Diagnosis and therapy of tuberculous meningitis in children

Diagnosis and therapy of tuberculous meningitis in children Department of Maternal and Pediatric Sciences, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,Via Commenda 9, 20122 Milan, Italy 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 devas- tating 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, thebest and most rapid way to confirm the diagnosis is controversial; the optimal choice, dose, and treat- ment 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 inadults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude todiagnosis and therapy is necessary, because TBM is a devastating disease.
Ó 2012 Elsevier Ltd. All rights reserved.
present knowledge on the diagnosis and treatment of pediatricTBM in order to offer the best solution to address this dramatic Tuberculous meningitis (TBM) occurs mainly in developing countries where tuberculosis (TB) is more common and the widerincidence of the human immunodeficiency virus (HIV) favors the onset of a great number of cases. However, TBM is also encounteredin industrialized countries, particularly in recent years, as a conse- Although early and rapid identification of TBM is crucial for quence of the large immigration of infected and the successful disease management, in most of the cases, diagnosis is frequent use of biological agents that favor TB dev significantly delayed. Initial signs and symptoms of disease are Children are among the subjects who most frequently suffer from non-specific and the suspicion of TBM usually arises only some days TBM due to their relative inability to contain primary Mycobacte- or weeks after the disease’s onset and is not different in children rium tuberculosis infection in the lung.TBM is a devastating who have or have not been vaccinated with Bacille Calmette-Gue- disease with about 30% mortality in the most severe forms; Fever, headache, anorexia, and vomiting characterize the moreover, 50% of survivors have neurological sequelae despite prodrome of disease in older children, whereas failure to thrive, apparently adequate administration of antibiotics.Early diag- poor appetite, vomiting, and sleep disturbances are more common nosis and prompt treatment are crucial for reducing the risk of in younger TBM is more easily suspected when these a negative evolution. However, especially in children, the best and symptoms are associated with a history of recent contact with most rapid way to diagnose the disease is controversial; the a case of documented TB or when, after the first days of disease, optimal choice, dose, and treatment duration of anti-tuberculosis relevant neurological manifestations, such as cranial nerve palsy, drugs are not precisely defined, and the actual importance of adjunctive therapies with steroids and neurosurgery have not beenadequately demonstrated. Consequently, the approach to pediatric TBM is frequently inadequate. This review is aimed at discussing Diagnosis of probable or possible TBM requires signs and symptoms of meningitis in association with clinical, CSF and cerebral * Corresponding author. Tel.: þ39 02 55032203; fax: þ39 02 50320206.
imaging findings suggestive of M. tuberculosis infection. The 1472-9792/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383 evidence of TB outside the CNS can further contribute to probable or a predominance of lymphocytes, an increase in protein content and possible diagnosis. A score that includes the most common findings a very low glucose concentration. These findings are different from in children with TBM and in which single findings are assigned those usually reported for typical bacterial meningitis in which CSF a point according to the frequency with which they are usually is opaque, pleocytosis is very high, and neutrophils are predomi- demonstrated has been created by Marais et According to these nant. Reduction in glucose content is usually less marked in authors, probable TBM is defined by a score between 10 and 12, comparison to purulent bacterial meningitis, where CSF glucose whereas possible TBM is defined by a score higher than 6 ().
values below 5 mg/dL will often be found. Clear appearance, whiteblood cell count between 50 and 500 per mL with 50% or more lymphocytes, protein content greater than 1 g/L and a glucose The low sensitivity and specificity of most of the relevant content less than 2.2 mmol/L are considered to be indicative of neurologic symptoms has been largely demonstrated by several TBM. However, atypical CSF findings have been repeatedly clinical trials. Prodromal stage 7 days, optic atrophy on fundal examination, focal deficit and abnormal movements were found to To improve diagnosis of probable or possible TBM, other CSF be independently predictive of TBM (p < 0.007) in a group of chil- tests have been recently studied. Among them, the evaluation of dren aged 1 months to 12 ybut optic atrophy is usually a late occurrence and abnormal movements are rare.
interferon-gamma (IFN-g) release by lymphocytes, the detection ofM. tuberculosis antigens and antibodies, and the immunocyto- chemical staining of mycobacterial antigens (ISMA) in the cyto- CSF modifications are common in children with TBM. In these plasm of CSF macrophages are those for which the greatest amount cases, CSF shows a clear appearance, moderate pleocytosis with of data is available. However, none of these seems to have elevatedsensitivity and specificity, although they can be useful in somecases to support the diagnosis.
Table 1Diagnostic criteria for classification of definite, probable or possible tuberculous The ADA activity test is a rapid test that represents the prolif- eration and differentiation of lymphocytes as a result of the acti-vation of cell-mediated immunity after M. tuberculosis infection.
