result was regularly found when patients infected by these isolates were studied.40,41 More reliable results have been obtained in more recent years when ampliﬁcation of multiple gene targets from CSF samples was performed. Kusum et al. evaluated a multiplex PCR using protein b, MPB64 and IS6110 primers and found that this method had a sensitivity of 94.4% and a speciﬁcity of 100% in culture-conﬁrmed cases.42 Recently, molecular methods capable of simultaneously identifying both M. tuberculosis and resistance of the strain to antibiotics have been developed. Among these, the Xpert M. tuberculosis/RIF assay seems to be the most promising, although no data regarding its use in extrapulmonary TB are available.43 Finally, preliminary studies have suggested that molecular methods could be used to quantify the bacterial load in CSF and consequently to evaluate treatment response.44 In conclusion, making a deﬁnite diagnosis of TBM is still a problem. In many cases, diagnosis remains probable or possible and treatment is initiated without the demonstration of the presence of M. tuberculosis in CSF. 3. Treatment Treatment of TBM is based on three different components: administration of anti-infective drugs active against M. tuberculosis, modulation of the destructive elements of the immune response, and management of increased intracranial pressure. 380 N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383 3.1. Anti-infective therapy Contrary to what applies to pulmonary tuberculosis, recommendations for anti-infective therapy in TBM are, in general, not based on well-conducted clinical trials. Few data, particularly in children, are available to guide the clinician who derives the schemes for treatment of TBM from those used for pulmonary TB. This explains why most experts recommend that the treatment of TBM follows the model of short-course chemotherapy with an intensive phase of treatment with several drugs followed by a continuation phase in which only two drugs are administered.45,46 Table 2 summarizes the main guidelines for treatment of pediatric TBM and Table 3 shows second-line drugs that could be used in case of resistant strains taking in account that very few data of their real efﬁcacy, safety and tolerability in children are available. Before the emergence of multidrug-resistant M. tuberculosis, three drugs were considered adequate for the ﬁrst phase. More recently, in order to address the problem of resistance, four antibiotics for the initial months of treatment are preferred. However, there is no agreement on the duration of each of the two phases and on the total length of therapy. The intensive phase can range from 2 to 6 months and total treatment from 6 months to one year.47 Unfortunately, studies comparing the different schemes of antibiotic administration in children are not available.48,49 Studies regarding the outcome of 6-month regimens have demonstrated that the relapse rate was not signiﬁcantly different from that reported when longer periods of antibiotic administration were used.48 This seems to speak in favor of the shortest therapy. However, because most of these data have been collected in adults, no deﬁnitive conclusions can be drawn when children with TBM have to be treated. According to Donald, in situations where the directly observed treatment and follow-up after treatment completion is impeccable, a 6-month treatment duration is probably satisfactory.47 When treatment supervision and/or follow-up are questionable, it may be better practice to prolong length of treatment.47 For several years now, the drugs considered essential by the World Health Organization (WHO) to treat pulmonary TB in children are isoniazid (INH), rifampicin (RMP),pyrazinamide (PZA), and ethambutol (EMB).50 Other drugs, such as streptomycin (SM) or other aminoglycosides, ethionamide (ETH) and cycloserine are Table 2 Main guidelines for the treatment of tuberculous meningitis in infants and children. British Infection Society Isoniazid 10e20 mg/kg/24 h (max 500 mg) orally for 12 months Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 12 months Pyrazinamide 30e35 mg/kg/24 h (max 2 g) orally for 2 months Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months Prednisolone 4 mg/kg/24 h orally for 4 weeks, followed by a reducing course over 4 weeks American Thoracic Society, CDC, and Infectious Diseases Society of America Isoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 9e12 months Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 9e12 months Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months Dexamethasone 8 mg/day/24 h orally for children weighing less than 25 kg and 12 mg/day for children weighing 25 kg or more for 3 weeks, followed by a reducing course over 3 weeks World Health Organization Isoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 6 months Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 6 months Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months Streptomycin 20e40 mg/kg (max 1 g) i.m. or i.v. for 2 months Prednisone 2 mg/kg/24 h orally for 4 weeks, followed by a reducing course over 1e2 weeks Table 3 Recommended daily dosages of second-line anti-tuberculous drugs for treatment of tuberculous meningitis in infants and children. Drug Dosage Ethionamide 20 mg/kg/24 h (max 1 g/day) orally as a single daily dose 10e15 mg/kg/24 h (max 1 g/day) orally as a single daily dose 20e40 mg/kg/24 h (max 1 g/day) i.m. or i.v. as a single daily dose 200e300 mg/kg/24 h orally in 2e4 doses 15e30 mg/kg/24 h (max 1000 mg) orally as a single daily dose 15e30 mg/kg/24 h (max 1 g/day) i.m. or i.v. as a single daily dose 15e20 mg/kg/24 h (max 800 mg) orally as a single daily dose 7.5e10 mg/kg/24 h (max 500 mg) orally as a single daily dose 7.5e10 mg/kg/24 h (max 500 mg) orally as a single daily dose 20e30 mg/kg/24 h (max 1.5 g) orally as a single daily dose Cycloserine Steptomycin Para-amino-salicylic acid Capreomycin Amikacin and Kanamycin Oﬂoxacin Levoﬂoxacin Moxiﬂoxacin Ciproﬂoxacin considered second-line drugs because of their toxicity.50 However, when TBM has to be treated ETH and cycloserine that have a reasonable CSF penetration, even better of that of EBM can be considered where they are available.51,52 Newer anti-tuberculosis drugs, such as ﬂuoroquinolones, have been scarcely used in pediatric TBM and are off-label in children, although for both penetration in CSF and in-vitro efﬁcacy against M. tuberculosis, they are considered promising therapeutic options.50 Independently from the drugs prescribed, the scheme of administration used, and the total duration of therapy, INH remains the drug most widely prescribed in children for initial TBM treatment.50 The choice of INH is based on several positive factors: the good absorption by the gastrointestinal tract, the rapid diffusion in body compartments including CSF and the low toxicity. Moreover, it rapidly kills most of the replicating M. tuberculosis and, consequently, protects companion drugs against the development of resistance, reduces the risk of infecting contacts and leads to a more rapid mitigation of disease symptoms. In children, INH is recommended at the dose of 10 mg/kg/day (range: 6e15 mg/kg/day, maximum 500 mg), generally useful to reach in CSF concentrations that are high enough to eliminate fully sensitive M. tuberculosis or resistant mutants with a relatively low minimum inhibitory concentration (MIC) even in patients who are fast acetylators.53,54 When M. tuberculosis resistance is suspected or demonstrated, the highest doses have to be administered, striking the right balance between toxicity and optimal efﬁcacy. RMP has the advantage of killing low or non-replicating M. tuberculosis, thus complementing INH activity and allowing the sterilization of lesions. Unfortunately, it has several limits because its concentrations in CSF do not exceed 10% of those in plasma,55 its absorption is negatively inﬂuenced by food and antacids56 and it has a relevant protein binding action that can signiﬁcantly reduce its clinical efﬁcacy.57 RMP is ofﬁcially recommended at the dose of 10e20 mg/kg/day45,46 but, considering the MIC of susceptible M. tuberculosis and the concentrations reached in CSF of children,58 it has been recommended to administer the highest dosage in young children and infants <10 kg and at least 15 mg/kg/day in older patients weighing between 10 and 20 kg.47 The dose of 10 mg/kg/day could lead to CSF levels <1.0 mg/mL, which is ineffective against most M. tuberculosis, particularly when strains with increased MIC are present. However, raising the dose has no effect on highly resistant mutants as their MIC is far too high. For the early phase of therapy, PZA and any of the second-line drugs are usually administered. PZA has a good penetration in CSF and, despite a very low early bactericidal activity in the ﬁrst N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383 days of treatment, it is important because in the course of time it becomes as effective as INH and RMP.59,60 Moreover, together with RMP, it makes an essential contribution to the sterilization of lesions and has an important role in reducing the risk of recurrence.61 PZA is recommended at the dose of 30e35 mg/kg/daily with the highest dosage for younger children. With these regimens, CSF concentration in excess of 20 mg/mL higher than the MIC of PZA is reached in most children.62 The fourth drug to complete the antibiotic regimen in the early phase of TBM therapy is usually chosen from EMB or SM. Both have limited CSF penetration, low bactericidal activity and do not contribute to the sterilization of lesions and reduction of the risk of relapse. Their contribution to the treatment of TBM is probably minor, although they protect companion drugs against the emergence of resistance.47 The growing emergence of