Cerebral malaria in children: using the retina to study the brain

Ian J. C. MacCormick, Nicholas A. V. Beare, Terrie E. Taylor, Valentina Barrera, Valerie A. White, Paul Hiscott, Malcolm E. Molyneux, Baljean Dhillon, Simon P. Harding
2014 Brain  
Cerebral malaria is a dangerous complication of Plasmodium falciparum infection, which takes a devastating toll on children in sub-Saharan Africa. Although autopsy studies have improved understanding of cerebral malaria pathology in fatal cases, information about in vivo neurovascular pathogenesis is scarce because brain tissue is inaccessible in life. Surrogate markers may provide insight into pathogenesis and thereby facilitate clinical studies with the ultimate aim of improving the treatment
more » ... and prognosis of cerebral malaria. The retina is an attractive source of potential surrogate markers for paediatric cerebral malaria because, in this condition, the retina seems to sustain microvascular damage similar to that of the brain. In paediatric cerebral malaria a combination of retinal signs correlates, in fatal cases, with the severity of brain pathology, and has diagnostic and prognostic significance. Unlike the brain, the retina is accessible to high-resolution, non-invasive imaging. We aimed to determine the extent to which paediatric malarial retinopathy reflects cerebrovascular damage by reviewing the literature to compare retinal and cerebral manifestations of retinopathy-positive paediatric cerebral malaria. We then compared retina and brain in terms of anatomical and physiological features that could help to account for similarities and differences in vascular pathology. These comparisons address the question of whether it is biologically plausible to draw conclusions about unseen cerebral vascular pathogenesis from the visible retinal vasculature in retinopathy-positive paediatric cerebral malaria. Our work addresses an important cause of death and neurodisability in sub-Saharan Africa. We critically appraise evidence for associations between retina and brain neurovasculature in health and disease, and in the process we develop new hypotheses about why these vascular beds are susceptible to sequestration of parasitized erythrocytes. Abbreviation: CI = confidence interval; CM = cerebral malaria; CMRgluc = cerebral metabolic rate (glucose); CMRO2 = cerebral metabolic rate (oxygen); CNP = capillary non-perfusion; CRAE = central retinal artery equivalent; CRVE = central retinal vein equivalent; DD = disc diameter; FA = fluorescein angiogram; FAZ = foveal avascular zone; ICAM-1 = intercellular adhesion molecule 1; LDR = length to diameter ratio; MRI = magnetic resonance imaging; OR = odds ratio; PfEMP-1 = Plasmodium falciparum erythrocyte membrane protein 1; SD = standard deviation I. J. C. MacCormick et al. by guest on October 6, 2016 http://brain.oxfordjournals.org/ Downloaded from Sequestration Sequestration is the histopathological hallmark of paediatric cerebral malaria . Sequestration results from the binding of parasitized erythrocytes to vascular endothelium. Parasitized erythrocytes also bind in vitro to other erythrocytes (rosetting), and to platelets (clumping, or auto-agglutination). Sequestration is mediated by adhesion between malarial antigens on the surface of the infected erythrocyte and several host receptors on the vascular endothelium. The P. falciparum surface antigen most studied is P. falciparum erythrocyte membrane protein 1 Using the retina to study the brain Brain
doi:10.1093/brain/awu001 pmid:24578549 pmcid:PMC4107732 fatcat:h4yoypgaj5dbphdjng7tx2hqla