Eyes are the window to the soul (and malaria in the brain)

From the Zhang lab, Vaccine and Infectious Disease Division

Eyes, lore has it, are the window to our souls. As it turns out, they’re also a window into the brain. A team of scientists led by Dr. Bo Zhang, an assistant professor of biostatistics in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Center, found that retinal examinations can help diagnose cerebral malaria, a severe form of malaria that often results in coma and if left untreated, is uniformly fatal.

"When it comes to malaria, the eyes really are a window onto the brain,” said Dr. Terrie Taylor, co-founder of the Blantyre Malaria Project in Malawi and a co-author of the study published in the American Journal of Tropical Medicine and Hygiene. In this case, the tell-tale sign on the window is retinopathy, or damage to the blood vessels in the retina. The ability to accurately diagnose cerebral malaria in comatose patients and differentiate it from non-malarial causes is critical to providing appropriate treatment for patients.

Malaria results from infection with the Plasmodium parasite, which infected female Anopheles mosquitoes pass to humans. Cerebral malaria occurs when Plasmodium falciparum – the deadliest of the malaria parasites – breaches the brain through the blood-brain barrier. Red blood cells infected with P. falciparum build up in the small blood vessels in the brain, impeding proper blood flow. This results in brain swelling, neurological damage, and ultimately, coma. Most cerebral-malaria patients are children under the age of 5 in sub-Saharan Africa.

One major challenge in treating cerebral malaria is forming an accurate diagnosis. Getting an accurate count of P. falciparum-infected blood cells in the brain isn’t feasible in living patients. Without this direct measurement, it’s tricky to determine whether the coma results from a buildup of infected blood cells in the brain, or from something else. "Although all children with malaria illnesses have malaria infection, the converse is NOT true,” said Dr. Taylor. In sub-Saharan Africa, the estimated prevalence of asymptomatic malarial infections in the community is as high as 50%. This makes it even more difficult to determine whether malaria is the true cause of a patient’s coma.

Left: a retina with swollen blood vessels.  Center: a retina with whitened surface and hemorrhages from the blood vessels.  Right: a retina with a whitened perifoveal region.
Retinopathy can be tracked in real-time in patients. The images show the progression of malarial retinopathy, starting from changes in blood-vessel morphology to the whitening of the central retina. Images provided by Dr. Bo Zhang.

This is where the eyes can help. The cellular structure and the blood-tissue barrier in the retina is remarkably similar to those of the central nervous system, making the retina a promising tissue for detecting malaria in the brain. Previous studies based on autopsies had found that patients with retinopathy also had buildup of P. falpicarum-infected red blood cells in the brain. Conversely, patients without retinopathy lacked this buildup, and also had non-malarial causes of death.

Dr. Zhang and his colleagues set out to determine whether this finding held up in a larger cohort of nearly 1200 pediatric patients in Malawi who met the WHO’s clinical definition of cerebral malaria. The team used statistical modeling to determine whether retinopathy was predictive of the concentration of a malaria-marking protein in the blood. (The concentration of this protein, while a reliable proxy for malaria, is difficult to measure in clinical settings. Like the rapid test for COVID-19, available tests only reveal the presence or absence of this protein, and not its concentration.)

The authors found that 10% of the patients were very likely to have non-malarial coma and therefore misdiagnosed. Furthermore, statistical models that included retinopathy were better at predicting cerebral malaria compared to models without it. In addition to its predictive power, retinopathy progress can be tracked in real-time. With advances in automated technology, healthcare workers without ophthalmoscopic training may be able to collect and interpret retinal images for retinopathy diagnosis. These factors make retinal examination an ideal diagnostic tool for cerebral malaria in clinical settings with limited resources.

Dr. Zhang emphasized the importance of collaboration in carrying out this study. In addition to the Blantyre Malaria Project, the team behind this discovery included lead-author Yuzhou Thomas Lin, a PhD student at Harvard University, and Dr. Dylan Small, a professor of statistics and data science at the University of Pennsylvania. As the WHO embarks on the goal to decrease the incidence and mortality rates of malaria by 90% by 2030, collaborations that draw on interdisciplinary expertise will be key.

The results from this study demonstrate that eyes provide a powerful insight into complications unfolding in the brain. "There are many potential causes of coma in parasitemic children, and identifying which children need treatment above and beyond antimalarial drugs is greatly simplified by examining the eyes,” said Dr. Taylor. “If malarial retinopathy is NOT seen, start antimalarial therapy, BUT strongly consider OTHER causes of coma. If it is present, focus on treating the malaria."

The Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. Bo Zhang contributed to this work.

Lin Y, Tebulo A, Small D, Seydel K, Taylor T, Zhang B. 2022. Using Malarial Retinopathy to Improve the Diagnosis of Pediatric Cerebral Malaria. The American Journal of Tropical Medicine and Hygiene. 108(1):69-75.