Brain Research Bulletin 145 (2019) 53–58

Contents lists available at ScienceDirect

Brain Research Bulletin

journal homepage: www.elsevier.com/locate/brainresbull

Review

Cerebral malaria T
a a,b,⁎
Ange Landela Luzolo , Dieudonné Mumba Ngoyi
a
Department of Parasitology, National Institute of Biomedical Research, BP 1187 Kinshasa, Gombe, Democratic Republic of the Congo
b
Department of Tropical Medicine, School of Medicine, University of Kinshasa, BP 834 Kinshasa XI, Democratic Republic of the Congo

A R T I C LE I N FO A B S T R A C T

Keywords: Malaria remains of significant public health concern under the tropics, causing millions of deaths annually. The
Cerebral malaria disease is caused by protozoans of the Plasmodium genus, of which harbors several distinct species. Human
Plasmodium falciparum infection occurs during the blood meal of an infected female mosquito belonging to the Anopheles genus. It is
Tropical neurology estimated that around 1% of children infected with Plasmodium falciparum develops a more severe form of
malaria, which may eventually lead to cerebral complications including cerebral malaria (CM). CM can be
positively diagnosed in patients unable to localize a painful stimulus, with peripheral asexual P. falciparum
parasitemia and no other identifiable causes of an encephalopathy. Unarousable comas along with the presence
of asexual forms of the parasite on a peripheral blood smear are hallmarks of the disease. While the molecular
mechanisms underlying the pathogenesis of CM have yet be fully elucidated, the pathology in itself indicates a
clear disease of the vascular endothelium. It is characterized by parasite sequestration, inflammatory cytokine
production and vascular leakage, eventually resulting in brain hypoxia. The condition requires systemic health
management consisting of focused nursing practices, supportive care, and anti-malarial drugs. The continued
understanding of pathogenic mechanisms leading to the onset of CM is fundamental and key for the expansion
and development of appropriate neuroprotective interventions. Future research perspectives may also include
the development of field-based and rapid diagnostic tests for CM, understanding of host-pathogen interactions to
advance development of prevention tools and therapies, and antimalarial drug trials.

1. Epidemiology Plasmodium falciparum (P.falciparum), Plasmodium vivax (P.vivax),

In 2016, 91 countries reported a total of 216 million cases of ma-
laria, an increase of 5 million cases over the previous year. During the
same year, the global tally of malaria associated deaths reached a
staggering 445 000, which is about the same mortality incidences that
were reported in 2015. Although reported cases of malaria have con-
tinued to decline globally since 2010, some regions have seen the rate
of decline stagnant or even reverse since 2014(World Health
Organization, 2017). Mortality rates have followed a similar pattern,
likely due to a general decrease in reported cases. Eighty percent of the
global burden of malaria is accounted for by reports from just 15
countries, all of which are located in Sub-Saharan Africa, with the ex-
ception of India. Given this distribution of malaria, it come as no sur-
prise that reports from the World Health Organization (WHO) re-
presenting the African region accounts for nearly all reported deaths
due to malaria (World Health Organization, 2017).
Malaria is a parasitic disease caused by protozoans of the
Plasmodium genus which harbors several distinct species. There are four
main species which are pathogenic to humans; these include
Plasmodium ovale (P. ovale), and Plasmodium malariae (P. malariae)). Of
the various species, P. falciparum is considered the most dangerous and
is responsible for the vast majority of the high mortality rates associated
with Plasmodium infection, especially on the African continent. While
typically a zoonotic disease infecting monkeys in South East Asia,
Plasmodium knowlesi can also infect humans with malaria, however at
far less frequency (De Silva, 2018). P. falciparum is the most prevalent
malaria parasite in sub-Saharan Africa, accounting for an estimated
99% of malaria cases in 2016. Outside of Africa, P. vivax is the pre-
dominant parasite in the WHO Region of the Americas, representing
64% of malaria cases, above 30% in the WHO South- East Asia and 40%
in the Eastern Mediterranean regions (World Health Organization,
2017).
Human transmission of Plasmodium occurs during the blood meal of
an infected female mosquito of the Anopheles genus. Once an individual
has been infected after a blood meal, malaria evolves either into the
simple form or the severe forms, which is a less frequent presentation.
The simple form is characterized and diagnosed typically by the pre-
sence of a fever or history of fever without any obvious signs of gravity.

