Mini-Review Article : Retinopathy in Cerebral Malaria

Malaria is one of the most lethal diseases worldwide, and cerebral malaria is the most severe form of the disease. Plasmodium falciparum is the leading cause of cerebral malaria.
The retina combines the window to the central nervous system with the direct ability to visualise neurodegenerative processes in the central nervous system. Retinal whitening, retinal vessel discolouration to pink-orange or white, retinal haemorrhage, and papilledema are characteristic findings of cerebral malaria. Ophthalmological examination of children with neurological emergencies is unavailable in most African countries, and cerebral malaria is frequently not diagnosed. In addition, few studies describe the neurological or ophthalmological complications related to cerebral malaria retinopathy.
The terms “malaria in children”, “cerebral malaria”, and “malaria retinopathy” were searched in the PubMed and Google Scholar databases, and the most representative of several articles on the same topic was selected. The search was not restricted to specific years.
The aim of the study to determine whether retinopathy is pathognomonic for cerebral malaria, as this will allow early treatment and prevent complications of the disease.
In conclusion ophthalmological examination in children suspected of cerebral malaria is mandatory for all patients in countries where malaria is endemic, and this form of the disease has a pathological picture that differentiates it from other neurological conditions.

Keywords: Malaria, Cerebral Malaria, Retinopathy, Children

Malaria remains one of the most lethal diseases in the world. Cerebral malaria (CM) is a severe complication of the disease, with a case fatality rate of 15% to 40% and long-term neurocognitive complications in 24% of survivors [1,2,3].

The World Health Organization (WHO) does not include malarial retinopathy in the criteria for CM diagnosis, although it is frequently undiagnosed. Misdiagnosis of CM is potentially fatal, as other possibilities and treatments are excluded. However, Plasmodium falciparum infection may also lead to coma in some children with retinopathy-negative CM, and these groups are still unknown, and thus all children with the WHO definition of CM should be treated for the severe form of the disease [4].

Severe malaria [5]:

WHO defines severe falciparum malaria as the presence of one or more of the following findings with positive P. falciparum asexual parasitaemia and exclusion of other causes:

1 – Impaired level of consciousness.

2 – Prostration: generalised weakness (i.e., a person cannot sit, stand, or walk without support).

3 – Convulsions: more than two episodes of seizure within 24 h.

4 – Metabolic acidosis: defined as a base deficit of > 8 mEq/L, a plasma bicarbonate level of < 15 mmol/L, or plasma lactate ≥ 5 mmol/L.

5- Anaemia: haemoglobin level of ≤ 5 g/ dL or a haematocrit of ≤ 15% with hyper-parasitaemia.

6 – Renal function impairment determined clinically or by laboratory tests.

7- Jaundice: plasma or serum bilirubin level > 50 µmol/L (3 mg/dL) with hyper-parasitaemia.

8 – Pulmonary oedema confirmed radiologically or clinically by low oxygen saturation (< 92%) and respiratory rate > 30/min.

9 – Prolonged bleeding from the nose, gums, or venepuncture sites; hematemesis or melena.

10 – Shock.

11 – Hyper-parasitaemia: P. falciparum parasitaemia > 10%.

Severe vivax and knowlesi malaria [5]

Defined as falciparum malaria without parasite density thresholds.

 CM definition

CM [6,7] is defined as a deep level of unconsciousness (inability to localise painful stimulus) in the presence of P. falciparum asexual parasitaemia after treatment of hypoglycaemia and exclusion of other encephalopathies, such as bacterial meningitis and locally prevalent viral encephalitis. To exclude post-ictal status in adults, coma (which in this case rarely extends for more than 1 h) should extend for more than 6 h after a generalised convulsion, whereas, in children, coma duration should be 1 h [8].

