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Twelve patients who feigned bereavement are described. Most appeared depressed on admission, and in over half bereavement was erroneously believed by staff to be an important cause of their depression. This type of behaviour, leading to admission to hospital, may be regarded as abnormal illness behaviour, and reasons are given for considering most of the cases as variants of the Münchausen syndrome. Motivation for these deceptions is discussed, and reference is made to features which might arouse suspicion that bereavement is feigned. [ABSTRACT FROM AUTHOR]

Background: The risk of injury in rugby is high, due to the contact nature of the game. Players are constantly exposed to impact and collision during training and match-play. Rugby union consists of various risk factors that predispose players to injury. The aim of the study was to determine the risk factors of injury and to predict the risk of injury per playing position during match-play., Methods: The study followed a quantitative, non-experimental, and cross-sectional research design. A total of 252 male rugby players, aged 18 to 20 years, who played in a collegiate rugby competition in South Africa (SA) for the 2022 season were conveniently sampled for the study. The playing position, time of injury (whether during a match or training), use of protective equipment, and phase of play in which the injury occurred were recorded. Injury data was captured by qualified healthcare professionals using an adapted injury surveillance questionnaire., Results: The study found that potential risk factors for injury included illegal or dangerous play, playing in the second half of the match (more specifically the third quarter of the match), and playing in the offensive part of the field (more specifically between the opposition-22 and halfway line). Contact events were the most common cause of match injury (91.1%). The half of the match in which an injury was sustained was significantly different between forwards and backs (P=0.011). A statistically significant association was found between playing position and the phase of play in which injury was sustained (P=0.021). Regression analysis showed that playing between the opposition-22 m line and the halfway line was a significant predictor of injury for both forwards and backs (P=0.035)., Conclusions: In conclusion, potential risk factors for injury were related to dangerous play, time during the match (specifically the third quarter of the match), and location of play (specifically between the opposition-22 m line and halfway line). The area of play was a significant predictor of injury for all players. It is recommended that greater efforts in collecting epidemiological data need to be made to broaden the knowledge base on injuries and provide strategies to coaches and players to reduce the risk of injury in rugby.

Background: The physical nature of the sport of rugby results in a high incidence of injury, even in university rugby, compared to other contact sport codes. Rugby Union lacks injury data focusing on university student-athletes, specifically in South Africa. The aim of the study was to determine the incidence of injury among male rugby players participating in the Varsity Cup Young Guns national rugby tournament., Methods: The study used a quantitative, cross-sectional, and correlational research design. A total of 252 rugby players, males aged 18 to 20 years, who played for their university rugby team in the 2022 Varsity Cup Young Guns national tournament were conveniently recruited to determine the incidence of overall, match, and training injuries (number of injuries/1000 hours) for the 2022 tournament., Results: The overall injury incidence for all players was 9.5 injuries/1000 player-hours. The injury incidence for all players during matches was 136.5 injuries/1000 match-hours, whereas during training it was 0.6 injuries/1000 training-hours. The injury incidence was greater for backs than forwards (150.6 injuries/1000 match-hours vs. 124.1 injuries/1000 match-hours, respectively). The lower limb was the most commonly injured anatomical site with 36.6% (95% CI: 27.7-48.3%), while the common types of injuries were the joints (41.6%, 95% CI: 29.9-49.9%) and muscles (28.7%, 95% CI: 20.8-38.0%). A statistically significant association was found between the playing position and the phase of play in which injury occurred (χ 2 (1)=160.2; P=0.021)., Conclusions: This study reported a high injury incidence, especially during matches, in the Varsity Cup Young Guns tournament. It is recommended that prospective, incidence-based studies be used to precisely determine the incidence, nature, severity and mechanisms of injury. An injury surveillance system should be implemented, specifically within Varsity Cup rugby to inform, support, and improve current injury prevention strategies.

