Regan Solomons

Update on the Diagnosis and Management of Tuberculous Meningitis in Children

Tuberculous meningitis (TBM), the most devastating manifestation of tuberculosis, is often missed or overlooked because of nonspecific symptoms and difficulties in diagnosis. It continues to be an important cause of neurologic handicap in resource-poor countries. Owing to the suboptimal performance of diagnostic tests of TBM, diagnosis relies on thorough history, clinical examination, and relevant investigations. The development of affordable, accurate diagnostic tests for TBM in resource-poor settings remains a priority. Short intensified treatment is safe and effective in both human immunodeficiency virus (HIV)-infected and HIV-uninfected children. Treatment of tuberculous hydrocephalus depends on the level of the cerebrospinal fluid obstruction. Corticosteroids reduce risk of neurodisability and death in HIV-uninfected children. Thalidomide should be considered in children compromised by tuberculosis abscesses and tuberculous-related optochiasmic arachnoiditis. In resource-poor countries, home-based TBM treatment after initial in-hospital stabilization is feasible in carefully selected patients. Early diagnosis and treatment of TBM is the single most important factor determining outcome.

A hypothetical astrocyte–microglia lactate shuttle derived from a 1H NMR metabolomics analysis of cerebrospinal fluid from a cohort of South African children with tuberculous meningitis

Tuberculosis meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis and is particularly intense in small children; there is no universally accepted algorithm for the diagnosis and substantiation of TB infection, which can lead to delayed intervention, a high risk factor for morbidity and mortality. In this study a proton magnetic resonance (1H NMR)-based metabolomics analysis and several chemometric methods were applied to data generated from lumber cerebrospinal fluid (CSF) samples from three experimental groups: (1) South African infants and children with confirmed TBM, (2) non-meningitis South African infants and children as controls, and (3) neurological controls from the Netherlands. A total of 16 NMR-derived CSF metabolites were identified, which clearly differentiated between the controls and TBM cases under investigation. The defining metabolites were the combination of perturbed glucose and highly elevated lactate, common to some other neurological disorders. The remaining 14 metabolites of the host’s response to TBM were likewise mainly energy-associated indicators. We subsequently generated a hypothesis expressed as an “astrocyte–microglia lactate shuttle” (AMLS) based on the host’s response, which emerged from the NMR-metabolomics information. Activation of microglia, as implied by the AMLS hypothesis, does not, however, present a uniform process and involves intricate interactions and feedback loops between the microglia, astrocytes and neurons that hamper attempts to construct basic and linear cascades of cause and effect; TBM involves a complex integration of the responses from the various cell types present within the CNS, with microglia and the astrocytes as main players.

Host Immune Response to Tuberculous Meningitis

BACKGROUND Tuberculous meningitis (TBM) is a severe complication of tuberculosis predominantly affecting young children. Early treatment is vital to prevent morbidity and mortality, emphasizing the importance of early diagnosis. The lack of sensitive methods for early diagnosis is the most common cause of delay. Attempts have been made to develop simplified tests for tuberculosis, but their diagnostic power remains poor. The clinical picture of TBM is mainly driven by the hosts immune response to Mycobacterium tuberculosis; therefore, identification of disease-specific biomarkers may have diagnostic and therapeutic value and improve our understanding of its pathogenesis. METHODS We investigated disease-specific biomarkers of childhood TBM in a cohort of children aged 3 months-13 years with symptoms and signs suggestive of meningitis. Cerebrospinal fluid (CSF) and serum from 56 patients with and 55 patients without TBM were assessed for 28 soluble mediators. RESULTS Unsupervised hierarchical clustering analysis revealed a disease-specific pattern of biomarkers for TBM relative to other types of meningitis. A biomarker-based diagnostic prediction model for childhood TBM based on CSF concentrations of interleukin 13 (cutoff value, 37.26 pg/mL), vascular endothelial growth factor (cutoff value, 42.92 pg/mL), and cathelicidin LL-37 (cutoff value, 3221.01 pg/mL) is presented with a sensitivity of 0.52 and a specificity of 0.95. CONCLUSIONS These data highlight the potential of biosignatures in the hosts CSF for diagnostic applications and for improving our understanding of the pathogenesis of TBM to discover strategies to prevent immunopathological sequelae.

