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ObjectiveTo investigate whether maternal common mental disorders (CMD) in the postnatal period are prospectively associated with child development at 2.5 and 3.5 years in a rural low-income African setting.MethodsThis study was nested within the C-MaMiE (Child outcomes in relation to Maternal Mental health in Ethiopia) population-based cohort in Butajira, Ethiopia, and conducted from 2005 to 2006. The sample comprised of 496 women who had recently given birth to living, singleton babies with recorded birth weight measurements, who were 15 to 44 years of age, and residing in six rural sub-districts. Postnatal CMD measurements were ascertained 2 months after delivery. Language, cognitive, and motor development were obtained from the child 2.5 and 3.5 years after birth using a locally adapted version of the Bayley Scales of Infant Development (3rd Ed). Maternal CMD symptoms were measured using a locally validated WHO Self-Reporting Questionnaire. A linear mixed-effects regression model was used to analyze the relationship between postnatal CMD and child development.ResultsAfter adjusting for confounders, there was no evidence for an association between postnatal CMD and overall child development or the cognitive sub-domain in the preschool period. There was no evidence of effect modification by levels of social support, socioeconomic status, stunting, or sex of the child.ConclusionsPrevious studies from predominantly urban and peri-urban settings in middle-income countries have established a relationship between maternal CMD and child development, which contrasts with the findings from this study. The risk and protective factors for child development may differ in areas characterized by high social adversity and food insecurity. More studies are needed to investigate maternal CMD’s impact on child development in low-resource and rural areas.

Background Survivors of invasive group B Streptococcus (iGBS) disease, notably meningitis, are at increased risk of neurodevelopmental impairment. However, the limited studies to date have a median follow-up to 18 months and have mainly focused on moderate or severe neurodevelopmental impairment, with no previous studies on emotional-behavioral problems among iGBS survivors. Methods In this multicountry, matched cohort study, we included children aged 18 months to 17 years with infant iGBS sepsis and meningitis from health demographic surveillance systems, or hospital records in Argentina, India, Kenya, Mozambique, and South Africa. Children without an iGBS history were matched to iGBS survivors for sex and age. Our primary outcomes were emotional-behavioral problems and psychopathological conditions as measured with the Child Behavior Checklist (CBCL). The CBCL was completed by the child’s primary caregiver. Results Between October 2019 and April 2021, 573 children (mean age, 7.18 years) were assessed, including 156 iGBS survivors and 417 non-iGBS comparison children. On average, we observed more total problems and more anxiety, attention, and conduct problems for school-aged iGBS survivors compared with the non-iGBS group. No differences were found in the proportion of clinically significant psychopathological conditions defined by the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). Conclusions Our findings suggested that school-aged iGBS survivors experienced increased mild emotional behavioral problems that may affect children and families. At-risk neonates including iGBS survivors need long-term follow-up with integrated emotional-behavioral assessments and appropriate care. Scale-up will require simplified assessments that are free and culturally adapted.

Background The COVID-19 pandemic leads to disruptions of health services worldwide. To evaluate the particular impact on neurological services a rapid review was conducted. Methods Studies reporting the provision of neurological services during the pandemic and/or adopted mitigation strategies were included in this review. PubMed and World Health Organization’s (WHO) COVID-19 database were searched. Data extraction followed categories used by WHO COVID-19 pulse surveys and operational guidelines on maintaining essential health services during COVID-19. Findings The search yielded 1101 articles, of which 369 fulfilled eligibility criteria, describing data from 210,419 participants, being adults (81%), children (11.4%) or both (7.3%). Included articles reported data from 105 countries and territories covering all WHO regions and World Bank income levels (low income: 1.9%, lower middle: 24.7%, upper middle: 29.5% and high income; 44.8%). Cross-sectoral services for neurological disorders were most frequently disrupted (62.9%), followed by emergency/acute care (47.1%). The degree of disruption was at least moderate for 75% of studies. Travel restrictions due to lockdowns (81.7%) and regulatory closure of services (65.4%) were the most commonly reported causes of disruption. Authors most frequently described telemedicine (82.1%) and novel dispensing approaches for medicines (51.8%) as mitigation strategies. Evidence for the effectiveness of these measures is largely missing. Interpretation The COVID-19 pandemic affects all aspects of neurological care. Given the worldwide prevalence of neurological disorders and the potential long-term neurological consequences of COVID-19, service disruptions are devastating. Different strategies such as telemedicine might mitigate the negative effects of the pandemic, but their efficacy and acceptability remain to be seen.

Working in Africa provides neuroscientists with opportunities that are not available in other continents. Populations in this region exhibit the greatest genetic diversity; they live in ecosystems with diverse flora and fauna; and they face unique stresses to brain health, including child brain health and development, due to high levels of traumatic brain injury and diseases endemic to the region. However, the neuroscience community in Africa has yet to reach its full potential. In this article we report the outcomes from a series of meetings at which the African neuroscience community came together to identify barriers and opportunities, and to discuss ways forward. This exercise resulted in the identification of six domains of distinction in African neuroscience: the diverse DNA of African populations; diverse flora, fauna and ecosystems for comparative research; child brain health and development; the impact of climate change on mental and neurological health; access to clinical populations with important conditions less prevalent in the global North; and resourcefulness in the reuse and adaption of existing technologies and resources to answer new questions. The article also outlines plans to advance the field of neuroscience in Africa in order to unlock the potential of African neuroscientists to address regional and global mental health and neurological problems.

Objective Nodding syndrome is a poorly understood epileptic encephalopathy characterized by a unique seizure type—head nodding—and associated with Onchocerca volvulus infection. We hypothesized that altered immune activation in the cerebrospinal fluid (CSF) and plasma of children with nodding syndrome may yield insights into the pathophysiology and progression of this seizure disorder. Method We conducted a case‐control study of 154 children (8 years or older) with long‐standing nodding syndrome and 154 healthy age‐matched community controls in 3 districts of northern Uganda affected by nodding syndrome. Control CSF samples were obtained from Ugandan children in remission from hematological malignancy during routine follow‐up. Markers of immune activation and inflammation (cytokines and chemokines) and complement activation (C5a) were measured in plasma and CSF using ELISA or Multiplex Luminex assays. O volvulus infection was assessed by serology for anti–OV‐16 IgG levels. Results The mean (SD) age of the population was 15.1 (SD: 1.9) years, and the mean duration of nodding syndrome from diagnosis to enrollment was 8.3 (SD: 2.7) years. The majority with nodding syndrome had been exposed to O volvulus (147/154 (95.4%)) compared with community children (86/154 (55.8%)), with an OR of 17.04 (95% CI: 7.33, 45.58), P < .001. C5a was elevated in CSF of children with nodding syndrome compared to controls (P < .0001). The levels of other CSF markers tested were comparable between cases and controls after adjusting for multiple comparisons. Children with nodding syndrome had lower plasma levels of IL‐10, APRIL, CCL5 (RANTES), CCL2, CXCL13, and MMP‐9 compared with community controls (P < .05 for all; multiple comparisons). Plasma CRP was elevated in children with nodding syndrome compared to community children and correlated with disease severity. Significance Nodding syndrome is associated with exposure to O. volvulus. Compared to controls, children with long‐standing symptoms of nodding syndrome show evidence of complement activation in CSF and altered immune activation in plasma.

We examined the mental health and quality of life (QoL) outcomes and their correlates of school-aged survivors of neonatal jaundice (NNJ), hypoxic-ischemic encephalopathy (HIE), and a comparison group. The Child Behavior Checklist and the Pediatric Quality of Life Inventory were administered to assess the mental health and QoL of 375 children (134 with NNJ, 107 with HIE, and 134 comparison group) aged 6 to 12 years [Median age 9 (interquartile range 7 to 11)]. The results showed that survivors of NNJ and HIE have mental health problems and QoL similar to the comparison group. Maternal mental health was the predominant covariate of mental health and QoL in survivors of NNJ and HIE. This result could indicate that mothers with mental health problems are more likely to have children with mental health issues, but also that caring for children with these adversities may affect mental health well-being of the caregivers. There is a need for early mental health screening and psychosocial intervention for caregivers and their children to enhance both their mental health and QoL.

BackgroundThere is little data on the long-term neurocognitive and educational outcomes among school-aged survivors of neonatal jaundice (NNJ) and hypoxic-ischemic encephalopathy (HIE) in Africa.This study investigates the long-term neurocognitive and educational outcomes and the correlates of these outcomes in school-aged survivors of NNJ or HIE in Kilifi, Kenya.MethodsWe conducted a cross-sectional study on neurocognitive and educational outcomes among school-aged survivors (6–12 years) of NNJ (n = 134) and HIE (n = 107) and compared them to a community comparison group (n = 134). We assessed nonverbal intelligence, planning, working memory, attention, syntax, pragmatics, word-finding, memory, perceptual-motor, mathematical, and reading abilities. We also collected information on medical history, caregivers’ mental health, and family environment.ResultsThe survivors of NNJ had lower mean total scores in word-finding [F (1, 250) = 3.89,p = 0.050] and memory [F (1, 248) = 6.74,p = 0.010] than the comparison group. The survivors of HIE had lower mean scores in pragmatics [F (1, 230) = 6.61,p = 0.011] and higher scores higher scores in non-verbal reasoning [F (1, 225) =4.10,p = 0.044] than the comparison group. Stunted growth was associated with almost all the outcomes in HIE.ConclusionSurvivors of NNJ and HIE present with impairment in the multiple domains, which need to be taken into consideration in the planning of educational and rehabilitative services.

