Cerebral malaria-using the retina to study the brain

Abstract

Cerebral malaria (CM) remains a common cause of death of children in Africa with annual mortality of 400 000. Malarial retinopathy is a unique set of fundus signs which has diagnostic and prognostic value in CM. Assessment of malarial retinopathy is now widely utilised in clinical care, and routinely incorporated into clinical studies to refine entry criteria. As a visible part of the central nervous system, the retina provides insights into the pathophysiology of this infectious small-vessel vasculitis with adherent parasitised red blood cells. Fluorescein angiography and optical coherence tomography (OCT) have shown that patchy capillary non-perfusion is common and causes ischaemic changes in the retina in CM. It is likely this is mirrored in the brain and may cause global neurological impairments evident on developmental follow up. Three types of blood-retina barrier breakdown are evident: large focal, punctate, and vessel leak. Punctate and large focal leak (haemorrhage in formation) are associated with severe brain swelling and fatal outcome. Vessel leak and capillary non-perfusion are associated with moderate brain swelling and neurological sequelae. These findings imply that death and neurological sequelae have separate mechanisms and are not a continuum of severity. Each haemorrhage causes a temporary uncontrolled outflow of fluid into the tissue. The rapid accumulation of haemorrhages, as evidenced by multiple focal leaks, is a proposed mechanism of severe brain swelling, and death. Current studies aim to use optic nerve head OCT to identify patients with severe brain swelling, and macula OCT to identify those at risk of neurological sequelae.

Fig. 1. Malarial retinopathy.

Features illustrated are white-centred haemorrhages, a superficial blot haemorrhage at the fovea, mild macular whitening (black arrow) and cotton wool spot (white arrow).

Fig. 2. Malarial retinopathy.

A Red-free image showing severe and extensive retinal whitening including macular whitening (black arrow) and peripheral whitening (open arrow). B Mid-phase fluorescein angiogram of the same patient showing corresponding capillary non-perfusion (white arrow), and vessel leak from post-capillary venules (open arrow).

Fig. 3. Macular OCT scans of 22-month-old patient with cerebral malaria.

Successive OCT scans of macular whitening showing inner retinal hyper-reflective lesions on either side of the foveal dip and temporal macula (righthand side). At one-year retinal thinning is evident in the previous hyper-reflective area. Reproduced from Tu et al. Sci Rep. 2021 Aug 3;11:(1)15722. 10.1038/s41598-021-94495-9.

Fig. 4. Fluorescein angiograms in cerebral malaria.

A Multiple large focal leaks and masking from existing retinal haemorrhages. The optic nerve head is also leaking. B Multiple punctate leaks in patients with cerebral malaria. Reproduced from MacCormick et al. J Infect Dis. 2022 Mar 15;225(6)1070–1080. 10.1093/infdis/jiaa541.

Fig. 5. Multiple correspondence analysis (MCA) plot showing fluorescein angiogram features cluster with different outcomes in children with cerebral malaria.

This analysis looks for associations in two dimensions, and the boxes are illustrative. Death clusters with large focal leaks (>1 site), punctate leak (>5 sites), arteriolar intravascular filling defects (IVDF), and severe brain swelling (grades 7–8). Neurological sequelae cluster with more severe larger venule leak (grades 2–3) and capillary leak (2 and 3–4), capillary nonperfusion (CNP) in the retinal periphery (3–4) and less severe brain swelling (grade 6). Absent or mild angiographic features, and mild or no brain swelling cluster with full recovery at discharge. Disc leak and large venule IVFD, which were plotted close to the origin, have been omitted from the plot for clarity. Zero indicates the absence of a feature and ascending numbers indicate worsening severity.