Cerebral palsy in African paediatric populations: A scoping review.

AIM: To review the epidemiology and outcomes of African children with cerebral palsy (CP) over a 21-year period. METHOD: The PubMed, Scopus, and Web of Science online databases were searched for original research on African children with CP aged 18 years and younger published from 2000 to 2021. RESULTS: A total of 1811 articles underwent review against explicit criteria; 93 articles were selected for inclusion in the scoping review. The reported prevalence of CP ranged from 0.8 to 10 per 1000 children. Almost half had perinatal risk factors, but up to 26% had no identifiable risk factor. At least one-third of children with CP had one or more comorbidities, most commonly epilepsy, intellectual disability, and malnutrition. African children with CP demonstrated excess premature mortality approximately 25 times that of the general population, predominantly from infections. Hospital-based and younger populations had larger proportions of children with severe impairments. African children with CP had inadequate access to care and education, yet showed functional improvements compared to controls for all evaluated interventions. INTERPRETATION: The prevalence of CP in Africa remains uncertain. African children with CP have different risk profiles, greater premature mortality, and more severe functional impairments and comorbidities compared to the Global North. Several barriers prevent access to optimal care. Larger African studies on validated and effective interventions are needed.

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.

Aperiodic electrophysiological activity in preterm infants is linked to subsequent autism risk.

Approximately 7% of preterm infants receive an autism spectrum disorder (ASD) diagnosis. Yet, there is a significant gap in the literature in identifying prospective markers of neurodevelopmental risk in preterm infants. The present study examined two electroencephalography (EEG) parameters during infancy, absolute EEG power and aperiodic activity of the power spectral density (PSD) slope, in association with subsequent autism risk and cognitive ability in a diverse cohort of children born preterm in South Africa. Participants were 71 preterm infants born between 25 and 36 weeks gestation (34.60 ± 2.34 weeks). EEG was collected during sleep between 39 and 41 weeks postmenstrual age adjusted (40.00 ± 0.42 weeks). The Bayley Scales of Infant Development and Brief Infant Toddler Social Emotional Assessment (BITSEA) were administered at approximately 3 years of age adjusted (34 ± 2.7 months). Aperiodic activity, but not the rhythmic oscillatory activity, at multiple electrode sites was associated with subsequent increased autism risk on the BITSEA at three years of age. No associations were found between the PSD slope or absolute EEG power and cognitive development. Our findings highlight the need to examine potential markers of subsequent autism risk in high-risk populations other than infants at familial risk.

Neurodevelopmental outcome of HIV-exposed but uninfected infants in the Mother and Infants Health Study, Cape Town, South Africa.

OBJECTIVES: To compare neurodevelopmental outcomes of HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) infants in a peri-urban South African population. HEU infants living in Africa face unique biological and environmental risks, but uncertainty remains regarding their neurodevelopmental outcome. This is partly due to lack of well-matched HUU comparison groups needed to adjust for confounding factors. METHODS: This was a prospective cohort study of infants enrolled at birth from a low-risk midwife obstetric facility. At 12 months of age, HEU and HUU infant growth and neurodevelopmental outcomes were compared. Growth was evaluated as WHO weight-for-age, length-for-age, weight-for-length and head-circumference-for-age Z-scores. Neurodevelopmental outcomes were evaluated using the Bayley scales of Infant Development III (BSID) and Alarm Distress Baby Scale (ADBB). RESULTS: Fifty-eight HEU and 38 HUU infants were evaluated at 11-14 months of age. Performance on the BSID did not differ in any of the domains between HEU and HUU infants. The cognitive, language and motor scores were within the average range (US standardised norms). Seven (12%) HEU and 1 (2.6%) HUU infant showed social withdrawal on the ADBB (P = 0.10), while 15 (26%) HEU and 4 (11%) HUU infants showed decreased vocalisation (P = 0.06). There were no growth differences. Three HEU and one HUU infant had minor neurological signs, while eight HEU and two HUU infants had macrocephaly. CONCLUSIONS: Although findings on the early neurodevelopmental outcome of HEU infants are reassuring, minor differences in vocalisation and on neurological examination indicate a need for reassessment at a later age.