BackgroundDiagnosing bacterial meningitis is essential to optimise the type and duration of antimicrobial therapy to limit mortality and sequelae. In sub-Saharan Africa, many public hospitals lack laboratory capacity, relying on clinical features to empirically treat or not treat meningitis. We investigated whether clinical features of bacterial meningitis identified prior to the introduction of conjugate vaccines still discriminate meningitis in children aged ≥60 days.MethodsWe conducted a retrospective cohort study to validate seven clinical features identified in 2002 (KCH-2002): bulging fontanel, neck stiffness, cyanosis, seizures outside the febrile convulsion age range, focal seizures, impaired consciousness, or fever without malaria parasitaemia and Integrated Management of Childhood Illness (IMCI) signs: neck stiffness, lethargy, impaired consciousness or seizures, and assessed at admission in discriminating bacterial meningitis after the introduction of conjugate vaccines. Children aged ≥60 days hospitalised between 2012 and 2016 at Kilifi County Hospital were included in this analysis. Meningitis was defined as positive cerebrospinal fluid (CSF) culture, organism observed on CSF microscopy, positive CSF antigen test, leukocytes ≥50/μL, or CSF to blood glucose ratio ResultsAmong 12,837 admissions, 98 (0.8%) had meningitis. The presence ofKCH-2002signs had a sensitivity of 86% (95% CI 77–92) and specificity of 38% (95% CI 37–38). Exclusion of ‘fever without malaria parasitaemia’ reduced sensitivity to 58% (95% CI 48–68) and increased specificity to 80% (95% CI 79–80). IMCI signs had a sensitivity of 80% (95% CI 70–87) and specificity of 62% (95% CI 61–63).ConclusionsA lower prevalence of bacterial meningitis and less typical signs than in 2002 meant the lower performance ofKCH-2002signs. Clinicians and policymakers should be aware of the number of lumbar punctures (LPs) or empirical treatments needed for each case of meningitis. Establishing basic capacity for CSF analysis is essential to exclude bacterial meningitis in children with potential signs.

Objective: The International League Against Epilepsy (ILAE) has revised the classification of epilepsies and seizures on several occasions since the original classification published in 1964. It is unclear if these changes have impacted the characterization of epilepsy, including the clinical validity of seizure semiology or epilepsy outcomes in resource-poor areas. We aim to address this important knowledge gap. Methods: We reviewed the clinical seizure semiology and etiological data of 483 persons with epilepsy identified from a population-based survey in rural Kenya. The seizure semiology and etiological data were classified using the 1981 (for seizures) and 1989 (for epilepsy) ILAE criteria and then reclassified according to the ILAE-2017 criteria. Logistic regression models adjusted for potential confounders were used to measure the associations between the seizure semiology and different clinical and electroencephalographic features of epilepsy. Results: Focal (formerly localization-related) and generalized epilepsies were lower in ILAE-2017 (56% and 29%) than that of ILAE-1989 (61% and 34%), P < .001 and P < .001. Combined focal and generalized epilepsy type in ILAE-2017 accounted for 11% of epilepsies. Individual seizure types were statistically similar in both ILAE-1981 and 2017. New classification categories in ILAE-2017 such as unknown seizures and epilepsies were identified, and the proportions were similar to the unclassified category in ILAE-1989, 6% and 5%, respectively. The most common causes of epilepsy were symptomatic (76%) in the ILAE-1989 criteria, with infectious (45%) and structural (36%) causes were highest in the ILAE-2017 criteria. Significance: Our study confirms that the two ILAE classification schemes are broadly consistent, but the introduction of the combined onset seizure category in ILAE-2017 significantly reduces the proportion of mutually exclusive focal and generalized seizures. The comprehensive classification of etiology categories in ILAE-2017 will facilitate appropriate treatment and improve prognosis.

Aim: To investigate geographical change over time in the burden of neurological impairments in school-aged children in a demographic surveillance area. Method: We investigated changes in neurological impairment prevalence in five domains (epilepsy and cognitive, hearing, vision, and motor impairments) using similar two-phase surveys conducted in 2001 (n=10 218) and 2015 (n=11 223) and determined changes in location-level prevalence, geographical clustering, and significant risk factors for children aged 6 to 9 years (mean7y 6mo, SD1y) of whom 50.4% were males. Admission trends for preterm birth, low birthweight (LBW), and encephalopathy were determined using admission data to a local hospital. Results: Overall prevalence for any neurological impairment decreased from 61 per 1000 (95% confidence interval [CI]48.0–74.0) in 2001 to 44.7 per 1000 (95% CI40.9–48.6) in 2015 (p Interpretation: There was a significant decline in the prevalence of neurological impairments and differential changes in the associations of some risk factors with neurological impairments over the study period. Limited geographical variation suggests that similar interventions are appropriate across the defined area.

Background The possibility that onchocerciasis may cause epilepsy has been suggested for a long time, but thus far, an etiological link has not been universally accepted. The objective of this review is to critically appraise the relationship between Onchocerca volvulus and epilepsy and subsequently apply the Bradford Hill criteria to further evaluate the likelihood of a causal association. Methods PubMed and gray literature published until September 15, 2020, were searched and findings from original research were synthesized. Adherence to the 9 Bradford Hill criteria in the context of onchocerciasis and epilepsy was determined to assess whether the criteria are met to strengthen the evidence base for a causal link between infection with O. volvulus and epilepsy, including the nodding syndrome. Results Onchocerciasis as a risk factor for epilepsy meets the following Bradford Hill criteria for causality: strength of the association, consistency, temporality, and biological gradient. There is weaker evidence supporting causality based on the specificity, plausibility, coherence, and analogy criteria. There is little experimental evidence. Considering the Bradford Hill criteria, available data suggest that under certain conditions (high microfilarial load, timing of infection, and perhaps genetic predisposition), onchocerciasis is likely to cause epilepsy including nodding and Nakalanga syndromes. Conclusion Applying the Bradford Hill criteria suggests consistent epidemiological evidence that O. volvulus infection is a trigger of epilepsy. However, the pathophysiological mechanisms responsible for seizure induction still need to be elucidated., Author summary There is growing epidemiological evidence that an infection with Onchocerca volvulus (the parasite causing onchocerciasis or river blindness) can trigger epilepsy, including nodding and Nakalanga syndromes. We studied the association between onchocerciasis and epilepsy using previously proposed criteria for causality and found strong arguments in favor of a causal relationship. The risk for children to develop epilepsy seems to be determined by the O. volvulus microfilarial load. However, the mechanism by which the O. volvulus parasite is able to trigger seizures remains to be elucidated. This form of epilepsy, called onchocerciasis-associated epilepsy (OAE), is an important public health problem in onchocerciasis-endemic regions with nonexistent or suboptimal onchocerciasis elimination programs. OAE is often characterized by sudden seizure onset in previously healthy children, between 3 to 18 years, without any other obvious cause of epilepsy. On the basis of the findings presented in this paper, it appears that onchocerciasis control may be able to prevent OAE. This further highlights the importance to eliminate onchocerciasis, particularly in areas with a high burden of epilepsy.

Objective Epilepsy is a common, chronic neurological disorder that disproportionately affects individuals living in low‐ and middle‐income countries (LMICs), where the treatment gap remains high and adherence to medication remains low. Community health workers (CHWs) have been shown to be effective at improving adherence to chronic medications, yet no study assessing the costs of CHWs in epilepsy management has been reported. Methods Using a Markov model with age‐ and sex‐varying transition probabilities, we determined whether deploying CHWs to improve epilepsy treatment adherence in rural South Africa would be cost‐effective. Data were derived using published studies from rural South Africa. Official statistics and international disability weights provided cost and health state values, respectively, and health gains were measured using quality adjusted life years (QALYs). Results The intervention was estimated at International Dollars ($) 123 250 per annum per sub‐district community and cost $1494 and $1857 per QALY gained for males and females, respectively. Assuming a costlier intervention and lower effectiveness, cost per QALY was still less than South Africa's Gross Domestic Product per capita of $13 215, the cost‐effectiveness threshold applied. Significance CHWs would be cost‐effective and the intervention dominated even when costs and effects of the intervention were unfavorably varied. Health system re‐engineering currently underway in South Africa identifies CHWs as vital links in primary health care, thereby ensuring sustainability of the intervention. Further research on understanding local health state utility values and cost‐effectiveness thresholds could further inform the current model, and undertaking the proposed intervention would provide better estimates of its efficacy on reducing the epilepsy treatment gap in rural South Africa.