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).Moreover, false positive results can Measurement of IFN-g release by lymphocytes stimulated by M. tuberculosis antigens has been demonstrated to be more accu- rate 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 siteWhen adapted to TBM, collected data vary sharply from study to study. Liao et al. found that the test was 100% sensitive and 100% specific,whereas other authors reported a very poor value of the test in diagnosing 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 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 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 speci M. tuberculosis cultured from another source Use of ISMA in the cytoplasm of CSF macrophages is based on (i.e., sputum, lymph node, gastric lavage, 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 recruitedmacrophages.Consequently, the positivity of the test indicates CNS, central nervous system; CT, computed tomography; MR, magnetic resonance; that viable M. tuberculosis isolates are present in CSF. A recent study NAAT, nucleic acid amplification test; TB, tuberculosis.
From Marais et al.,modified.
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 attempt to standardize clinical case definition of TBM for use in of 73.5% and specificity of 90.7% with positive and negative predictive values of 52.9% and 96.0% respectivelyThis means that However, all the methods for the confirmation of the diagnosis this test can be useful, in actual fact, to exclude TBM, but that its of TBM risk further delay in diagnosis and initiation of therapy.
sensitivity is too low to diagnose definite TBM.
Culture requires >2e3 weeks to give results. Moreover, bothmicroscopic AFB detection and culture isolation have low sensi- tivity, particularly in children in whom these allow for identifica- Similarly to clinical and laboratory findings, cerebral imaging tion of only about 20% of cases. Finally, modern molecular methods can also contribute to diagnosing probable or possible TBM.
can have, at the same time, both low sensitivity and low specificity.
However, discrimination between TBM and another cerebral Sensitivity of traditional microbiological tests seems to be strictly disease is frequently very difficult. The most common brain dependent on the amount of CSF that is sampled, the frequency of computed tomography (CT) or magnetic resonance (MR) features in LPs, the time devoted to the microscopic search for the organism, children with TBM are hydrocephalus, which can be demonstrated and the moment in which the CSF is drawn. The minimum volume in about 80% of cases,and basal meningeal enhancement, found of CSF to obtain reliable results seems to be 6 mL,an amount in 75% of young patients.Infarction, as a result of ongoing difficult to be safely obtained in younger children that have a low vasculitis, particularly of the basal ganglia and of the areas of the total volume of CSF.In comparison with a single LP, four LPs can medial striates and thalamoperforating arteries, and tuberculoma increase sensitivity of microscopy examination and culture from can be found in a smaller number of TBM pediatric cases.MR 37% and 52% to 87% and 83%, respectively.However, in pediatrics has a higher sensitivity than CT in the identification of CNS modi- several lumbar punctures are not easily performed, mainly because fication, although it does not seem to offer more help in dis- of the aversion of parents to let their children undergo repeated tinguishing TBM from other CNS diseases such as viral encephalitis, invasive procedures. Thirty minutes are considered the minimum cryptococcal meningitis or cerebral lymphomas that can have time needed for a correct evaluation of CSF by microscopand in similar cerebral imaging.However, a combination of basal a busy laboratory this may not be possible. Finally, antibiotic meningeal enhancement, infarction and hydrocephalus was found administration rapidly reduces the number of pathogens in the CSF.
to have a high specificity for the diagnosis of TBM, whereas basal Anti-tuberculosis drugs are usually started immediately after TBM meningeal enhancement was reported as the most sensitive is suspected and consequently LPs are negative even in children feature.Recently, it was reported that border zone necrosis (BZN) actually suffering from the disease.
of the brain parenchyma in areas adjacent to meningeal inflam- Accuracy of nucleic acid-based amplification (NAA) tests, mation can occur in 50% of children with Detection and though better than that of conventional microscopic confirmation of cytotoxic edema associated with BZN using was not considered completely satisfactory for many years diffusion-weighted MR can offer further support to probable or possible TBM diagnosis. However, it has to be highlighted that in M. tuberculosis, in comparison with culture, ranged from 2% to 100% stage 1 TBM imaging findings may be normal, yet it is at that stage and from 75% to 100%, respectively.The most important reason that treatment should be started in order to prevent brain damage.
