Objectives: To relate retinal findings in children treated for severe malaria to disease outcome and to determine the course of changes in the fundus. Methods: A prospective study of children with cerebral malaria (CM) and severe malarial anemia admitted to the Malaria Research Project, Blantyre, Malawi, during 2 malaria seasons. Indirect and direct ophthalmoscopy were performed on admission and daily, subject to the patient's cooperation. Results: Threehundredtwenty-sixpatients(91%)withcomplicated malaria were recruited. Two hundred seventy-eight patients had CM and of these 170 (61%) had some degree of retinopathy; 25 (53%) of 47 with severe malarial anemia hadretinopathy.InCM,retinopathywasassociatedwithsubsequent death (relative risk, 3.7; 95% confidence interval, 1.6-8.5) and papilledema conferred the highest risk (rela-tive risk, 4.5; 95% confidence interval, 2.7-7.6). Increasing severity of retinal signs was related to increasing risk of a fatal outcome (PϽ.05), independent of papilledema. In survivors, retinal signs were associated with prolonged time to recover consciousness (PϽ.001). Patients with severe malarial anemia had better outcomes and less severe retinopathy than those with CM. In 116 patients with CM, fundi were followed up longitudinally during admission and in 27 patients after hospital discharge. A large increase in retinal hemorrhages was associated with death (P=.02). Retinal signs resolved over 1 to 4 weeks without retinal sequelae. Conclusions: In childhood CM, severity of retinopathy is related to prolonged coma and death. Our results support the hypothesis that retinal signs in CM are related to cerebral pathophysiology.

Background In patients with cerebral malaria (CM), retinal angiography allows the study of infected central nervous system microvasculature in vivo. We aimed to examine retinal perfusion in children with CM by use of fluorescein angiography to investigate the pathophysiology of CM. Methods We performed fluorescein angiography on children with CM admitted to Queen Elizabeth Central Hospital, Malawi. We related angiograms to funduscopic findings. Results Fluorescein angiography was performed for 34 patients with CM, and impaired perfusion was identified in 28 (82%). Areas of capillary nonperfusion (CNP) were seen in 26 patients (76%). Multiple, scattered areas of CNP were typical and topographically matched to retinal whitening. Larger retinal vessels were occluded in 9 patients (26%) who had associated ischemia. These vessels appeared white on ophthalmoscopy. Intravascular abnormalities were seen in 9 patients (26%), including filling defects and mottling of the blood column. Limited fluorescein leakage occurred in 15 patients (44%) and was not related to angiographic intravascular abnormalities or visible vessel discoloration. Conclusions Impaired perfusion occurs in the retinal microvasculature of most children with CM. This is evidence for hypoxia and ischemia as important components in the pathogenesis of CM. Vessel occlusion and filling defects are likely to be due to sequestration of infected erythrocytes. Interventions which improve perfusion or limit hypoxic injury may be beneficial in CM.

IntroductionThe causes of coma and death in cerebral malaria remain unknown. Malarial retinopathy has been identified as an important clinical sign in the diagnosis and prognosis of cerebral malaria. As part of a larger autopsy study to determine causes of death in children with coma presenting to hospital in Blantyre, Malawi, who were fully evaluated clinically prior to death, we examined the histopathology of eyes of patients who died and underwent autopsy.Methodology/Principal FindingsChildren with coma were admitted to the pediatric research ward, classified according to clinical definitions as having cerebral malaria or another cause of coma, evaluated and treated. The eyes were examined by direct and indirect ophthalmoscopy. If a child died and permission was given, a standardized autopsy was carried out. The patient was then assigned an actual cause of death according to the autopsy findings. The eyes were examined pathologically for hemorrhages, cystoid macular edema, parasite sequestration and thrombi. They were stained immunohistochemically for fibrin and CD61 to identify the components of thrombi, β-amyloid precursor protein to detect axonal damage, for fibrinogen to identify vascular leakage and for glial fibrillary acidic protein to detect gliosis. Sixty-four eyes from 64 patients were examined: 35 with cerebral malaria and 29 with comas of other causes. Cerebral malaria was distinguished by sequestration of parasitized erythrocytes, the presence and severity of retinal hemorrhages, the presence of cystoid macular edema, the occurrence and number of fibrin-platelet thrombi, the presence and amount of axonal damage and vascular leakage.Conclusions/SignificanceWe found significant differences in retinal histopathology between patients who died of cerebral malaria and those with other diagnoses. These histopathological findings offer insights into the etiology of malarial retinopathy and provide a pathological basis for recently described retinal capillary non-perfusion in children with malarial retinopathy. Because of the similarities between the retina and the brain it also suggests mechanisms that may contribute to coma and death in cerebral malaria.

Accurate diagnosis of cerebral malaria (CM) is important for patient management, epidemiological and end point surveillance, and enrolling patients with CM in studies of pathogenesis or therapeutic trials. In malaria-endemic areas, where asymptomatic Plasmodium falciparum parasitemia is common, a positive blood film in a comatose individual does not prove that the coma is due to malaria. A retinopathy consisting of two unique features – patchy retinal whitening and focal changes of vessel color – is highly specific for encephalopathy of malarial etiology. White-centered retinal hemorrhages are a common but less specific feature. Either indirect or direct ophthalmoscopy can be used to identify the changes, and both procedures can be learned and practiced by nonspecialist clinicians. In view of its important contributions to both clinical care and research, examination of the retina should become a routine component of the assessment of a comatose child or adult when CM is a possible diagnosis.