Abstract
BackgroundIn cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling.MethodsWe used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria.ResultsThree types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21–33.78 and OR = 8.58, 95% CI = 2.56–29.08, respectively) and brain swelling (P < .05). Vessel leak and macular nonperfusion were associated with neurological disability (OR = 3.71, 95% CI = 1.26–11.02 and OR = 9.06, 95% CI = 1.79–45.90). Large focal leak was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages.ConclusionsBlood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.
Highlights
In cerebral malaria, the retina can be used to understand disease pathogenesis
Our results introduce the concept that neurological vessel leak and Capillary nonperfusion (CNP) are typical states for cerebral malaria (CM), and survivable with a risk of neurological sequelae, but that severe brain swelling and death become much more likely in the face of multiple hemorrhagic breaks in the Blood-retina barrier (BRB)/
Our fluorescein angiography (FA) data show that leakage in the retina is not homogenous but consists of 3 types, which are associated with different clinical outcomes
Summary
Histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. We performed a prospective cohort study of FA features and clinical outcomes in children with retinopathy-positive CM. We defined pediatric CM according to World Health Organization criteria: P falciparum parasitemia, Blantyre Coma Score
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