Pathophysiology of malaria

10. falciparum is the main cause of CM. Infected mosquitoes, after biting humans, introduce parasites in the liver and formsporozoites, which are released in the blood as merozoites to infect red blood cells (RBCs) and asexually multiply within these cells to form trophozoites, which consume haemoglobin. Infected RBCs produce adhesion molecules, which lead to attachment to the vessel endothelium and to each other. The adhesion of parasitised blood cells (pRBC) within the vasculature is termed sequestration and is the mechanism whereby they are removed by the spleen. In RBCs, trophozoites mature into schizonts, which rupture the pRBC and release more merozoites in the circulation. Sequestration occurring in the brain and other organs is the histopathological hallmark of CM [9]. The mechanism underlying the sequestration of pRBCs within the CNS microvasculature and its association with coma, convulsions, raised intracranial pressure (ICP), death, and neurological injury is not well understood [10. CM is associated with severe anaemia, metabolic acidosis, and disseminated intravascular coagulation [10].

Diagnosis of malaria

Seizures, hypertonia, hyperventilation, and anaemia are not specific to malaria, and thus the diagnosis of CM in children is more difficult. In most African countries, higher-level diagnostic laboratory and radiological investigations are unavailable, which delays CM diagnosis [11] . Malaria microscopy is the gold standard for malaria diagnosis, with the advantage of parasite quantification and species identification. Microscopy accuracy to diagnose malaria depends on the quality of the reagents and the microscope and the experience of the observer [12]. Immunochromatographic tests (rapid diagnostic tests) are an alternative to microscopy for malaria diagnosis, especially in places with low resources and less experienced health personnel [12].

Complications of CM

In CM, most children recover rapidly without complications, whereas approximately 15% develop neurological disabilities such as spasticity, ataxia, hemiplegia, speech disorders, blindness [13,14], cognitive impairment, behavioural difficulties, epilepsy [15, and attention deficit disorders [15,2].

 Retinopathy

The retina combines easy access to the central nervous system with the direct ability to visualise neurodegenerative processes in vivo in a non-invasive way [16]. The retina blood supply is provided by two vascular systems: the outer retinal vasculature or the choroid and the inner retinal vasculature. The retina is protected from blood-borne toxins or infectious agents by the blood-retinal barrier (BRB). The BRB consists of two morphologically distinct parts: the outer retinal, choroidal BRB, which is formed by fenestrated endothelial cells in conjunction with retinal pigment epithelial cells (RPE), and the inner retinal BRB, which is formed by non-fenestrated endothelial cells in conjunction with Müller glial cells [17]. The outer BRB is a specific adaptation of the retinal tissue, whereas the inner BRB is identical to the blood-brain barrier in the central nervous system [18,19].

Pathophysiology of retinopathy signs in CM

Many studies have been conducted to investigate the pathophysiology of retinal signs in CM. [20,21,22]. These studies hypothesised that macular whitening results from metabolic or hypoxic stress that leads to oncotic oedema of second-order neurones in the inner retina. Using fluorescein angiography in children from Kenya, it was found that intravascular metabolic stress was responsible, rather than capillary obstruction, which was not seen in association with macular whitening. Fluorescein did not breach the BRB or accumulate in extracellular oedema in the retinal area infected with malaria parasites; this finding supports the hypothesis of metabolic stress or hypoxia from toxic malarial products, cytokines, or nitric oxide as a cause for retinopathy [20]. Retinal whitening (macula whitening sparing the central fovea and peripheral whitening of the fundus), retinal vessel discolouration to pink-orange or white, retinal haemorrhage, and papilledema are characteristic findings for CM [23,24] (Fig. 1a, 1b, 1c). Orange or white discolouration of the retinal vessels result from the hemoglobinisation of erythrocytes infected with mature parasites [11, 25, and 26]. Retinal whitening and retinal vessel discolouration are considered specific symptoms of CM. Retinal haemorrhage is more common in children than in adults. In autopsy studies, retinal haemorrhage was found to be associated with CM severity and cerebral haemorrhage [27]. Papilledema is a nonspecific symptom and is rare in children and adults with CM. In children, papilledema indicates a poor prognosis [25].

A prominent difference between children and adults with CM is vessel discolouration [25].

Figure 1a:  A large number of retinal haemorrhages in a child with cerebral malaria.

