Focal breakdown of the blood retinal barrier is associated with fatal brain swelling in paediatric cerebral malaria

Abstract

Purpose : Cerebral malaria (CM) is an important cause of death in African children, in which severe brain swelling leads to respiratory arrest. However the mechanisms underlying this are unclear. Possibilities include vasogenic and cytotoxic oedema. Since the retina and brain sustain similar damage from CM, and since the blood brain barrier (BBB) and inner blood-retina barrier (BRB) are similar, we hypothesised that angiographic features of malarial retinopathy would be associated with death and severe brain swelling, and could indicate which mechanisms are most important.

Methods : We performed a prospective observational study of associations between fluorescein angiography (FA) within 24 hours of admission in children with retinopathy-positive (ret+) CM. A subset of children had assessment of brain swelling at admission on MRI. FA and MR images were dual graded manually, masked to clinical information. Thirteen FA variables were measured. Severe brain swelling was defined prospectively in terms of signs likely to be life threatening. Data were visualised and associations tested using regression models in Stata 13. Since causal pathways were unclear we recorded unadjusted associations rather than risk over-adjusting models. The study was approved by ethics committees at each collaborating institution.

Results : Between 2009 and 2014, 549 children with ret+CM had admission ophthalmoscopy. Of these 260 had admission FA, and 134 had admission FA and MRI. Children were more likely to have FA and/or MRI if they had more severe retinopathy or had more prolonged coma. 21/134 had severe brain swelling and 19/134 died. We found strong unadjusted associations (OR (95%CI)) between death and two types of focal retinal leakage (n=260: large focal 13.9 (5.6-34.6), punctate focal 10.3 (3.1-34.4)). These types of leak were also associated with severe brain swelling (n=134: large focal 4.8 (1.5-15.5), punctate focal 3.6 (1.2-11.1)).

Conclusions : This is the largest study of FA features in CM to date. Associations between focal leakage, death, and severe brain swelling suggest that in paediatric CM fatal brain swelling results from breakdown of the BBB. Targets for new adjuvant treatments may be discovered by studying the causes of leak in the retina.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Large focal leak (left panel), and punctate focal leak (right panel)