title: Cerebral malaria in children: using the retina to study the brain.
abstract: 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 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.
authors.affiliation: 1 Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PO Box 30096, Chichiri, Blantyre 3, Malawi2 University of Liverpool, Department of Eye and Vision Science, Faculty of Health & Life Sciences, University of Liverpool Room 356, 4th Floor, UCD Building, Daulby Street, Liverpool L69 3GA, UK ian.maccormick@gmail.com.
authors.forename: Ian J C
authors.initials: IJ
authors.lastname: MacCormick
authors.affiliation: 2 University of Liverpool, Department of Eye and Vision Science, Faculty of Health & Life Sciences, University of Liverpool Room 356, 4th Floor, UCD Building, Daulby Street, Liverpool L69 3GA, UK3 Royal Liverpool University Hospital, St. Paul's Eye Unit, Prescot St, Liverpool, Merseyside L7 8XP, UK.
authors.forename: Nicholas A V
authors.initials: NA
authors.lastname: Beare
authors.affiliation: 5 Blantyre Malaria Project, Blantyre, Malawi6 Michigan State University, Department of Osteopathic Medical Specialities, West Fee Hall, 909 Fee Road, Room B305, East Lansing, MI 48824, USA.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.affiliation: 2 University of Liverpool, Department of Eye and Vision Science, Faculty of Health & Life Sciences, University of Liverpool Room 356, 4th Floor, UCD Building, Daulby Street, Liverpool L69 3GA, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Barrera
authors.affiliation: 7 Vancouver General Hospital, Department of Pathology and Laboratory Medicine, Vancouver, B.C. V5Z1M9, Canada.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: White
authors.affiliation: 2 University of Liverpool, Department of Eye and Vision Science, Faculty of Health & Life Sciences, University of Liverpool Room 356, 4th Floor, UCD Building, Daulby Street, Liverpool L69 3GA, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Hiscott
authors.affiliation: 1 Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PO Box 30096, Chichiri, Blantyre 3, Malawi4 University of Malawi College of Medicine, College of Medicine, P/Bag 360 Chichiri, Blantyre 3 Malawi8 Liverpool School of Tropical Medicine, Liverpool School of Tropical Medicine, Pembroke Place , Liverpool, L3 5QA , UK.
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.affiliation: 9 University of Edinburgh, Department of Ophthalmology, Edinburgh, UK10 Princess Alexandra Eye Pavilion, Edinburgh, UK.
authors.forename: Baljean
authors.initials: B
authors.lastname: Dhillon
authors.affiliation: 2 University of Liverpool, Department of Eye and Vision Science, Faculty of Health & Life Sciences, University of Liverpool Room 356, 4th Floor, UCD Building, Daulby Street, Liverpool L69 3GA, UK3 Royal Liverpool University Hospital, St. Paul's Eye Unit, Prescot St, Liverpool, Merseyside L7 8XP, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Harding
mesh_terms: D015415:Biomarkers; D002648:Child; D006801:Humans; D016779:Malaria, Cerebral / Q000175:diagnosis*; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D012171:Retinal Vessels / Q000473:pathology*
chemical_list: D015415:Biomarkers
keywords: cerebral malaria; cerebral microvasculature; haemorheology; retinal microvasculature; surrogate marker