Prevalence and mortality of epilepsies with convulsive and non-convulsive seizures in Kilifi, Kenya.

OBJECTIVES: The prevalence of all epilepsies (both convulsive and non-convulsive seizures) in Low- and Middle-Income Countries (LMIC), particularly sub-Saharan Africa is unknown. Under estimation of non-convulsive epilepsies in data from these countries may lead to inadequate and sub-optimal allocation of resources to control and prevent epilepsy. We determined the prevalence of all types of epilepsies and compared the mortality between convulsive seizures and non-convulsive seizures in a resource limited rural area in Kenya. METHODS: Trained clinicians identified cases of epilepsy in a randomly selected sample of 4,441 residents in the Kilifi Health and Demographic Surveillance System site using a cross-sectional survey design. Seizure types were classified by epileptologists using the current guidelines of the International League Against Epilepsy (ILAE). We estimated prevalence for epilepsy with convulsive seizures and non-convulsive seizures and for epilepsy with non-convulsive seizures only and compared premature mortality between these groups of seizures. RESULTS: Of the 4441 people visited, 141 had lifetime epilepsy and 96 active epilepsy, which is a crude prevalence of 31.7/1,000 persons (95% CI: 26.6-36.9) and 21.6/1,000 (95% CI: 17.3-25.9), respectively. Both convulsive and non-convulsive seizures occurred in 7% people with epilepsy (PWE), only convulsive seizures in 52% and only non-convulsive seizures in 35% PWE; there was insufficient information to classify epilepsy in the remainder 6%. The age- and sex-adjusted prevalence of lifetime people was 23.5/1,000 (95% CI: 11.0-36.0), with the adjusted prevalence of epilepsy with non-convulsive seizures only estimated at 8.2/1,000 (95%CI:3.9-12.6). The mortality rate in PWE was 6.3/1,000 (95%CI: 3.4-11.8), compared to 2.8/1,000 (2.3-3.3) in those without epilepsy; hazard ratio (HR) =2.31 (1.22-4.39; p=0.011). The annual mortality rate was 11.2/1,000 (95%CI: 5.3-23.4) in PWE with convulsive and non-convulsive seizures and none died in PWE with non-convulsive seizures alone. CONCLUSIONS: Our study shows that epilepsy with non-convulsive seizures is common and adds to the prevalence of previously reported estimates of active convulsive epilepsy. Both epilepsy with convulsive seizures and that with non-convulsive seizures should be identified for optimising treatment and for planning resource allocation.

Prevalence, risk factors and behavioural and emotional comorbidity of acute seizures in young Kenyan children: a population-based study.

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 (ß = 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.

Burden, risk factors, and comorbidities of behavioural and emotional problems in Kenyan children: a population-based study.

BACKGROUND: Three-quarters of the burden of mental health problems occurs in low-and-middle-income countries, but few epidemiological studies of these problems in preschool children from sub-Saharan Africa have been published. Behavioural and emotional problems often start in early childhood, and this might be particularly important in Africa, where the incidence of perinatal and early risk factors is high. We therefore aimed to estimate the prevalence and risk factors of behavioural and emotional problems in young children in a rural area on the Kenyan coast. METHODS: We did a population-based epidemiological study to assess the burden of behavioural and emotional problems in preschool children and comorbidities in the Kilifi Health and Demographic Surveillance System (KHDSS, a database formed of the population under routine surveillance linked to admissions to Kilifi County Hospital). We used the Child Behaviour Checklist (CBCL) to assess behavioural and emotional problems. We then determined risk factors and medical comorbidities associated with behavioural and emotional problems. The strength of associations between the risk factors and the behavioural and emotional problems was estimated using generalised linear models, with appropriate distribution and link functions. FINDINGS: 3539 families were randomly selected from the KHDSS. Of these, 3273 children were assessed with CBCL. The prevalence of total behavioural and emotional problems was 13% (95% CI 12-14), for externalising problems was 10% (9-11), and for internalising problems was 22% (21-24). The most common CBCL syndrome was somatic problems (21%, 20-23), whereas the most common DSM-IV-oriented scale was anxiety problems (13%, 12-14). Factors associated with total problems included consumption of cassava (risk ratio 5·68, 95% CI 3·22-10·03), perinatal complications (4·34, 3·21-5·81), seizure disorders (2·90, 2·24-3·77), and house status (0·11, 0·08-0·14). Seizure disorders, burn marks, and respiratory problems were important comorbidities of behavioural and emotional problems. INTERPRETATION: Behavioural and emotional problems are common in preschool children in this Kenyan rural area and are associated with preventable risk factors. Behavioural and emotional problems and associated comorbidities should be identified and addressed in young children. FUNDING: Wellcome Trust.

Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial.