Objective We determined the reliability of The Kiddie-Schedule for Affective Disorders and Schizophrenia for School- Age Children–Present and Lifetime (K-SADS-PL) for screening and diagnosing ADHD in children. Method K-SADS-PL was administered to 2,074 children in the community. Psychometric properties, factorial structure, and clinical validity of K-SADS-PL in screening or diagnosis of ADHD were examined. Results Internal consistency was excellent for items in the screening interview (Macdonald’s Omega [ω] = 0.89; 95% confidence interval [CI] [0.87, 0.94]) and diagnostic supplement (ω = 0.95; 95% CI [0.92, 0.99]). The standardized coefficients for items in the screening interview were acceptable (0.59-0.85), while fit indices for single factorial structure reached acceptable levels. Screening items were associated with high sensitivity (97.8%; 95% CI [97.2, 98.5%]) and specificity (94.0%; 95% CI [93.0, 95.0%]) for diagnosis of ADHD in the supplement. The test-retest and interinformant reliability as measured by intraclass correlation coefficient was good for most of the items. Conclusion This large study shows that K-SADS-PL can be reliably used to screen and diagnose ADHD in children in Kenya.

Background Health risk behaviors during adolescence may cluster into patterns that might be predicted by specific factors, among which HIV may have an important role. Method In a cross-sectional study conducted between 2017 and 2018, clustering of HRB and its associated factors was investigated in rural Kenya among 588 adolescents (36% perinatally HIV infected; 28% perinatally HIV exposed but uninfected; and 36% HIV unexposed/uninfected). Latent class analysis of 22 behaviors followed by multinomial logistic regression were conducted. Four risk behavior classes were identified. Results No significant differences were found in behavioral class membership across the three HIV groups (p = 0.366). The risk of membership to the higher risk behavioral classes relative to class 1 (the substance and drug abstinent low risk takers) increased with older adolescent age (p = 0.047), increased among adolescent who experienced mental distress (p p p = 0.0037) was found to be protective. Conclusion The results highlight a need to include screening and interventions for internalizing mental health problems and deficits in executive functioning, as well as steps to involve family members and communities to address psychosocial risk factors in adolescents in Kenya.

BACKGROUND: Estimates of children and adolescents with disabilities worldwide are needed to inform global intervention under the disability-inclusive provisions of the Sustainable Development Goals. We sought to update the most widely reported estimate of 93 million children METHODS: We analyzed Global Burden of Disease Study 2017 data on the prevalence of childhood epilepsy, intellectual disability, and vision or hearing loss and on years lived with disability (YLD) derived from systematic reviews, health surveys, hospital and claims databases, cohort studies, and disease-specific registries. Point estimates of the prevalence and YLD and the 95% uncertainty intervals (UIs) around the estimates were assessed. RESULTS: Globally, 291.2 million (11.2%) of the 2.6 billion children and adolescents (95% UI: 249.9–335.4 million) were estimated to have 1 of the 4 specified disabilities in 2017. The prevalence of these disabilities increased with age from 6.1% among children aged CONCLUSIONS: The number of children and adolescents with these 4 disabilities is far higher than the 2004 estimate, increases from infancy to adolescence, and accounts for a substantial proportion of all-cause YLD.

Bringing up a child with disabilities in a low-income setting is challenged by inadequate resources, limited psycho-social support and poverty. Not surprisingly, many caregivers experience fatigue, distress and isolation. To address and investigate these issues, action was taken to set up twenty self-help groups focusing on caregiver empowerment. A realist evaluation design was adopted to evaluate impacts associated with the self-help process and to identify mechanisms determining the outcomes. Monthly monitoring visits were conducted to the groups during a ten-month set-up period, at the end of which eleven active groups remained, nine having dissolved due to disputes, corruption and extreme environmental conditions. A facilitated intervention was delivered to the active groups (N = 154) over a six-month period. The members were guided to review and discuss topics such as economic empowerment, personal situation, peer support, community inclusion, access to health and education. Evaluation employed mixed methods using questionnaires (n = 75) and semi-structured interviews (n = 36) pre- and post-intervention. At baseline, the burden of caregiving was characterised by aloneness, challenges, stigma and discrimination. Post-intervention, caregiver agency was defined by togetherness, capacity-building, acceptance and well-being. Significant impacts associated with caregiver perceptions included increased social support, reduced severity of child's disability and decreased effects of extrinsic factors affecting the caregiver's role. Mechanisms of 'handling goods and money' and 'social ties and support' appeared to underpin the outcomes. Caregiver empowerment was associated with newly developed skills, social connectedness and resource mobilisation. Documentation of group processes contributes to the evidence on community-based inclusive development.

Highlights • Most people with active convulsive epilepsy in rural South Africa are diagnosed. • Most individuals diagnosed have some blood level of anti-seizure medication. • Most individuals do not have optimal levels of medication. • The epilepsy treatment gap is high in rural South Africa, especially in children. • Identifying the epilepsy care cascade may better allow for targeting of interventions., Purpose The percentage of people who are diagnosed with epilepsy (diagnostic gap), access, receive and adhere (treatment gap) to anti-seizure medication (ASM) in low- and middle- income countries remains low. We explored the epilepsy care cascade, measured the diagnostic and treatment gaps, and examined socio-demographic factors associated with adherence to ASMs in rural South Africa. Methods Utilizing a population-based cohort of 311 people with active convulsive epilepsy (ACE) residing in rural northeastern South Africa, a questionnaire was administered to examine associations between demographic and socioeconomic factors and the epilepsy treatment gap. Blood was taken to measure levels of ASMs. Results Of the 311 individuals diagnosed, 93 % of individuals reported being previously told they had epilepsy and 94 % reported previously attending a health facility for their epilepsy. ASMs were detected in 138 individuals (76 %) and optimal levels were detected in 67 individuals, resulting in a treatment gap of 63 % (95 % confidence interval [95 %CI]: 56 %–70 %). Self-reported specificity of ASM use was 23 % (95 %CI: 12–39 %) and individuals ≥18 years were significantly more likely to report taking ASM than children and were significantly (p = 0.011) more likely to be adherent. Conclusion Most people with epilepsy in rural South Africa had been previously diagnosed with epilepsy and had accessed care for epilepsy, yet the level of ASM adherence remained low, significantly lower amongst children. Understanding ways of improving knowledge of and adherence to ASM in rural South Africa is necessary, especially amongst children. The epilepsy care cascade can be useful in identifying gaps in care and targeting interventions to reduce these gaps.

Fetal hemoglobin (HbF) and peripheral hemoglobin oxygen saturation (SpO2) both predict clinical severity in sickle cell disease (SCD), while reticulocytosis is associated with vasculopathy, but there are few data on mechanisms. HbF, SpO2 and routine clinical and laboratory measures were available in a Tanzanian cohort of 1175 SCD individuals aged ≥ 5 years and the association with SpO2 (as response variable transformed to a Poisson distribution) was assessed by negative binomial model with age and sex as covariates. Increase in HbF was associated with increased SpO2 (rate ratio, RR = 1.19; 95% confidence intervals [CI] 1.04, 1.37 per natural log unit of HbF; p = 0.0004). In univariable analysis, SpO2 was inversely associated with age, reticulocyte count, and log (total bilirubin) and directly with pulse, SBP, hemoglobin, and log(HbF). In multivariable regression log(HbF) (RR 1.191; 95%CI 1.04, 1.37; p = 0.013), pulse (RR 1.01; 95%CI 1.00, 1.01; p = 0.026), SBP (RR 1.008; 95%CI 1.00, 1.02; p = 0.014), and hemoglobin (1.120; 95%CI 1.05, 1.19; p = 0.001) were positively and independently associated with SpO2 while reticulocyte count (RR 0.985; 95%CI 0.97, 0.99; p = 0.019) was independently inversely associated with SpO2. In SCD, improving SpO2, in part through cardiovascular compensation and associated with reduced reticulocytosis, may be a mechanism by which HbF reduces disease severity., Highlights • Fetal hemoglobin may moderate sickle cell disease through increased oxygen saturation. • Low oxygen saturation is associated with reticulocytosis which might moderate cerebral vasculopathy and stroke risk. • Higher pulse rate and systolic blood pressure in those with higher SpO2 suggests cardiovascular compensation for low SpO2. Fetal hemoglobin (HbF) is normally synthesized during intrauterine life and it starts to decline before birth being replaced by adult hemoglobin (HbA). However some individuals continue to synthesize HbF to adulthood and are relatively protected from severe sickle cell disease. The mechanism of HbF protection in SCD has not been entirely established. This study reports a positive association between HbF and oxygen saturation (SpO2). Higher SpO2 is associated with decreased reticulocytes but increased pulse rate and systolic blood pressure, suggesting SpO2 is maintained in part through cardiovascular compensation. Increasing HbF may reduce disease severity partly through increasing SpO2.

