Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study.
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.


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
US National Institutes of Health and Wellcome Trust.
Michigan State University, International Neurologic and Psychiatric Epidemiology Program, East Lansing, MI, USA. Electronic address: birbeck@msu.edu.
Gretchen L
GL
Birbeck
Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Malawi, and The Liverpool School of Tropical Medicine, University of Liverpool, Liverpool, UK.
Malcolm E
ME
Molyneux
Johns Hopkins Health Systems, Department of Neurology, Baltimore, MD, USA.
Peter W
PW
Kaplan
University of Malawi College of Medicine, Blantyre Malaria Project, Blantyre, Malawi; Michigan State University, College of Osteopathic Medicine, East Lansing, MI, USA.
Karl B
KB
Seydel
University of Malawi College of Medicine, Blantyre Malaria Project, Blantyre, Malawi.
Yamikani F
YF
Chimalizeni
University of Malawi College of Medicine, Blantyre Malaria Project, Blantyre, Malawi.
Kondwani
K
Kawaza
University of Malawi College of Medicine, Blantyre Malaria Project, Blantyre, Malawi; Michigan State University, College of Osteopathic Medicine, East Lansing, MI, USA.
Terrie E
TE
Taylor
D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004569:Electroencephalography; D004827:Epilepsy / Q000453:epidemiology* / Q000209:etiology* / Q000401:mortality; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D016779:Malaria, Cerebral / Q000150:complications* / Q000453:epidemiology*; D008295:Malawi / Q000453:epidemiology; D008297:Male; D009422:Nervous System Diseases / Q000209:etiology; D016017:Odds Ratio; D009887:Ophthalmoscopy / Q000379:methods; D010372:Pediatrics; D012164:Retinal Diseases / Q000150:complications* / Q000453:epidemiology*; D012189:Retrospective Studies; D012307:Risk Factors; D011795:Surveys and Questionnaires