Correlation of hemorrhage, axonal damage, and blood-tissue barrier disruption in brain and retina of Malawian children with fatal cerebral malaria

Abstract

Background: The retinal and brain histopathological findings in children who died from cerebral malaria (CM) have been recently described. Similar changes occur in both structures, but the findings have not been directly compared in the same patients. In this study, we compared clinical retinal findings and retinal and cerebral histopathological changes in a series of patients in Blantyre, Malawi, who died of CM.Methods: The features systematically compared in the same patient were: (1) clinical, gross and microscopic retinal hemorrhages with microscopic cerebral hemorrhages, (2) retinal and cerebral hemorrhage-associated and -unassociated axonal damage, and fibrinogen leakage, and (3) differences in the above features between the pathological categories of CM without microvascular pathology (CM1) and CM with microvascular pathology (CM2) in retina and brain.Results: Forty-seven patients were included: seven CM1, 28 CM2, and 12 controls. In the 35 malaria cases retinal and cerebral pathology correlated in all features except for non-hemorrhage associated fibrinogen leakage. Regarding CM1 and CM2 cases, the only differences were in the proportion of patients with hemorrhage-associated cerebral pathology, and this was expected, based on the definitions of CM1 and CM2. The retina did not show this difference. Non-hemorrhage associated pathology was similar for the two groups.Comment: As postulated, histopathological features of hemorrhages, axonal damage and non-hemorrhage associated fibrinogen leakage correlated in the retina and brain of individual patients, although the difference in hemorrhages between the CM1 and CM2 groups was not consistently observed in the retina. These results help to underpin the utility of ophthalmoscopic examination and fundus findings to help in diagnosis and assessment of cerebral malaria patients, but may not help in distinguishing between CM1 and CM2 patients during life.

Triggering receptor expressed on myeloid cells 1 (TREM‐1) and cytokine gene variants in complicated and uncomplicated malaria

“…Although one cannot rule out the presence of residual parasite materials in circulation to activate cells, even on day 14, our participants were aparasitaemic by microscopy and had fully recovered. Thus, the loss of EPCR expression during the acute state may be attributed to parasite factors that could limit the activation of a cytoprotective and anti‐inflammatory function of PC and disrupt the blood brain barrier . The limitation may precipitate increased inflammatory responses to cause haemorrhage in sites of parasite sequestration .…”

Severe malaria: what’s new on the pathogenesis front?

“…Also called vasogenic oedema, this process is consistent with the description of ring haemorrhages, a characteristic sign of BBB disruption, in pediatric CM (Taylor et al, 2004; Dorovini-Zis et al, 2011). In addition, these ring hemorrhages correlate positively between retinal and cerebral tissues, owing to their common embryological origin from the neuroectoderm (Barrera et al, 2015; Greiner et al, 2015). Malaria retinopathies seen in pediatric CM are therefore a direct reflection of the neurovascular disease process, and the high frequency of ring haemorrhages both in the brain and in the retina in fatal disease point towards the occurrence of vasogenic oedema.…”

EPCR and Malaria Severity: The Center of a Perfect Storm

“…For instance, the severity of the retinopathy is associated with a higher risk of patient death [70] and parallels the extent of parasite sequestration in retina and brain microvasculature [71, 72]. In addition, there is a correlation between retinal and brain hemorrhages and the presence of fibrinogen leakage in the retinal and brain microvasculature, indicative of barrier breakdown [73, 74]. The presence of blocked capillaries in the retina can be quantified using advanced approaches, such as fluorescein angiography.…”