Cerebral malaria in children: using the retina to study the brain

Abstract

Cerebral malaria is a dangerous complication of Plasmodium falciparum infection, which takes a devastating toll on children in sub-Saharan Africa. Although autopsy studies have improved understanding of cerebral malaria pathology in fatal cases, information about in vivo neurovascular pathogenesis is scarce because brain tissue is inaccessible in life. Surrogate markers may provide insight into pathogenesis and thereby facilitate clinical studies with the ultimate aim of improving the treatment and prognosis of cerebral malaria. The retina is an attractive source of potential surrogate markers for paediatric cerebral malaria because, in this condition, the retina seems to sustain microvascular damage similar to that of the brain. In paediatric cerebral malaria a combination of retinal signs correlates, in fatal cases, with the severity of brain pathology, and has diagnostic and prognostic significance. Unlike the brain, the retina is accessible to high-resolution, non-invasive imaging. We aimed to determine the extent to which paediatric malarial retinopathy reflects cerebrovascular damage by reviewing the literature to compare retinal and cerebral manifestations of retinopathy-positive paediatric cerebral malaria. We then compared retina and brain in terms of anatomical and physiological features that could help to account for similarities and differences in vascular pathology. These comparisons address the question of whether it is biologically plausible to draw conclusions about unseen cerebral vascular pathogenesis from the visible retinal vasculature in retinopathy-positive paediatric cerebral malaria. Our work addresses an important cause of death and neurodisability in sub-Saharan Africa. We critically appraise evidence for associations between retina and brain neurovasculature in health and disease, and in the process we develop new hypotheses about why these vascular beds are susceptible to sequestration of parasitized erythrocytes.

Keywords: cerebral malaria; cerebral microvasculature; haemorheology; retinal microvasculature; surrogate marker.

Figure 1

The features of paediatric malarial retinopathy are: retinal haemorrhages (often white-centred), retinal whitening, and orange or white discolouration of vessels. Papilloedema is often seen but is not specific for cerebral malaria. Angiographic signs include capillary non-perfusion, vessel mottling, and leakage. (A) Colour retinal image showing white-centred haemorrhages and retinal whitening extending from the macula into the temporal periphery (horizontal raphe). (B) Fluorescein angiography shows severe capillary non-perfusion in the retinal periphery (marked in yellow). Capillary non-perfusion typically coincides with retinal whitening. (C) Leakage of fluorescein from retinal venules. (D) Vessel mottling can be seen on a magnified fluorescein angiogram image. Images are from different subjects.

Figure 2

(A) Illustration of shear rate in parabolic (laminar) flow. Shear rate is a function (dy / dr) of flow velocity (y) and vessel width (r). At a given velocity shear rate is greater in narrow vessels than wide vessels. Blood is a shear thinning fluid, meaning that blood viscosity decreases with increasing shear rate. Shear stress is the product of viscosity and shear rate. (B) Phase separation with heterogeneous haematocrit in vessel branches. Variable haematocrit arises when erythrocytes are distributed unevenly as a result of phase separation. Erythrocytes flow in a central column surrounded by a cuff of plasma. The proportion of erythrocytes to plasma in vessel branches depends on branching angle, daughter vessel width, and daughter vessel flow rate. Daughter vessels branching at near 90° have a relatively high proportion of plasma and therefore lower haematocrit than the parent vessel.

Figure 3

Retinal vascular anatomy seen on fluorescein angiography during venous filling, showing arteriole and venule segments from the optic disc, the foveal avascular zone at the centre of the macula, and the horizontal raphe.

Figure 4

Comparison of retinal and cerebral venous watershed regions. (A) Fluorescein angiogram showing capillary non-perfusion at the macula and horizontal raphe, which is an arteriolar and venular watershed between the supero-temporal and infero-temporal arcades. Axial (B) and coronal (C) MRI images show extensive high T₂ signal in the subcortical white matter of a different child with cerebral malaria (white arrows). The cerebral white matter is the site of a venous watershed between superficial and deep venous systems.