Background: Population-based data show high proportions of severe cases of cerebral palsy (CP) in resource-poor regions such as sub-Saharan Africa, where most children have potentially preventable risk factors (factors that may increase the likelihood of CP occurrence but can be mitigated through medical interventions)., Objectives: This study aimed to describe the demographic and clinical profile of children living with CP accessing services at Tygerberg Hospital over a period of 10 years (2010-2020), identify the potential gaps in care (proportion of individuals in a country requiring but not receiving suboptimal or inadequate care), and comparison with a similar study at the same centre two decades ago., Method: This 10-year retrospective study investigated causes and morbidities in children with CP, attending a central hospital in the Western Cape, South Africa., Results: A total of 613 children with CP were identified. Perinatal causes were predominant, especially in 57.7% ( n = 354) of the cohort: perinatal asphyxia (41.1%) and preterm birth (16.6%). Postnatal causes constituted 15.2% ( n = 93), which included tuberculous meningitis (3.6%) and bacterial meningitis (3.6%). The most common complications were intellectual impairment (61.8%; n = 379); epilepsy (30.8%; n = 189) and visual impairment (54.7%; n = 234). A third of the cohort had severe CP, classified as Gross Motor Function Classification System IV and V (38%)., Conclusion: Most of the previously documented main drivers of CP are still present and the implementation of healthcare prevention strategies remains inadequate., Contribution: This study provides longitudinal evidence to confirm that CP in a South African setting is associated with a high burden of potentially preventable causes., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2024. The Authors.)

Next generation sequencing (NGS)-based tests have become routine first-line investigative modalities in paediatric neurology clinics in many high-income countries (HICs). Studies from these countries show that these tests are both cost-effective and reliable in diagnosing many complex childhood neurological diseases. However, NGS-based testing in low-and middle-income countries (LMICs) is limited due to affordability constraints. The primary objective of this study was to evaluate the diagnostic yield and impact of targeted gene panel sequencing in a selected paediatric cohort attending a tertiary paediatric neurology clinic in the Western Cape Province of South Africa. This retrospective study included 124 consecutive paediatric patients with neurological disease, aged 6 weeks to 17 years, referred for NGS-based multi-gene panel testing over a 41-month period. Twenty-four different disease group-specific panels were utilized. A caregiver experience questionnaire was administered when a pathogenic variant was identified. The overall study diagnostic yield (DY) was 45% (56/124 patients). The diagnostic yield in this study is similar to previously reported paediatric cohorts in HICs. The high yields for neuromuscular disorders (52%) and early epileptic encephalopathies (41%) suggest that NGS-based panels may be more cost-effective as first-line testing in well-defined phenotypes. The latter finding argues for early inclusion of all children with developmental epileptic encephalopathies (DEE), as early diagnosis leads to better treatment and avoidance of unnecessary investigations., (© 2024. The Author(s).)

