Tuberculous meningitis with hydrocephalus Contribution of PCR assay of CSF before VP shunting

A 10-month-old infant with tuberculous (Tb) meningitis accompanying hydrocephalus was successfully treated with a VP shunt operation soon after a PCR assay of CSF was found to be negative for Mycobacterium tuberculosis. PCR assay of CSF is helpful for determination of the timing for VP shunting in Tb meningitis. Received: 15 March 1996 Revised: 9 January 1998     

Role of the BACTEC radiometric method in the evaluation of patients with clinically probable tuberculous meningitis

Background:

Confirmation of tuberculous meningitis (TBM) and initiation of treatment are often delayed due to limitations in isolating Mycobacterium tuberculosis from cerebrospinal fluid (CSF).

Objectives:

To evaluate the role of the BACTEC radiometric method in a clinical setting for the early diagnosis of TBM.

Materials and Methods:

Patients meeting criteria for clinically probable TBM over a 3 year period were included. Clinical features, results of CSF investigations (protein, glucose, cell count, Ziehl-Neelsen staining, culture in Löwenstein-Jensen (LJ) medium and BACTEC) and brain CT imaging were reviewed. Drug sensitivity was tested using BACTEC. Patients were started on standard treatment and functional outcome, and response at discharge and follow-up were assessed. Patients were divided according to whether or not M. tuberculosis was isolated by BACTEC and the clinical, radiological, and laboratory features compared.

Results:

Sixty patients were evaluated. The mean age was 30 years ± 11.7 years. Headache and fever were the most common symptoms and the mean duration was 26 days. CT findings were hydrocephalus (n=21), basal exudates (n=16), and tuberculoma (n=14). In 40 patients, M. tuberculosis was isolated by BACTEC and average 15 days was required for detection, whereas it was 30 days in LJ medium. Results of drug-sensitivity testing (n=32) were obtained average 7 days after isolation. Patients from whom M. tuberculosis had been isolated by BACTEC more often had tuberculomas in CT imaging (P=0.018).

Conclusion:

Use of the BACTEC method allows early confirmation in patients with clinically probable TBM. It can guide clinicians in the rational use of anti-tuberculosis treatment by confirming diagnosis and identifying drug- sensitivity.     

Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe

Purpose of Review

Tuberculous meningitis is the most devastating manifestation of infection with Mycobacterium tuberculosis and represents a medical emergency. Approximately one half of tuberculous meningitis patients die or suffer severe neurologic disability. The goal of this review will be to review the pathogenic, clinical, and radiologic features of tuberculous meningitis and to highlight recent advancements in translational and clinical science.

Recent Findings

Pharmacologic therapy includes combination anti-tuberculosis drug regimens and adjunctive corticosteroids. It is becoming clear that a successful treatment outcome depends on an immune response that is neither too weak nor overly robust, and genetic determinants of this immune response may identify which patients will benefit from adjunctive corticosteroids. Recent clinical trials of intensified anti-tuberculosis treatment regimens conducted in Indonesia and Vietnam, motivated by the pharmacologic challenges of treating M. tuberculosis infections of the central nervous system, have yielded conflicting results regarding the survival benefit of intensified treatment regimens. More consistent findings have been observed regarding the relationship between initial anti-tuberculosis drug resistance and mortality among tuberculous meningitis patients.

Summary

Prompt initiation of anti-tuberculosis treatment for all suspected cases remains a key aspect of management. Priorities for research include the improvement of diagnostic testing strategies and the optimization of host-directed and anti-tuberculosis therapies.

     

Multiplex PCR for rapid diagnosis of tuberculous meningitis

Rapid and specific diagnosis of tubercular meningitis is of paramount importance to decrease morbidity and mortality. The aim of the study was to evaluate multiplex PCR using protein b, MPB 64, and IS6110 primers directed against M. tuberculosis complex for the diagnosis of tuberculous meningitis (TBM). Multiplex PCR was performed on 18 TBM confirmed cases (culture was positive), 92 clinically suspected TBM cases and 100 non-TBM (control group) patients. Multiplex PCR had a sensitivity of 94.4% for confirmed cases and specificity of 100% for confirmed TBM cases. In 92 clinically diagnosed but unconfirmed TBM cases, multiplex PCR was positive in 84.78% cases. The overall sensitivity of microscopy, culture and multiplex cases were 1.81, 16.73, and 86.63% and specificity was 100, 100, and 100% respectively. Multiplex PCR using protein b, MPB 64, and IS6110 primers has a high sensitivity and specificity in diagnosis of tubercular meningitis.     

