An exploratory investigation of the CSF metabolic profile of HIV in a South African paediatric cohort using GCxGC-TOF/MS.

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.

Variables included in cerebral palsy registries globally: A scoping review.

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.

Epileptic spasms: A South African overview of aetiologies, interventions, and outcomes.

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.

Risk factors of poor developmental outcome in children with tuberculous meningitis.

BACKGROUND: Neurodevelopmental delay is a significant long-term complication of childhood tuberculous meningitis (TBM). The objective of this study was to assess risk factors for neurodevelopmental delay in children with TBM. METHODS: We conducted a retrospective cohort study of children diagnosed with TBM at Tygerberg Hospital, Cape Town, South Africa, over a 30-year period between 1985 and 2015. We assessed the relationship between demographic, clinical, laboratory and neuro-imaging characteristics, and cognitive impairment at the conclusion of anti-tuberculous treatment. Poor outcome was defined as moderate-to severe cognitive impairment. RESULTS: A total of 327 TBM patients were included, 71 (21.7%) suffered a poor outcome. Multivariate analysis revealed that decreased level of consciousness (adjusted OR (aOR): 4.68; 95%CI: 2.43-13.88; p = 0.005), brainstem dysfunction (aOR: 3.20; 95%CI: 1.70-6.00; p < 0.001), and radiological infarction (aOR: 3.47; 95%CI: 1.87-6.45; p < 0.001) were associated with a poor developmental outcome. Left hemispherical (single and multiple) stroke and bilateral stroke were associated with poor developmental outcomes. CONCLUSION: Certain neurological signs as well as radiological infarct characteristics are important predictors of poor developmental outcome. Anticipation of the likely level of cognitive impairment at diagnosis allows more accurate prognostication and prompt institution of supportive and rehabilitative measures, after the acute illness.

Validation of host cerebrospinal fluid protein biomarkers for early diagnosis of tuberculous meningitis in children: a replication and new biosignature discovery study.

Purpose: The diagnosis of tuberculous meningitis (TBM) in children is often delayed due to diagnostic difficulties. New tools are urgently needed to improve the diagnosis of the disease in this vulnerable group. The present study aimed to validate the accuracy of recently identified host cerebrospinal (CSF) biomarkers as candidates for the diagnosis of TBM in children.Materials and methods: We collected CSF samples from 87 children aged 3 months to 13 years, that were consecutively admitted at a tertiary hospital in Cape Town, South Africa, on suspicion of having TBM. We evaluated the concentrations of 67 selected host protein biomarkers using a multiplex platform.Results: Previously identified 3-marker (VEGF-A + IFN-γ + MPO) and 4-marker (IFN-γ + MPO + ICAM-1 + IL-8) signatures diagnosed TBM with AUCs of 0.89 (95% CI, 0.81-0.97) and 0.87 (95% CI, 0.79-0.95) respectively; sensitivities of 80.6% (95% CI, 62.5-92.5%) and 81.6% (95% CI, 65.7-92.3%), and specificities of 86.8% (71.9-95.6%) and 83.7% (70.4-92.7%) respectively. Furthermore, a new combination between the analytes (CC4b + CC4 + procalcitonin + CCL1) showed promise, with an AUC of 0.98 (95% CI, 0.94-1.00).Conclusions: We have shown that the accuracies of previously identified candidate CSF biomarkers for childhood TBM was reproducible. Our findings augur well for the future development of a simple bedside test for the rapid diagnosis of TBM in children.

Intrapartum Basal Ganglia-Thalamic Pattern Injury and Radiologically Termed "Acute Profound Hypoxic-Ischemic Brain Injury" Are Not Synonymous.

