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Page 2 of 15 Cheng et al. Vessel Plus 22020;4:17 I http://dx.doi.org/10.20517/2574-1209.2020.08

Clinically, malaria can be either uncomplicated or severe. Uncomplicated malaria presents as a non-
specific, flu-like syndrome and diagnosis is based only on clinical features, which is often unreliable.
Approximately 1% of diagnosed cases will progress to severe malaria for reasons that are not fully
[2]
understood and amongst these, up to 30% will be at risk of developing life-threatening or debilitating
[3]
complications . Severe malaria is defined by precise diagnostic criteria related to specific signs and
symptoms, with cerebral malaria (CM) and severe malarial anaemia (SMA) being two of the most serious
life-threatening complications associated with P. falciparum infection. Both target children under the age
of five and although not yet fully understood, the pathogenesis of CM and SMA is likely to be different.
The clinical hallmark of CM is a diffuse, symmetrical encephalopathy with coma and a general absence
of focal neurological signs. CM is characterised by the sequestration (binding) of infected red blood cells
(iRBCs) in the vasculature of most organs, including the brain, coupled with an uncontrolled inflammatory
response . This sequestration of iRBCs during CM is associated with endothelial dysfunction leading to
[4]
coma, respiratory distress syndrome and placental malaria when it occurs in the brain, lungs or during
pregnancy, respectively. SMA is defined by a haemoglobin (Hb) concentration < 5g/dL and a packed cell
[5]
volume (PCV) < 15% in children, and by Hb < 7g/dL and PCV < 20% in adults . SMA is also associated
with increased clearance of both iRBCs and non-infected red blood cells (nRBCs), as well as altered
[6-8]
haematopoiesis . In both CM and SMA cases however, iRBCs remain within the vasculature, adhere to
and activate endothelial cells that are then likely to release pathogenic factors into the surrounding tissues
such as the brain parenchyma. This review will focus mainly on CM and its association with extracellular
vesicles.

PATHOGENESIS OF CM: FROM HOST CELLS TO EXTRACELLULAR VESICLES
As mentioned above, CM is characterised by sequestration of iRBCs within the cerebral vasculature
although the neurological lesion extends beyond blood vessel alteration to damage to the brain
parenchyma, with clear involvement of the blood-brain barrier (BBB). There is a fine and complex interplay
between the cells on each side of the BBB, with vascular cells, (i.e., endothelial cells, platelets, T cell
lymphocytes, macrophages and to lesser extent neutrophils), microglial cells, neurones, and astrocytes,
[9]
all having either target or effector roles (and sometimes both) at some point in disease development .
In addition, extracellular vesicles (EVs) are potentially released by all these cells adding another level of
complexity to this intercellular crosstalk. A combination of ex vivo studies using patient samples (biological
fluids or post-mortem tissues), in vitro assays mimicking the intravascular lesion, and in vivo experiments
using mostly murine models allows for a better understanding of the cellular interactions and pathogenesis
of the disease.

How much of CM is attributable to the sequestration of iRBCs is still unknown. Post-mortem studies have
shown various levels of iRBC accumulation within the microvasculature of the brain in patients with
diagnosed CM, but this was similarly observed in patients who died of non-CM causes [10,11] . Of note, this
observation is correlated with the severity of the disease in both children and adults [10,12] . Post-mortem
histopathology in Malawian children with clinically defined CM (coma and P. falciparum parasitaemia)
identified different disease patterns: (1) iRBCs sequestration only; (2) iRBCs sequestration with associated
peri-vascular changes such as haemorrhages or micro-thrombi; and (3) little to no sequestration .
[11]
In the latter, the real cause of death was only identified after autopsy, adding to the complexity of CM
and the difficulty in establishing a precise diagnosis. In this study , only fundus examination allowed
[11]
discrimination between malarial and non-malaria coma. In Vietnamese adults, iRBC sequestration was
more frequent in patients with CM than in those without, and was correlated with coma and time of
[12]
death . Consequently, vascular congestion was proposed as a cause for coma since sequestration leads to
decreased cerebral blood flow, impaired brain function and cerebral hypoxia.