Childhood tuberculous meningitis : challenging current management strategies

[摘要] ENGLISH ABSTRACT: Tuberculous meningitis (TBM) continues to be an important cause of mortality andneurological disability in resource-limited countries. Many questions remain about thebest approaches to prevent, diagnose, and treat TBM, and there are still too fewanswers.The aim of this dissertation was to challenge current management strategies inchildhood TBM.Accurate prediction of outcome in TBM is of critical importance when assessing the efficacyof different interventions. I conducted a retrospective cohort study of 554 children withTBM less than 13 years of age admitted to Tygerberg Children's Hospital over a 20year period (1985-2005) and reclassified all patients according to the criteria of all thecurrently available staging systems in childhood TBM (chapter 4). In this study, I found thatthe 'Refined Medical Research Council (MRC) staging system after 1 week had thehighest predictive value of all TBM staging systems. It is created by subdivision of stage2 (2a and 2b) of the existing MRC staging system. Additionally, I proposed and validateda simplified TBM staging system which is less dependent on clinical ability andneurological expertise than current staging systems. The simplified staging system wastermed the 'Tygerberg Children's Hospital Scale (TCH) and relies solely on the patient'sability to visually fixate and follow and the motor response to pain on both sides. Itdemonstrated excellent predictive power of outcome after 1 week and did not differsignificantly from the 'Refined MRC staging system in this regard. The optimal anti-TB drug regimen and duration of treatment for TBM is unknown. It hasbeen suggested that intensive short-course (6 months) anti-TB therapy may be sufficientand safe. I conducted a prospective descriptive study of 184 consecutively treated childrenwith TBM and found that short-course intensified anti-TB therapy aimed at treating TBMpatients (anti-TBM therapy) is sufficient and safe in both HIV-uninfected and HIVinfectedchildren with drug susceptible TBM (chapter 5). The overall study mortality of3.8% at completion of treatment compares favourably with the median mortality rate of 33% (range 5-65%) reported in a recent review describing outcome in TBM treatmentstudies.TB-immune reconstitution inflammatory syndrome (IRIS) is a potentially life-threateningcomplication in HIV-infected children with TB of the central nervous system. Little isknown about the incidence, case fatality, underlying immunopathology and treatmentapproaches in HIV-infected children with neurological TB-IRIS. In a case series, I foundthat neurological TB-IRIS should be considered when new neurological signs develop afterinitiation of antiretroviral therapy (ART) in children with TBM (chapter 6.1). Manifestationsof neurological TB-IRIS include headache, seizures, meningeal irritation, a decreasedlevel of consciousness, ataxia and focal motor deficit. I also discussed the rational forusing certain treatment modalities, includingthalidomide.Neurological tuberculous mass lesions (tuberculomas and pseudo-abscesses) may develop orenlarge in children on anti-TBM treatment. These lesions respond poorly to therapy, andmay require surgical excision, but may be responsive to thalidomide, a potent inhibitor oftumour necrosis factor-alpha (TNF-alpha). The optimal dose and duration of thalidomidetherapy and the correlation with magnetic resonance imaging (MRI) is yet to be explored.The primary objective of our next study was to investigate whether serial MRI is usefulin evaluating treatment response and duration of thalidomide therapy (chapter 6.2). Asecondary objective was to determine the value of thalidomide in the treatment of theselesions. In a prospective observational study over three years, serial MRI was performedin 16 consecutive children compromised by TB pseudo-abscesses who were treated withthalidomide. The rapid clinical response of most patients suggests that thalidomide providessubstantial clinical benefit in this clinical context. I also identified a MRI marker of curethat is evolution of lesions from early stage 'T2 bright with edema to 'T2 black. Thisfinding could be useful in the future management of these patients. Transcranial Doppler imaging (TCDI) is potentially a valuable investigational tool inchildren with TBM, a condition often complicated by pathology relevant to Dopplerimaging such as raised intracranial pressure (ICP) and cerebral vasculopathies. Serial TCDIwas performed on 20 TBM children with the aim of investigating cerebral haemodynamics and the relationship between pulsatility index (PI) and ICP (chapter 6.3). In this study, Ifound that TCDI-derived pulsatility index (PI) is not a reliable indicator of raised ICP inchildren with tuberculous hydrocephalus which I attributed this to individual variation oftuberculous vascular disease, possibly compromising cerebral vascular compliance andresistance. The study did confirm the efficacy of medical therapy in children withtuberculous communicating hydrocephalus. In all cases, the ICP normalized within 7 daysafter initiation of acetazolamide and furosemide.In the same cohort of children with TBM I also measured cerebral blood flow velocities(BFV) in the anterior cerebral artery (ACA), middle cerebral artery (MCA) and posteriorcerebral artery (PCA) on admission and after day 3 and 7. I found persistent high BFV in allthe basal cerebral arteries suggesting stenosis due to vasculitis rather than functionalvasospasm. Additionally, I found that complete MCA occlusion, subnormal mean MCAvelocities (less than 40 cm/s) and a reduced PI (less than 0.4) correlated with radiologicalproven large cerebral infarcts. No side-to-side differences in MCA BFV or subnormal PI'swere detected in four TBM children with territory infarcts on admission. I attributed this tothe occlusion of a limited number (one or two) of the 9 MCA perforators which has beenshown not to affect the hemodynamics of the MCA.I concluded by highlighting the many questions that remain about the best approaches toprevent, diagnose, and treat TBM (chapter 2). In a second literature review, aimed atclinicians working in resource-limited countries, I describe novel approaches to themanagement of childhood TBM, including a treatment algorithm for tuberculoushydrocephalus, the role for short-course intensified anti-TBM treatment and home-basedanti-TBM treatment (chapter 3).Even with the best diagnostic and treatment modalities, outcome in childhood TBM willremain poor if diagnosis is delayed. Our efforts should be on increased awareness and earlierdiagnosis.

[发布机构] Stellenbosch University