A treatment-support intervention evaluated in South African paediatric populations with HIV infection or tuberculous meningitis.

OBJECTIVES: To evaluate a paediatric treatment-support intervention for home-based treatment of HIV infection or tuberculous meningitis (TBM). METHODS: A randomised-controlled study comparing local standard care (controls) with standard care plus intervention (combining adherence education, reinforcement and monitoring) in children aged 0-14 years. We recorded adherence measures (self-report, pill-count, drug-assays for isoniazid and rifampicin in urine and pyrazinamide in saliva), difficulties administering medication and PedsQL™questionnaires for health-related quality-of-life (HRQoL) and family impact. RESULTS: In the HIV group (6-months follow-up, n = 195), more children had above-median HRQoL-scores in the intervention group than in the control group (P = 0.009). Problems reported administering medication declined between baseline and follow-up for controls (P = 0.043). Disclosure of HIV status to the child increased between baseline and follow-up in both groups (intervention P < 0.001; control P = 0.031). In the TBM group (3-months follow-up, n = 43), all adherence measures remained high for both intervention and controls, except for rifampicin which declined between baseline and follow-up in the intervention group (P = 0.031). The intervention group maintained above median HRQoL-scores between baseline and follow-up, when the number of children with above-median HRQoL-scores decreased in the controls (P = 0.063). More children in the intervention group had above-median family impact-scores than controls (P = 0.040). CONCLUSIONS: The low-cost, culturally friendly treatment-support intervention had beneficial effects on health-related quality of life, family impact, caregiver disclosure of HIV status to the child, increased caregiver reporting of medication non-adherence and caregiver reporting of difficulties administering medication. Treatment adherence was not significantly affected in either HIV or TBM group.

Favourable outcome in a child with symptomatic diagnosis of Glutaric aciduria type 1 despite vertical HIV infection and minor head trauma.

The first case of Glutaric aciduria Type 1(GA1) in an African child was reported in 2001. GA1 has a prevalence of 1:5000 in black South Africans. Although early diagnosis is essential for a favourable outcome, newborn screening is not routine in South Africa where an estimated 320,000 children have HIV infection. Neurodevelopmental delay and encephalopathy are complications of both HIV and GA1. In such a setting it is important to recognise that HIV and GA1 can occur simultaneously. We present an HIV-infected South African male child of Xhosa descent with macrocephaly who commenced combination antiretroviral therapy (ART) at 8 weeks of age in a clinical trial which included a neurodevelopmental sub-study. He developed short-lived focal seizures at 16 months after minor head trauma. Neurological examination was normal. Neuroimaging showed temporal lobe atrophy, subtle hyperintense signal change in the globus pallidus, and focal haemosiderosis in the right Sylvian fissure region. As findings were not in keeping with HIV encephalopathy, a urine metabolic screen was undertaken which suggested GA1. Genetic testing confirmed Arg293Trp mutation. He began L-carnitine and a low protein diet as a restricted diet was not practicable. At 21 months he developed pulmonary tuberculosis, requiring 6 months treatment. He did not develop any neurologic motor symptoms. Serial neurodevelopmental and neuropsychological test scores until 9 years were similar to healthy neighbourhood controls, except for mild language delay at 3½ years. Detection of GA1, probably facilitated through participation in a clinical trial, was pivotal for a favourable outcome. The concomitant use of ART and anti-tuberculous therapy in a child with GA1 appears safe.

Spastic diplegia in children with HIV encephalopathy: first description of gait and physical status.