The role of aspirin in childhood tuberculous meningitis

Arterial stroke is the main cause of poor outcome in childhood tuberculous meningitis. Aspirin has an antithrombotic action at low dose and anti-ischemic and anti-inflammatory properties, which are dose-related. The aim of the study was to explore the possible benefits of aspirin in children with tuberculous meningitis. A total of 146 consecutive children with a diagnosis of probable tuberculous meningitis were studied. Patients were randomized into 3 groups: (1) placebo group, (2) low-dose aspirin group, and (3) high-dose aspirin group. Twenty-nine additional patients who received aspirin before admission were excluded from the randomized study, but continued on low-dose aspirin. Aspirin, irrespective of dose, did not show any significant benefit regarding morbidity (hemiparesis and developmental outcome) and mortality. Aspirin was well tolerated, but 1 death was probably related to aspirin. The fact that the outcome of the high-dose aspirin group compared favorably with the other treatment groups despite younger age and more severe neurological involvement at baseline needs further investigation.     

Tuberculous meningitis in Bacille Calmette-Guerin-vaccinated children: clinical spectrum and outcome

The Bacille Calmette-Guérin vaccination (BCG) contributed widely to reduce tuberculosis incidence in developing countries. The aim of this report was to assess the clinical "spectrum" and outcome of tuberculous meningitis in 16 Bacille Calmette-Guérin-vaccinated Tunisian children. They were 9 boys and 7 girls aged 2 to 168 months (median 72 months ± 65.88). Patients presented mainly with nonspecific symptoms. Neurologic severity was classified as grade I (n = 6) and grade II or III (n = 10). At short-term course, the majority of patients developed serious complications: hydrocephalus (n = 12), seizures (n = 8), tuberculoma (n = 6), and acute respiratory failure (n = 2). Three patients died. Among survivors, 4 patients showed a complete recovery while 9 developed permanent sequelae which were mild (n = 6) to severe (n = 3). Despite the Bacille Calmette-Guérin vaccination, tuberculous meningitis remains a life-threatening condition; vaccinated children have shown common presentation of tuberculous meningitis in terms of severity and poor outcome.     

Childhood Tubercular Meningitis: An Institutional Experience and Analysis of Predictors of Outcome

Tubercular meningitis constitutes an important cause of morbidity and mortality in developing countries, and various factors determine its outcome. We studied demographic and clinical profiles of childhood tubercular meningitis, and identified predictors of outcome. This prospective study was performed in 65 children aged ≤18 years, hospitalized with a diagnosis of tubercular meningitis. Boys outnumbered girls. Most patients presented with a poor clinical grade. Headache and vomiting comprised common features. Cerebrospinal fluid was characterized by predominant lymphocytosis. Many patients were diagnosed for Mycobacterium tuberculosis via polymerase chain reaction. Hydrocephalus comprises a common finding via computed tomography. Low Glasgow Coma Scores, seizures, basal exudates, and infarcts predict outcomes. Children with headaches, fevers, and altered sensorium should be investigated promptly for tubercular meningitis. Timely intervention may lead to early diagnoses and reductions in morbidity and mortality.     

Detection of mycobacterial antigen in cerebrospinal fluid: diagnostic and prognostic significance

Inhibition enzyme-linked immunosorbent assay (ELISA) was standardised to quantitate circulating mycobacterial antigens in cerebrospinal fluid (CSF) specimens. Of the 40 patients with clinical diagnosis of tuberculous meningitis, the assay was found to be positive in 26 patients. In a control group of 42 patients with non-tuberculous neurological diseases the assay was negative. The assay showed a sensitivity of 65 and 100% specificity for tuberculous meningitis. In 8 patients with tuberculous meningitis receiving chemotherapy, multiple CSF examinations were subjected to this assay. The antigen concentration showed a gradual decrease between 3 and 4 weeks after the commencement of antituberculosis chemotherapy. There was a positive correlation between clinical recovery and antigen concentration. Detection of mycobacterial antigen in CSF specimen by inhibition ELISA has not only diagnostic utility but also could be applied to monitor antituberculosis chemotherapy in patients with tuberculous meningitis. The assay is reproducible and feasible for routine immunology laboratory. It also could be considered as a diagnostic aid when repeated bacteriological cultures are negative in CSF specimens of patients with tuberculous meningitis.     

