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Epilepsy, Other Neurological Disorders Linked to Survival of Cerebral Malaria

CHICAGO—More than 30 percent of children who survive bouts with cerebral malaria suffer from neurologic pathologies such as epilepsy and attention deficit hyperactivity disorder (ADHD), according to a study conducted in the African nation of Malawi.

Doctors who studied 93 children who survived cerebral malaria — a disease that can be fatal about 20 percent of the time — said they were significantly more likely to be diagnosed with epilepsy, unprovoked seizures, developmental abnormalities, and ADHD when compared to similar children who were hospitalized for non-cerebral malaria conditions.

“In our very short follow-up of between six and 21 months, we have already had about 6 percent of our kids develop clear epilepsy; another 10 percent have had their first unprovoked seizure,” said Gretchen Birbeck, MD, MPH, associate professor of neurology and epidemiology at Michigan State University in East Lansing. “About 6 or 7 percent have behavioral problems. What is remarkable in these children is that their parents are quite clear: ‘My child was not like this before he became ill.’ It is quite an abrupt change.”

Dr. Birbeck, director of the International Neurological and Psychiatric Epidemiology Program, noted that previous research has linked cerebral malaria to epilepsy. However, she said these studies have been retrospective; used diagnostic criteria associated with high misclassification rates — estimated to be as much as 20 percent in error; and likely included children with a pre-existing predisposition toward seizures such as a family history of epilepsy or antecedent developmental delay.

STUDY PROTOCOLS

“We conducted a prospective, exposure-control study of child survivors of cerebral malaria compared to concurrently hospitalized, age-matched children without cerebral malaria,” she said, discussing her poster at this year's AAN annual meeting here. “We tried to do an historical screen to determine if these children were normal before their illness in both our exposed children and in our control group of healthy kids,” said Dr. Birbeck. “Then we followed them up at one-month post discharge and then every three months asking about interim illnesses but also about interim seizures, whether those seizures occurred during acute illness or were unprovoked or appeared to be unprovoked.

The children were matched in age — within six months of each other. The family members were also assessed for histories of epilepsy. The children were given ophthalmological examinations for cerebral malaria-induced retinopathy on admission —a test that has been shown to be 97 percent sensitive for cerebral malaria. Serial acute EEGs were obtained for the children with cerebral malaria. The children underwent a neurological assessment at discharge and then were followed.

STUDY RESULTS

Among findings, approximately 5.4 percent of children who survived cerebral malaria developed epilepsy, compared with none of the control children — a statistically significant finding (p=0.003); nearly 10.5 percent of the children who survived the disease developed unprovoked seizures compared with none of the control group (p=0.0003); 22.6 percent of the children who survived cerebral malaria had developmental abnormalities compared with 1.0 percent of the control children (p<0.0001). Those abnormalities included developmental regression, motor and/or language problems.

Overall, about 31.2 percent of the children who survived cerebral malaria had some sort of adverse neurological outcome compared with 1.6 percent of those children who did not have the disease (p<0.0001).

“We think that among the 80 percent of the four million survivors of cerebral malaria about a third of them have long-term neurological problems, which translates into a huge public health problem for the region which really has not been appreciated,” Dr. Birbeck said.

“We looked at what predicted whether someone would do badly and we found that a seizure is the predictor,” she said. “When we perform EEG tests on the children who have cerebral malaria and no clinical evidence of a seizure, 19 percent of them were seizing. And seizures in general were the number one predictor of bad outcomes — in fact, it was the only real predictor.”

Dr. Birbeck also observed a particular EEG pattern among some of the children with cerebral malaria. Spindle coma, an EEG pattern not previously described in children, frequently accompanied by an unusual arousal pattern of marked background slowing with stimulation, was present in 19.5 percent of cases. “The novel EEG pattern identified, which is associated with good neurologic outcomes, warrants further study,” she said.

Figure

Patients with cerebral malaria may have multiple retinal hemorrhages.

EXPERTS COMMENT

“Clearly something is happening in the brains of these children who have survived cerebral malaria,” commented Robyn Honea, PhD, a research associate in neurology at the University of Kansas in Kansas City.

“We should require further study that could replicate the novel EEG findings,” she said. Dr. Honea also suggested further research regarding the link between cerebral malaria and its effect on epilepsy and ADHD — conditions that appear to have different mechanisms in the brain.

Dr. Birbeck said her study may have general implications for clinician. “When a tropical disease physician discharges a child from the hospital after the child has survived cerebral malaria — particularly children who had seizures during the acute malaria — if you have the capacity you should try to follow them up.

“That would be worthwhile because you don't want to miss the new diagnosis of epilepsy and have these children go untreated. A lot of places do have some facilities for rehabilitation, which would be helpful for children who are at high risk of motor and language problems.”

Dr. Birbeck added that by identifying the children at risk doctors can prescribe newer, safer medications.

Her study was funded by the National Institutes of Health, the Wellcome Trust and the Charles E. Culpeper Medical Scholars program.