Aim: To identify cerebral palsy (CP) variables collected in CP registries from high-income countries (HICs) and low- and middle-income countries (LMICs) to assist with the development of a regional CP registry relevant to the African region., Method: A systematic search of online databases to identify peer-reviewed publications and grey literature about CP risk-factor variables, using Ovid MEDLINE, Embase Ovid, CINAHL, and Google Scholar., Results: A total of 197 studies published from global CP registries between 1990 and 2023 were identified. CP registries both from HICs and from LMICs included variables on prenatal CP risk factors. LMIC registries focused more on socioeconomic factors (the physical structure of the family home [21.1%, n = 8, in LMICs vs 1.7%, n = 2, in HICs]). Prenatal modifiable and non-modifiable risk factors were emphasized in HICs. LMIC registries included more postnatal CP risk-factor variables than HIC registries, including history of postnatal jaundice (15.8%, n = 6, in LMICs vs 6.9%, n = 8, in HICs) and postnatal head trauma (10.5%, n = 4, in LMICs vs 5.2%, n = 6, in HICs)., Interpretation: CP registries are currently more available in HICs than in LMICs. Differences in CP risk factors account for most of the differences in variables included in HICs and LMICs. Comparing variables used by CP registries in HICs and LMICs suggests the importance of understanding contextually relevant factors for regional registry design., (© 2024 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Tuberculous meningitis (TBM)-the extrapulmonary form of tuberculosis, is the most severe complication associated with tuberculosis, particularly in infants and children. The gold standard for the diagnosis of TBM requires cerebrospinal fluid (CSF) through lumbar puncture-an invasive sample collection method, and currently available CSF assays are often not sufficient for a definitive TBM diagnosis. Urine is metabolite-rich and relatively unexplored in terms of its potential to diagnose neuroinfectious diseases. We used an untargeted proton magnetic resonance ( 1 H-NMR) metabolomics approach to compare the urine from 32 patients with TBM (stratified into stages 1, 2 and 3) against that from 39 controls in a South African paediatric cohort. Significant spectral bins had to satisfy three of our four strict cut-off quantitative statistical criteria. Five significant biological metabolites were identified-1-methylnicotinamide, 3-hydroxyisovaleric acid, 5-aminolevulinic acid, N-acetylglutamine and methanol-which had no correlation with medication metabolites. ROC analysis revealed that methanol lacked diagnostic sensitivity, but the other four metabolites showed good diagnostic potential. Furthermore, we compared mild (stage 1) TBM and severe (stages 2 and 3) TBM, and our multivariate metabolic model could successfully classify severe but not mild TBM. Our results show that urine can potentially be used to diagnose severe TBM., (© 2024. The Author(s).)

Tuberculous meningitis (TBM) occurs when tuberculosis (TB) bacilli disseminate and seed into the meninges, triggering a severe inflammatory response that often leads to brain infarction. It is the most severe and debilitating form of childhood TB with high mortality, and children who survive TBM often suffer lifelong physical and neuro-disability resulting in emotional, social, and economic burdens for families. In the early stages the symptoms may be non-specific and so the diagnosis is often made late when the patient already has significant brain injury. To facilitate earlier diagnosis, it is important to understand how patients are evaluated. This study aimed to chart health systems for paediatric TBM care at both primary healthcare (PHC) and hospital level in Cape Town, South Africa. We conducted fourteen in-depth interviews and eight days of semi-structured observations of patient flow across eight healthcare facilities. We found that children with TBM navigate multiple levels of care categorised into pre-admission and primary care, hospital admission and inpatient care, and post-discharge follow-up care. Healthcare workers identified the following health system barriers along the TBM care pathway for children: limited post-training and mentorship opportunities to manage TBM, overburdened facilities, time constraints, lack of recognition of TBM symptoms, delays in referral between PHC and hospital, lack of standardized diagnostic algorithms, limited diagnostic tests and a lack of child-friendly, easy-to-administer treatment. Regular and compulsory training on TB and TBM in children, including continuous mentoring and support to healthcare workers working in child health and TB services in high TB-burden settings, can facilitate early recognition of symptoms and rapid referral for diagnosis. Algorithms outlining referral criteria for patients with possible TBM at both PHC facilities and district level hospitals can guide healthcare providers and facilitate timely referral between different levels of healthcare services. An integrated data system and alert functions could flag multiple healthcare visits and improve communication between different healthcare facilities during diagnosis and treatment. Children and families affected by TBM are an especially vulnerable sub-population requiring high priority attention and support., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Patience Baloyi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: HIV can invade the central nervous system (CNS) early during infection, invading perivascular macrophages and microglia, which, in turn, release viral particles and immune mediators that dysregulate all brain cell types. Consequently, children living with HIV often present with neurodevelopmental delays., Methods: In this study, we used proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy to analyze the neurometabolic profile of HIV infection using cerebrospinal fluid samples obtained from 17 HIV+ and 50 HIV- South African children., Results: Nine metabolites, including glucose, lactate, glutamine, 1,2-propanediol, acetone, 3-hydroxybutyrate, acetoacetate, 2-hydroxybutyrate, and myo-inositol, showed significant differences when comparing children infected with HIV and those uninfected. These metabolites may be associated with activation of the innate immune response and disruption of neuroenergetics pathways., Conclusion: These results elucidate the neurometabolic state of children infected with HIV, including upregulation of glycolysis, dysregulation of ketone body metabolism, and elevated reactive oxygen species production. Furthermore, we hypothesize that neuroinflammation alters astrocyte-neuron communication, lowering neuronal activity in children infected with HIV, which may contribute to the neurodevelopmental delay often observed in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Thirion, Loots, Williams, Solomons and Mason.)