Chronic bilateral hearing loss in an immunocompetent patient: An atypical course of tuberculous meningitis

Congenital, infectious, toxic, and demyelinating disorders are common etiological causes of deafness. Tuberculous meningitis, as one of the infectious causes, should be considered in the differential diagnosis since tuberculosis represents an endemic public health problem in developing countries. Multiple cranial nerve palsies can be expected due to basal meningitis; however, presentation with bilateral hearing loss is quite rare. Early diagnosis and treatment are crucial to prevent mortality and residual neurologic deficits. The focus of this discussion is a 42-year-old female presenting with bilateral hearing loss and nonspecific complaints who was finally diagnosed with chronic tuberculous meningitis. We also demonstrate the characteristic radiological and histopathological findings.Congenital, infectious, toxic, vascular, tumoral, and demyelinating disorders are common etiologic factors that can result in deafness. Acoustic trauma, endolymphatic hydrops, and senility are relatively rare causes that should also be taken into account. Bilateral hearing loss is an unusual clinical presentation, resulting from any one of these conditions. Among the infectious causes, tuberculosis still represents an endemic public health problem in developing countries and tuberculous meningitis, which is the most common form of CNS involvement, accounts for 1-2% of these cases.1 Sufferers generally describe constitutional symptoms including fever and night sweats or various complaints arising from basal meningitis like headache, nausea, and/or vomiting; however, presentation with bilateral hearing loss is quite rare. The objective of this case presentation is to include tuberculous meningitis in the differential diagnosis of progressive bilateral hearing loss, and emphasize the importance of early diagnosis and treatment to prevent morbidity and mortality.     

A case report of tuberculous meningitis: limits of detection using polymerase chain reaction (PCR) and treatments]

A 40-year-old man with intractable meningitis was transferred to our hospital 6 weeks after onset. On admission, he showed consciousness disturbance, meningeal signs and right oculomotor nerve palsy. MRI demonstrated prominent cisternal enhancement and hydrocephalus. We suspected tuberculous meningitis as the diagnosis, and treated with antituberculotics, though he died of midbrain infarction day 11 of the treatment. Before and during the admission, bacterial cultures, PCR, smear examination of cerebrospinal fluid(CSF) were repeated. But no evidence of tuberculosis was obtained. Cultures of the brainstem fragments detected mycobacterium, which was finally confirmed by a PCR method after his death. PCR provides a rapid and reliable diagnosis of tuberculous meningitis, although there is a potential for false-negative. Thus the clinical, radiological and CSF findings should be stressed. Corticosteroids treatment should be considered in cases with ischemic lesions.     

To compare CSF adenosine deaminase levels and CSF-PCR for tuberculous meningitis

This study was planned to compare the adenosine deaminase (ADA) levels and polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) as a rapid method to diagnose tuberculosis meningitis (TBM). Fifty-four adult patients with suspected TBM and 37 controls were included in this study. The median ADA level was 21 U/L of most likely TBM, 14 U/L of unconfirmed TBM and 5 U/L of controls. PCR for Mycobacterium tuberculosis was positive in 12 out of 27 most likely TBM cases, 5 out of 27 unconfirmed TBM cases and 3 out of 37 controls. Using a cut off level of >10 U/L, CSF-ADA had a sensitivity of 92.5% and specificity of 97% for the diagnosis of TBM. PCR for M. tuberculosis had a sensitivity of 44.5% and specificity 92% in the most likely TBM cases. This study shows that CSF-ADA is a more sensitive indicator than PCR for the diagnosis of M. tuberculosis.     

Chronic meningitis in Thailand. Clinical characteristics, laboratory data and outcome in patients with specific reference to tuberculosis and cryptococcosis