BACKGROUND: Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). METHODS AND FINDINGS: This randomized controlled trial included children (0.5-10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥ 99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan-Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7 g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥ 99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI -7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥ 99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI -12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner. CONCLUSIONS: A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201102000277177.

Abnormal intra-aural pressure waves associated with death in African children with acute nontraumatic coma.

BACKGROUND: We explored the relationship between tympanic membrane displacement (TMD) measurements, a tool to monitor intracranial pressure noninvasively, and clinical features and death in children with acute coma in Kilifi, Kenya. METHODS: Between November 2007 and September 2009, we made serial TMD measurements and clinical observations on children with acute coma (Blantyre coma score (BCS) ≤ 2) on the pediatric high dependency unit of Kilifi District Hospital, and on well children presenting to the hospital's outpatient department for routine follow-up. We examined middle ear function using tympanometry and measured cardiac pulse (CPA) and respiratory pulse pressure amplitudes (RPA) using the TMD analyzer. RESULTS: We recruited 75 children (32 (43%) females; median age 3.3 (IQR: 2.0, 4.3) years). Twenty-one (28%) children died. Higher TMD measurements predicted death. Adjusting for diagnosis, every 50 nl rise in both semirecumbent and recumbent CPA was associated with increased odds of death associated with intracranial herniation (OR: 1.61, 95% confidence interval (CI): 1.07, 2.41; P = 0.02 and OR: 1.35, 95% CI: 1.10, 1.66; P ≤ 0.01 respectively). CONCLUSION: Raised TMD pulse pressure measurements are associated with death and may be useful in detecting and monitoring risk of intracranial herniation and intracranial pressure in childhood coma.

Value of Plasmodium falciparum histidine-rich protein 2 level and malaria retinopathy in distinguishing cerebral malaria from other acute encephalopathies in Kenyan children.

BACKGROUND: The diagnosis of cerebral malaria is problematic in malaria-endemic areas because encephalopathy in patients with parasitemia may have another cause. Abnormal retinal findings are thought to increase the specificity of the diagnosis, and the level of histidine-rich protein 2 (HRP2) may reflect the parasite biomass. METHODS: We examined the retina and measured plasma HRP2 levels in children with acute nontraumatic encephalopathy in Kenya. Logistic regression, with HRP2 level as an independent variable and World Health Organization-defined cerebral malaria and/or retinopathy as the outcome, was used to calculate malaria-attributable fractions (MAFs) and retinopathy-attributable fractions (RAFs). RESULTS: Of 270 children, 140 (52%) had peripheral parasitemia, 80 (30%) had malaria retinopathy, and 164 (61%) had an HRP2 level of >0 U/mL. During 2006-2011, the incidence of HRP2 positivity among admitted children declined by 49 cases per 100 000 per year (a 78% reduction). An HRP2 level of >0 U/mL had a MAF of 93% for cerebral malaria, with a MAF of 97% observed for HRP2 levels of ≥ 10 U/mL (the level of the best combined sensitivity and specificity). HRP2 levels of >0 U/mL had a RAF of 77% for features of retinopathy combined, with the highest RAFs for macular whitening (99%), peripheral whitening (98%), and hemorrhages (90%). CONCLUSION: HRP2 has a high attributable fraction for features of malarial retinopathy, supporting its use in the diagnosis of cerebral malaria. HRP2 thresholds improve the specificity of the definition.

The validation of a three-stage screening methodology for detecting active convulsive epilepsy in population-based studies in health and demographic surveillance systems.

BACKGROUND: There are few studies on the epidemiology of epilepsy in large populations in Low and Middle Income Countries (LMIC). Most studies in these regions use two-stage population-based screening surveys, which are time-consuming and costly to implement in large populations required to generate accurate estimates. We examined the sensitivity and specificity of a three-stage cross-sectional screening methodology in detecting active convulsive epilepsy (ACE), which can be embedded within on-going census of demographic surveillance systems.We validated a three-stage cross-sectional screening methodology on a randomly selected sample of participants of a three-stage prevalence survey of epilepsy. Diagnosis of ACE by an experienced clinician was used as 'gold standard'. We further compared the expenditure of this method with the standard two-stage methodology. RESULTS: We screened 4442 subjects in the validation and identified 35 cases of ACE. Of these, 18 were identified as false negatives, most of whom (15/18) were missed in the first stage and a few (3/18) in the second stage of the three-stage screening. Overall, this methodology had a sensitivity of 48.6% and a specificity of 100%. It was 37% cheaper than a two-stage survey. CONCLUSION: This was the first study to evaluate the performance of a multi-stage screening methodology used to detect epilepsy in demographic surveillance sites. This method had poor sensitivity attributed mainly to stigma-related non-response in the first stage. This method needs to take into consideration the poor sensitivity and the savings in expenditure and time as well as validation in target populations. Our findings suggest the need for continued efforts to develop and improve case-ascertainment methods in population-based epidemiological studies of epilepsy in LMIC.