AIM: The aim of this study was to explore the physical status and gait patterns of children with spastic diplegia secondary to human immunodeficiency virus encephalopathy (HIVE). METHOD: A cross-sectional study was conducted on children diagnosed with HIVE and spastic diplegia. Sociodemographic and clinical background information was obtained, followed by three-dimensional gait analysis (3DGA) and a physical examination including assessments of muscle tone, strength, motor control, contractures, and bony deformities of the lower extremities. RESULTS: Fourteen children (eight males, six females; mean age 5 y 8 mo [SD 9 mo], range 4 y 4 mo-6 y 10 mo) were studied. The cohort was divided into two groups based on distinctive gait patterns. Nine participants in group I showed only limited abnormalities. Group II displayed a more pathological gait pattern including stiff knee and equinus ankle abnormalities. Results of 3DGA, as with the physical examination outcomes, showed increased impairments from proximal to distal (except for hip extension). INTERPRETATION: This study provides a first description of distinctive gait patterns and related physical characteristics of children with HIVE and spastic diplegia. Further research is necessary.

Global COVID-19 childhood disability data coordination: A collaborative initiative of the International Alliance of Academies of Childhood Disability.

PURPOSE: The International Alliance of Academies of Childhood Disability created a COVID-19 Task Force with the goal of understanding the global impact of COVID-19 on children with disabilities and their families. The aim of this paper is to synthesize existing evidence describing the impact of COVID-19 on people with disabilities, derived from surveys conducted across the globe. METHODS: A descriptive environmental scan of surveys was conducted. From June to November 2020, a global call for surveys addressing the impact of COVID-19 on disability was launched. To identify gaps and overlaps, the content of the surveys was compared to the Convention on the Rights of the Child and the International Classification of Functioning, Disability and Health. RESULTS: Forty-nine surveys, involving information from more than 17,230 participants around the world were collected. Overall, surveys identified that COVID-19 has negatively impacted several areas of functioning - including mental health, and human rights of people with disabilities and their families worldwide. CONCLUSION: Globally, the surveys highlight that impact of COVID-19 on mental health of people with disabilities, caregivers, and professionals continues to be a major issue. Rapid dissemination of collected information is essential for ameliorating the impact of COVID-19 across the globe.

Mapping the link between socio-economic factors, autistic traits and mental health across different settings.

LAY ABSTRACT: Autistic individuals are more likely than non-autistic individuals to experience a mental health condition in their lifetime, and this includes externalising and internalising symptoms. We know very little about how different environments and family conditions impact these symptoms for autistic individuals. Improving our understanding of these relationships is important so that we can identify individuals who may be in greater need of support. In this article, we seek to improve our understanding of how environmental and family conditions impact externalising and internalising symptoms in autistic and non-autistic people. To do this, we conducted analyses with two cohorts in very different settings - in Europe and South Africa - to ensure our findings are globally representative. We used advanced statistical methods to establish environmental and family conditions that were similar to each other, and which could be combined into specific 'factors'. We found that four similar 'factors' could be identified in the two cohorts. These were distinguished by personal characteristics and environmental conditions of individuals, and were named Person Characteristics, Family System, Parental and Material Resources. Interestingly, just 'Family System' was associated with internalising and externalising symptoms, and this was the same in both cohorts. We also found that having high traits of autism impacted this relationship between Family System and mental health conditions with opposite directions in the two settings. These results show that characteristics in the Family System are associated with internalising and externalising symptoms, and autistic persons are particularly impacted, reinforcing the notion that family stressors are important to consider when implementing policy and practice related to improving the mental health of autistic people.

Tuberculous meningitis: barriers to adherence in home treatment of children and caretaker perceptions.

INTRODUCTION: In-hospital treatment of children with tuberculous meningitis (TBM) is not a feasible option in many resource-poor countries. Home-based treatment has shown to be a viable alternative. Adherence is an important factor determining success of treatment. OBJECTIVE: Identify possible barriers to adherence of home-based treatment and caretaker perception of the disease. METHOD: A qualitative study consisting of 11 in-depth semi-structured interviews was performed based on principles of the health belief model. RESULTS: Barriers of adherence identified include poor understanding of the disease and transmission route, difficulty with medication administration and side effects, lack of access to the health-care facility, long waiting times and hidden costs of transportation. Caretakers showed good appreciation of the adverse effects of noncompliance and benefits obtained from taking treatment in the home environment. CONCLUSION: Improved doctor-patient communication, information brochures, structural changes to hospital settings, provision of financial and peer support all contribute to optimal TBM home-based treatment.