OBJECTIVE: Human cases of acute profound hypoxic-ischemic (HI) injury (HII), in which the insult duration timed with precision had been identified, remains rare, and there is often uncertainty of the prior state of fetal health. STUDY DESIGN: A retrospective analysis of 10 medicolegal cases of neonatal encephalopathy-cerebral palsy survivors who sustained intrapartum HI basal ganglia-thalamic (BGT) pattern injury in the absence of an obstetric sentinel event. RESULTS: Cardiotocography (CTG) admission status was reassuring in six and suspicious in four of the cases. The median time from assessment by admission CTG or auscultation to birth was 687.5 minutes (interquartile range [IQR]: 373.5-817.5 minutes), while the median time interval between first pathological CTG and delivery of the infant was 179 minutes (IQR: 137-199.25 minutes). The mode of delivery in the majority of infants (60%) was by unassisted vaginal birth; four were delivered by delayed caesarean section. The median (IQR) interval between the decision to perform a caesarean section and delivery was 169 minutes (range: 124-192.5 minutes). CONCLUSION: The study shows that if a nonreassuring fetal status develops during labor and is prolonged, a BGT pattern HI injury may result, in the absence of a perinatal sentinel event. Intrapartum BGT pattern injury and radiologically termed "acute profound HI brain injury" are not necessarily synonymous. A visualized magnetic resonance imaging (MRI) pattern should preferably solely reflect the patterns description and severity, rather than a causative mechanism of injury. KEY POINTS: · BGT HI injury pattern on MRI may develop in the absence of a perinatal sentinel event.. · BGT pattern injury may not be synonymous with "acute profound HI brain injury.". · MRI pattern and severity thereof should be described rather than a causative mechanism of injury..

Thalidomide Use for Complicated Central Nervous System Tuberculosis in Children: Insights From an Observational Cohort.

BACKGROUND: Much of the neurological sequelae of central nervous system (CNS) tuberculosis (TB) is due to an excessive cytokine-driven host-inflammatory response. Adjunctive corticosteroids, which reduce cytokine production and thus dampen the inflammation, improve overall survival but do not prevent morbidity. This has prompted investigation of more targeted immunomodulatory agents, including thalidomide. METHODS: We describe a retrospective cohort of 38 children consecutively treated with adjunctive thalidomide for CNS TB-related complications over a 10-year period. RESULTS: The most common presenting symptom was focal motor deficit (n = 16), followed by cranial nerve palsies and cerebellar dysfunction. Three of the 38 children presented with large dural-based lesions, manifesting as epilepsia partialis continua (EPC), 4 presented with blindness secondary to optochiasmatic arachnoiditis, and 2 children developed paraplegia due to spinal cord TB mass lesions. Duration of adjunctive thalidomide therapy (3-5 mg/kg/day) varied according to complication type. In children compromised by TB mass lesions, the median treatment duration was 3.9 months (interquartile range [IQR], 2.0-5.0 months), whereas in children with optic neuritis it was 2.0 months (IQR, 1.3-7.3 months) and in EPC it was 1.0 months (IQR, 1-2.5 months). Satisfactory clinical and radiological response was observed in 37 of the children. None of the children experienced rashes, hepatitis, or hematologic derangements or complained of leg cramps. CONCLUSIONS: This study is the largest cohort of adult or pediatric patients treated with adjunctive thalidomide for CNS TB-related complications. The drug has proved to be safe and well tolerated and appears to be clinically efficacious. The potential role of thalidomide or analogues in the treatment of other tuberculous meningitis-related complications requires further exploration.

Tuberculous Meningitis: Pathogenesis, Immune Responses, Diagnostic Challenges, and the Potential of Biomarker-Based Approaches.

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis (TB), causing high mortality or disability. Clinical management of the disease is challenging due to limitations of the existing diagnostic approaches. Our knowledge on the immunology and pathogenesis of the disease is currently limited. More research is urgently needed to enhance our understanding of the immunopathogenesis of the disease and guide us toward the identification of targets that may be useful for vaccines or host-directed therapeutics. In this review, we summarize the current knowledge about the immunology and pathogenesis of TBM and summarize the literature on existing and new, especially biomarker-based, approaches that may be useful in the management of TBM. We identify research gaps and provide directions for research which may lead to the development of new tools for the control of the disease in the near future.

