Johan F. Schoeman

Tuberculous meningitis: a uniform case definition for use in clinical research

Tuberculous meningitis causes substantial mortality and morbidity in children and adults. More research is urgently needed to better understand the pathogenesis of disease and to improve its clinical management and outcome. A major stumbling block is the absence of standardised diagnostic criteria. The different case definitions used in various studies makes comparison of research findings difficult, prevents the best use of existing data, and limits the management of disease. To address this problem, a 3-day tuberculous meningitis workshop took place in Cape Town, South Africa, and was attended by 41 international participants experienced in the research or management of tuberculous meningitis. During the meeting, diagnostic criteria were assessed and discussed, after which a writing committee was appointed to finalise a consensus case definition for tuberculous meningitis for use in future clinical research. We present the consensus case definition together with the rationale behind the recommendations. This case definition is applicable irrespective of the patients age, HIV infection status, or the resources available in the research setting. Consistent use of the proposed case definition will aid comparison of studies, improve scientific communication, and ultimately improve care.

Twenty Years of Pediatric Tuberculous Meningitis: A Retrospective Cohort Study in the Western Cape of South Africa

OBJECTIVE. Tuberculous meningitis is the most severe extrapulmonary complication of tuberculosis, with high morbidity and mortality rates. The objective of this study was to assess the relationship between presenting clinical characteristics and outcome of pediatric tuberculous meningitis. PATIENTS AND METHODS. We present a retrospective cohort study of all of the children diagnosed with tuberculous meningitis in a large university hospital in South Africa between January 1985 and April 2005. We compared demographic, clinical, and diagnostic characteristics with clinical outcome after 6 months of treatment. RESULTS. We included 554 patients. Common characteristics on admission were young age (82%; <5 years), stage II or III tuberculous meningitis (97%), nonspecific symptoms existing for >1 week (58%), poor weight gain or weight loss (91%), loss of consciousness (96%), motor deficit (63%), meningeal irritation (98%), raised intracranial pressure (23%), brainstem dysfunction (39%), and cranial nerve palsies (27%). Common features of tuberculous meningitis on computed tomography scan of the brain were hydrocephalus (82%), periventricular lucency (57%), infarctions (32%), and basal meningeal enhancement (75%). Clinical outcome after 6 months was as follows: normal (16%), mild sequelae (52%), severe sequelae (19%), and death (13%). All of the patients diagnosed with stage I tuberculous meningitis had normal outcome. Factors associated with poor outcome in univariate analyses were as follows: African ethnicity, young age, HIV coinfection, stage III tuberculous meningitis, absence of headache and vomiting, convulsions, decreased level of consciousness, motor deficits, cranial nerve palsies, raised intracranial pressure, brainstem dysfunction and radiographic evidence of hydrocephalus, periventricular lucency, and infarction. Ethnicity, stage of disease, headache, convulsions, motor function, brainstem dysfunction, and cerebral infarctions were independently associated with poor outcome in multivariate logistic regression analysis. CONCLUSIONS. Tuberculous meningitis starts with nonspecific symptoms and is often only diagnosed when brain damage has already occurred. Earlier diagnosis will improve outcome significantly. We were able to identify presenting variables independently associated with poor clinical outcome.

Tuberculous meningitis: more questions, still too few answers

Tuberculous meningitis is especially common in young children and people with untreated HIV infection, and it kills or disables roughly half of everyone affected. Childhood disease can be prevented by vaccination and by giving prophylactic isoniazid to children exposed to infectious adults, although improvements in worldwide tuberculosis control would lead to more effective prevention. Diagnosis is difficult because clinical features are non-specific and laboratory tests are insensitive, and treatment delay is the strongest risk factor for death. Large doses of rifampicin and fluoroquinolones might improve outcome, and the beneficial effect of adjunctive corticosteroids on survival might be augmented by aspirin and could be predicted by screening for a polymorphism in LTA4H, which encodes an enzyme involved in eicosanoid synthesis. However, these advances are insufficient in the face of drug-resistant tuberculosis and HIV co-infection. Many questions remain about the best approaches to prevent, diagnose, and treat tuberculous meningitis, and there are still too few answers.