for the low sensitivity of some of the first polymerase chain reac-tion (PCR)-based methods was the use of a single target for amplification. Most studies have used the IS6110 gene ofM. tuberculosis that is usually present in multiple copies in the The evidence of TB infection or disease outside the CNS can bacterial genome assuring high sensitivity. Unfortunately, this gene significantly increase the probability or possibility that a child with is absent in a significant number of isolates, so that a false negative cerebral signs and symptoms can have TBM. However, a great result was regularly found when patients infected by these isolates number of patients, especially when HIV negative, will present were More reliable results have been obtained in more with normal chest radiography or negative tuberculin skin recent years when amplification of multiple gene targets from CSF testiMoreover, particularly in high TB prevalence areas, samples was performed. Kusum et al. evaluated a multiplex PCR a positive skin test with an unrelated illness has been frequently using protein b, MPB64 and IS6110 primers and found that this documented. Taking samples from sites of frequent TB infection method had a sensitivity of 94.4% and a specificity of 100% in such as lymph nodes, lung and gastric fluid can increase the like- culture-confirmed Recently, molecular methods capable of lihood of a positive culture. Gastric aspiration was positive in 68% of simultaneously identifying both M. tuberculosis and resistance of the strain to antibiotics have been developed. Among these, the In conclusion, considering the need for a rapid diagnosis of TBM, Xpert M. tuberculosis/RIF assay seems to be the most promising, all possible efforts to demonstrate the probable or possible pres- although no data regarding its use in extrapulmonary TB are ence of this disease must be pursued using all available laboratory available.Finally, preliminary studies have suggested that tests and imaging techniques. Moreover, the potential severity of molecular methods could be used to quantify the bacterial load in TBM calls for the immediate treatment of all the doubtful cases.
CSF and consequently to evaluate treatment response.
In conclusion, making a definite diagnosis of TBM is still a problem. In many cases, diagnosis remains probable or possibleand treatment is initiated without the demonstration of the pres- Independently from the characteristics and duration of the prodromal stage, a definite diagnosis of TBM can be made onlywhen, after a lumbar puncture (LP) in a patient with signs andsymptoms of central nervous system (CNS) disease, acid-fast bacilli (AFB) are seen and/or M. tuberculosis is detected by molecularmethods and/or cultured in cerebrospinal fluid (CSF). The same Treatment of TBM is based on three different components: conclusion can be drawn from autopsy when M. tuberculosis is administration of anti-infective drugs active against M. tuberculosis, identified in histological lesions of the CNS. This is in line with what modulation of the destructive elements of the immune response, has been defined by most of the authors who have made the and management of increased intracranial pressure.
N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383 Table 3Recommended daily dosages of second-line anti-tuberculous drugs for treatment oftuberculous meningitis in infants and children.
Contrary to what applies to pulmonary tuberculosis, recom- mendations 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.
10e15 mg/kg/24 h (max 1 g/day) orallyas a single daily dose 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 15e30 mg/kg/24 h (max 1000 mg) orallyas a single daily dose summarizes the main guidelines for treatment of pedi- atric TBM and 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.
7.5e10 mg/kg/24 h (max 500 mg) orallyas a single daily dose 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 thetotal length of therapy. The intensive phase can range from 2 to 6 considered second-line drugs because of their toxicity.However, months and total treatment from 6 months to one yearUnfor- when TBM has to be treated ETH and cycloserine that have tunately, studies comparing the different schemes of antibiotic a reasonable CSF penetration, even better of that of EBM can be administration in children are not available.Studies regarding considered where they are available.Newer anti-tuberculosis the outcome of 6-month regimens have demonstrated that the drugs, such as fluoroquinolones, have been scarcely used in pedi- relapse rate was not significantly different from that reported when atric TBM and are off-label in children, although for both penetra- longer periods of antibiotic administration were used.This seems tion in CSF and in-vitro efficacy against M. tuberculosis, they are to speak in favor of the shortest therapy. However, because most of these data have been collected in adults, no definitive conclusions Independently from the drugs prescribed, the scheme of admin- can be drawn when children with TBM have to be treated.
istration used, and the total duration of therapy, INH remains the drug According to Donald, in situations where the directly observed most widely prescribed in children for initial TBM treatment.The treatment and follow-up after treatment completion is impeccable, choice of INH is based on several positive factors: the good absorption a 6-month treatment duration is probably satisfactory.When by the gastrointestinal tract, the rapid diffusion in body compart- treatment supervision and/or follow-up are questionable, it may be ments including CSF and the low toxicity. Moreover, it rapidly kills better practice to prolong length of treatment.
most of the replicating M. tuberculosis and, consequently, protects For several years now, the drugs considered essential by the companion drugs against the development of resistance, reduces the World Health Organization (WHO) to treat pulmonary TB in chil- risk of infecting contacts and leads to a more rapid mitigation of dren are isoniazid (INH), rifampicin (RMP),pyrazinamide (PZA), and disease symptoms. In children, INH is recommended at the dose of ethambutol Other drugs, such as streptomycin (SM) or 10 mg/kg/day (range: 6e15 mg/kg/day, maximum 500 mg), generally other aminoglycosides, ethionamide (ETH) and cycloserine are useful to reach in CSF concentrations that are high enough to elimi-nate fully sensitive M. tuberculosis or resistant mutants with a rela-tively low minimum inhibitory concentration (MIC) even in patients who are fast acetylatorsWhen M. tuberculosis resistance is sus- Main guidelines for the treatment of tuberculous meningitis in infants and children.