Risk factors for ischemic stroke in children with tuberculous meningitis.

PURPOSE: Cerebrovascular complications are commonly observed in children with tuberculous meningitis. We aimed to determine which clinical factors were associated with stroke at admission in children with tuberculous meningitis and, in children stroke-free at admission, which factors were associated with development of stroke on treatment. METHODS: We analysed a cohort of 474 children diagnosed with 'definite' and 'probable' tuberculous meningitis, with prospectively collected data, at Tygerberg Hospital, Cape Town, South Africa from 1985 to 2005. We considered either hemiparesis or radiological arterial ischemic infarction as evidence of stroke. RESULTS: At admission, 339 (71.5%) children presented with stroke. Features associated with stroke at admission included age <3 years (odds ratio (OR) 3.70; 95% confidence interval (CI): 2.44-5.63; p < 0.01), convulsions (OR: 2.25; 95% CI: 1.46-3.45; p < 0.01) and hydrocephalus (OR: 1.63; 95% CI: 1.05-2.53; p = 0.03). In the group of children without stroke at admission (n = 135), 33 (24.4%) developed stroke by 1 month. Similar factors predicted stroke and included age <3 years (OR: 2.60; 95% CI: 1.17-5.80; p = 0.02), convulsions (OR: 2.25; 95% CI: 1.46-3.45; p < 0.01), CSF cell count <10 or >500/L (OR: 3.12; 95% CI: 1.03-9.43; p = 0.04) and hydrocephalus (OR: 2.99; 95% CI: 1.30-6.89; p = 0.01). CONCLUSION: A large proportion of children with tuberculous meningitis present with stroke at admission. Of those with no evidence of stroke at admission, a quarter develop stroke by 1 month, suggesting that there could be a brief window in which to give preventive therapy.

Risk-Stratification of Children Presenting to Ambulatory Paediatrics with First-Onset Seizures: Should We Order an Urgent CT Brain?

INTRODUCTION: A computed tomography (CT) brain scan is an often-utilised emergency department imaging modality to detect emergent intra-cranial pathology in a child with a first seizure. Identifying children at low risk of having a clinically significant intra-cranial abnormality could prevent unnecessary radiation exposure and contrast/sedation-related risks. OBJECTIVES: To identify clinical variables which could predict clinically significant CT brain abnormalities and use recursive partitioning analysis to define a low-risk group of children in whom emergent CT brain can be deferred. METHODS: Retrospective cross-sectional review of 468 children who underwent emergent CT brain after presenting to a low- and middle-income paediatric emergency department following first seizure. RESULTS: In total 133/468 (28.4%) of CT brain scans had clinically significant abnormalities. Failure to return to neurological baseline and focal neurological deficit persisting >36 h had statistical significance in a multiple regression analysis. Recursive partitioning analysis, applied to a subgroup without suspected tuberculous meningitis (n = 414), classified 153 children aged between 6 months and 5 years, who had a normal neurological baseline, had returned to baseline post-seizure, and were not in status epilepticus, as non-clinically significant scans and 98% were correctly classified. CONCLUSION: Our study re-inforces the American Academy of Neurology recommendation that children with persistent post-ictal abnormal neurological status and/or post-ictal focal deficit be prioritised for emergent CT brain. Having excluded children with suspected tuberculous meningitis, the remaining subgroup aged 6 months to 5 years presenting with a non-status first seizure, normal neurological baseline and return to baseline post-seizure, are at very low risk of having a clinically significant CT brain abnormality.

Application of Cerebrospinal Fluid Host Protein Biosignatures in the Diagnosis of Tuberculous Meningitis in Children from a High Burden Setting.

