Malarial retinopathy is a collective term for characteristic retinal changes associated with malaria infection (mainly Plasmodium falciparum). It was first reported in children in Malawi in 1993.
Cerebral malaria is a severe complication defined as unarousable coma in patients with malaria infection. It is frequently observed in patients with cerebral malaria and other severe forms of malaria.
According to the 2023 WHO World Malaria Report, 249 million malaria cases were reported worldwide, with an estimated mortality rate of 14.3 per 100,000 population 1). The majority of patients are concentrated in sub-Saharan Africa and Southeast Asia 1).
Severe infection with Plasmodium falciparum is most common, but some features have also been reported with Plasmodium vivax infection.
In cases associated with cerebral malaria, patients are in a coma, making it difficult to report subjective symptoms. After regaining consciousness, the following symptoms may be observed.
Fundus findings are usually bilateral and symmetric. Four characteristic findings are shown below.
Retinal Whitening
Macular whitening: Appears in the macula except the fovea. It is poorly demarcated and widely distributed.
Peripheral opacity: In some cases, opacity occurs only in the periphery. Indirect ophthalmoscopy under mydriasis is important for diagnosis.
Fluorescein angiography findings: The opaque areas correspond to non-perfusion zones.
Vascular discoloration
Orange to white discoloration: Retinal vessels (especially in the periphery) turn orange or white.
Tram-line discoloration: In larger vessels, it appears as a double contour.
Pediatric population: To date, this finding has been reported only in children.
Retinal Hemorrhage
White-centered hemorrhage: Hemorrhage resembling Roth spots. In severe cases, it can involve all retinal layers.
Preretinal and subretinal hemorrhage: Hemorrhage may extend beyond the retinal boundaries.
Correlation with cerebral hemorrhage: The number of retinal hemorrhages shows a positive correlation with cerebral hemorrhage.
Papilledema
Optic disc edema: Observed in various comas including cerebral malaria.
Poor prognostic indicators: Their presence in cerebral malaria patients is associated with increased mortality1).
Other findings may include nystagmus, ocular floating movements, and cystoid macular edema.
Cotton-wool spots also appear in some malaria patients, but unlike the typical whitening of malarial retinopathy, they show a more distinct and localized distribution1).
Fundus findings are usually bilateral and symmetrical. Unilateral findings are rare, and dilated fundus examination of both eyes is important for diagnosis.
The cause of malarial retinopathy is the sequestration of infected red blood cells in the retinal microvasculature. Plasmodium falciparum is the most common cause, and the parasites multiplying inside red blood cells alter the properties of the red blood cell membrane, adhering to the vascular endothelium and causing microcirculatory disturbances.
Risk factors for malarial retinopathy are as follows:
Retinal findings are extremely important in the diagnosis of cerebral malaria. Using indirect ophthalmoscopy after pupil dilation, the four characteristic findings described in the Clinical Findings section are confirmed.
In children with coma and parasitemia, detection of malarial retinopathy has a positive predictive value of 95% and a negative predictive value of 90% for the diagnosis of cerebral malaria. In contrast, clinical diagnosis using only WHO criteria without dilated fundus examination has a positive predictive value of only 77%.
Misdiagnosis is a problem in resource-limited settings. In a prospective autopsy study in Malawi, 23% of children who died with a diagnosis of cerebral malaria lacked histopathological features of cerebral malaria.
OCT provides useful information for the diagnosis of malarial retinopathy.
| OCT finding | Significance |
|---|---|
| Hyperreflective foci in the inner retina | Intracapillary accumulation of infected red blood cells |
| Hyperreflectivity of the retinal nerve fiber layer | Axonal infarction |
| Hyperreflective band sparing the fovea | Ischemic changes in the inner retinal layers |
In a systematic review by Wilson et al., the three specific OCT biomarkers mentioned above were reported1).