The charts of 114 consecutive patients with chronic meningitis admitted to a general hospital in Bangkok, Thailand, between 1993 and 1999 were retrospectively reviewed. The most common causative agents were Cryptococcus neoformans (54%) and Mycobacterium tuberculosis (37%). HIV and other underlying diseases had a major impact on the presentation of chronic cryptococcal meningitis patients. Compared to HIV-negative cryptococcal meningitis patients (21%), HIV-positives (79%) had a significantly lower incidence of focal signs (p = 0.02), hydrocephalus (p = 0.03) and seizures (p = 0.001) during hospital stay, furthermore, a lower leucocyte level, a significantly higher glucose level (p = 0.02) and a lower protein level (p = 0.03) in the first cerebrospinal fluid examination. Of the 43 patients with chronic tuberculous meningitis, only 3 were HIV positive. Focal neurologic deficits were found more frequently in tuberculous meningitis patients (p = 0.001) when compared to cryptococcal meningitis patients without HIV. Cerebral infarction on cerebral CT was indicative of tuberculous meningitis. Cryptococcal meningitis patients with HIV infection had a worse outcome compared to non-AIDS patients. Advanced stage of the disease on admission, decreased level of consciousness prior to and on the admission day and raised intracranial pressure above 40 cm H(2)O at any given time were predictive of a poor outcome in tuberculous meningitis patients.     

Clinical correlation of CT changes in 64 Chinese patients with tuberculous meningitis

Summary CT changes in 64 Chinese patients with proven tuberculous meningitis were compared with the clinical features at diagnosis. In patients presenting with advanced disease, hydrocephalus and cerebral infarction were common, and the hydrocephalus in these patients was more likely to require surgery at a later date for control of raised intracranial pressure. New infarctions were only seen in follow-up scans of patients who had presented with disturbed consciousness. Meningeal enhancement, the commonest finding, and intracranial tuberculomata were not related to the severity of disease at presentation. A normal scan in a drowsy patient virtually excludes the diagnosis of tuberculous meningitis. Present address: MRI Centre. Churchill Clinic, London SE1 7PW. UK     

Acute polyradiculopathies in HIV-infected patients

We studied 17 consecutive cases of acute polyradiculopathy (PR) diagnosed in HIV-infected patients to investigate the possible causes of this syndrome in our milieu. Sixteen patients presented with lumbosacral PR and one patient had predominantly cervical PR. Electrophysiological study showed a predominantly motor axonal neuropathy in all patients examined. Six patients had a laboratory-confirmed aetiology for the PR: cytomegalovirus (CMV) was isolated from cerebrospinal fluid (CSF) in three cases, meningeal lymphomatosis was diagnosed by CSF cytology in two cases, and one patient had cryptococcal meningitis. Another patient was thought to have acute axonal polyradiculoneuritis associated with HIV infection. CMV and Mycobacterium tuberculosis were the probable agents in four and three patients, respectively. Finally, in three patients a cause could not be established. Both ganciclovir and foscarnet were effective in the treatment of definite or probable CMV PR. The present study confirms that acute lumbosacral PR in HIV-infected patients must be considered a syndrome with different causes. CMV and M. tuberculosis infections were the most frequent causative agents in our series (41% and 18% of the cases, respectively). Early empirical therapy is often necessary as definite diagnosis may be delayed or never achieved. Our experience suggests that, at least in our milieu, antituberculous drugs should be considered in some cases together with ganciclovir or foscarnet in the empirical therapy for PR in HIV-infected patients. Received: 14 April 1997 / Accepted: 6 June 1997     

Rapid diagnosis of tuberculous meningitis by polymerase chain reaction (PCR)]

Using polymerase chain reaction (PCR), a rapid and highly sensitive method was developed for the diagnosis of tuberculous meningitis. The mycobacterium tuberculosis (M. tuberculosis) genome was detected in CSF of 5 of 6 patients with clinically diagnosed tuberculous meningitis, but not present in CSF from 10 patients with other types of meningitis and 10 normal controls. Furthermore, we detected M. tuberculosis in CSF of 2 of 24 patients with clinically possible tuberculous meningitis. This is highly useful method for the rapid diagnosis of tuberculous meningitis over other conventional method.     

Interferon γ quantification in cerebrospinal fluid compared with PCR for the diagnosis of tuberculous meningitis