BACKGROUND: The diagnosis of tuberculous meningitis (TBM) especially in children is challenging. New tests are urgently needed for the diagnosis of the disease, especially in resource-limited settings. METHODS: We collected cerebrospinal fluid (CSF) samples from children presenting with symptoms requiring investigation for meningitis at a tertiary hospital in Cape Town, South Africa. Children were later classified as TBM or no TBM using published case definitions. Using a multiplex platform, we investigated the concentrations of biomarkers comprising a previously established 3-marker biosignature (VEGF, IL-13, and LL-37) and other potentially useful host biomarkers as diagnostic candidates for TBM. FINDINGS: Out of 47 children, age, 3 months to 13 years, 23 were diagnosed with TBM and six (16%) were HIV-infected. We validated the previously identified CSF biosignature (sensitivity of 95.7% (95% CI, 79.0-99.2%) and specificity of 37.5% (95% CI, 21.2-57.3%)). However, substitution of IL-13 and LL-37 with IFN-γ and MPO, respectively, resulted in improved accuracy (area under the ROC curve (AUC) = 0.97, 95% CI, 0.92-1.00, up to 91.3% (21/23) sensitivity and up to 100% (24/24) specificity). An alternative four-marker biosignature (sICAM-1, MPO, CXCL8, and IFN-γ) also showed potential, with an AUC of 0.97. CONCLUSION: We validated a previously identified CSF biosignature and showed that refinement of this biosignature by incorporation of other biomarkers diagnosed TBM with high accuracy. Incorporation of these biomarkers into a point-of-care or bedside diagnostic test platform may result in the improved management of TBM in children.

Complementary surveillance strategies are needed to better characterise the epidemiology, care pathways and treatment outcomes of tuberculosis in children.

BACKGROUND: Tuberculosis (TB) in young and HIV-infected children is frequently diagnosed at hospital level. In settings where general hospitals do not function as TB reporting units, the burden and severity of childhood TB may not be accurately reflected in routine TB surveillance data. Given the paucibacillary nature of childhood TB, microbiological surveillance alone will miss the majority of hospital-managed children. The study objective was to combine complementary hospital-based surveillance strategies to accurately report the burden, spectrum and outcomes of childhood TB managed at referral hospital-level in a high TB burden setting. METHODS: We conducted a prospective cohort study including all children (< 13 years) managed for TB at a large referral hospital in Cape Town, South Africa during 2012. Children were identified through newly implemented clinical surveillance in addition to existing laboratory surveillance. Data were collected from clinical patient records, the National Health Laboratory Service database, and provincial electronic TB registers. Descriptive statistics were used to report overall TB disease burden, spectrum, care pathways and treatment outcomes. Univariate analysis compared characteristics between children identified through the two hospital-based surveillance strategies to characterise the group of children missed by existing laboratory surveillance. RESULTS: During 2012, 395 children (180 [45.6%] < 2 years) were managed for TB. Clinical surveillance identified 237 (60%) children in addition to laboratory surveillance. Ninety (24.3%) children were HIV co-infected; 113 (29.5%) had weight-for-age z-scores <- 3. Extra-pulmonary TB (EPTB) was diagnosed in 188 (47.6%); 77 (19.5%) with disseminated TB. Favourable TB treatment outcomes were reported in 300/344 (87.2%) children with drug-susceptible and 50/51 (98.0%) children with drug-resistant TB. Older children (OR 1.7; 95% CI 1.0-2.8), children with EPTB (OR 2.3; 95% CI 1.5-3.6) and in-hospital deaths (OR 5.4; 95% CI 1.1-26.9) were more frequently detected by laboratory surveillance. TB/HIV co-infected children were less likely to be identified through laboratory surveillance (OR 0.3; 95% CI 0.2-0.5). CONCLUSIONS: The burden and spectrum of childhood TB disease managed at referral hospital level in high burden settings is substantial. Hospital-based surveillance in addition to routine TB surveillance is essential to provide a complete picture of the burden, spectrum and impact of childhood TB in settings where hospitals are not TB reporting units.