⁎
Corresponding author at: Department of Parasitology, National Institute of Biomedical Research, BP 1187 Kinshasa, Gombe, Democratic Republic of the Congo.
E-mail addresses: alandela@inrb.cd (A.L. Luzolo), dieudonne.mumba@inrb.cd (D.M. Ngoyi).

https://doi.org/10.1016/j.brainresbull.2019.01.010
Received 30 April 2018; Received in revised form 28 December 2018; Accepted 3 January 2019
Available online 15 January 2019
0361-9230/ © 2019 Published by Elsevier Inc.

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A.L. Luzolo, D.M. Ngoyi
The syndrome of severe malaria is defined by the presence of
Plasmodium in peripheral blood, in addition to clinical or laboratory
confirmation of severe vital organ dysfunction (Idro et al., 2016). While
several clinical forms have been described, there are three major
manifestations which are most widely recognized. These major mani-
festations include cerebral malaria (CM), severe malarial anemia (SMA)
and respiratory distress (Kotlyar et al., 2014). Other manifestations
such as metabolic acidosis, hypoglycemia, hypoargininemia and acute
renal failure have also been described in the medical literature (World
Health Organization, 2000)(Abier Javaid, Rukhsana Kausar, 2017)
(Lopansri et al., 2003).
CM typically presents as a serious neurological complications in-
duced by infection with P. falciparum (Nanfack et al., 2017). It is esti-
mated that around 1% of children infected with P. falciparum will de-
velop CM (Storm and Craig, 2014). The reasons and biological
pathways explaining why some individuals, unlike others, develop CM
remain unclear. While the exact mechanisms for the development of CM
are yet to be fully elucidated there have been some risk factors asso-
ciated with this type of disease progression. The development of CM is
rare in adults, however, it is much more common in children under 5
years of age who live in areas of high transmission (Ilunga-Ilunga et al.,
2016). It appears that younger children can be partially protected from
CM by transferred maternal immunity and most children older than 3
years will have been exposed to and survived previous malarial infec-
tions, decreasing the likelihood of developing CM. This maternally
transferred state of partial immunity is termed premunition and chil-
dren who have developed premunition are at much lower risk for de-
veloping the severe forms of disease, including both severe malarial
anemia and CM. In low transmission areas, however, CM occurs to older
children and adults (Postels and Birbeck, 2013). Additional risk factors
for the development of CM have shown that blood group phenotypes A
and B increase the odds for the development of CM, while type O is
significantly associated with protection(Rout et al., 2012). Due to the
complications associated with severe forms of P. falciparum infection,
worldwide, CM is a leading cause of malaria mortality, responsible for
almost 20% of adult deaths and 15% of childhood deaths (Wang et al.,
2015). Surprisingly, despite the clearance of the malaria parasite and
post-recovery, its documented that roughly 11% of children display
neurological deficits upon discharge, indicating long-term damage from
the development of CM (Polimeni and Prato, 2014).
2. Clinical manifestations and sequelae
According to the criteria outlined by the WHO, CM is a likely di-
agnosis if a patient cannot localize a painful stimulus, has peripheral
asexual P. falciparum parasitemia and has no other identified causes of
an encephalopathy (World Health Organization, 2000). Generally, pa-
tients have a history of a 2 or 3 day fever along with the subsequent
abrupt onset of convulsions and/or severely impaired consciousness,
which is most frequently observed in children affected by CM.
The main symptoms of CM include headache, muscle pain and al-
tered state of consciousness. Mild neck stiffness has been reported,
however, neck rigidity and photophobia along with signs of raised in-
tracranial tension are typically absent. Fixed jaw closure and tooth
grinding (bruxism) are also common manifestations. Motor abnormal-
ities like decerebrate rigidity, decorticate rigidity and opisthotonos can
occur in individuals with CM. Other symptoms and signs include sei-
zures, enlargement of liver and spleen, jaundice, pulmonary edema,
renal dysfunction, pallor, hypoglycemia, bleeding, hypotension and
severe anemia(Koshy and Koshy, 2014). Since age is an important
factor in CM, it appears that adults and children share only some
