Elsevier

The Lancet

Volume 360, Issue 9342, 26 October 2002, Pages 1287-1292
The Lancet

Articles
Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features

https://doi.org/10.1016/S0140-6736(02)11318-3Get rights and content

Summary

Background

The diagnosis of tuberculous meningitis is difficult. Discrimination of cases from those of bacterial meningitis by clinical features alone is often impossible, and current laboratory methods remain inadequate or inaccessible in developing countries. We aimed to create a simple diagnostic aid for tuberculous meningitis in adults on the basis of clinical and basic laboratory features.

Methods

We compared the clinical and laboratory features on admission of 251 adults at an infectious disease hospital in Vietnam who satisfied diagnostic criteria for tuberculous (n=143) or bacterial (n=108) meningitis. Features independently predictive of tuberculous meningitis were modelled by multivariate logistic regression to create a diagnostic rule, and by a classification-tree method. The performance of both diagnostic aids was assessed by resubstitution and prospective test data methods.

Findings

Five features were predictive of a diagnosis of tuberculous meningitis: age, length of history, white-blood-cell count, total cerebrospinal fluid white-cell count, and cerebrospinal fluid neutrophil proportion. A diagnostic rule developed from these features was 97% sensitive and 91% specific by resubstitution, and 86% sensitive and 79% specific when applied prospectively to a further 42 adults with tuberculous meningitis, and 33 with bacterial meningitis. The corresponding values for the classification tree were 99% and 93% by resubstitution, and 88% and 70% with prospective test data.

Interpretation

This study suggests that simple clinical and laboratory data can help in the diagnosis of adults with tuberculous meningitis. Although the usefulness of the diagnostic rule will vary depending on the prevalence of tuberculosis and HIV-1 infection, we suggest it be applied to adults with meningitis and a low cerebrospinal fluid glucose, particularly in settings with limited microbiological resources.

Introduction

The prompt diagnosis and treatment of tuberculous meningitis saves lives.1, 2, 3, 4, 5 However, about 30% of patients with tuberculous meningitis die despite anti-tuberculosis chemotherapy.6 Delays in diagnosis and treatment are regarded as major contributing factors in the high mortality reported in many recent series.7, 8, 9, 10 The diagnosis of tuberculous meningitis relies on isolation of Mycobacterium tuberculosis from the cerebrospinal fluid. Unfortunately, culture is too slow and insensitive to aid clinical decision-making. Direct Ziehl-Neelsen staining of the cerebrospinal fluid for acid-fast bacilli remains the cornerstone of rapid diagnosis, but this technique lacks sensitivity.6 Newer diagnostic techniques, such as those that use PCR, have not been assessed completely,11 and are not possible in most settings in the developing world where most cases of tuberculous meningitis are seen.12, 13 Consequently, the decision to treat a patient for tuberculous meningitis is frequently empirical, irrespective of the diagnostic facilities available to clinicians. Until new, affordable, sensitive, and specific diagnostic assays become available, clinicians must depend on the discriminative clinical and laboratory features of the disease for successful diagnosis and treatment.

The presenting clinical features of tuberculous meningitis in adults are similar to those of many meningo-encephalitides, which result in frequent diagnostic confusion. Delays in starting appropriate antibiotics for tuberculous meningitis or pyogenic meningitis worsens prognosis, yet physicians are often reluctant to start months of antituberculosis treatment without firm evidence. Diagnostic uncertainty arises commonly in patients who present with a few days of headache, fever, and neck-stiffness; undefined treatment in the community; a low concentration of glucose in cerebrospinal fluid (<50% of that in blood), and neutrophils and lymphocytes in the cerebrospinal fluid.

Multivariate logistic regression has been used to model the clinical predictors of tuberculous meningitis in 232 children.14 Five presenting clinical features were found to be independently predictive of tuberculous meningitis: prodromal stage 7 days or longer, optical atrophy on fundal examination, focal deficit, abnormal movements, and cerebrospinal fluid leucocytes comprising less than 50% polymorphs. The researchers developed a simple diagnostic rule. Sensitivity was 98·4% and specificity 43·5% when one or more predictor variables were present, and specificity was 98·3% and sensitivity 54·5% if three or more were present. However, there are several problems with this rule. First, the performance of the rule varies according to the prevalence of tuberculosis. Second, the rule can be difficult to apply: if antituberculosis chemotherapy is started on the basis of one diagnostic variable, more than 50% will be wrongly treated; if treatment is only begun in the presence of three variables, nearly half will not receive appropriate treatment. In the first scenario, patients are unnecessarily exposed to the risks of drug toxicity. In the second, many patients could die. Finally, a rule developed in children might not be applicable to adults.

Nevertheless, there are strong arguments for developing a simple diagnostic algorithm for tuberculous meningitis in areas of high tuberculosis prevalence. First, tuberculous meningitis tends to be commonest in areas with the least clinical and laboratory resources. Second, a diagnostic rule developed and used in high tuberculosis prevalence areas is likely to perform consistently. And third, early diagnosis and treatment improves outcome.1, 2, 3, 4, 5 We aimed to develop such a diagnostic algorithm on the basis of clinical and laboratory findings of adult patients in Vietnam.

Section snippets

Patients

The adults described in this study were admitted to the Clinical Research Unit at the Centre for Tropical Diseases, Ho Chi Minh City, Vietnam. The Centre for Tropical Diseases is a 500-bed infectious diseases hospital that serves the local community, and acts as the tertiary referral centre for infectious disease for the whole of southern Vietnam. The hospital treats about 30 000 inpatients and 52 000 outpatients each year. The Clinical Research Unit is a 15-bed ward for patients with

Results

357 adults were admitted to the Centre for Tropical Diseases with meningitis between 1997 and 2000. 251 satisfied the diagnostic criteria for inclusion in this study: 143 with tuberculous meningitis, and 108 with bacterial meningitis. 66 of the 251 adults were tested for antibodies to HIV-1: eight were positive (seven with tuberculous meningitis, one with bacterial meningitis).

163 of 357 adults received antituberculosis chemotherapy for suspected tuberculous meningitis: M tuberculosis was

Discussion

The diagnosis of tuberculous meningitis in adults is difficult whatever the resources available to the physician. This study used diagnostic criteria derived from cerebrospinal fluid culture results and observed response to specific treatment. Such criteria suggest that even in the best settings cerebrospinal fluid culture is insensitive, and some cases of tuberculous meningitis or bacterial meningitis will never be proven microbiologically.

Because untreated tuberculous meningitis is always

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