Tuberculous meningitis (TBM) is a severe form of tuberculosis with high neuro-morbidity and mortality, especially among the paediatric population (aged ≤12 years). Little is known of the associated metabolic changes. This study aimed to identify characteristic metabolic markers that differentiate severe cases of paediatric TBM from controls, through non-invasive urine collection. Urine samples selected for this study were from two paediatric groups. Group 1: controls (n = 44): children without meningitis, no neurological symptoms and from the same geographical region as group 2. Group 2: TBM cases (n = 13): collected from paediatric patients that were admitted to Tygerberg Hospital in South Africa on the suspicion of TBM, mostly severely ill; with a later confirmation of TBM. Untargeted 1H NMR-based metabolomics data of urine were generated, followed by statistical analyses via MetaboAnalyst (v5.0), and the identification of important metabolites. Twenty nine urinary metabolites were identified as characteristic of advanced TBM and categorized in terms of six dysregulated metabolic pathways: 1) upregulated tryptophan catabolism linked to an altered vitamin B metabolism; 2) perturbation of amino acid metabolism; 3) increased energy production-metabolic burst; 4) disrupted gut microbiota metabolism; 5) ketoacidosis; 6) increased nitrogen excretion. We also provide original biological insights into this biosignature of urinary metabolites that can be used to characterize paediatric TBM patients in a South African cohort., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Isaiah, Loots, van Reenen, Solomons, van Elsland, Tutu van Furth, van der Kuip and Mason.)

Background: The pathogenesis of tuberculous meningitis (TBM) involves infection by Mycobacterium tuberculosis in the meninges and brain. However, recent studies have shown that the immune response and inflammatory processes triggered by TBM can have significant effects on gut microbiota. Disruptions in the gut microbiome have been linked to various systemic consequences, including altered immunity and metabolic dysregulation. Inflammation caused by TBM, antibiotic treatment, and changes in host immunity can all influence the composition of gut microbes. This complex relationship between TBM and the gut microbiome is of great importance in clinical settings. To gain a deeper understanding of the intricate interactions between TBM and the gut microbiome, we report innovative insights into the development of the disease in response to treatment. Ultimately, this could lead to improved outcomes, management strategies and quality of life for individuals affected by TBM., Method: We used a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach to investigate metabolites associated with gut metabolism in paediatric participants by analysing the urine samples collected from a control group (n = 40), and an experimental group (n = 35) with confirmed TBM, which were subdivided into TBM stage 1 (n = 8), stage 2 (n = 11) and stage 3 (n = 16)., Findings: Our metabolomics investigation showed that, of the 78 initially selected compounds of microbiome origin, eight unique urinary metabolites were identified: 2-methylbutyrlglycine, 3-hydroxypropionic acid, 3-methylcrotonylglycine, 4-hydroxyhippuric acid, 5-hydroxyindoleacetic acid, 5-hydroxyhexanoic acid, isobutyrylglycine, and phenylacetylglutamine as urinary markers of dysbiosis in TBM., Conclusion: These results - which are supported by previous urinary studies of tuberculosis - highlight the importance of gut metabolism and of identifying corresponding microbial metabolites as novel points for the foundation of improved management of TBM patients., (© 2024. The Author(s).)