It can detect blood flow deficits in the deep capillary plexus1). Flow voids are observed in the deep capillary plexus around the fovea, providing a means to quantitatively assess the extent of macular ischemia.
Differentiation from the following diseases is necessary.
Orange to white discoloration of retinal vessels is characteristic of malaria retinopathy and is an important finding for differentiation.
In malaria-endemic areas, laboratory tests and imaging are often unavailable. Parasitemia in peripheral blood may be an incidental finding. Detection of malarial retinopathy has a high diagnostic accuracy with a positive predictive value of 95% for cerebral malaria, providing a means to improve diagnostic accuracy in resource-limited settings.
There is no specific treatment for malarial retinopathy. The mainstay of treatment is systemic antimalarial therapy based on local drug sensitivity and resistance patterns.
In a case reported by Bezzina et al. (2024), a 41-year-old male developed cerebral malaria after traveling to West Africa without taking antimalarial prophylaxis, and was treated with artesunate, ceftriaxone, dexamethasone, and acyclovir 1). After one week of treatment in the intensive care unit, he was extubated and regained consciousness.
No treatment for retinopathy itself has been reported. Conservative management and follow-up are performed1).
Most children with cerebral malaria regain consciousness within 48 hours, but about 10% develop persistent neurological deficits and about 20% die.
The severity of retinopathy correlates with the duration of coma and risk of death. The presence of optic disc edema and peripheral retinal whitening carries the highest relative risk.
In adults, even uncomplicated malaria may show mild retinopathy, but more severe retinopathy is associated with more severe systemic disease.
The pathology of malarial retinopathy is based on the sequestration of infected red blood cells in the microvasculature of the retina and brain. The pathophysiology consists of three main factors 1).
These processes result in reduced tissue perfusion, leading to ischemia and organ damage.
The retina has the highest pericyte density in the body, and pericytes are involved in microvascular stabilization, blood flow regulation, and angiogenesis control2). Astrocytes regulate tight junction integrity by releasing trophic factors, antioxidants, and inflammatory cytokines, while Müller cells surround blood vessels via foot processes across all retinal layers and regulate endothelial cell permeability through the release of gliotransmitters2).
Studies in mouse models have found that malaria parasites cross the blood-retinal barrier and infiltrate the neural retina, possibly via Müller glial cells.
In patients with cerebral malaria, thrombi composed of fibrin and platelets are formed. Thrombosis of retinal microvessels induces ischemia and hypoxia, leading to intracellular edema and loss of retinal transparency.
This is thought to be caused by a drastic decrease in hemoglobin levels in infected red blood cells that accumulate at the bifurcations of retinal capillaries and peripheral retinal vessels.
Postmortem immunohistochemical analysis has similarly shown increased expression of VEGFR1 and aquaporin 4 in retinal and brain tissues 1). The retina and brain are thought to share common microvascular pathology. This is also the basis for diagnosing cerebral malaria through malarial retinopathy.
Bezzina et al. (2024) reported a case of a 41-year-old male with malarial retinopathy associated with cerebral malaria, in which OCT revealed patchy hyperreflective changes at the outer plexiform layer (OPL) and outer nuclear layer (ONL) levels, and OCT-A showed blood flow deficits in the deep capillary plexus, indicating the presence of type II acute macular neuroretinopathy (AMN)1). This is the first report of isolated type II AMN in malarial retinopathy.
The deep capillary plexus anatomically corresponds to a watershed zone. Early ischemic changes may be confined to the deep OPL region, presenting as type II AMN, while inner layer damage (superficial and intermediate capillary plexus areas) may reflect more severe ischemia 1). If this hypothesis is correct, the AMN subtype could serve as an indicator of systemic ischemic severity.
In malaria-endemic areas, even access to an ophthalmoscope is difficult. Research on diagnosis using serum biomarkers is ongoing.
The usefulness of methods that capture retinal images and subject them to automated analysis or remote expert review is being investigated. Providing fundus examination equipment and disseminating training remain challenges.
