Non-invasive images suggest cerebral malaria may have different phenotypes

If confirmed in new study, transcranial Doppler ultrasound could help guide treatment of deadly disease

In a hospital in Kinshasa, Democratic Republic of the Congo, Nicole O’Brien, MD, a Critical Care physician from Nationwide Children’s, would look at a row of 20 children with cerebral malaria. By disease statistics, 4 to 8 would die and as many as 6 would live with a neurologic disability.

All had fevers and seizures; some were comatose. “They looked pretty much the same,” says Dr. O’Brien, who is also director of the Global Health Certificate Program at Nationwide Children's and an assistant professor of clinical medicine at The Ohio State University College of Medicine.

But using the transcranial Doppler ultrasound machine she carried by backpack to this and other hospitals in the DRC, she and colleagues found different. By examining the blood vessels in the children’s brains, they found that while the kids looked similar outside, they could identify five distinct changes in the blood flow in their brains, or five possible phenotypes.

Of 160 kids with cerebral malaria, 26 percent showed evidence of excessive blood flow, 28 percent low flow, 22 percent blockage in the tiniest of vessels, 13 percent narrowing vessels and 7 percent excessive flow limited to the back of their brains. Almost all kids had only one of these conditions and in almost all cases the condition persisted until the child got better or died.

“Up until now, therapeutic trials to improve the outcome of children with cerebral malaria have largely failed,” Dr. O’Brien says. “The trials treated all cerebral malaria as the same but this research suggests that’s not the case.”

The research is published in The Journal of Pediatrics.  

“The public health impact of cerebral malaria is enormous,” Dr. O’Brien says. “A child dies from malaria every 60 seconds, and our basic understanding of the physiologic mechanisms that contribute to that are severely limited.”

Dr. O’Brien did this study after receiving a Fulbright grant that allowed her to spend three months in each of three consecutive years in the DRC, to investigate possible mechanisms of the disease leading to neurologic damage and death. She and colleagues used noninvasive ultrasound to look at children’s brains daily for 8 days or until discharge or death.

“I’ve been using transcranial Doppler ultrasound for 10 years and I was surprised,” Dr. O’Brien says. “With every kid looking so similar outside, you expect them to be similar inside.”

Overall mortality was 24 percent; children with low flow were most likely to die. Overall, neurologic defects were apparent in 21 percent of children; those with narrowing blood vessels were most likely to survive with defects.

 “It seems that one mechanism predominates in each individual patient,” says Terrie Taylor, DO, university distinguished professor, tropical medicine, Michigan State University. “That is fascinating, and if it holds up, would certainly help in targeting treatment.”

Dr. O’Brien shared her data with Dr. Taylor, who is not part of this study, last year in Malawi, where Dr. Taylor studies cerebral malaria under an $8 million NIH grant. “The importance was obvious. I shared her breakthrough with our NIH program officer and he encouraged us to apply for a supplement.”

The result is Dr. O’Brien recently received an $800,000 National Institutes of Health supplement grant to use advanced neuroimaging, lab tests and electroencephalograms to confirm the mechanisms associated with each phenotype seen in these children with cerebral malaria. The grant allows her to return to Africa for four months each of the next four years.

If the new study confirms the associations, Dr. O’Brien will then seek a large-scale investigational trial looking at potential therapies. “The therapies would likely be different for each phenotype since giving a therapy for one phenotype is potentially harmful in another phenotype,” she says.

A Doppler ultrasound machine could become a portable, easy-to-use tool to determine the appropriate treatment for each child, Dr. O’Brien says. “If we’re able to prove what we think, this is generalizable across sub-Saharan Africa, where cerebral malaria is killing hundreds of thousands of kids.”

Citation: O’Brien NF, Taty TM, Moore-Clingenpeel M, Mabiala JB, Pongo JM, Musungufu DA, Uchama M, Yotebieng M. Transcranial Doppler ultrasonography provides insights into neurovascular changes in children with cerebral malaria. The Journal of Pediatrics. 2018 Sep 14 [Epub ahead of print]