symptoms of CM during the early time points of the disease. The dif-
ferences in adult and child CM symptoms have been extensively re-
viewed elsewhere (Hawkes et al., 2013) but briefly, these include non-
specific fever, impaired consciousness, convulsion and neurological
abnormalities along with coma that may last for three days at a stretch.
54
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Brain Research Bulletin 145 (2019) 53–58
Considering these clinical signs and symptoms are also associated
with other encephalopathies and those living in malaria endemic areas
will often host parasites at subclinical levels, a definitive diagnosis is
significantly improved through the confirmation of malaria-specific
retinopathy (Taylor et al., 2004)(Birbeck et al., 2010). CM is char-
acterized by malignant retinopathy (Seydel et al., 2015) and this phe-
nomenon reflects the pathological process occurring in the brain in-
cluding cerebral sequestration of parasites (Lewallen et al., 2008). The
confirmation of a malarial retinopathy is better than any other clinical
or laboratory feature in distinguishing malarial from a non-malarial
induced coma. The malarial retinopathy diagnosis consists of four main
components: retinal whitening, vessel changes, retinal hemorrhages,
and papilledema. The first two of these abnormalities are specific to
malaria, and are not seen in other ocular or systemic conditions (Beare
et al., 2006). Retinopathy is not only reported in children but can also
be observed in adults (Nanfack et al., 2017). Interestingly, several
studies have indicated that autopsies of some patients with CM reveal
no evidence of sequestration of infected Red Blood Cells (iRBCs) in the
cerebrovascular system. Retinopathy-negative CM may represent an
asymptomatic incidental parasitemia with a second exposure (possibly
viral) producing fever and coma. A clinical-autopsy study supported
this hypothesis, finding other infectious and non-infectious causes of
coma in patients dying of retinopathy-negative CM (Postels et al.,
2012).
In African children, neurological abnormalities in survivors of CM
are common, with rates in retinopathy-positive patients approaching
approximately 30%. These Impairments manifest as three primary
deficits including differences in cognitive and behavioral aspect, motor
abnormalities, and even epilepsy. Temporal, cognitive and motor ab-
normalities typically appear first, followed by disruptive behavioral
disorders, and finally epilepsy (Postels and Birbeck, 2013). Many sur-
vivors of CM have long-term brain damage, as well as behavioral pro-
blems including mental health problems (common in children)(Idro
et al., 2016). These long-term impairments are also observed in adults,
where roughly 3% will have sequelae after CM in the form of hemi-
plegia, cerebral palsy, cortical blindness, deafness, cerebellar ataxia and
impaired cognition and learning (Selvaraj, 2015).
3. Pathogenic mechanisms
Despite decades of research on CM, there is still a paucity of
knowledge about what actual causes CM and why certain people are
more prone to developing it. Although sequestration of P. falciparum
infected red blood cells (iRBCs) has been linked to pathology, it is still
unclear if this is directly or solely responsible for the clinical syndrome.
The pathogenesis of CM is likely a multi-factorial process, with se-
questration, inflammation and endothelial dysfunction in the micro-
vasculature of the brain being the largest contributing factors that
eventual lead to coma induction in patients suffering from the severe
form of malaria.
CM is a disease of vascular endothelium mainly caused by P. falci-
parum. It is characterized by parasite sequestration, which causes an
engorgement of cerebral capillaries and post-capillary venules with
iRBCs, triggering an inflammatory cytokine response, resulting in vas-
cular leakage (Gillrie et al., 2012). These events eventually result in
brain hypoxia, as indicated by increased lactate and alanine con-
centrations observed in such patients. However, the sequence of events
initiating these pathophysiological processes, as well as the contribu-
tion of their complex interplay leading to the development of CM re-
mains for the most part unknown (Dunst et al., 2017). Recent data
however, has suggested that a combination of parasite variant types,
mainly defined by the variant surface antigen, P. falciparum erythrocyte
membrane protein 1 (PfEMP1), along with the corresponding host re-