Ventriculoperitoneal shunting in childhood tuberculous meningitis

Hydrocephalus is a common complication of tuberculous meningitis (TBM) in children. In this study, 217 patients with stage II and III TBM and hydrocephalus (TBMH) were reviewed. Ventriculoperitoneal shunting (VPS) was performed in the acute stage if the hydrocephalus was non-communicating or following failed medical therapy if the hydrocephalus was communicating. Following this protocol only 65 of 217 (29.9%) patients eventually required VPS. Non-communicating hydrocephalus was present in 38 of 65 (58.5%) and communicating hydrocephalus in 27 of 65 (41.5%) of the shunted cases. These 65 cases were followed for 6 months and their outcome assessed. Good outcome or moderate disability was seen in 55.4% and 12.3% died. Different factors relating to outcome are discussed. The shunted patients in this study had a high complication rate of 32.3%, with shunt infection and shunt obstruction each occurring in 9 of 65 (13.5%) of cases. TBM complicated by hydrocephalus remains a devastating condition and VPS in these patients has a high complication rate. Identifying those patients who may be managed without shunting will save costs and reduce complications, however early VPS in patients with non-communicating hydrocephalus is still indicated.Hydrocephalus is a common complication of tuberculous meningitis (TBM) in children. In this study, 217 patients with stage II and III TBM and hydrocephalus (TBMH) were reviewed. Ventriculoperitoneal shunting (VPS) was performed in the acute stage if the hydrocephalus was non-communicating or following failed medical therapy if the hydrocephalus was communicating. Following this protocol only 65 of 217 (29.9%) patients eventually required VPS. Non-communicating hydrocephalus was present in 38 of 65 (58.5%) and communicating hydrocephalus in 27 of 65 (41.5%) of the shunted cases. These 65 cases were followed for 6 months and their outcome assessed. Good outcome or moderate disability was seen in 55.4% and 12.3% died. Different factors relating to outcome are discussed. The shunted patients in this study had a high complication rate of 32.3%, with shunt infection and shunt obstruction each occurring in 9 of 65 (13.5%) of cases. TBM complicated by hydrocephalus remains a devastating condition and VPS in these patients has a high complication rate. Identifying those patients who may be managed without shunting will save costs and reduce complications, however early VPS in patients with non-communicating hydrocephalus is still indicated.

Serial CT Scanning in Childhood Tuberculous Meningitis: Prognostic Features in 198 Cases

Serial cranial computed tomographic (CT) scanning and intracranial pressure monitoring were performed on 198 children with stage II and III tuberculous meningitis. The aims of the study were to document the course of tuberculous hydrocephalus during medical and surgical treatment, as well as the prognostic significance of parenchymal changes in the brain as demonstrated by CT. Lumbar cerebrospinal fluid pressure was monitored continuously for a 1-hour period in all patients on admission and at weekly intervals in patients with communicating hydrocephalus for the 1st month of treat ment. Cranial CT scanning was done on admission and repeated in survivors after 1 month and again after 6 months of antituberculous therapy. The raised intracranial pressure of 112 children with communicating hydrocephalus, as demonstrated by air-encephalography, was treated medically (with daily acetazolamide and furosemide) for 1 month. Thirty-one children with noncommunicating hydrocephalus were referred for immediate ventriculoperitoneal shunting. No significant difference was found in the eventual ventricular size or clinical outcome between the two treatment groups. Lumbar cerebrospinal fluid pressure changes in the children with communicating hydrocephalus closely followed changes in the degree of hydrocephalus during the course of treatment.The main cause of permanent neurologic disability was basal ganglia infarction, which occurred unilaterally in 21% and bilaterally in 10% of patients on admission and developed in a further 22% of children during treatment. A prominent subarachnoid space, which was seen on the CT scan of 36% of patients after the 1st month of treatment and which reverted to normal, probably relates to the poor nutritional state of these patients on admission. Serial CT scanning was found to be valuable in defining the respective roles of raised intracranial pressure and parenchymal disease in the outcome of tuberculous meningitis. (J Child Neurol 1995; 10:320-329).

Adjunctive Thalidomide Therapy for Childhood Tuberculous Meningitis: Results of a Randomized Study

Childhood tuberculous meningitis is associated with serious long-term sequelae, including mental retardation, behavior disturbances, and motor handicap. Brain damage in tuberculous meningitis results from a cytokine-mediated inflammatory response, which causes vasculitis and obstructive hydrocephalus. Thalidomide, a potent tumor necrosis factor α inhibitor, was well tolerated and possibly showed some clinical benefit in children with tuberculous meningitis during a pilot study. The purpose of the present study was to assess the effect of adjunctive thalidomide in addition to standard antituberculosis and corticosteroid therapy on the outcome of tuberculous meningitis. Thalidomide (24 mg/kg/day orally) or placebo was administered in a double-blind randomized fashion for 1 month to patients with stage 2 or 3 tuberculous meningitis. The study was terminated early because all adverse events and deaths occurred in one arm of the study (thalidomide group). Thirty of the 47 children enrolled received adjunctive thalidomide, of whom 6 (20%) developed a skin rash, 8 (26%) hepatitis, and 2 (6%) neutropenia or thrombocytopenia. Four deaths (13%) occurred in patients with very severe neurologic compromise at baseline; two deaths were associated with a rash. Motor outcome after 6 months of antituberculosis therapy was similar in the two groups, even though the thalidomide group showed greater neurologic compromise on admission. In addition, the mean IQ of the two treatment groups did not differ significantly (mean IQ thalidomide group 57.8 versus mean IQ control group 67.5; P = 16). These results do not support the use of adjunctive high-dose thalidomide therapy in the treatment of tuberculous meningitis. (J Child Neurol 2004;19:250-257).