Introduction:  Because cerebrospinal fluid (CSF) samples are difficult to obtain for paediatric HIV, few studies have attempted to profile neurometabolic dysregulation., Aim and Objective: The aim of this exploratory study was to profile the neurometabolic state of CSF from a South African paediatric cohort using GCxGC-TOF/MS. The study included 54 paediatric cases (< 12 years), 42 HIV-negative controls and 12 HIV-positive individuals., Results: The results revealed distinct metabolic alterations in the HIV-infected cohort. In the PLS-DA model, 18 metabolites significantly discriminated between HIV-infected and control groups. In addition, fold-change analysis, Mann-Whitney U tests, and effect size measurements verified these findings. Notably, lactose, myo-inositol, and glycerol, although not significant by p-value alone, demonstrated practical significance based on the effect size., Conclusions: This study provided valuable insights on the impact of HIV on metabolic pathways, including damage to the gut and blood-brain barrier, disruption of bioenergetics processes, gliosis, and a potential marker for antiretroviral therapy. Nevertheless, the study recognized certain constraints, notably a limited sample size and the absence of a validation cohort. Despite these limitations, the rarity of the study's focus on paediatric HIV research underscores the significance and unique contributions of its findings., (© 2024. The Author(s).)

UPDATE ON THE DIAGNOSIS AND MANAGEMENT OF TUBERCULOUS MENINGITIS IN CHILDREN: Ronald van Toorn, Regan Solomons Seminars in Pediatric Neurology Volume 21, Issue 1, March 2014, Pages 12-18 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: To better understand the aetiologies of epileptic spasms in infants, as well as the safety and efficacy of high dose corticosteroids in tuberculosis and human immunodeficiency virus (HIV) endemic resource-limited settings., Method: This was a retrospective analysis of infants with epileptic spasms managed at the tertiary referral centres in the Western Cape, South Africa., Results: Of 175 children with epileptic spasms, the median age at onset was 6 months (interquartile range 4-8 months). Structural aetiologies were most common (115 out of 175 [66%]), with two-thirds related to perinatal insults. A lead time to treatment (LTTT) of less than 1 month was more likely in the epileptic encephalopathy/developmental and epileptic encephalopathy (DEE) group: 58 out of 92 (63%), compared to 28 out of 76 (37%) of those with developmental encephalopathy (p = 0.001). Failure to recognize preceding developmental delay was common. Ninety-nine children (57%) received first line hormonal therapy such as adrenocorticotropic hormone. A total of 111 out of 172 children (65%) from the developmental encephalopathy and epileptic encephalopathy/DEE groups had clinical and/or electroencephalogram resolution of spasms within 14 days. In our population, children in whom an aetiology could not be identified were statistically more likely to have moderate to profound developmental delay at 1 year of age: 33 out of 44 (p = 0.001). Based on reported incidence of epileptic spasms, 23 to 58 cases per annum would be expected but a far smaller proportion presented to our centres., Interpretation: Whilst this is the largest cohort of infants with epileptic spasms from sub-Saharan Africa, the study size is less than expected; this may reflect misdiagnosis and failure of referral pathways. Despite a reported shorter LTTT, infants with DEE had worse developmental outcomes compared to international studies. Hormonal therapy was safe and effective in our setting, despite exposure to high levels of tuberculosis and HIV., What This Paper Adds: The number of unreferred cases of epileptic spasms in South Africa remains high. Caregivers and health care workers in primary care facilities often fail to recognize developmental delay. The burden of disease from hypoxic-ischaemic encephalopathy remains high in our resource-limited setting. Hormonal treatment (e.g. adrenocorticotropic hormone) was safe and effective despite the high prevalence of human immunodeficiency virus and tuberculosis., (© 2022 Mac Keith Press.)