Supplemental Digital Content is available in the text., Background and Purpose— We determined prevalences of neurological complications, vascular abnormality, and infarction in Tanzanian children with sickle cell disease. Methods— Children with sickle cell disease were consecutively enrolled for transcranial Doppler; those with slightly elevated (>150 cm/s), low (150 cm/s was associated with frequent painful crises and low hemoglobin level. Absent/low CBFv was associated with low hemoglobin level and history of unilateral weakness. In 49 out of 67 children with low/absent/elevated transcranial Doppler undergoing magnetic resonance imaging, 43% had infarction, whereas 24 out of 48 (50%) magnetic resonance angiographies were abnormal. One had hemorrhagic infarction; none had microbleeds. Posterior circulation infarcts occurred in 14%. Of 11 children with previous seizure undergoing magnetic resonance imaging, 10 (91%) had infarction (5 silent) compared with 11 out of 38 (29%) of the remainder (P=0.003). Of 7 children with clinical stroke, 2 had recurrent stroke and 3 died; 4 out of 5 had absent CBFv. Of 193 without stroke, 1 died and 1 had a stroke; both had absent CBFv. Conclusions— In one-third of Tanzanian children with sickle cell disease, CBFv is outside the normal range, associated with frequent painful crises and low hemoglobin level, but not hemolysis. Half have abnormal magnetic resonance angiography. African children with sickle cell disease should be evaluated with transcranial Doppler; those with low/absent/elevated CBFv should undergo magnetic resonance imaging/magnetic resonance angiography.

Summary: Background: Neurological impairments might significantly contribute to reduced life expectancy in low-income and middle-income countries (LMICs). There are no empirical studies of premature mortality in children with neurological impairments in Africa. This study estimated the risk of premature mortality in children with neurological impairments and identified risk factors and causes of death. Methods: We did a cohort study based on a two-stage epidemiological survey in the Kilifi Health and Demographic Surveillance System (Kilifi, Kenya). Study participants were children aged 6–9 years. In the first stage, five trained field workers administered a low-cost screening tool to a random sample of households. In the second stage, we assessed for neurological impairments in five domains (epilepsy, cognitive impairments, vision impairments, hearing impairments, and motor impairments) using comprehensive clinical evaluation and extensive neuropsychological assessments. From the two-stage survey we identified a cohort of children with neurological impairment and a cohort of matched controls. We also enrolled an age-matched sample from the general population. The primary outcome was all-cause mortality. Mortality rates, standardised mortality ratio (SMR), and hazard ratios (HR) for risk factors were estimated and causes of death identified. Findings: We enrolled 306 children with neurological impairment, 9912 survey controls, and 22 873 age-matched participants from the general population, and followed up the cohorts between June 1, 2001, and Aug 31, 2018. Median follow-up was 14·5 years (IQR 8·6–17·2). 11 (3·9%) of 284 children with neurological impairment, 92 (1·0%) of 9009 controls, and 272 (1·2%) of 22 873 participants in the general population sample died during the follow-up. Overall mortality rates were 309·8 per 100 000 person-years of observation (95% CI 126·7–492·9) in children with neurological impairment, 80·8 per 100 000 person-years of observation (64·3–97·3) in controls, and 98·8 per 100 000 person-years of observation (87·1–110·6) in the general population sample (mortality rate ratio 3·83, 95% CI 2·05–7·16, p

Background: Neurological disorders (ND) have a profound consequence on human productivity, quality of life and survival. There are limited data on the burden of ND in Tanzania due to insufficient coverage of civil and vital registration systems. Objectives: This study was conducted to estimate mortality of ND in all ages in Tanzania using data from the Sample Vital Registration with Verbal Autopsy (SAVVY) study. Methods: Multistage random sampling was employed to select 23 districts, 1397 census enumeration areas and 154,603 households. During the baseline survey conducted between 2011 and 2014, deaths which occurred 12 months prior to the baseline survey were documented followed by verbal autopsy interviews. Causes of death were certified using International Classification of Diseases. Results: The baseline survey enrolled a total of 650,864 residents. A total of 6645 deaths were reported to have occurred 12 months before the date of survey. Death certification was available for 5225 (79%) deaths. The leading causes of death were cerebrovascular diseases with a cause-specific mortality fraction (CSMF) of 1.64% (95% CI: 1.30–1.99) and 3.82% (95% CI: 2.92–4.72) in all ages and adults older than 50 years, respectively. Stroke accounted for 92% of all cerebrovascular deaths. Mortality of epilepsy was estimated with a CSMF of 0.94% (95% CI: 0.68–1.20); meningitis with a CSMF of 0.80% (95% CI: 0.56–1.04); cerebral palsy and other paralytic syndromes with a CSMF of 0.46% (95% CI: 0.27–0.65); and intrauterine hypoxia in neonates with a CSMF of 2.06% (95% CI: 1.12–3.01). Overall, mortality of ND was estimated with a CSMF of 4.99% (95% CI: 4.40–5.58). Conclusions: The SAVVY survey provides estimates of mortality burden of ND in Tanzania. The study provides a basis for monitoring trends of ND and contributes to advancing knowledge of the burden of diseases. Integrating morbidities measures into the SAVVY design will provide comprehensive measures of burden of ND taking into account lifetime disabilities created by ND.

Background: Epilepsy remains a leading chronic neurological disorder in Low- and Middle-Income Countries. In Uganda, the highest burden is among young rural people. We aimed to; (i) describe socio-economic status (including schooling), and household poverty in adolescents living with epilepsy (ALE) compared to unaffected counterparts in the same communities and (ii) determine the factors associated with the overall quality of life (QoL). Methods: This was a cross-sectional survey nested within a larger study of ALE compared to age-matched healthy community children in Uganda. Between Sept 2016 to Sept 2017, 154 ALE and 154 healthy community controls were consecutively recruited. Adolescents recruited were frequency and age-matched based on age categories 10–14 and 15–19 years. Clinical history and standardized assessments were conducted. One control participant had incomplete assessment and was excluded. The primary outcome was overall QoL and key variables assessed were schooling status and household poverty. Descriptive and multivariable linear regression analysis were conducted for independent associations with overall QoL. Results: Mean (SD) age at seizure onset was 8.8 (3.9) years and median (IQR) monthly seizure burden was 2 (1–4). Epilepsy was associated with living in homes with high household poverty; 95/154 (61.7%) ALE lived in the poorest homes compared to 68/153 (44.5%) of the healthy adolescents, p = 0.001. Nearly two-thirds of ALE had dropped out of school and only 48/154 (31.2%) were currently attending school compared to 136/153 (88.9%) of healthy controls, p Conclusions: ALE in this rural area are from the poorest households, are more likely to drop out of school and have the lowest QoL. Those with poorer seizure control are most affected. ALE should be included among vulnerable population groups and in addition to schooling, strategies for seizure control and addressing the epilepsy treatment gap in affected homes should be specifically targeted in state poverty eradication programs.

Background Acute symptomatic seizures and febrile seizures are common in children admitted to hospitals in Africa and may be markers of brain dysfunction. They may be associated with behavioural and emotional problems, but there are no published community-based studies in Africa. Methods We screened 7047 children aged 1–6 years (randomly sampled from 50,000 in the community) for seizures (using seven questions) and invited those who screened positive and a proportion of negatives for a clinical assessment. Risk factors were identified using a parental questionnaire. Behavioural and emotional problems were examined using the Child Behaviour Checklist (CBCL) in 3273 children randomly selected from 7047. Generalised linear models with appropriate link functions were used to determine risk factors and associations between behavioural or emotional problems and acute seizures. Sobel–Goodman mediation tests were used to investigate if the association between acute seizures and CBCL scores was mediated by co-diagnosis of epilepsy. Results Acute seizures were identified in 429 (6.1%) preschool children: 3.2% (95% confidence interval CI: 2.9–3.5%) for symptomatic seizures, and 2.9% (95% CI: 2.6–3.3%) for febrile seizures. Risk factors for acute seizures included family history of febrile seizures (odds ratio OR = 3.19; 95% CI: 2.03–5.01) and previous hospitalisation (OR = 6.65; 95% CI: 4.60–9.63). Total CBCL problems occurred more frequently in children with acute seizures (27%; 95% CI: 21–34%) than for those without seizures (11%; 95% CI: 11–12%; chi-squared p ≤ 0.001). Acute seizures were associated with total CBCL problems (adjusted risk ratio (aRR) = 1.92; 95% CI: 1.34–2.77), externalising problems (aRR = 1.82; 95% CI: 1.21–2.75) and internalising problems (aRR = 1.57; 95% CI: 1.22–2.02), with the proportion of the comorbidity mediated by a co-diagnosis of epilepsy being small (15.3%; 95% CI: 4.5–34.9%). Risk factors for this comorbidity included family history of febrile seizures (risk ratio (RR) = 3.36; 95% CI: 1.34–8.41), repetitive acute seizures (β = 0.36; 95% CI: 0.15–0.57) and focal acute seizures (RR = 1.80; 95% CI: 1.05–3.08). Conclusions Acute seizures are common in preschool children in this area and are associated with behavioural and emotional problems. Both conditions should be assessed and addressed in children. Electronic supplementary material The online version of this article (10.1186/s12916-018-1021-y) contains supplementary material, which is available to authorized users.