Tuberculous cerebrovascular disease: A review

Cerebrovascular complications of tuberculous meningitis are common, and may represent its most serious legacy. They present in clinically diverse ways, and continue to develop during the initial stages of treatment. Magnetic resonance imaging is the imaging modality of choice in detecting brain infarcts, typically revealing multiple or bilateral lesions in the territories of the middle cerebral artery perforating vessels. Vessel pathology appears to be a consequence of its immersion in the local inflammatory exudate. Infiltrative, proliferative and necrotising vessel pathologies have been described, but the relative contributions of each and of luminal thrombosis to brain damage remain unclear. There is some evidence that vasospasm may mediate strokes early in the course of the disease and proliferative intimal disease later strokes. Anti-tuberculous chemotherapy appears to be relatively ineffective in preventing vascular complications, perhaps suggesting an immune mechanism. However, a preventive role for corticosteroids remains to be proven. Study of the molecular pathogenesis of TBM vasculopathy is in its infancy. This review focuses in particular on pathogenetic aspects of tuberculous cerebrovascular disease, with a view to its future targeted prevention.

Tuberculous Hydrocephalus: Comparison of Different Treatments With Regard to Icp, Ventricular Size and Clinical Outcome

The effect of different treatment regimes on intracranial pressure (ICP), degree of hydrocephalus and clinical outcome was evaluated in 81 children with tuberculous meningitis. 24 children underwent CSF shunting, while 57 with communicating hydrocephalus were randomly assigned to three treatment groups: antituberculous drugs only; or additional intrathecal hyaluronidase or oral acetazolamide and furosemide in addition to antituberculous treatment. The addition of acetazolamide and furosemide was significantly more effective in achieving normal ICP than antituberculous drugs alone. No difference was found in mortality or number of disabled survivors between groups. Of those surviving, nearly two‐thirds with stage II tuberculous meningitis were mildly disabled and nearly one‐half with stage III were severely disabled at follow‐up, emphasising the need for early diagnosis of tuberculous meningitis in the young child.

Childhood Pseudotumor Cerebri: Clinical and Intracranial Pressure Response to Acetazolamide and Furosemide Treatment in a Case Series

The purpose of this study was to investigate the efficacy of combined therapy with acetazolamide and furosemide in normalizing intracranial pressure in children with pseudotumor cerebri. The role of repeated lumbar cerebrospinal fluid pressure monitoring in evaluating the response to therapy is also demonstrated. Continuous 1-hour lumbar cerebrospinal fluid pressure monitoring was done in eight children with pseudotumor cerebri on admission and at weekly intervals until the baseline pressure had normalized. (One child had two episodes of pseudotumor cerebri). All patients were treated with oral acetazolamide and furosemide until papilledema had cleared. Raised intracranial pressure was present on admission in all nine episodes of pseudotumor cerebri. Six children had an increased baseline cerebrospinal fluid pressure, whereas raised intracranial pressure was diagnosed in three children on account of an abnormal pulse wave and/or pressure waves. The mean baseline pressure was significantly lower after the 1st week of treatment than on admission (P = .007) and normalized in all patients within 6 weeks of start of therapy. All children had a rapid clinical response. Combined therapy with acetazolamide and furosemide is an effective first-line method of treating raised intracranial pressure in children with pseudotumor cerebri. The good correlation found between the clinical response and normalization of baseline cerebrospinal fluid pressure suggests that clinical monitoring of treatment is adequate in most children with this condition. (J Child Neurol 1994;9:130-134).

Comparison of diagnostic criteria of tuberculous meningitis in human immunodeficiency virus-infected and uninfected children

Introduction: Tuberculous (TB) meningitis is sometimes difficult to diagnose in young children. The decision to start anti-TB treatment of TB meningitis is usually made on clinical grounds and results of special investigations, such as cerebrospinal fluid examination and cranial computerized tomography (CT), because bacteriologic yield is low and the results delayed. Aim: To determine whether the clinical, laboratory, and radiologic criteria used in the diagnosis of TB meningitis in human immunodeficiency virus (HIV)-uninfected children apply to HIV-infected children. Methods: Retrospective, case-control study. Clinical, laboratory, and radiologic features of TB meningitis were compared in 34 HIV-infected and 56 HIV-uninfected patients matched for age and stage of TB meningitis. Results: All clinical differences found between the 2 groups at admission were related to the underlying HIV disease. Neurologic presentation and cerebrospinal fluid findings at admission did not differ significantly between the 2 groups. Significantly more HIV-infected than HIV-uninfected children had evidence of TB on chest radiography. The classic CT signs of TB meningitis (obstructive hydrocephalus and basal enhancement) were significantly less prominent in the HIV-infected group (P < 005). Conclusion: The diagnostic criteria for clinical diagnosis of TB meningitis apply to HIV-infected children. However, cranial CT findings in this group may be misleading and delay the diagnosis of TB meningitis.