Association of maternal depression and anxiety with toddler social-emotional and cognitive development in South Africa: a prospective cohort study.

OBJECTIVE: A robust literature has identified associations between prenatal maternal depression and adverse child social-emotional and cognitive outcomes. The majority of prior research is from high-income countries despite increased reporting of perinatal depression in low/middle-income countries (LMICs). Additionally, despite the comorbidity between depression and anxiety, few prior studies have examined their joint impact on child neurodevelopment. The objective of the current analysis was to examine associations between prenatal maternal depression and anxiety with child social-emotional and cognitive development in a cohort from the Western Cape Province of South Africa. DESIGN: Prenatal maternal depression and anxiety were measured using the Edinburgh Postnatal Depression Scale and the State-Trait Anxiety Inventory Scale at 20-24 weeks' gestation. Child neurobehaviour was assessed at age 3 using the Brief Infant-Toddler Social Emotional Assessment and the Bayley Scales of Infant Development III Screening Test (BSID-III ST). We used linear regression models to examine the independent and joint association between prenatal maternal depression, anxiety and child developmental outcomes. RESULTS: Participants consisted of 600 maternal-infant dyads (274 females; gestational age at birth: 38.89 weeks±2.03). Children born to mothers with both prenatal depression and trait anxiety had higher social-emotional problems (mean difference: 4.66; 95% CI 3.43 to 5.90) compared with children born to mothers with no prenatal depression or trait anxiety, each condition alone, or compared with mothers with depression and state anxiety. Additionally, children born to mothers with prenatal maternal depression and trait anxiety had the greatest reduction in mean cognitive scores on the BSID-III ST (mean difference: -1.04; 95% CI -1.99 to -0.08). CONCLUSIONS: The observed association between comorbid prenatal maternal depression and chronic anxiety with subsequent child social-emotional and cognitive development underscores the need for targeting mental health support among perinatal women in LMICs to improve long-term child neurobehavioural outcomes.

Associations of adverse maternal experiences and diabetes on postnatal maternal depression and child social-emotional outcomes in a South African community cohort.

Previous literature has identified associations between diabetes during pregnancy and postnatal maternal depression. Both maternal conditions are associated with adverse consequences on childhood development. Despite an especially high prevalence of diabetes during pregnancy and maternal postnatal depression in low- and middle-income countries, related research predominates in high-income countries. In a South African cohort with or without diabetes, we investigated associations between adverse maternal experiences with postnatal maternal depression and child social-emotional outcomes. South African mother-child dyads were recruited from the Bishop Lavis community in Cape Town. Participants consisted of 82 mother-child dyads (53 women had GDM or type 2 diabetes). At 14-20 months postpartum, maternal self-report questionnaires were administered to assess household socioeconomic status, food insecurity, maternal depressive symptoms (Edinburgh Postnatal Depression Scale (EPDS)), maternal trauma (Life Events Checklist), and child social-emotional development (Brief Infant Toddler Social Emotional Assessment, Ages and Stages Questionnaires: Social-Emotional, Second Edition). Lower educational attainment, lower household income, food insecurity, living without a partner, and having experienced physical assault were each associated with postnatal maternal depressive symptoms and clinical maternal depression (EPDS ≥ 13). Maternal postnatal depression, lower maternal educational attainment, lower household income, household food insecurity, and living in a single-parent household were each associated with child social-emotional problems. Stratified analyses revealed maternal experiences (education, income, food insecurity, trauma) were associated with postnatal maternal depressive symptoms and child social-emotional problems only among dyads with in utero exposure to diabetes. Women with pre-existing diabetes or gestational diabetes in LMIC settings should be screened for health related social needs to reduce the prevalence of depression and to promote child social-emotional development.

Home-based treatment of childhood neurotuberculosis.