Standardized Methods for Enhanced Quality and Comparability of Tuberculous Meningitis Studies.

Tuberculous meningitis (TBM) remains a major cause of death and disability in tuberculosis-endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of TBM clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrollment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention TBM studies should improve the quality of future research outputs, can facilitate multicenter studies and meta-analyses of pooled data, and could provide the foundation for a global TBM data repository.

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

BACKGROUND: The 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. METHODS: In 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. RESULTS: Here 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. CONCLUSION: These 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.

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 host's 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 host's CSF for diagnostic applications and for improving our understanding of the pathogenesis of TBM to discover strategies to prevent immunopathological sequelae.

Uniform research case definition criteria differentiate tuberculous and bacterial meningitis in children.

BACKGROUND: Tuberculous meningitis (TBM) research is hampered by low numbers of microbiologically confirmed TBM cases and the fact that they may represent a select part of the disease spectrum. A uniform TBM research case definition was developed to address these limitations, but its ability to differentiate TBM from bacterial meningitis has not been evaluated. METHODS: We assessed all children treated for TBM from 1985 to 2005 at Tygerberg Children's Hospital, Cape Town, South Africa. For comparative purposes, a group of children with culture-confirmed bacterial meningitis, diagnosed between 2003 and 2009, was identified from the National Health Laboratory Service database. The performance of the proposed case definition was evaluated in culture-confirmed TBM and bacterial meningitis cases. RESULTS: Of 554 children treated for TBM, 66 (11.9%) were classified as "definite TBM," 408 (73.6%) as "probable TBM," and 72 (13.0%) as "possible TBM." "Probable TBM" criteria identified culture-confirmed TBM with a sensitivity of 86% and specificity of 100%; sensitivity was increased but specificity reduced when using "possible TBM" criteria (sensitivity 100%, specificity 56%). CONCLUSIONS: "Probable TBM" criteria accurately differentiated TBM from bacterial meningitis and could be considered for use in clinical trials; reduced sensitivity in children with early TBM (stage 1 disease) remains a concern.

The value of transcranial Doppler imaging in children with tuberculous meningitis.

PURPOSE: Transcranial Doppler imaging (TCDI) is potentially a valuable investigational tool in children with tuberculous meningitis (TBM), a condition often complicated by pathology relevant to Doppler imaging such as raised intracranial pressure (ICP) and cerebral vasculopathies. METHODS: Serial TCDI was performed on 20 TBM children with the aim of investigating cerebrovascular haemodynamics and the relationship between pulsatility index (PI) and ICP. RESULTS: We observed a poor correlation between ICP and PI in children with communicating hydrocephalus (p = 0.72). No decline in PI was noted following 7 days of medical therapy for communicating hydrocephalus (p = 0.78) despite a concomitant decline in ICP. Conversely, a decline in PI was noted in all four children with non-communicating hydrocephalus who underwent cerebrospinal fluid diversion. High blood flow velocities (BFV) in all the basal cerebral arteries were observed in 14 children (70 %). The high BFV persisted for 7 days suggesting stenosis due to vasculitis rather than functional vasospasm. Complete middle cerebral artery (MCA) occlusion, subnormal mean MCA velocities (<40 cm/s) and PIs (<0.4) correlated with radiologically proven large cerebral infarcts. CONCLUSIONS: TCDI-derived PI is not a reliable indicator of raised ICP in children with tuberculous hydrocephalus. This may be attributed to individual variation of tuberculous vascular disease, possibly compromising cerebral vascular compliance and resistance. Basal artery stenosis secondary to vasculitis is observed during the acute stage of TBM in the majority of children.

Utility of next generation sequencing in paediatric neurological disorders: experience from South Africa.

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.

1H-NMR metabolomics investigation of CSF from children with HIV reveals altered neuroenergetics due to persistent immune activation.

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 (1H-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.