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How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

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MacCormick, Ian J C, Barrera, Valentina, Beare, Nicholas A V, Czanner, Gabriela, Potchen, Michael, Kampondeni, Samuel, Heyderman, Robert S, Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164, Molyneux, Malcolm, Mallewa, Macpherson, White, Valerie A, Milner, Dan, Hiscott, Paul, Taylor, Terrie E, Seydel, Karl B and Harding, Simon P (2020) 'How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?'. Journal of Infectious Disease, Issue jiaa541. (In Press)

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Abstract

Background
In 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.
Methods
We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain MRI, and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria.
Results
Three types of retinal leakage were seen: Large focal leak (LFL), punctate leak (PL) and vessel leak. LFL and PL were associated with death (OR 13.20, 95%CI 5.21-33.78 and 8.58, 2.56-29.08 respectively), and brain swelling (p<0.05). Vessel leak and macular non-perfusion were associated with neurological disability (3.71, 1.26-11.02 and 9.06, 1.79-45.90). LFL was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages.
Conclusions
Blood-retina barrier breakdown occurs in three 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 non-perfusion were not associated with severe brain swelling, but with neurological deficits, suggesting hypoxic injury in survivors.

Item Type: Article
Subjects: QZ Pathology > Pathogenesis. Etiology > QZ 40 Pathogenesis. Etiology
WA Public Health > Health Problems of Special Population Groups > WA 320 Child Welfare. Child Health Services.
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WL Nervous System > WL 200 Meninges. Blood-brain barrier
WL Nervous System > WL 300 General works (Include works on brain alone)
WS Pediatrics > WS 100 General works
WW Ophthalmology > Eye Structures and their Diseases > WW 270 Retina
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1093/infdis/jiaa541
Depositing User: Cathy Waldron
Date Deposited: 03 Sep 2020 12:54
Last Modified: 29 Oct 2020 12:09
URI: https://archive.lstmed.ac.uk/id/eprint/15376

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