ceptors which causes coagulation and host endothelial cell activation
(or inflammation) are equally important contributing factors disease
progression(Storm and Craig, 2014).
A.L. Luzolo, D.M. Ngoyi
Once malaria has been contracted following a blood meal from a
host mosquito, after liver stage, P. falciparum begins infecting the red
blood cells of the infected individual. These iRBCs circulate through the
organs of the body, including the brain, heart, bone marrow, liver, lung,
skin, intestine and kidney. While there are several P. falciparum geno-
types that can be present in the human host, only a subset of these can
be sequestered in the brain (Montgomery et al., 2006). This seques-
tration in the brain occurs by the adhesion of iRBCs to specific host
receptors including Endothelial Protein C Receptor (EPCR) and Inter-
cellular Adhesion Molecule (ICAM) -1.
This Cytoadherence of iRBCs to endothelial cell receptors is medi-
ated by P. falciparum erythrocyte membrane protein (PfEMP)-1, which
is one of the P. falciparum surface antigens (Scherf et al., 2008)
(Pasternak and Dzikowski, 2009). Attachment points to endothelium
have been shown by electron microscopy to be dense protrusions,
termed knobs, on the surface of iRBCs, where varying cytoadherence
proteins are anchored. The parasite variants containing the conserved
domain cassettes (DC) 8 and 13 are most associated with triggering a
severe malaria event in children (Claessens et al., 2012) and specifically
those with the PfEMP-1 DC8 receptors are universally associated with
CM (Bertin et al., 2013). The PfEMP1-DC8 host receptor has been
identified as EPCR which is located on brain endothelium cells and the
binding of the iRBCs to the EPCR (Turner et al., 2013), as well as ICAM-
1, which has been shown to be associated with the development of CM.
Once bound to EPCR, the iRBCs block the conversion of inactive
protein C to activated protein C, which is an inhibitor of thrombin
generation, potentially contributing to the localized endothelial acti-
vation. The adhesion of iRBCs to the endothelium eventually reduces
levels of available EPCR binding sites, necessary for a normal home-
ostasis regulation. It has been suggested that since the brain en-
dothelium contains a relatively low expression level of these receptors
compared to other tissues, this make the brain particularly susceptible
to inflammation caused by reduced control of thrombin production.
This suggests an important role for localized coagulation/inflammation
related pathology in CM (Moxon et al., 2013). By dysregulating and
increasing thrombin production, this affects various signaling pathways
which ultimately lead to an increased angiopoietin-2 (Ang-2) / angio-
poietin-1 (Ang-1) ratio, Tumor Necrosis Factor (TNF) and Von Will-
ebrand Factor (VWF) production, resulting in the loss of endothelial
barrier function (Moxon et al., 2013).
Ang-1 stabilizes the endothelium while its antagonist, Ang-2, in-
duces vascular permeability and is involved in the regulation of various
endothelial receptors. Ang-1 and Ang-2 are regulated by nitric oxide
(NO), which is produced in the endothelium by using L-arginine as a
substrate. NO production leads to vasorelaxation along with the
downregulation of adhesion molecules, as well as a reduction in
thrombosis (Bergmark et al., 2012). Malaria infection can reduce levels
of L-arginine, resulting in hypoargininemia which subsequently causes
the bioavailability of NO to be dramatically reduced(Anstey, 1996)
(Lopansri et al., 2003). Reducing active NO in the system can lead to
the endothelium over-expressing some of its receptors, including ICAM-
1 (Turner et al., 1994), a known binding receptor for iRBCs (Dobbie
et al., 1999). By increasing the presentation of ICAM-1 due to the re-
duction of NO may lead to further sequestration of iRBCs and unin-
fected RBCs, leukocytes and activated platelets which likely contribute
to the metabolic acidosis and thrombocytopenia observed in CM.
As mentioned, infection with malaria typically causes Von
Willebrand Factor (VWF) to be upregulated in the blood plasma. This
upregulation of VWF is thought to be caused by the activation of en-
dothelial cells resulting in an increase of thrombin production during
infection (Wagner, 1990) and specifically in cases of CM. By increasing
cellular excretion of VWF, this results in above average levels of this
glycoprotein being released in circulation within the host. With the
