SummaryBackgroundCerebral malaria, a disorder characterised by coma, parasitaemia, and no other evident cause of coma, is challenging to diagnose definitively in endemic regions that have high rates of asymptomatic parasitaemia and limited neurodiagnostic facilities. A recently described malaria retinopathy improves diagnostic specificity. We aimed to establish whether retinopathy-positive cerebral malaria is a risk factor for epilepsy or other neurodisabilities.MethodsBetween 2005 and 2007, we did a prospective cohort study of survivors of cerebral malaria with malaria retinopathy in Blantyre, Malawi. Children with cerebral malaria were identified at the time of their index admission and age-matched to concurrently admitted children without coma or nervous system infection. Initially matching of cases to controls was 1:1 but, in 2006, enrolment criteria for cerebral malaria survivors were revised to limit inclusion to children with cerebral malaria and retinopathy on the basis of indirect ophthalmoscopic examination; matching was then changed to 1:2 and the revised inclusion criteria were applied retrospectively for children enrolled previously. Clinical assessments at discharge and standardised nurse-led follow-up every 3 months thereafter were done to identify children with new seizure disorders or other neurodisabilities. A Kaplan-Meier survival analysis was done for incident epilepsy.Findings132 children with retinopathy-positive cerebral malaria and 264 age-matched, non-comatose controls were followed up for a median of 495 days (IQR 195–819). 12 of 132 cerebral malaria survivors developed epilepsy versus none of 264 controls (odds ratio [OR] undefined; p<0·0001). 28 of 121 cerebral malaria survivors developed new neurodisabilities, characterised by gross motor, sensory, or language deficits, compared with two of 253 controls (OR 37·8, 95% CI 8·8–161·8; p<0·0001). The risk factors for epilepsy in children with cerebral malaria were a higher maximum temperature (39·4°C [SD 1·2] vs 38·5°C [1·1]; p=0·01) and acute seizures (11/12 vs 76/120; OR 6·37, 95% CI 1·02–141·2), and male sex was a risk factor for new neurodisabilities (20/28 vs 38/93; OR 3·62, 1·44–9·06).InterpretationAlmost a third of retinopathy-positive cerebral malaria survivors developed epilepsy or other neurobehavioural sequelae. Neuroprotective clinical trials aimed at managing hyperpyrexia and optimising seizure control are warranted.FundingUS National Institutes of Health and Wellcome Trust.

BackgroundCurrent 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 FindingsThis 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 ≤ 7g/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.ConclusionsA 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 registrationPan African Clinical Trials Registry PACTR201102000277177

Malawi has a high rate of latent RHD, which is consistent with other results from sub-Saharan Africa. This study strongly supports the need for a RHD prevention and control program in Malawi.

NCT00522132.

Objectives: Patients surviving retinopathy-positive cerebral malaria (CM) are at high risk for the development of epilepsy, developmental disabilities, and behavioral abnormalities. We aimed to establish whether retinopathy-negative CM is also a risk factor for these outcomes. Between 2005 and 2007, survivors of CM and concurrently hospitalized controls in Blantyre, Malawi, were followed to assess the development of neurologic abnormalities. At discharge and every 3 months thereafter, incident cases of epilepsy and developmental disabilities were ascertained using screening questionnaires and confirmatory neurologic examinations. Incident cases of epilepsy and developmental disabilities were compared in retinopathy-negative CM survivors to controls and retinopathy-positive CM survivors. Methods:Results: Thirty-five retinopathy-negative CM survivors were enrolled. Their neurologic outcomes were compared to 132 retinopathy-positive CM survivors and 272 controls. Compared to survivors of retinopathy-positive CM, children without malaria retinopathy have an equal odds of adverse neurologic outcome (odds ratio [OR] ϭ 1.0, 95% confidence interval [CI] 0.4-2.2). Eleven of 35 survivors of retinopathy-negative CM had at least 1 adverse neurologic outcome compared to 2 of 272 controls (OR 61.9, 95% CI 13.0-295.5). In retinopathy-negative CM survivors, a Blantyre Coma Scale score Յ1 on admission was associated with an adverse outcome. Conclusions:Compared with controls, children surviving either retinopathy-negative or -positive CM are at similar high risk for adverse neurologic outcomes. Studies to evaluate preventive and therapeutic strategies in children with both retinopathy-negative and -positive CM are needed to improve mortality, morbidity, or both. Neurology Cerebral malaria (CM) is defined as an otherwise unexplained coma in a patient with circulating Plasmodium falciparum parasitemia.1 Children with CM are not a homogeneous group. A clinical-autopsy study revealed that approximately 23% of children meeting case criteria for CM lacked evidence of sequestration of parasitized red blood cells in cerebral vasculature.2 This pathologic finding is thought to indicate that P falciparum was most likely responsible for the patient's illness and coma. Premorbid differentiation of children with case-defined CM but without cerebral sequestration was impossible until the description of malaria retinopathy and correlation of retinopathy status with autopsy findings. The presence of malaria retinopathy is 95% sensitive and 90% specific for the histologic presence of sequestered parasitized erythrocytes and suggests that the clinical syndrome in an individual patient is likely caused by P falciparum. Retinopathy-negative CM may represent an asymptomatic incidental parasitemia with a second exposure (possibly viral) producing fever and coma.4 A clinical-autopsy study supported

Impaired consciousness and HIV infection increased the odds of death from ABM in Malawian children. Use of pneumococcal conjugate vaccine could greatly reduce the burden of ABM in Malawi.

No abstract

We investigated the benefit of 2 candidate adjunctive therapies in bacterial meningitis: glycerol, which has shown promise in earlier studies, and acetaminophen, which is reportedly beneficial in adult septicemia. In a hospital in Blantyre, Malawi, we enrolled 360 children aged ≥ 2 months with proven bacterial meningitis (36% HIV infected) in a double-blind, randomized, placebo-controlled trial of glycerol and acetaminophen in a 2 × 2 factorial design. Of 4 groups, first group received oral glycerol, second received rectal acetaminophen, third received both therapies and the fourth received placebos only. Adjuvant therapies were given for the first 48 hours of antibiotic therapy. Endpoints were mortality and neurological sequelae. Baseline findings were similar across all groups, except that many children had prior antibiotics in the acetaminophen group and many were anemic in the acetaminophen and glycerol group. Outcomes were similar for all groups. We found no benefit from oral glycerol or rectal acetaminophen in, mostly pneumococcal, meningitis in Malawian children.