OBJECTIVES: Eighty-five percent of the 33 million children with epilepsy (CWE) worldwide live in low- and middle-income countries (LMICs). There is limited research into epilepsy-related comorbidities in LMICs, and there are no studies of the long-term progression of behavioral and intellectual difficulties in childhood epilepsy in sub-Saharan Africa. We aimed to assess behavior and cognition at three-year follow-up in CWE in rural Tanzania. METHODS: In 2010, a cross-sectional study identified 112 CWE 6 to 14 years of age and 113 age- and sex-matched controls in the Hai district of northern Tanzania. From March to June 2013, cases and controls (now 10 to 18 years of age) were followed up. At baseline, behavior was assessed using the Rutter A Questionnaire and cognition using the Goodenough–Harris Drawing Test. Details of current seizure frequency and antiepileptic drug (AED) use among CWE were collected. RESULTS: At follow-up, cases had significantly more behavioral difficulties compared with controls (48% of 108 cases versus 14% of 103 controls (p < 0.001)). Additionally, 69% of the cases and 16% of the controls had cognitive impairment (p < 0.001). In CWE with decreased seizure frequency from baseline to follow-up, behavior had improved significantly. At follow-up, there was no significant difference in behavior between CWE with decreased seizure frequency and those with good seizure control throughout. SIGNIFICANCE: Behavioral difficulties and cognitive impairment are common among CWE in this population. Improved access to AED treatment and subsequent improved seizure control may reduce the frequency of behavioral difficulties seen in this population.

The treatment of refractory and super refractory status epilepticus is a "terra incognita" from the point of view of evidence-based medicine. As randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches available, we carried out an online multinational audit (registry) in which neurologists or intensivists caring for patients with status epilepticus may prospectively enter patients who required general anesthesia to control the status epilepticus (SE). To date, 488 cases from 44 different countries have been collected. Most of the patients had no history of epilepsy and had a cryptogenic etiology. First-line treatment was delayed and not in line with current guidelines. The most widely used anesthetic of first choice was midazolam (59%), followed by propofol and barbiturates. Ketamine was used in most severe cases. Other therapies were administered in 35% of the cases, mainly steroids and immunotherapy. Seizure control was achieved in 74% of the patients. Twenty-two percent of patients died during treatment, and four percent had treatment actively withdrawn because of an anticipated poor outcome. The neurological outcome was good in 36% and poor in 39.3% of cases, while 25% died during hospitalization. Factors that positively influenced outcome were younger age, history of epilepsy, and low number of different anesthetics tried. This article is part of a Special Issue entitled "Status Epilepticus".

Childhood epilepsy is common in Africa. However, there are little data on the developmental and behavioral problems experienced by children living with epilepsy, especially qualitative data that capture community perceptions of the challenges faced by these children. Identifying these perceptions using qualitative approaches is important not only to help design appropriate interventions but also to help adapt behavioral tools that are culturally appropriate. We documented the description of these problems as perceived by parents and teachers of children with or without epilepsy. The study involved 70 participants. Data were collected using in-depth interviews and focus group discussions and were analyzed using NVIVO to identify major themes. Our analysis identified four major areas that are perceived to be adversely affected among children with epilepsy. These included internalizing and externalizing problems such as aggression, temper tantrums, and excessive crying. Additionally, developmental delay, especially cognitive deficits and academic underachievement, was also identified as a major problematic area. There is a need to supplement these findings with quantitative estimates and to develop psychosocial and educational interventions to rehabilitate children with epilepsy who have these difficulties.

Epilepsy is a common neurologic disorder directly affecting about 70 million people in the world, with about 90% residing in lower‐and middle‐income countries.1 The treatment gap for epilepsy is large (up to 90%) in these areas, and this is in part due to negative attitudes toward biomedical services, cost of accessing diagnosis and treatment, and traditional beliefs about the cause of epilepsy.2, 3 People with epilepsy (PWE) are thought to have more hospital admissions than those with other chronic neurologic disorders,4 and is the third most common after stroke and spinal cord injuries in sub‐Saharan Africa (SSA).5 Epilepsy‐related hospital admissions are increasing in high‐income countries; for example, the rate of hospital use increased from 66 to 68/100,000 persons/year over 10 years in England and Wales,4 and by 27% over 12 years in the United States.6 In the American study, epilepsy accounted for more than half of all hospital stays among admissions of PWE, with respiratory‐related complications being the most common causes for admission.6 The hospital admission rates would be expected to be higher in SSA compared to the West because of the higher prevalence of epilepsy7 and the larger treatment gap.3 In addition, epilepsy in Africa is associated with increased complications such as status epilepticus, burns, and head injuries,8 which often require treatment at the hospital. Nevertheless, there are few published studies that document the burden, causes, and duration of hospitalization in PWE in SSA, where epilepsy may add a considerable burden on the health system. In Zambia PWE had a poorer socioeconomic status compared to their peers with other medical conditions,9 but the focus of this study was not to examine the burden of hospitalization due to epilepsy. This study estimates the incidence of admissions with epilepsy, the associated disability‐adjusted life years (DALYs) and determines the important causes and risk factors of admission to a rural hospital among PWE. We further examined the risk factors associated with the major outcomes (duration of hospitalization and mortality) among PWE.

A high level of unmet communication need exists amongst children with developmental disabilities in sub-Saharan Africa. This study investigated preliminary evidence of the impact associated with a home-based, caregiver-implemented intervention employing AAC methods, with nine children in rural Kenya who have complex communication needs. The intervention used mainly locally-sourced low-tech materials, and was designed to make use of the child's strengths and the caregiver's natural expertise. A pretest-posttest design was used in the study. Data were gathered using an adapted version of the Communication Profile, which was based on the International Classification of Functioning, Disability, and Health (ICF) framework. The non-parametric Wilcoxon signed-rank test was applied to data from the first two sections of the Communication Profile-Adapted. Qualitative analysis was conducted on the final section. The data provided evidence of statistically significant positive changes in caregiver perceptions of communication at the levels of Body Structure and Function, and Activities for Communication. Also, analysis of the Participation for Communication section revealed some expansion to the children's social activities. The potential impact of the home-based intervention would benefit from investigation on a larger scale. Limitations of the study are discussed.

A lack of research exists around the most common forms of sexual risk behaviors among adolescents, including their underlying factors, in Sub-Saharan Africa. Using an Ecological Model of Adolescent Behavior, we explore the perceptions of 85 young people and 10 stakeholders on sexual risk behavior of adolescents in Kilifi County on the coast of Kenya. Our findings show that transactional sex, early sexual debut, coerced sex, and multiple sexual partnerships are prevalent. An urgent need exists to develop measures to counter sexual risk behaviors. The results contribute to understanding the range of risks and protective factors in differing contexts, tackling underlying issues at individual, family, local institutional, wider socio-economic, and political levels.

Objectives To determine the magnitude, risk factors and causes of premature mortality associated with epilepsy in low and middle income countries (LMIC). Methods We conducted a systematic search of the literature reporting mortality and epilepsy in the World Bank-defined LMIC. We assessed the quality of the studies based upon representativeness, ascertainment of cases, diagnosis, and mortality, and extracted data on standardized mortality ratios (SMR) and mortality rates in people with epilepsy. We examined risk factors and causes of death. Results The annual mortality rate was estimated at 19.8 (range 9.7-45.1) deaths per 1000 people with epilepsy with a weighted median SMR of 2.6 (range 1.3-7.2) among higher-quality population-based studies. Clinical cohort studies yielded 7.1 (range 1.6-25.1) deaths per 1000 people. The weighted median SMRs were 5.0 in males and 4.5 in females; relatively higher SMRs within studies were measured among children and adolescents, those with symptomatic epilepsies, and those reporting less adherence to treatment. The main causes of death in people with epilepsy living in LMICs include those directly attributable to epilepsy, which yield a mean proportional mortality ratio (PMR) of 27.3% (range 5%-75.5%) derived from population-based studies. These direct causes comprise status epilepticus, with reported PMRs ranging from 5%-56.6%, and sudden unexpected death in epilepsy, with reported PMRs ranging from 1%-18.9%. Important causes of mortality indirectly related to epilepsy include drowning, head injury, and burns. Significance Epilepsy in LMIC has a significantly greater premature mortality, as in high-income countries, but in LMIC the excess mortality is more likely to be associated with causes attributable to lack of access to medical facilities such as status epilepticus, and preventable causes such as drowning, head injuries and burns. This excess premature mortality could be substantially reduced with education about the risk of death and improved access to treatments, including AEDs.