Figure 1 b: Macular whitening around the inferior fovea and temporal macula (solid black arrow). White-centred haemorrhages are temporal to the disc and on the superior macula. Peripheral whitening is outside the vascular arcades (solid white arrow). The open arrow indicates glare.

Figure 1 c:   Vessel changes, including examples of tramlining (solid arrow) and orange vessel (open arrow).

Despite the protocols for malaria eradication, and the use of new partially effective vaccines in most African countries, CM is a common cause of death in children. CM is accompanied by characteristic retinal abnormalities, termed malarial retinopathy, which is diagnostic and prognostic [12]. Children with hyper-parasitaemia (>4–5% infected erythrocytes) are at increased risk of severe malaria and death. No characteristic clinical symptoms and signs reliably distinguish severe malaria from other severe infections in children [12].

In 1878, Poncet first described the retinal findings associated with malaria [28]. He noted that nearly all cases of ‘pernicious malaria’ were accompanied by retinal haemorrhage. The first description of retinal findings, known as malaria retinopathy, comes from studies of children in Malawi in 1993 [29]. The retinal findings were investigated by fundus photography and angiography in children from Kenya, Mali in 2002 [30], and Gambia in 2004 [26].

The rate of malaria-associated retinopathy in children varies from 61%-79% [14,22], with a mortality rate of 41.7% in children with malarial retinopathy [31].

In an autopsy study, retinopathy changes in CM were 90% sensitive and 85% specific for the underlying cerebral pathology, typically associated with P. falciparum; this indicates that malaria parasites were responsible for the patient’s cerebral findings [32]. Children with CM as per the WHO definition but without retinal findings are called false-negative CM; they represented 10% of cases [33]. In the past, retinal findings were not described in falciparum malaria owing to ophthalmoscopy technical issues. In Ghana, later ophthalmoscopy revealed retinal vein changes in 26% of children with CM, which resolved within one week. [34]. In Malawian children with CM, the fatal outcome and length of coma are related to the number of retinal haemorrhage events at the time of CM diagnosis [25]. Malarial retinopathy resolves during the patient’s recovery from the coma in CM with no permanent retinal abnormalities [25]. Malarial retinopathy is not found in all children with CM. However, at least 2/3 of them have retinopathy, and the prognosis is worse in those with extensive retinal changes [11]. Beare et al. reported malarial retinopathy in 61% of children, and the outcome and death from malaria are related to the number of retinal haemorrhage events [35]. In Yaounde, 59.09% of their study population with CM had a retinal haemorrhage, 54,54% had whitening and vessel discolouration in 18,18%; it was also found that neuro-malaria is associated with severe and frequent outcomes related to retinopathy findings, especially in children under five years of age [36]. In a reported case in Ghana with CM and retinal findings, no neurological or ophthalmological complications were found after long-term follow-up with serial EEG and electrophysiologic testing [37]. The first report of decreased visual acuity associated with retinal findings in children with CM was in Thailand in 2014 [38]. The retinal changes in children are not the same as those in adults owing to age-specific differences in the pathophysiology of CM, as the changes in children can be seen in complicated and uncomplicated malaria [39,40]. In central India, malarial retinopathy has a low incidence in CM, but the mortality from this form of the disease is high [31]. There is a need for more ophthalmologists in Africa to perform ophthalmological examinations on all children with malaria [23]. Comatose children in countries with endemic or epidemic malaria should undergo funduscopic examination, especially in Africa, to exclude other neurological causes [41], because retinopathy, owing to the sequestration of parasitised RBCs in the microvasculature, is the only sign to differentiate malarial and non-malarial coma in children [32], and to reduce the rate of false-positive diagnosis of CM rate [37].

Ophthalmological examination in children suspected of CM is mandatory in countries with endemic malaria; it has pathological characteristics that differentiate CM from other neurological conditions.

 Search strategy and selection criteria

The terms “malaria in children”, “cerebral malaria”, and “malaria retinopathy” were searched in the PubMed and Google Scholar databases, and the most representative of several articles on the same topic was selected. Our search was not restricted to specific years.

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Funding

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Acknowledgements

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