Aicardi-Goutières syndrome (AGS) refers to a group of genetic diseases characterised by severe inflammatory encephalopathy that usually present within the first year of life, resulting in progressive loss of cognition, spasticity, dystonia and motor disability. Pathogenic variants in the adenosine deaminase acting on RNA ( Adar ) enzyme have been linked to AGS type 6 (AGS6, Online Mendelian Inheritance in Man (OMIM) 615010). In knockout mouse models, loss of Adar activates the interferon (IFN) pathway and causes autoimmune pathogenesis in the brain or liver. Bilateral striatal necrosis (BSN) has previously been reported in case series of children with biallelic pathogenic variants in Adar We describe a unique, previously unreported case of a child with AGS6, with clinical manifestations of BSN and recurrent transient episodes of transaminitis. The case highlights the importance of Adar in protecting the brain and liver from IFN-induced inflammation. Adar -related disease should therefore be considered in the differential diagnosis of BSN accompanied by recurrent episodes of transaminitis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of rare neurodevelopmental disorders, characterised by early-onset seizures that are often intractable, electroencephalographic abnormalities, and developmental delay or regression. There is a paucity of data from sub-Saharan Africa on the genetic basis of DEE. The aim of this study was to investigate the genetic background of DEE using targeted next generation sequencing (NGS) analysis in a tertiary pediatric neurology outpatient department at Tygerberg Hospital, South Africa. In addition, we assessed the value of the genetic results to the parents and managing physicians., Methods: A prospective cohort study of 41 consecutive children with DEE (onset before 3 years of age) that were recruited over a 2-year period (2019-2021). Pre- and post-test genetic counselling were offered to all study participants. The results were categorized as either: positive (pathogenic/likely pathogenic variant identified), inconclusive (variant(s) of unknown significance identified), or negative (no variants identified). Result interpretation and careful matching of the variant to the clinical phenotype was performed. Subsequently, questionnaires were administered to both the physicians and the parents., Results: A genetic underlying cause for DEE was identified in 18 of 41 children (diagnostic yield 43.9%). Variants in SCN1A (n=7), KANSL1 (n=2), KCNQ2 (n=2) and CDKL5 (n=2) were identified in more than one patient. Rarer genes included IQSEC2, SMC1A and STXBP1. All of the identified pathogenic variants fully explained and matched the respective phenotypic description of the patient at the time of clinical diagnosis. In 26% of patients the genetic result facilitated precision medicine management changes to anti-seizure medication. Both parents and physicians expressed benefit of genetic testing in patients with DEE., Conclusion: Targeted NGS analysis proved an efficient diagnostic tool in detection of a genetic cause of DEE in a large proportion of South African children. The 43.9% diagnostic yield is similar to previously reported international pediatric cohorts. Additionally, the genetic findings proved useful for targeted therapeutic decision-making and accurate genetic counseling., Competing Interests: Declaration of Competing Interests None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: None declared.