pected or demonstrated, the highest doses have to be administered,striking the right balance between toxicity and optimal ef Isoniazid 10e20 mg/kg/24 h (max 500 mg) orally for 12 months RMP has the advantage of killing low or non-replicating Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 12 months M. tuberculosis, thus complementing INH activity and allowing Pyrazinamide 30e35 mg/kg/24 h (max 2 g) orally for 2 months the sterilization of lesions. Unfortunately, it has several limits Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months because its concentrations in CSF do not exceed 10% of those in Prednisolone 4 mg/kg/24 h orally for 4 weeks, followed by a its absorption is negatively influenced by food andantacidsand it has a relevant protein binding action that can American Thoracic Society, CDC, and Infectious Diseases Society of America ficantly reduce its clinical efficacy.RMP is officially recom- e15 mg/kg/24 h (max 300 mg) orally for 9e12 months Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 9e12 months mended at the dose of 10e20 mg/kg/daybut, considering the Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months MIC of susceptible M. tuberculosis and the concentrations reached Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months in CSF of it has been recommended to administer the Dexamethasone 8 mg/day/24 h orally for children weighing less than 25 kg highest dosage in young children and infants <10 kg and at least and 12 mg/day for children weighing 25 kg or more for 3 weeks, 15 mg/kg/day in older patients weighing between 10 and 20 followed by a reducing course over 3 weeks 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 Isoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 6 monthsRifampin 10e20 mg/kg/24 h (max 600 mg) orally for 6 months strains with increased MIC are present. However, raising the dose Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months has no effect on highly resistant mutants as their MIC is far too high.
Streptomycin 20e40 mg/kg (max 1 g) i.m. or i.v. for 2 months For the early phase of therapy, PZA and any of the second-line Prednisone 2 mg/kg/24 h orally for 4 weeks, followed by a 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 the severity of increased intracranial preShunting is becomes as effective as INH and RMP.Moreover, together with RMP, it makes an essential contribution to the sterilization of communicating or when medical treatment fails even if it is not lesions and has an important role in reducing the risk of recur- known which kind of shunting is the In communicating rence.PZA is recommended at the dose of 30e35 mg/kg/daily hydrocephalus, diuretics are generally effective in reducing the risk with the highest dosage for younger children. With these regimens, of long-term neurologic impairment. Endoscopic third ven- CSF concentration in excess of 20 mg/mL higher than the MIC of PZA triculostomy is considered a possible option, particularly in patients who have experienced multiple episodes of shunt dysfunct 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 notcontribute to the sterilization of lesions and reduction of the risk of Despite undeniable advances in the identification of markers of relapse. Their contribution to the treatment of TBM is probably definite, probable or possible TBM have been made in recent years, minor, although they protect companion drugs against the emer- most of the problems that pediatricians and neurologists have to face in TBM are still unsolved. The most important difficulty regards The growing emergence of resistant strains has raised the early diagnosis because in those patients in whom TBM is sus- question of the importance of resistance to TBM outcome. Available pected early enough present treatment is sufficient to bring about data clearly indicate that resistance to both INH and RMP signifi- complete cure in the majority of cases, at least when pathogens are cantly worsen the final outcome.The effect of resistance to fully drug susceptible and treatment is complied with. More diffi- a single drug is more controversial. Regarding INH, some studies culties in achieving cure can arise when treatment is delayed and indicate that INH resistance does not influence TBM outcome, when multidrug-resistant pathogens are the cause of the disease. In whereas other studies seem to associate INH resistance to a signif- this case prognosis is poor, particularly in children because it is not icant higher risk of death.These different findings may be due to definitively clear what has to be done when resistance of different doses of INH used and different resistant mutants.
M. tuberculosis to one or more antibiotics is present, which duration However, in order to minimize risks, it has been suggested that of treatment is to be recommended and what is the actual role of duration of treatment for TBM caused by INH-resistant organisms adjunctive therapy. New studies in children are urgently needed. In should be extended and always include PZA as well as a new anti- 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.
This study was supported by a grant from the Italian In meningitis, most of the damage derives from the immune Ministry of Health (Bando Giovani Ricercatori 2007).
response elicited by the presence of bacterial pathogens in theCNS.This leads to a very relevant inflammatory process with The authors have no conflict of interest significant infiltrative, proliferative and necrotizing vessel pathol- ogies.Anti-tuberculous chemotherapy and the administration ofthalidomide and salicylates appear to be relatively ineffective in preventing vascular complications that remain the major unre- Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore solved problem related to TBM. Corticosteroids have been used in Policlinico, Milan, Italy and all the papers included in this review TBM for over 50 years, although the real importance of these drugs have been approved by local Ethical Committees.
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