TY - JOUR
T1 - How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?
AU - Maccormick, Ian J.C.
AU - Barrera, Valentina
AU - Beare, Nicholas A.V.
AU - Czanner, Gabriela
AU - Potchen, Michael
AU - Kampondeni, Samuel
AU - Heyderman, Robert S.
AU - Craig, Alister
AU - Molyneux, Malcolm E.
AU - Mallewa, Macpherson
AU - White, Valerie A.
AU - Milner, Dan
AU - Hiscott, Paul
AU - Taylor, Terrie E.
AU - Seydel, Karl B.
AU - Harding, Simon P.
PY - 2022/3/15
Y1 - 2022/3/15
N2 - 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 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. 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.ConclusionsBlood-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.
AB - 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 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. 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.ConclusionsBlood-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.
KW - blood-brain barrier
KW - brain swelling
KW - cerebral malaria
KW - fluorescein angiography
KW - malarial retinopathy
U2 - 10.1093/infdis/jiaa541
DO - 10.1093/infdis/jiaa541
M3 - Article
SN - 0022-1899
VL - 225
SP - 1070
EP - 1080
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 6
ER -