INTRODUCTION: In-hospital treatment is widely recognized as the gold standard of treatment for children with neurotuberculosis due to the complexity of care and serious consequences of non-compliance. The continuous rise in the incidence of tuberculosis (TB), fuelled by an HIV-pandemic, has resulted in severe bed shortages in tertiary, secondary and TB hospitals in the Western Cape. OBJECTIVE: To evaluate the feasibility of home-based directly observed therapy (DOT) in TBM. METHOD: Suitability screening by social workers, in-hospital monitoring of mother-child interaction, medication side effects and intolerance followed by a supervised outpatient surveillance program. RESULTS: Forty of the 52 children screened were approved for home-based treatment. Thirty-four of these 40 patients (85%) completed TBM treatment successfully at home, and no patient defaulted treatment. CONCLUSION: Home-based treatment of childhood neurotuberculosis is feasible in selected patients under close supervision. Mothers could be considered as primary DOT supporters.

Diagnostic accuracy of the Molteno Adapted Scale for developmental delay in South African toddlers.

Background: There is currently a great need in South Africa for culturally appropriate neurodevelopmental screening measures in order to facilitate early identification of neurodevelopmental problems in children. Neurodevelopmental screening has the potential to decrease the burden at health-care facilities as it is time, resource and cost effective. Aim: To assess the use of the Molteno Adapted Scale (MAS), a locally developed screening measure, to suggest an optimal cut-off score and investigate its accuracy in detecting developmental delays. Method: The MAS was assessed by evaluating three components: accuracy, efficacy and usefulness. For each of 136 participants, MAS scores were compared with dichotomised scores from the Griffiths Mental Development Scales (GMDS). Receiver operating characteristic (ROC) curves were generated to determine the accuracy of the MAS in identifying developmental delay defined by the GMDS. Sensitivity, specificity and predictive values were calculated for potential MAS cut-off scores. Results: The MAS had an excellent area under the ROC curve, indicating good test accuracy. A developmental quotient of 83 was identified as optimal for screening purposes, with acceptable sensitivity (71.4%) and specificity (90.7%) as well as predictive values (29.4% positive predictive value and 98.3% negative predictive value) for developmental delay on the GMDS. Conclusion: The present study provides preliminary evidence supporting the use of the MAS for screening.

Neurocognitive and functional impairment in adult and paediatric tuberculous meningitis.

In those who survive tuberculous meningitis (TBM), the long-term outcome is uncertain; individuals may suffer neurocognitive, functional and psychiatric impairment, which may significantly affect their ability to lead their lives as they did prior to their diagnosis of TBM. In children who survive, severe illness has occurred at a crucial timepoint in their development, which can lead to behavioural and cognitive delay. The extent and nature of this impairment is poorly understood, particularly in adults. This is in part due to a lack of observational studies in this area but also inconsistent inclusion of outcome measures which can quantify these deficits in clinical studies. This leads to a paucity of appropriate rehabilitative therapies available for these individuals and their caregivers, as well as burden at a socioeconomic level. In this review, we discuss what is known about neurocognitive impairment in TBM, draw on lessons learnt from other neurological infections and discuss currently available and emerging tools to evaluate function and cognition and their value in TBM. We make recommendations on which measures should be used at what timepoints to assess for impairment, with a view to optimising and standardising assessment of neurocognitive and functional impairment in TBM research.

Five year neurodevelopment outcomes of perinatally HIV-infected children on early limited or deferred continuous antiretroviral therapy.