increased release of the ultra large VWF proteins, it is believed that this
could lead to sequestration of platelets, recruitment of iRBCs and al-
terations of endothelial cell permeability, which eventually can result in
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Brain Research Bulletin 145 (2019) 53–58
microvascular thrombosis. To further support this notion, recent studies
using a mouse model of cerebral malaria demonstrated that infection
with Plasmodium berghei in mice harboring a null mutation for VWF
delayed the progression of CM while increasing their survival rates
(O’regan et al., 2016).
Along with the upregulation of VWF, several cytokines and che-
mokines have repeatedly been associated with CM severity. iRBCs in
the circulation and the rupture of iRBCs eventually trigger an immune
response, increasing the local production of inflammatory cytokines,
such as TNF-α. Increased levels of these inflammatory mediators could
account for the additional sequestration of leukocytes in the cerebral
microvasculature present during CM. This increase of leukocyte se-
questration likely contributes to an amplification of local inflammation,
an increased expression of endothelial receptors and the subsequent
shedding of soluble endothelial receptors, which leads to eventual en-
dothelial damage (Dunst et al., 2017).
Additionally, the cytoadherence of iRBCs and uninfected RBCs to
endothelial receptors ultimately leads to reduction in microvascular
flow. This obstruction in vascular flow will cause a reduction in the
typical delivery of oxygen and glucose to vital organs and tissues.
Impediment of the brain microvasculature represents one suspected
mechanism that could contribute to the induction of comas observed in
individuals suffering from in CM (Ponsford et al., 2012). While the
exact causes of coma are not known, a range of other mechanisms have
also been postulated in addition to the aforementioned micro-
vasculature obstruction hypothesis (Postels and Birbeck, 2013).
In additional to endothelial dysregulation, some classic histo-
pathological findings in fatal cases of CM have also identified intense
sequestration of parasites in the cerebral microvasculature. While
abundant parasite concentrations have been found those who have
succumbed to CM, there have also been numerous reports showing
minimal parasite sequestration in the microvasculature, making this
particular trait more uncertain in cases of CM. Adding further un-
certainty, autopsy studies of individuals infected with P. vivax suffering
from severe malaria showed little evidence for microvascular accumu-
lation of P. vivax-iRBCs. While this finding is of interest, it should be
noted that other studies have shown that P. vivax-iRBCs bind to en-
dothelial cells via receptors, such as ICAM-1, show a similar affinity,
but a lower frequency than P. falciparum-iRBCs (Dayananda et al.,
2018), which could suggest that P.falciparum behaves differently in the
microvasculature of those infected.
While it is clear that endothelial deregulation plays a critical role in
the pathogenesis of CM, this effect appears to also be a general side
effect of malaria infection and not confined to just cerebral tissue alone.
Sequestration and endothelial abnormalities have been also detected in
the lung, heart, kidney, skin and intestine, however, these events do not
appear to be as prominent as those observed in the brain of CM patients
(Macpherson and Warrell, 1985). Collectively, leakage in the perivas-
cular space can result from the different mechanism of pathology de-
scribed and could eventually affect the supporting cells such as astro-
cytes and pericytes leading to localized breakdown of the blood-brain
barrier (BBB) (Medana and Turner, 2006).
4. Diagnosis
The diagnosis of CM is quite vague and since malaria is so common
in the tropical world, CM should be considered in every comatose pa-
tient with a history of fever who has been in an affected area within the
prior two months of symptom onset. Since cerebral dysfunction can be
caused by other factors in addition to malaria, such as bacterial or viral
infections, fever and even hypoglycemia, it is vital to rule out other
variables to increase diagnosis of CM. To increase confidence of an
accurate CM diagnosis, there should be asexual forms of P. falciparum
present in both the thin and thick stained blood films/smear (Dondorp,
2005) (Misra et al., 2011).