The NeuroDev study will deeply phenotype cognition, behavior, dysmorphias, and neuromedical traits on an expected cohort of 5,600 Africans (1,800 child cases, 1,800 child controls, and 1,900 parents) and will collect whole blood for exome sequencing and biobanking.

OBJECTIVE: We sought to further examine the relationship between tympanometry and mortality after noting an unexpected association on assessment of baseline data of a study whose primary aim was to investigate the utility of noninvasive tympanic membrane displacement measurement for monitoring intracranial pressure in childhood coma. METHODS: We recruited children who presented with acute nontraumatic coma to the high-dependency unit of Kilifi District Hospital on the rural coast of Kenya. We excluded children with sickle cell disease, epilepsy, and neurodevelopmental delay. We performed tympanometry on the right ear before tympanic membrane displacement analyzer measurements. All children were managed according to standard World Health Organization guidelines. RESULTS: We recruited 72 children with a median age of 3.2 years (interquartile range [IQR]: 2.0–4.3 years); 31 (43%) were female. Thirty-eight (53%) had cerebral malaria, 8 (11%) acute bacterial meningitis, 4 (6%) sepsis, and 22 (30%) encephalopathy of unknown etiology. Twenty (28%) children died. Tympanometry was normal in 25 (35%) children. Adjusting for diagnosis and clinical features of increased intracranial pressure, both associated with death on univariable analysis, children with abnormal tympanometry had greater odds of dying than did those with normal tympanometry (adjusted odds ratio: 17.0; 95% confidence interval: 1.9–152.4; P = .01). Children who died had a lower compliance (0.29 mL; IQR: 0.09–0.33 mL) compared with those who survived (0.48 mL; IQR: 0.29–0.70 mL) (P < .01). CONCLUSIONS: Abnormal tympanometry appears to be significantly associated with death in children with acute nontraumatic coma. This finding needs to be explored further through a prospective study that incorporates imaging and intensive physiologic monitoring.

Background: The prevalence of epilepsy in sub-Saharan Africa seems to be higher than in other parts of the world, but estimates vary substantially for unknown reasons. We assessed the prevalence and risk factors of active convulsive epilepsy across five centres in this region. Methods: We did large population-based cross-sectional and case-control studies in five Health and Demographic Surveillance System centres: Kilifi, Kenya (Dec 3, 2007-July 31, 2008); Agincourt, South Africa (Aug 4, 2008-Feb 27, 2009); Iganga-Mayuge, Uganda (Feb 2, 2009-Oct 30, 2009); Ifakara, Tanzania (May 4, 2009-Dec 31, 2009); and Kintampo, Ghana (Aug 2, 2010-April 29, 2011). We used a three-stage screening process to identify people with active convulsive epilepsy. Prevalence was estimated as the ratio of confirmed cases to the population screened and was adjusted for sensitivity and attrition between stages. For each case, an age-matched control individual was randomly selected from the relevant centre's census database. Fieldworkers masked to the status of the person they were interviewing administered questionnaires to individuals with active convulsive epilepsy and control individuals to assess sociodemographic variables and historical risk factors (perinatal events, head injuries, and diet). Blood samples were taken from a randomly selected subgroup of 300 participants with epilepsy and 300 control individuals from each centre and were screened for antibodies to Toxocara canis, Toxoplasma gondii, Onchocerca volvulus, Plasmodium falciparum, Taenia solium, and HIV. We estimated odds ratios (ORs) with logistic regression, adjusted for age, sex, education, employment, and marital status. Results: 586 607 residents in the study areas were screened in stage one, of whom 1711 were diagnosed as having active convulsive epilepsy. Prevalence adjusted for attrition and sensitivity varied between sites: 7·8 per 1000 people (95% CI 7·5-8·2) in Kilifi, 7·0 (6·2-7·4) in Agincourt, 10·3 (9·5-11·1) in Iganga-Mayuge, 14·8 (13·8-15·4) in Ifakara, and 10·1 (9·5-10·7) in Kintampo. The 1711 individuals with the disorder and 2032 control individuals were given questionnaires. In children (aged

The mechanisms of death and neurologic sequelae in African children with cerebral malaria are undetermined. Because pathologic features are confined to the cerebral vasculature, perturbations in cerebral hemodynamics may be responsible. We compared the transcranial Doppler findings in 50 children with cerebral malaria with those of 115 conscious Kenyan children. In addition, 10 children with cerebral malaria were studied during intracranial pressure monitoring and nine children were studied during the agonal stages. In the children with cerebral malaria, cerebral blood flow velocity was increased in 30%, usually associated with seizures. Of the 11 children who developed neurologic sequelae, six had sonographic abnormalities associated with lateralizing deficits, including four children with hemiparesis (in two children the contralateral middle cerebral artery could not be insonated and two had transient increases in blood flow velocity associated with seizures). In the children with severe intracranial hypertension, there was a significant linear relationship between the cerebral perfusion pressure and blood flow velocity, suggesting that autoregulation was impaired. Sonographic features of progressive intracranial hypertension, were observed in three children with cerebral malaria who died. Perturbations of cerebral hemodynamics are associated with a poor outcome in Kenyan children with cerebral malaria.

Status epilepticus is common in patients admitted to hospitals in resource poor countries (RPC). However, there appear to be differences in the epidemiology, aetiology and outcome of status epilepticus in these regions compared to the West, although there is little data from the former regions. RPC countries are those classified by the World Bank as low income or middle-low income countries encompass those situated in the tropical and subtropical regions. The International League Against Epilepsy (ILAE) definition of status epilepticus (ILAE, 1993) is problematic in these areas, since patients often present to health facilities, without adequate documentation of the duration of convulsion. Thus more pragmatic definitions have been developed (Sadarangani et al., 2008). Most studies on status epilepticus in RPC describe convulsive status epilepticus (CSE) (Misra et al., 2008;Sadarangani et al., 2008), since non-convulsive epilepticus is rarely detected in these regions. Although one study non-convulsive status epilepticus was detected in 11% of adults with altered mental status (Narayanan and Murthy, 2007). The incidence of convulsive status epilepticus appears to be higher in RPC than the West, but there has been only one epidemiological study conducted. In this study, the incidence of children fulfilling the ILAE definition of CSE who presented to a Kenyan District General Hospital was 35/100,000/year, with 268/100,000/year in children aged 1-11 months old. The incidence is higher if those with probable epilepsy are also included (35/100,000/year, with 268/100,000/year). These figures are likely to be an underestimate; since many children with CSE are not admitted hospital, either because convulsions are thought to be caused by traditional causes or the children die before they reach hospital. Thus the rate in this area of Kenya is 2-5 times that of similar study in London, United Kingdom (Chin et al., 2006). CSE appears to be more common in children than adults; mainly because acute symptomatic seizures or febrile status epilepticus are more common, particularly in RPC(Sadarangani et al., 2008;Tabarki et al., 2001). A significant proportion of people with epilepsy in RPC have an episode of CSE, usually in childhood and often as the first reported seizure. Thus in a cross-sectional study of active convulsive epilepsy in Kenya, 35% of those identified with active convulsive epilepsy had a history of prolonged seizures (probable CSE), of which 75% were associated with a febrile illness(Edwards et al., 2008). Thus, the high incidence of acute symptomatic epilepsy in many RPC may account for the increased incidence and prevalence of epilepsy in these regions. Most CSE is symptomatic, with the increased incidence attributed to the increased incidence of infections (Misra et al., 2008;Sadarangani et al., 2008). In malaria endemic areas, malaria is an important cause of CSE in children (Sadarangani et al., 2008), whist bacterial meningitis and viral encephalitis are important causes in other areas (Murthy et al., 2007). Patients appear to be in status for longer periods, although there is little reliable data on the duration of CSE in patients presenting to hospital. The increase duration may be due to the lack of treatment prior to admission to hospital, inadequate treatment on admission to hospital and/or a reduction in the responsiveness to the benzodiazepines. The mortality associated with CSE in RPC is greater (11-15%), both in adults (Murthy et al., 2007) and children (Sadarangani et al., 2008); but the long-term outcome in terms of premature mortality and neurocognitive sequelae is undetermined. Risk factors for mortality i.e. young age (< 1 years), aetiology (particularly bacterial meningitis), focal seizures and duration of seizure, are similar to the West. The neuro-cognitive outcome of CSE appears worse with 36% of Tunisian children having intellectual disability or epilepsy (Tabarki et al., 2001). The risk factors for neuro-cognitive impairment include young age (