resistant strains has raised the question of the importance of resistance to TBM outcome. Available data clearly indicate that resistance to both INH and RMP signiﬁcantly worsen the ﬁnal outcome.45 The effect of resistance to a single drug is more controversial. Regarding INH, some studies indicate that INH resistance does not inﬂuence TBM outcome,63,64 whereas other studies seem to associate INH resistance to a significant higher risk of death.65 These different ﬁndings may be due to different doses of INH used and different resistant mutants. However, in order to minimize risks, it has been suggested that duration of treatment for TBM caused by INH-resistant organisms should be extended and always include PZA as well as a new antiM. tuberculosis antibiotic.47 381 the severity of increased intracranial pressure.71e74 Shunting is preferred by most experts when hydrocephalus is noncommunicating or when medical treatment fails even if it is not known which kind of shunting is the best.74 In communicating hydrocephalus, diuretics are generally effective in reducing the risk of long-term neurologic impairment. Endoscopic third ventriculostomy is considered a possible option, particularly in patients who have experienced multiple episodes of shunt dysfunction.75 4. Conclusions Despite undeniable advances in the identiﬁcation of markers of deﬁnite, probable or possible TBM have been made in recent years, most of the problems that pediatricians and neurologists have to face in TBM are still unsolved. The most important difﬁculty regards early diagnosis because in those patients in whom TBM is suspected early enough present treatment is sufﬁcient to bring about complete cure in the majority of cases, at least when pathogens are fully drug susceptible and treatment is complied with. More difﬁculties in achieving cure can arise when treatment is delayed and when multidrug-resistant pathogens are the cause of the disease. In this case prognosis is poor, particularly in children because it is not deﬁnitively clear what has to be done when resistance of M. tuberculosis to one or more antibiotics is present, which duration of treatment is to be recommended and what is the actual role of adjunctive therapy. New studies in children are urgently needed. In the meantime, when treating a child with suspected TBM, the most aggressive attitude is to be used both for diagnosis and for therapy, because TBM is an extremely devastating disease. 3.2. Adjunctive steroids In meningitis, most of the damage derives from the immune response elicited by the presence of bacterial pathogens in the CNS.66 This leads to a very relevant inﬂammatory process with signiﬁcant inﬁltrative, proliferative and necrotizing vessel pathologies.67 Anti-tuberculous chemotherapy and the administration of thalidomide and salicylates appear to be relatively ineffective in preventing vascular complications that remain the major unresolved problem related to TBM. Corticosteroids have been used in TBM for over 50 years, although the real importance of these drugs in this disease is not completely deﬁned. A meta-analysis recently carried out that comprised 7 randomized controlled trials involving a total number of 1140 participants, both children and adults, has demonstrated that in HIV-negative subjects prednisolone or dexamethasone signiﬁcantly reduced the risk of death (relative risk [RR], 0.78; 95% conﬁdence interval [CI], 0.67e0.91) or disabling residual neurological deﬁcit (RR 0.82; 95% CI, 0.70e0.97) with mild and treatable adverse events.68 On the contrary, no effect was reported in HIV-infected patients. The positive effect on HIVnegative subjects was found independently from the severity of the disease, thus suggesting that this therapy should be added to anti-infective therapy in all children with TBM.69,70 The best steroid and the most effective scheme of administration are not known because no data comparing different regimens are available at the moment. Moreover data collected in children are few. According to the suggestions of some American and European Scientiﬁc Societies,45,46 it could be suggested the use of oral compounds for 3 or 4 weeks with subsequent reduction in few days. 3.3. Management of increased intracranial pressure Hydrocephalus is common in children with TBM. Its management is debated. Diuretics, repeated LPs or CSF diversion through ventriculoperitoneal or atrial shunting can be used, according to Funding: This study was supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2007). Competing interests: to declare. The authors have no conﬂict of interest Ethical approval: This review was approved by the Ethical Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy and all the papers included in this review have been approved by local Ethical Committees. References 1. Bidstrup C, Andersen PH, Skinhøj P, Andersen AB. 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