Distinguishing children with CM from those with non-malarial
A.L. Luzolo, D.M. Ngoyi
comas or an incidental parasitemia is difficult, especially in malaria-
endemic areas with high rates of asymptomatic parasitemia, which
often are found together. Without access to additional diagnostic tools
such as an electroencephalography (EEG), CT or MRI imaging facility,
coupled with limited laboratory resources, drives the CM confirmation
to be carried out according to the syndromic approach excluding other
causes of encephalopathies. This approach while necessary from a
medical standpoint in resource poor settings, eventually leads to a di-
rect overestimation of cases as a consequence(Taylor et al., 2004)
(Birbeck et al., 2010)(Misra et al., 2011). To better understand the di-
rect consequences of CM and to improve a more accurate prevalence
and diagnosis, lower cost tools needs to be developed and implemented
to better visualize the brain (Beare et al., 2006) and surrounding re-
gions in cases that appear to be caused by severe malaria.
Given that access to advance brain imaging technology is largely
unfeasible in rural and developing areas where malaria is most pre-
valent, other useful tools that can aid in a CM diagnosis is the use of a
funduscopy. This examination of the fundus of the eye can help rule out
the hypothesis of a malignant retinopathy that are not induced in severe
malaria cases. Since the retina is part of the central nervous system
during embryo development and harbors similar cellular structure like
the blood-tissue barrier, makes investigation into the effects of malaria
on such tissue a promising approach to gage what may be occurring in
the microvasculature of the brain. Given that retinopathy induced from
malaria has unique retinal signatures, the expanded use of funduscopy
can serve as a diagnostic test for severe malaria, especially in challen-
ging environments (Beare et al., 2006).
However, despite the potential promise of funduscopy in the diag-
nosis of CM, in current practice, funduscopy is not widely used in re-
source-limited countries due to a lack of information on its effectiveness
by health care providers in endemic regions, specifically in Sub-Saharan
Africa (Swamy et al., 2018). Despite implementation issues, harboring a
retinopathy has been significantly associated with mortality in children
who have developed CM. The use of funduscopy can and should be used
to aid in both prognosis and triage of patients who are suspect of having
severe malaria, which will to optimize the use of resources and enable a
more effective treatment of children, specifically who are affected by
CM(Singh et al., 2016). Additionally, funduscopy, when combined with
other tools will provide the best diagnostic outcome for these patients.
The use of MRI for the evaluation of neurological parameters, to-
modensitometry to measure accurate brain volume along with state of
the art bioluminscent imagining and intra-vital microscopy will not
only improve diagnosis but will also enable a more accurate prevalence
of cases of CM worldwide (Seydel et al., 2015).
In addition to imagining technologies, the existence and continued
exploration for biomarkers that are signatures in CM cases will effec-
tively contributes to a better diagnostic approach for the disease. Some
biomarkers that could be useful in CM cases and have been associated
with such includes, increased levels of histidine-rich protein II, raised
levels of plasma osteoprotegrin and abnormal ratios of Ang-1&2 pro-
teins, all of which could further serve as diagnostic and prognostic
markers(De Jong et al., 2016) (Yusuf et al., 2017).
5. Treatment
While the exact diagnosis of CM poses challenges, its best practice
once a diagnosis of CM is entertained to immediately begin aggressive
treatment. The mainstays of effective therapy include supportive nur-
sing care, various antimalarial treatments, and anticipation of compli-
cations that are typical present in individuals suffering from CM. When
possible, patients suffering from severe malaria should be managed in
an intensive care unit or its local equivalent where critical observation
and management can take place (Postels and Birbeck, 2013).
Since severe malaria is a multi-organ disease, supportive treatment
for all types of multiple systems failure should be anticipated and ad-
dressed. Upon initial assessment and if the patient is stable, antimalarial
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Brain Research Bulletin 145 (2019) 53–58