Background With strict adherence to international recommended treatment guidelines, the case fatality for severe malnutrition ought to be less than 5%. In African hospitals, fatality rates of 20% are common and are often attributed to poor training and faulty case management. Improving outcome will depend upon the identification of those at greatest risk and targeting limited health resources. We retrospectively examined the major risk factors associated with early (, A retrospective examination of major risk factors associated with in-hospital deaths in children with severe malnutrition has identified admission features that could help distinguish those at highest risk., Editors' Summary Background. Severe malnutrition is thought to be responsible, at least in part, for a large proportion of the many millions of deaths every year among children below the age of five years. The World Health Organization (WHO) has developed guidelines for management of the severely malnourished child in the hospital. These guidelines outline ten initial steps for routine care, followed by treatment of associated conditions and rehabilitation. However, death rates among children admitted to hospital with severe malnutrition are worryingly high, commonly 20% or sometimes even higher. Many hospitals have reported that following introduction of the WHO guidelines, the death rates have been cut, but not to a level that the WHO defines as acceptable (5% or lower). Why Was This Study Done? In the region where this study was done, an area on the coast of Kenya, East Africa, malnutrition is very common. The local hospital, Kilifi District Hospital, currently reports a death rate of approximately 19% among children admitted with severe malnutrition, even with implementation of the WHO guidelines. A group of researchers based at the hospital wanted to see if they could identify those children who were most likely to die. Their aim was to see which aspects of the children's medical condition put them at highest risk. This information would be useful in ensuring that high-risk children received the most appropriate care. What Did the Researchers Do and Find? The researchers studied all severely malnourished children over three months of age who were admitted to the Kilifi District Hospital between September 2000 and June 2002. The children were treated according to the WHO guidelines, and the research group collected data on the condition of the children after treatment (their “outcomes”), as well as for relevant clinical signs and symptoms. The study involved 920 children, of whom 176 died in hospital (a death rate of 19%). They then examined the data to see which characteristics on admission were associated with early death (less than 48 h) and later deaths. They found that four clinical features, which could be easily ascertained at the bedside on admission, were associated with a large proportion of the early deaths. These four signs were slow heart rate, weak pulse volume, depressed consciousness level, and a delayed capillary refilling time (as tested by pressing a fingernail bed to blanche the finger, releasing it, and observing the time taken to reperfuse the capillaries—or recolor the nailbed). The researchers proposed that these findings, together with a number of other features that were associated with the later deaths could be used to identify three groups of patients differing in their need for emergency care: a high-risk group (with any of the four signs listed above, or hypoglycemia, and among whom mortality was 34%); a moderate-risk group (among whom mortality was 23%); and a low-risk group (mortality 7%). What Do These Findings Mean? First, the death rate amongst these children was very high even though WHO guidelines were used to guide management. The signs reported here as indicators of poor outcome may prove useful in future in identifying high-risk individuals to ensure they receive the right treatment. However, the indicators proposed here would need further evaluation before current guidelines for treatment of the severely malnourished child could be changed. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030500. • Information on severe malnutrition is available from the World Health Organization • Management guidelines from the WHO can also be downloaded in many languages • UNICEF, the United Nations Children's Fund, provides relevant resources and statistics as well as information about its programs addressing malnutrition worldwide • Information from Médecins Sans Frontières (MSF) on acute malnutrition worldwide and MSF's response to current emergencies

1. H.p.l.c. methods are described for the measurement of pyrimethamine and sulphadoxine in small volumes of plasma dried on filter paper strips. 2. Pyrimethamine/sulphadoxine (Fansidar, Hoffman LaRoche) was given by mouth and by intramuscular injection to children with uncomplicated falciparum malaria but with high parasitaemia (n = 8 for both routes; pyrimethamine 1.25 mg kg-1, sulphadoxine 25 mg kg-1). 3. Plasma concentrations of pyrimethamine and sulphadoxine associated with synergistic effects against pyrimethamine-resistant strains of Plasmodium falciparum in vitro were achieved within 1 h of administration and were maintained beyond the end of sampling. 4. After both oral and parenteral administration the plasma concentrations of both compounds were lower than those predicted by data from healthy subjects. 5. Areas under the plasma concentration-time curves of sulphadoxine after oral and i.m. administration did not differ significantly, although maximum plasma drug concentrations were higher after the i.m. route (P = 0.03). 6. The AUC values of pyrimethamine did not differ significantly between the two routes of administration. However, after i.m. administration AUC(0,24 h) values were smaller (P = 0.03), and the time to maximum plasma drug concentration (tmax) was longer (P = 0.004) than when the drug was given orally.

Background. Identifying severe, life-threatening falciparum malaria in African children allows for the prompt institution of appropriate management. In the past 2 decades, hyperlactatemia and acidosis have been identified as being associated with mortality in patients with severe malaria, but measurement of blood lactate concentration and base excess is expensive and technically demanding. In this large, prospective study, we examined the prognostic value of acidosis and hyperlactatemia and compared these markers to clinically assessed variables. Methods. We examined several clinical and laboratory measurements as prognostic markers of mortality in 14,605 parasitemic children admitted to 3 hospitals in Africa. Whole-blood lactate concentration and acid/base status were used to identify subjects who had hyperlactatemia and acidosis. Results. Using cut-points established by sensitivity and specificity curves, the sensitivities and positive predictive values for both lactate concentration and base excess were low, the specificities were moderate, and the negative predictive values were high (197%). No reliable clinical surrogates for hyperlactatemia or acidosis were identified. Addition of lactate concentration and base excess to predictive models with previously identified clinical features (Blantyre Coma Score, deep breathing, prostration, and weight-for-age Z score) and 1 laboratory measure (blood glucose level) did not appreciably improve models to predict mortality. Conclusions. Measurements of lactate concentration and acid/base balance are expensive to perform, and performance of the latter can be problematic. Severe falciparum malaria may be readily recognized in children at admission to hospitals in sub-Saharan Africa with use of simple, inexpensive means and does not require knowledge of lactate concentration and base excess. Falciparum malaria is responsible for 11 million deaths per year, with 170% of the burden of infections, morbidity, and mortality occurring in children in subSaharan Africa [1]. Most of these children are cared for in health facilities that are underresourced, particularly in terms of laboratory investigations. However, whether laboratory investigations (beyond simple clinical ob

BACKGROUND: To date, it has been widely assumed that malaria is a common cause of morbidity and mortality in children with sickle cell disease (SCD) in malaria-endemic countries, and as a result, malarial prophylaxis is commonly recommended. Nevertheless, few data are available that support this practice. METHODS: We conducted a retrospective analysis of the data collected prospectively from children aged 0-13 years who were admitted to Kilifi District Hospital during the period from July 1998 through June 2005. We studied the prevalence, clinical features, and outcome of malarial infections in these children, stratified by SCD status. RESULTS: Although we estimated the prevalence of SCD in children to be only 0.8% (71 of 8531 children) during the period from August 2006 through September 2008 in the community surrounding the hospital, 555 (1.6%) of 34,529 children admitted to the hospital during the study period (i.e., from July 1998 through June 2005) were children with SCD; in fact, a total of 309 children with SCD were admitted 555 times. The prevalence of Plasmodium falciparum parasitemia was lower among children with SCD than it was among children without SCD (86 [15.6%] of 551 children vs. 13,835 [41.3%] of 33,500 children; P < .001). Similarly, among those infected with P. falciparum parasites, the mean parasite density was significantly lower among children with SCD than it was among children without SCD (2205 vs. 23,878 parasites/microL; P < .001). Fourteen (16.3%) of 86 parasitemic patients with SCD had features consistent with severe malaria, compared with 3424 (24.7%) of 13,835 parasitemic patients without SCD (odds ratio, 0.59; P < .07). We found no association between malarial parasitemia and death. CONCLUSIONS: We found no evidence to support the conclusion that the risk of malaria is higher among children with SCD than it is among children without SCD in a rural area on the coast of Kenya. Further studies should be undertaken to help policy makers develop appropriate guidelines regarding malarial prophylaxis for patients with SCD in malaria-endemic regions.

