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Summary: Background: Cerebral 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. Methods: Between 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. Findings: 132 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). Interpretation: Almost 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. Funding: US National Institutes of Health and Wellcome Trust. [Copyright &y& Elsevier]

Background: Cerebral 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.Methods: Between 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.Findings: 132 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).Interpretation: Almost 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.Funding: US National Institutes of Health and Wellcome Trust. [ABSTRACT FROM AUTHOR]

Background: Electroencephalography at hospital presentation may offer important insights regarding prognosis that can inform understanding of cerebral malaria (CM) pathophysiology and potentially guide patient selection and risk stratification for future clinical trials. Electroencephalogram (EEG) findings in children with CM in Uganda and Malawi were compared and associations between admission EEG findings and outcome across this diverse population were assessed. Demographic, clinical and admission EEG data from Ugandan and Malawian children admitted from 2009 to 2012 with CM were gathered, and survivors assessed for neurological abnormalities at discharge., Results: 281 children were enrolled (Uganda n = 122, Malawi n = 159). The Malawian population was comprised only of retinopathy positive children (versus 72.5% retinopathy positive in Uganda) and were older (4.2 versus 3.7 years; p = 0.046), had a higher HIV prevalence (9.0 versus 2.8%; p = 0.042), and worse hyperlactataemia (7.4 versus 5.2 mmol/L; p < 0.001) on admission compared to the Ugandan children. EEG findings differed between the two groups in terms of average voltage and frequencies, reactivity, asymmetry, and the presence/absence of sleep architecture. In univariate analyses pooling EEG and outcomes data for both sites, higher average and maximum voltages, faster dominant frequencies, and retained reactivity were associated with survival (all p < 0.05). Focal slowing was associated with death (OR 2.93; 95% CI 1.77-7.30) and a lower average voltage was associated with neurological morbidity in survivors (p = 0.0032)., Conclusions: Despite substantial demographic and clinical heterogeneity between subjects in Malawi and Uganda as well as different EEG readers at each site, EEG findings on admission predicted mortality and morbidity. For CM clinical trials aimed at decreasing mortality or morbidity, EEG may be valuable for risk stratification and/or subject selection.

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., Methods: 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., 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] = 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 ≤ 1 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.