therapy should be administered, either orally or parenteral methods
should be used depending on the situation. Globally, the most common
treatments of malaria fall within two classes, derivatives of artemisinin,
which include artesunate and arthemether or those generated from
cinconcha alkaloids, such as, quinine and quinidine. Typically when
available, drugs derived from artemisinin are the first line of defense for
CM. Clinical trials conducted in both Africa and Asia have suggested
that compounds such as artesunate are more effective as an initial
treatment when compared to quinine in cases of CM (Dondorp, 2005)
(Dondorp et al., 2010)(John et al., 2010). Once a patient has received
the initial intravenous and/or rectal administration of selected anti-
malarial therapy and are able to tolerate oral medication, it is re-
commended that they continue on artemisinin-based combination
therapy (ACT) to clear the parasite load.
Since patients suffering from CM will experience more than just the
parasite burden, additional lifesaving medical interventions are typi-
cally necessary to increase survival chances. If patients are experiencing
a coma, it is vital to ensure that the airway is not constricted and when
necessary, intubation and mechanical ventilation may be required.
Seizures are also typical in those suffering from CM and require medical
management to further ensure the best possible prognosis. Treatment of
seizures typically requires administration of anticonvulsants such as
diazepam or phenobarbital to reduce such events (Ikumi et al., 2008)
(John et al., 2010). To further stabilize patients with CM, acet-
aminophen can be administered to reduce fever; intravenous dextrose
and fluids can alleviate hypoglycemia and severe dehydrations that are
often observed in such cases. Additionally, if the patient appears to be
suffering from critical anemia a blood transfusion may also be required
if a favorable outcome is to be expected. Another complication that is
observed in CM cases is lactic acidosis, which is induced due to the
severe stress that the body is under when suffering from severe malaria.
This condition can be and is often fatal if not corrected, however if
standard treatment of CM ensues including the administration of fluids
and stabilization interventions, the acidosis typically becomes man-
ageable as the body begins to recover. There have also been some
studies showing that albumin infusions can reduce mortality but not
necessarily acidosis when compared to saline treatments to manage the
condition (Maitland et al., 2005)(John et al., 2010).
In efforts to reduce the high mortality observed in patients suffering
from CM, additional adjunctive therapies have been implemented in an
effort to provide the best possible outcomes for these patients. Most of
these additional therapies have focused on specific biological pathways
in attempts to better modulate the bodies response to this critical
conditions (John et al., 2010). Adjunctive therapies have focused on
modulating the immune response, reducing iron burdens, minimizing
oxidative stress, blood volume expansion, increasing NO production,
reducing blood coagulation and lowering intracranial pressure. While
these interventions may be useful in some instances, the scientific lit-
erature supporting their effectiveness is still lacking (Varo et al., 2018).
6. Future perspectives
The pathogenic mechanisms of CM remain very much unclear and
the expanded and complete understanding of these complex mechan-
isms is important to develop more appropriate neuroprotective inter-
ventions for cases of severe malaria. Thus, future work may need to
focus not on single attributes associated with disease but more com-
plicated interactions based on both host and pathogen characteristics.
In an effort to improve mortality rates and decrease abnormal
neurological outcomes, a number of agents have been studied as ad-
juncts to standard antimalarials. Unfortunately, so far, the search to
identify a successful adjunctive therapy has been unsuccessful. In ma-
jority of clinical trials, drug candidates are administered in mono-
therapy. Yet, pathogenesis of CM remains a multi-factorial process and
sequence of events remain incompletely understood. A combination of
two or more adjunctive therapies, appropriately selected, could perhaps
A.L. Luzolo, D.M. Ngoyi Brain Research Bulletin 145 (2019) 53–58

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