Summary Background The UK has had universal free health care and public health programmes for more than six decades. Several policy initiatives and structural reforms of the health system have been undertaken. Health expenditure has increased substantially since 1990, albeit from relatively low levels compared with other countries. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to examine the patterns of health loss in the UK, the leading preventable risks that explain some of these patterns, and how UK outcomes compare with a set of comparable countries in the European Union and elsewhere in 1990 and 2010. Methods We used results of GBD 2010 for 1990 and 2010 for the UK and 18 other comparator nations (the original 15 members of the European Union, Australia, Canada, Norway, and the USA; henceforth EU15+). We present analyses of trends and relative performance for mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE). We present results for 259 diseases and injuries and for 67 risk factors or clusters of risk factors relevant to the UK. We assessed the UK's rank for age-standardised YLLs and DALYs for their leading causes compared with EU15+ in 1990 and 2010. We estimated 95% uncertainty intervals (UIs) for all measures. Findings For both mortality and disability, overall health has improved substantially in absolute terms in the UK from 1990 to 2010. Life expectancy in the UK increased by 4·2 years (95% UI 4·2–4·3) from 1990 to 2010. However, the UK performed significantly worse than the EU15+ for age-standardised death rates, age-standardised YLL rates, and life expectancy in 1990, and its relative position had worsened by 2010. Although in most age groups, there have been reductions in age-specific mortality, for men aged 30–34 years, mortality rates have hardly changed (reduction of 3·7%, 95% UI 2·7–4·9). In terms of premature mortality, worsening ranks are most notable for men and women aged 20–54 years. For all age groups, the contributions of Alzheimer's disease (increase of 137%, 16–277), cirrhosis (65%, −15 to 107), and drug use disorders (577%, 71–942) to premature mortality rose from 1990 to 2010. In 2010, compared with EU15+, the UK had significantly lower rates of age-standardised YLLs for road injury, diabetes, liver cancer, and chronic kidney disease, but significantly greater rates for ischaemic heart disease, chronic obstructive pulmonary disease, lower respiratory infections, breast cancer, other cardiovascular and circulatory disorders, oesophageal cancer, preterm birth complications, congenital anomalies, and aortic aneurysm. Because YLDs per person by age and sex have not changed substantially from 1990 to 2010 but age-specific mortality has been falling, the importance of chronic disability is rising. The major causes of YLDs in 2010 were mental and behavioural disorders (including substance abuse; 21·5% [95 UI 17·2–26·3] of YLDs), and musculoskeletal disorders (30·5% [25·5–35·7]). The leading risk factor in the UK was tobacco (11·8% [10·5–13·3] of DALYs), followed by increased blood pressure (9·0 % [7·5–10·5]), and high body-mass index (8·6% [7·4–9·8]). Diet and physical inactivity accounted for 14·3% (95% UI 12·8–15·9) of UK DALYs in 2010. Interpretation The performance of the UK in terms of premature mortality is persistently and significantly below the mean of EU15+ and requires additional concerted action. Further progress in premature mortality from several major causes, such as cardiovascular diseases and cancers, will probably require improved public health, prevention, early intervention, and treatment activities. The growing burden of disability, particularly from mental disorders, substance use, musculoskeletal disorders, and falls deserves an integrated and strategic response. Funding Bill & Melinda Gates Foundation.

Over the last decade, a number of observations have suggested that platelets may play a role in the pathophysiology of severe malaria. However, somewhat paradoxically, thrombocytopenia is not associated clearly with outcome. We studied the relationship between thrombocytopenia and cytokines in Kenyan children with severe malaria and showed that thrombocytopenia (platelet count < 150 x 10(9)/L) strongly correlates with high levels of interleukin (IL)-10. Several studies have shown that high levels of IL-10 are associated with a favorable outcome in severe malaria. Taken together, these data suggest why thrombocytopenia has a complex relationship with severe disease and suggest one mechanism whereby IL-10 may modify the outcome of severe disease.

Young African children with severe malaria are given quinine using a regimen designed for Thai adults. We measured quinine in the blood, plasma and plasma water of young children in Kenya after rapid intravenous and intramuscular dosing, and calculated the therapeutic range of unbound quinine. The peak plasma quinine concentration after rapid intravenous dosing was 12.3 +/- 3.7 mg/L (mean +/- SD), 43% higher than in adults given the same regimen previously; this was due to a smaller apparent volume of distribution in the children. The therapeutic range of unbound quinine was calculated as 0.2-2.0 mg/L. Simulations of unbound quinine were made for the standard quinine regimen: unbound drug concentrations rose above the therapeutic range after each dose. The possible risks of quinine-induced visual impairment are discussed. Alternative, lower dose regimens for young African children with severe malaria are described.

AIM: To investigate the pharmacokinetics and clinical efficacy of intravenous (i.v.) and intramuscular (i.m.) lorazepam (LZP) in children with severe malaria and convulsions. METHODS: Twenty-six children with severe malaria and convulsions lasting > or =5 min were studied. Fifteen children were given a single dose (0.1 mg kg(-1)) of i.v. LZP and 11 received a similar i.m. dose. Blood samples were collected over 72 h for determination of plasma LZP concentrations. Plasma LZP concentration-time data were fitted using compartmental models. RESULTS: Median [95% confidence interval (CI)] LZP concentrations of 65.1 ng ml(-1) (50.2, 107.0) and 41.4 ng ml(-1) (22.0, 103.0) were attained within median (95% CI) times of 30 min (10, 40) and 25 min (20, 60) following i.v. and i.m. administration, respectively. Concentrations were maintained above the reported therapeutic concentration (30 ng ml(-1)) for at least 8 h after dosing via either route. The relative bioavailability of i.m. LZP was 89%. A single dose of LZP was effective for rapid termination of convulsions in all children and prevention of seizure recurrence for >72 h in 11 of 15 children (73%, i.v.) and 10 of 11 children (91%, i.m), without any clinically apparent respiratory depression or hypotension. Three children (12%) died. CONCLUSION: Administration of LZP (0.1 mg kg(-1)) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without significant cardiorespiratory effects. I.m administration of LZP may be more practical in rural healthcare facilities in Africa, where venous access may not be feasible.

Globally, sickle cell disease (SCD) has its highest prevalence and worst prognosis in sub-Saharan Africa. Nevertheless, relatively few studies describe the clinical characteristics of children with SCD in this region. We conducted a prospective observational study of children with SCD attending a specialist out-patient clinic in Kilifi, Kenya. A total of 124 children (median age 6.3 years) were included in the study. Splenomegaly was present in 41 (33%) subjects and hepatomegaly in 25 (20%), both being common in all age groups. A positive malaria slide was found at 6% of clinic visits. The mean haemoglobin concentration was 73 g/l, compared to 107 g/l in non-SCD controls (P < 0.001). Liver function tests were elevated; plasma bilirubin concentrations were 46 micromol/l and aspartate aminotransferase was 124 iu/l. Forty-eight (39%) children were admitted to hospital and two died. Children with SCD in Kilifi have a similar degree of anaemia and liver function derangement to patients living in developed countries, but splenomegaly persists into later childhood. The prevalence of malaria was lower than expected given the prevalence in the local community. This study provides valuable data regarding the clinical characteristics of children living with SCD in a rural setting in East Africa.

Tumour necrosis factor-alpha (TNF alpha) levels were measured by bioassay and immunoassay in sera of children infected with Plasmodium falciparum and uninfected children in the same community in Kilifi District, Kenya. Seventy-one children, mean age 2.9 years (range 4 months-6.8 years), were enrolled; 34 children had severe malaria, 23 had mild (non-severe) malaria and 14 had no malaria. TNF alpha levels were significantly elevated in children with severe malaria compared with those with non-severe malaria and the uninfected group (P < 0.001 and P < 0.00001, respectively). The levels correlated directly with parasite densities (r = 0.54, P < 0.002). Among the children with severe malaria, TNF alpha levels correlated directly with the degree of anaemia but inversely with age. High tumour necrosis factor levels were associated with manifestations of severe malaria infection but declined to normal levels after effective antimalarial treatment.

Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.

Background Seizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage. Methods An everyday memory battery was administered on 152 children with cerebral malaria (CM) (mean age, 7 y 4 months [SD 13 months]; 77 males) 156 children (mean age, 7 y 4 months [SD, 14 months]; 72 males) with malaria plus complex seizures (MS) and 179 children (mean age, 7 y 6 months [SD, 13 months]; 93 males) unexposed to either condition. Results CM was associated with poorer everyday memory [95% CI, -2.46 to -0.36, p = 0.004] but not MS [95% CI, -0.91 to 1.16, p = 1.00] compared to unexposed children. Children with exposure to CM performed more poorly in recall [95% CI, -0.79 to -0.04, p = 0.024] and recognition subtests [95% CI, -0.90 to -0.17, p = 0.001] but not in prospective memory tests compared to controls. The health factors that predicted impaired everyday memory outcome in children with exposure to CM was profound coma [95% CI, 0.02 to 0.88, p = 0.037] and multiple episodes of hypoglycaemia [95% CI, 0.05 to 0.78, p = 0.020], but not seizures. Discussion The findings show that exposure to CM was associated with a specific impairment of everyday memory. Seizures commonly observed in severe malaria may not have a causal relationship with poor outcome, but rather be associated with profound coma and repeated metabolic insults (multi-hypoglycaemia) that are strongly associated with impaired everyday memory.

Plasmodium falciparum remains one of the most common causes of central nervous system infection worldwide. Recently, differences between the pathophysiology of cerebral malaria in African children and nonimmune adults have been discovered, new syndromes occurring after malaria infection described, and mechanisms for the pathogenesis proposed. In addition, new antimalarial agents have been examined worldwide and initial studies on supportive studies conducted. This paper reviews these new advances, putting them into the perspective of the more established knowledge.