PURPOSE: To assess the utility of interferon gamma (INF-gamma) levels in cerebrospinal fluid (CSF), for the diagnosis of tuberculous meningitis (TBM), and compare these results with aPCR technique. METHODS: We studied CSF samples from patients with proven or probable TBM and a control group, composed by patients with other causes of meningitis and without meningitis. INFgamma levels were measured by radioimmunoassay. A PCR technique was performed using IS6110 primers. RESULTS: Of the 127 patients studied, 20 (15.6%) had TBM, 59 (46%) had meningitis of another aetiology and 49 (38.4%) had were HIV and non-HIV patients with normal CSF. The area below the ROC curve for interferon gamma levels in the diagnosis of TBM was 0.94. A cut-off of 6.4 IU/mL yielded a sensitivity of 70% and a specificity of 94%. False positive results were observed in 7 of the 59 patients (11.8%) with non-TB meningitis, (patients with herpetic meningoencephalitis and meningitis due to intracellular microorganisms). INF-gamma sensitivity was higher than PCR (70% vs. 65%). Both tests performed together showed higher sensitivity (80%) and specificity (92.6%). CONCLUSION: CSF INF-gamma levels (> 6.4 IU/mL) are very valuable in TBM diagnosis. PCR and INF-gamma could be simultaneously used to increase the diagnostic yield.     

Tuberculous meningitis: pitfalls in diagnosis

OBJECTIVES: The diagnosis of tuberculous meningitis is easily missed because the variety of symptoms give rise to problems with the differential diagnosis. MATERIAL: Five cases of difficult to diagnose tuberculous meningitis are presented. RESULTS: Several reasons for the diagnostic delay are highlighted. The fact that tuberculous meningitis is rather rare in developed countries contributes to this problem. Recommendations for a quick diagnosis are given. CONCLUSION: The diagnosis of tuberculous meningitis in developed countries is often made after a substantial delay. In case of suspicion on the diagnosis additional examination should be performed and treatment should be started immediately.     

Diagnosis of tuberculosis infection based on synthetic peptides from Mycobacterium tuberculosis antigen 85 complex

Aim

The laboratory diagnosis of pulmonary tuberculosis (TB) and tuberculous meningitis (TBM) is particularly challenging. The aim of the present work is to develop an immunoassay for the diagnosis of TB infection, using synthetic peptides of antigen (Ag) 85 complex of M. tuberculosis (Mtb) H₃₇Rv.

Methods

Four peptides (7–10 amino acids long) corresponding to group-specific epitopes of Ag 85 complex of Mtb were synthesized. All peptides were evaluated by enzyme-linked immunosorbent assay (ELISA) for immunoreactivity with sera and CSF samples of TB and TBM patients respectively. The diagnostic value of the four peptides was evaluated in both the samples.

Results

It was observed that Ag 85 peptide 1, 3 and 4 had the highest positive rates in the pulmonary patients; however, Ag 85 peptide 1 and 2 had shown good positivity in the TBM subjects.

Conclusions

The synthetic peptide based ELISA using Ag 85 complex peptides is a sensitive, specific, rapid and cost effective immunoassay for early diagnosis of pulmonary and extrapulmonary TB. In addition, these synthetic peptides are comparatively easy to produce in a reproducible manner compared with the whole antigen.     

Serial MRI to determine the effect of dexamethasone on the cerebral pathology of tuberculous meningitis: an observational study

BACKGROUND: Adjunctive dexamethasone increases survival from tuberculous meningitis, but the underlying mechanism is unclear. We aimed to determine the effect of dexamethasone on cerebral MRI changes and their association with intracerebral inflammatory responses and clinical outcome in adults treated for tuberculous meningitis. METHODS: Cerebral MRI was undertaken, when possible, at diagnosis and after 60 days and 270 days of treatment in adults with tuberculous meningitis admitted to two hospitals in Vietnam. Patients were randomly assigned either dexamethasone (n=24) or placebo (n=19) and received 9 months of treatment with standard first-line antituberculosis drugs. We assessed associations between MRI findings, treatment allocation, and resolution of fever, coma, cerebrospinal fluid inflammation, and neurological outcome. FINDINGS: 83 scans were done for 43 patients: 19 given placebo, 24 given dexamethasone. Basal meningeal enhancement (82%) and hydrocephalus (77%) were the most common presenting findings. Fewer patients had hydrocephalus after 60 days of treatment with dexamethasone than after placebo treatment (p=0.217). Tuberculomas developed in 74% of patients during treatment and in equal proportions in the treatment groups; they were associated with long-term fever, but not relapse or poor clinical outcome. The basal ganglia were the most common site of infarction; the proportion with infarction after 60 days was halved in the dexamethasone group (27%vs 58%, p=0.130). INTERPRETATION: Dexamethasone may affect outcome from tuberculous meningitis by reducing hydrocephalus and preventing infarction. The effect may have been under-estimated because the most severe patients could not be scanned.