Retinal Pathology of Pediatric Cerebral Malaria in Malawi

Abstract

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.

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

“…50 Furthermore, IHC enabled us to obtain detailed information about the perivascular expression pattern and to pinpoint neuronal and perivascular hypoxia due to cerebral hypoperfusion. Considered together with the bulk of data on hypoperfusion in murine and human CM, 15,17,20,23,25,28,76 this new approach seems appropriate for further mechanistic research. The results overall suggest that cerebral hypoperfusion leads to tissue hypoxia in murine CM and that this is likely a key event in development of acute cerebral disease.…”

“…Noninvasive imaging of retinal and rectal vessels in patients with CM clearly demonstrates hypoperfusion and occlusion of the microcirculation, [15][16][17][18][19][20][21] which is reflected by a clear association with a poor clinical outcome. 16,[21][22][23] Murine models of CM have important similarities to CM in humans 2,24 including increased intracranial pressure and a significant decrease in cerebral blood flow, which progressively deteriorates as the clinical condition becomes aggravated.…”

Absence of an Association Between Plasmodium falciparum Infection and Post-Ivermectin Loa-Related Non-Neurologic Serious Adverse Events

“…2 In this respect, it is interesting to note that Loa-related SAEs and severe malaria share many clinical features, including fever, impaired consciousness, and white-centered retinal hemorrhages. 6 In addition, Plasmodium infection has been observed in a number of individuals who developed post-ivermectin SAEs. 7 Thus, Plasmodium infection has been considered as a potential cofactor facilitating the development of SAEs.…”

In the Eye of Experimental Cerebral Malaria

“…The diagnostic importance of the visual system in patients with CM has recently been highlighted, 22 and the optic nerve has been proposed as an important diagnostic marker for patient classification, risk assessment, and monitoring of CM. 23 White and colleagues 24 specifically showed that although the detection of hemorrhages per se in the retina is not a clear predictor of outcome in patients with CM, the number and severity of hemorrhages correlate with morbidity. Ma and colleagues, 25 who were the first to examine the pathologic abnormalities of the optic nerves in murine CM, demonstrated loss of axonal viability in this disease in any central nervous system tissue, which corroborated with reports of demyelination in human CM.…”