INTRODUCTION: Early antiretroviral therapy (ART) has improved neurodevelopmental outcomes of HIV-infected (HIV-positive) children; however, little is known about the longer term outcomes in infants commencing early ART or whether temporary ART interruption might have long-term consequences. In the children with HIV early antiretroviral treatment (CHER) trial, HIV-infected infants ≤12 weeks of age with CD4 ≥25% were randomized to deferred ART (ART-Def); immediate time-limited ART for 40 weeks (ART-40W) or 96 weeks (ART-96W). ART was restarted in the time-limited arms for immunologic/clinical progression. Our objective was to compare the neurodevelopmental profiles in all three arms of Cape Town CHER participants. METHODS: A prospective, longitudinal observational study was used. The Griffiths mental development scales (GMDS), which includes six subscales and a global score, were performed at 11, 20, 30, 42 and 60 months, and the Beery-Buktenica developmental tests for visual motor integration at 60 months. HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled for comparison. Mixed model repeated measures were used to compare groups over time, using quotients derived from standardized British norms. RESULTS: In this study, 28 ART-Def, 35 ART-40W, 33 ART-96W CHER children, and 34 HEU and 39 HU controls were enrolled. GMDS scores over five years were similar between the five groups in all subscales except locomotor and general Griffiths (interaction p < 0.001 and p = 0.02 respectively), driven by early lower scores in the ART-Def arm. At 60 months, scores for all groups were similar in each GMDS scale. However, Beery visual perception scores were significantly lower in HIV-infected children (mean standard scores: 75.8 ART-Def, 79.8 ART-40W, 75.9 ART-96W) versus 84.4 in HEU and 90.5 in HU (p < 0.01)). CONCLUSIONS: Early locomotor delay in the ART-Def arm resolved by five years. Neurodevelopmental outcomes at five years in HIV-infected children on early time-limited ART were similar to uninfected controls, apart from visual perception where HIV-infected children scored lower. Poorer visual perception performance warrants further investigation.

Coagulant and fibrinolytic status in tuberculous meningitis.

BACKGROUND: The long-term neurologic sequelae of childhood tuberculous meningitis (TBM) mainly result from ischemia owing to cerebral vasculitis. Deep vein thrombosis occurs in adults with pulmonary tuberculosis owing to hypercoaguability. The present study aimed to investigate coagulation status during acute childhood TBM. METHODS: Coagulation status, including the natural anticoagulants, antithrombin, protein C and protein S; procoagulant FVIII; fibrinolytic factors, tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) as well as anticardiolipin antibodies (ACA), was determined in 16 children with TBM before and during treatment. RESULTS: A prothrombotic profile was found as expressed by a decrease of anticoagulant (protein S) and increase of the procoagulant (factor VIII) activity. Raised PAI-1 and normal tissue plasminogen activator values indicated deficient fibrinolysis. This hypercoagulable state was more pronounced in stage 3 patients than in stage 2 patients. The bleeding time on admission ranged from 1.2 to 10 minutes [mean 4.2 minutes]. The mean platelet count on admission was 577.9 +/- 188.6 x 10/L and increased further during the course of the treatment. CONCLUSIONS: The hypercoagulable state in childhood TBM is comparable to that described in adults with pulmonary tuberculosis and may further increase the risk for infarction. Therapeutic measures that reduce the risk for thrombosis could therefore be potentially beneficial in childhood TBM.

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.

Vascular endothelial growth factor and blood-brain barrier disruption in tuberculous meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is characterized by disruption of the blood-brain barrier (BBB), cerebral edema and increased intracranial pressure (ICP). Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema. AIMS: To investigate whether in children with TBM disruption of the BBB relates to VEGF production and to assess the effect of corticosteroids on Mycobacterium tuberculosis-induced VEGF production by mononuclear leukocytes. METHODS: Blood and CSF samples were collected from 26 children with stage 2-3 TBM and 20 controls. All patients received antituberculous and adjuvant corticosteroid therapy. Children were evaluated by ICP recording, computerized tomography scanning and outcome assessment at 6 months follow-up. BBB disruption was quantified by cerebrospinal fluid (CSF)-serum albumin ratios. VEGF concentrations were measured by enzyme-linked immunosorbent assay. In vitro human monocytic THP-1 cells were stimulated with M. tuberculosis sonicate or culture supernatant, and VEGF production was measured in the presence or absence of corticosteroids. RESULTS: CSF VEGF concentrations were significantly higher in TBM patients than in the controls and correlated with mononuclear cell counts (r = 0.64; P = 0.001) and CSF-serum albumin ratio (r = 0.49; P = 0.015). CSF VEGF did not significantly correlate with elevated ICP. In vitro induction of VEGF production by M. tuberculosis sonicate or culture supernatant could be completely abrogated by corticosteroid treatment. CONCLUSIONS: Inflammatory cells secrete VEGF during TBM. CSF VEGF correlates with BBB disruption. Inhibition of VEGF may explain part of the clinical effect of adjuvant corticosteroid therapy in TBM.

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 alpha 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.