Improved diagnosis of childhood tuberculous meningitis using more than one nucleic acid amplification test.

BACKGROUND Early treatment is critical to reducing tuberculous meningitis (TBM) related morbidity and mortality. Diagnosis based on cerebrospinal fluid (CSF) culture is impractical due to slow turnaround times, while microscopy has poor sensitivity. Enhanced detection methods are essential to guide early treatment initiation, especially in vulnerable young children. METHODS We assessed the diagnostic accuracy of the GenoType(®) MTBDRplus and Xpert(®) MTB/RIF assays on CSF collected from paediatric meningitis suspects prospectively enrolled at Tygerberg Hospital, Cape Town, South Africa. Fluorescent auramine-O microscopy, liquid culture for Mycobacterium tuberculosis, GenoType and Xpert assays were performed on all CSF samples. RESULTS Of 101 meningitis suspects, 55 were diagnosed with TBM and 46 served as non-TBM controls. Using a pre-defined TBM case definition as reference standard, sensitivities and specificities were 4% and 100% for fluorescent microscopy, 22% and 100% for culture, 33% and 98% for GenoType, 26% and 100% for Xpert, 22% and 100% for microscopy and culture combined and 49% and 98% for GenoType and Xpert combined. Culture, GenoType and Xpert combined performed best, with 56% sensitivity and 98% specificity. CONCLUSION Although commercial nucleic-acid amplification tests performed on CSF revealed incrementally improved diagnostic accuracy, providing rapid microbiological confirmation, they cannot serve as a rule-out test.

Commercial nucleic acid amplification tests in tuberculous meningitis—a meta-analysis ☆ ☆☆

Although nucleic acid amplification tests (NAATs) promise a rapid, definitive diagnosis of tuberculous meningitis, the performance of first-generation NAATs was suboptimal and variable. We conducted a meta-analysis of studies published between 2003 and 2013, using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool to evaluate methodological quality. The diagnostic accuracy of newer commercial NAATs was assessed. Pooled estimates of diagnostic accuracy for commercial NAATs measured against a cerebrospinal fluid Mycobacterium tuberculosis culture-positive gold standard were sensitivity 0.64, specificity 0.98, and diagnostic odds ratio 64.0. Heterogeneity was limited; P value = 0.147 and I(2) = 33.85%. The Xpert MTB/RIF® test was evaluated in 1 retrospective study and 4 prospective studies, with pooled sensitivity 0.70 and specificity 0.97. The QUADAS-2 tool revealed low risk of bias, as well as low concerns regarding applicability. Heterogeneity was pronounced among studies of in-house tests. Commercial NAATs proved to be highly specific with greatly reduced heterogeneity compared to in-house tests. Sub-optimal sensitivity remains a limitation.

Standardized Methods for Enhanced Quality and Comparability of Tuberculous Meningitis Studies

Summary This viewpoint defines a tuberculous meningitis core dataset, including demographic and clinical information, key patient management and monitoring data, and standardized reporting of patient outcomes. Wide adoption of standardized methods will provide a robust evidence base to improve patient outcomes.

Cerebrospinal fluid in tuberculous meningitis exhibits only the L-enantiomer of lactic acid

BackgroundThe defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study.MethodsIn this follow-up study, we used targeted ultra-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UPLC–ESI–MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples.ResultsHere we report for the first time that the lactic acid observed in the CSF of confirmed TBM cases was in the L-form and solely a response from the host to the infection, with no contribution from any bacteria. The significance of elevated lactic acid in TBM appears to be that it is a crucial energy substrate, used preferentially over glucose by microglia, and exhibits neuroprotective capabilities.ConclusionThese results provide experimental evidence to support our conceptual astrocyte–microglia lactate shuttle model formulated from our previous NMR-based metabolomics study — highlighting the fact that lactic acid plays an important role in neuroinflammatory diseases such as TBM. Furthermore, this study reinforces our belief that the determination of enantiomers of metabolites corresponding to infectious diseases is of critical importance in substantiating the clinical significance of disease markers.

Familial-Environmental Risk Factors in South African Children With Attention-Deficit Hyperactivity Disorder (ADHD): A Case-Control Study.