We present an 11-year-old girl who manifested with unprovoked right-sided focal motor seizures. CT revealed a large lobulated hypodense mass in the left temporoparietal lobe, with perilesional oedema and postcontrast peripheral enhancement. Diagnostic uncertainty resulted in further neuroimaging, which included MRI with modalities including diffusion-weighted imaging, perfusion imaging, as well as spectroscopy. We discuss the radiological features of the lesion, which steered us in the direction of an infective cause. Definitive diagnosis was achieved by brain needle biopsy, which demonstrated necrotising granulomatous inflammation indicative of tuberculous infection on histology. In addition, GeneXpert yielded a positive result. We believe this unique case highlights the diagnostic dilemma clinicians face in differentiating ring-enhancing lesions on neuroimaging in tuberculosis-endemic regions. It also highlights the potential benefit of a brain needle biopsy (histology and GeneXpert) in cases of uncertainty., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Before August 2021, the only regimen recommended by the World Health Organization (WHO) to treat pediatric drug-susceptible tuberculous meningitis was a 12-month regimen consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide (2HRZE/10HR). The comparative effectiveness of shorter regimens is unknown., Methods: To inform a WHO guideline update, we undertook a systematic review and meta-analysis to evaluate outcomes from regimens of 6- to less than 12-months' duration that included, at a minimum, isoniazid, rifampicin, and pyrazinamide. We included studies that applied rigorous diagnostic criteria and reported outcomes for ≥10 children or adolescents. Using generalized linear mixed models, we estimated the random effects pooled proportions of patients with key outcomes., Results: Of 7 included studies, none compared regimens head-to-head. Three studies (724 patients) used a 6-month intensive regimen, which includes isoniazid and rifampicin at higher doses, pyrazinamide, and ethionamide instead of ethambutol (6HRZEto). Outcomes for this versus the 12-month regimen (282 patients, 3 studies) were, respectively, as follows: death, 5.5% (95% confidence interval [CI], 2.1%-13.4%) vs 23.9% (95% CI, 17.5%-31.7%); treatment success (survival with or without sequelae), 94.6% (95% CI, 73.9%-99.1%) vs 75.4% (95% CI, 68.7%-81.1%); and neurological sequelae among survivors, 66.0% (95% CI, 55.3%-75.3%) vs 36.3% (95% CI, 30.1%-43.0%). Relapse did not occur among 148 patients followed-up for 2 years after completing the 6-month intensive regimen., Conclusions: Our findings are limited by the small number of studies and substantial potential for confounding. Nonetheless, the 6HRZEto regimen was associated with high treatment success and is now recommended by WHO as an alternative to the 12-month regimen., (© The Author(s) 2022.. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB) that arises when a caseating meningeal granuloma discharges its contents into the subarachnoid space. It accounts for ~1% of all disease caused by Mycobacterium tuberculosis and the age of peak incidence is from 2-4 years. The exact pathogenesis of TBM is still not fully understood and the mechanism(s) by which the bacilli initially invade the blood-brain-barrier are still to be elucidated. This study investigated the involvement of the host genome in TBM susceptibility, by considering common variants (minor allele frequency (MAF) >5%) using microarray genotyping and rare variants (MAF <1%) via exome sequencing. A total of 123 TBM cases, 400 pulmonary TB (pTB) cases and 477 healthy controls were genotyped on the MEGA array. A genome-wide association study (GWAS) comparing 114 TBM cases to 395 healthy controls showed no association with TBM susceptibility. A second analysis comparing 114 TBM cases to 382 pTB cases was conducted to investigate variants associated with different TB phenotypes. No significant associations were found with progression from pTB to TBM. Ten TBM cases and 10 healthy controls were exome sequenced. Gene set association tests SKAT-O and SKAT Common Rare were used to assess the association of rare SNPs and the cumulative effect of both common and rare SNPs with susceptibility to TBM, respectively. Ingenuity Pathway Analysis (IPA) of the top-hits of the SKAT-O analysis showed that NOD2 and CYP4F2 are both important in TBM pathogenesis and highlighted these as targets for future study. For the SKAT Common Rare analysis Centriolar Coiled-Coil Protein 110 ( CCP110) was nominally associated ( p = 5.89x10 -6 ) with TBM susceptibility. In addition, several top-hit genes ascribed to the development of the central nervous system (CNS) and innate immune system regulation were identified. Exome sequencing and GWAS of our TBM cohort has identified a single previously undescribed association of CCP110 with TBM susceptibility. These results advance our understanding of TBM in terms of both variants and genes that influence susceptibility. In addition, several candidate genes involved in innate immunity have been identified for further genotypic and functional investigation., Competing Interests: NB is currently an employee and shareholder of GlaxoSmithKline (Stevenage, UK). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schurz, Glanzmann, Bowker, van Toorn, Solomons, Schoeman, van Helden, Kinnear, Hoal and Möller.)

Tuberculous meningitis disproportionately affects young children. As the most devastating form of tuberculosis, it is associated with unacceptably high rates of mortality and morbidity even if treated. Challenging to diagnose and treat, tuberculous meningitis commonly causes long-term neurodisability in those who do survive. There remains an urgent need for strengthened surveillance, improved rapid diagnostics technology, optimised anti-tuberculosis drug therapy, investigation of new host-directed therapy, and further research on long-term functional and neurodevelopmental outcomes to allow targeted intervention. This review focuses on the neglected field of paediatric tuberculous meningitis and bridges current clinical gaps with research questions to improve outcomes from this crippling disease.