We investigated familial and environmental risk factors in a cohort of South African children diagnosed with attention-deficit hyperactivity disorder (ADHD). A prospective, hospital-based case control study was conducted comprising 50 children diagnosed with ADHD and 50 matched non-ADHD controls. The adjusted effect of familial-environmental risk factors on ADHD was determined by systematic assessment. Birth complications, parental psychiatric disorder, maternal ADHD, early childhood trauma, and nonmaternal child care were significant risk factors for ADHD. Prolonged breastfeeding was found to be protective. In a multivariable logistic regression model, 5 criteria (birth complications, breastfeeding <3 months, at least 1 parent with tertiary education, presence of parental psychiatric disorder, and nonmaternal primary caregiver) differentiated ADHD from non-ADHD controls with a sensitivity and specificity of 74% and 86%, respectively. We found a correlation between certain familial and environmental risk factors and ADHD. A 5-criterion multivariable logistic regression model may offer clinical guidance in ADHD diagnosis.CITATION: Van Dyk, L. et al. 2015. Familial-Environmental Risk Factors in South African Children With Attention-Deficit Hyperactivity Disorder (ADHD): A Case-Control Study. Journal of Child Neurology, 30(10):1327–1332, doi:10.1177/0883073814560630.

Hemiconvulsion-hemiplegia-epilepsy syndrome in South African children: insights from a retrospective case series.

INTRODUCTION Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a recognized sequel of febrile partial status in children younger than 4 years. OBJECTIVE To describe the clinical features, neuroradiology and outcome in 8 South African children with HHE syndrome. METHOD A retrospective descriptive study of 8 consecutive cases of HHE syndrome presenting to tertiary hospitals in the Western Cape over a 2 year period. RESULTS The median age of onset of convulsive status was 16 months (range: 9-36 months). Gender distribution was equal. The duration of the initial episode of status exceeded 2 h in all children. All children were reported to have been developmentally normal prior to the onset of the first seizure and none previously suffered seizures or had a family history of febrile seizures and epilepsy. In 7 of the 8 cases the initial seizure was not associated with fever or preceding illness. Imaging demonstrated cerebral hemiatrophy in all and additional crossed cerebellar atrophy in 2 children. Moderate to severe intellectual disability ensued in the majority of children. The severity of the intellectual disability correlated with the degree of the motor deficit and occurred irrespective of the cerebral hemisphere involved. CONCLUSION In contrast to developed countries, HHE syndrome is still prevalent in South Africa. The neurological morbidity in South African children is significant and highlights the need for improved emergency care of status epilepticus.

Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis

Background: In Africa, tuberculosis is generally regarded as persisting as one of the most devastating infectious diseases. The pediatric population is particularly vulnerable, with infection of the brain in the form of tuberculous meningitis (TBM) being the most severe manifestation. TBM is often difficult to diagnose in its early stages because of its non-specific clinical presentation. Of particular concern is that late diagnosis, and subsequent delayed treatment, leads to high risk of long-term neurological sequelae, and even death. Using advanced technology and scientific expertise, we are intent on further describing the biochemistry behind this devastating neuroinflammatory disease, with the goal of improving upon its early diagnosis. Method: We used the highly sensitive analytical platform of gas chromatography-mass spectrometry (GC-MS) to analyze amino acid profiles of cerebrospinal fluid (CSF) collected from a cohort of 33 South African pediatric TBM cases, compared to 34 controls. Results: Through the use of a stringent quality assurance procedure and various statistical techniques, we were able to confidently identify five amino acids as being significantly elevated in TBM cases, namely, alanine, asparagine, glycine, lysine, and proline. We found also in an earlier untargeted metabolomics investigation that alanine can be attributed to increased CSF lactate levels, and lysine as a marker of lipid peroxidation. Alanine, like glycine, is an inhibitory neurotransmitter in the brain. Asparagine, as with proline, is linked to the glutamate-glutamine cycle. Asparagine is associated with the removal of increased nitrites in the brain, whereas elevated proline coincides with the classic biochemical marker of increased CSF protein in TBM. All five discriminatory amino acids are linked to ammonia due to increased nitrites in TBM. Conclusion: A large amount of untapped biochemical information is present in CSF of TBM cases, of which amino acid profiling through GC-MS has potential in aiding in earlier diagnosis, and hence crucial earlier treatment.