CEREBRAL

MALARIA
MTZ RESEARCH DEPARTMENT
Presented by:
EBENISHA CHOONYA MAJATA
(MTZ Research Scientist)
 Introduction
• A serious neurological complication induced by infection with P.
falciparum (Nanfack et al.,2015).
• Around 1-2% of children infected with P. falciparum develop
CM(Storm&Craig, 2014)
• A leading cause of malaria mortality, responsible for almost 20% of adult
deaths and 15% of childhood deaths(Wang, Qian,&Cao, 2015)
 Continued….
1-2% of cases, mostly in children, malaria becomes severe and life
threatening(why are young children prone to severe malaria and CP?)
228 million clinical cases and over 400000 deaths
1/3rd at risk
In 2018, 228 million cases, 405, 000 deaths, 68% were children under
five.
In 2021, 241 million cases and 627000 deaths were recorded.
 PATHOPHYSIOLOGY
• Exact factors that play a role in neuropathogenesis leading CM is still unclear
• Two main theories: mechanical hypothesis and cytokine storm hypothesis
Mechanical hypothesis: selective cytoadherence and sequestration of parasitized erythrocytes in
cerebral venules cause obstruction to blood flow in the brain leading to coma and death.
Cytokine storm hypothesis: Cytokines and chemokines play a role in the pathogenesis and have
both protective and harmful effects. The most studied cytokine, TNF, in CM, upregulates ICAM-1
on the vascular endothelium of pRBCs.

•
Malaria hypothesis first proposed by JBS Halden in 1949. Thalassaemia conferred a survival
advantage against malaria.
At around the same time, Allison(Allison 1954) and others speculated that malaria selection
might also have explained the high frequency of hemoglobin S(HbS) in malaria endemic
areas.
HbS variant confers approx. >80% protective effect in heterozygous carriers while @-
thalassaemia confers a protective of approx. 40% in homozygous(MalariaGEN 2014; Ndila
et al 2018). Others include G6PD deficiency, the O blood group, and variants of gene for
complement receptor 1(CR1)(Kwiatkowski 2005; Williams 2016; Rowe et al. 1997; Opi et al.
2018)
 CLINICAL FEATURES
CM – most severe neurological complication by P. falciparum and is a
clinical syndrome whose hall mark is impaired consciousness.
Clinical features involve a relapsing diurnal fever.
Pt with acute infection can present with a diffuse CM encephalopathy, a
rapid progressive Comma, and/or seizures without return to consciousness
Exact factors that play a role in neuropathogenesis leading
 Host genetic susceptibility
• Given that more than one million children per year were dying from P. falciparum in Africa alone
prior to the twenty-first century , malaria is, from a genetic standpoint, the evolutionary driver
resulting in genetic erythrocyte diseases.
• This is supported by the observations that, despite homozygote mortality, the HbS allele has a high
prevalence in areas endemic with malaria. Other host genetic factors include inflammatory factors
and regulatory regions, such as Type 1 Interferon receptor variants in Malawi , IL17 in Nigeria and
IL4 and IL22 in populations in Mali.
• In addition, epidemiological studies reported association of outcomes of malarial infections with
age and previous exposure to epigenetic modifications . This arises from a recent discovery that the
production of the citric acid cycle metabolites succinate and fumarate increased during severe
malaria, including CM.
 Radiological investigattions-MRI
• Praveen K Sahu et al., 2021- Brain MRI reveals different courses of
disease in pediatric and adult cerebral malaria. Severe brain swelling was
associated with fatal outcome in African Children. In contrast,
neuroimaging investigations failed to identify cerebral features in Asian
adults.
 Comparisons of brain volumes on admission
between age and disease groups
.
• A. Normalized brain volumes in uncomplicated malaria and non fatal and
fatal cerebral malaria.
• B. Correlation between age and normalized brain volume in nonfatal and
fatal cerebral malaria.
• C. Representative sagittal T2-weighted MRI of patients with UM and CM.
Differences in apparent diffusion coeffient values and pathogenic
patterns btn adults and children with fetal and non fetal CM
• a. decreased ACD values are the signature of cytotoxic edema triggered by
obstruction of circulation by sequestration.
b. In nonfatal CM, specific hypoxia-sensitive regions of the brain are
affected, and these differ with age: cytotoxic edema evidenced by ADC
decrease develop in white matter in children(c) and in the basal ganglia in
adults(d).
 TREATMENT
Artemisinins have become the drug of choice, and artesunate is the first-line therapy for treating severe and CM in both
children and adults.
Main difference with uncomplicated malaria management is the route of administration.
Beyond IV artesunate, ‘’no brain specific drug’’ is available. Although not widely available, respiratory support and artificial
ventilation are crucial.
Seizure management, up to 70% of children have seizures. Treatment with benzodiazepines are less likely to cause secondary
neurological damage.
A four-dose regimen(iv) of MosquirixTM(RTS,S/AS01) vaccine showed protection from severe and CM in 32.2% of
children aged 5-17 months.

• Elective adjunctive neuro-protective therapies are currently unavailable.

 Cerebral Malaria in pregnancy?
malaria and pregnancy
• More common
• More atypical
• More fatal mortality is 13% compared to nonpregnant population(6.5%).
• Selective treatment
• Recent studies indicate that about 10000 women and newborns die every
year malaria infection during pregnancy.
 Vaccines - RTS,S and R21
September 28, 2022 – A new vaccine for malaria developed by scientists at
the University of Oxford was up to 80% effective at preventing disease in
young children, according to trial results published in early September.This
new vaccine, called R21, is potentially an improved version of another
vaccine, called RTS,S, which the World Health Organization approved last
October for broad use in regions with significant malaria transmission.
RTS,S was the first-ever vaccine for a human parasitic infection.
Phase 3 clinical trials—both the predicted and observed efficacy were down
closer to 40%-50%.-RTS, S.
 R21-Vaccince
For R21, only 450 children aged 5-17 months, a small number,
were included in the recent trial conducted in Burkina Faso,
where malaria infections are seasonal. 80%efficacy.
THANK YOU FOR
FOR ATTENTION
 references
1. WHO. Malaria Key Facts. Geneva, World Health Organization, 2019. https://www.who.int/news-
room/fact-sheet s/detai l/malar ia. Accessed 08 May 2019.
2. Kochar DK, Das A, Kochar SK, Saxena V, Sirohi P, Garg S, et al. Severe Plasmodium vivax malaria:
a report on serial cases from Bikaner in northwestern India. Am J Trop Med Hyg. 2009;80:194–8.
3. Battle KE, Lucas TCD, Nguyen M, Howes RE, Nandi AK, Twohig KA, et al. Mapping the global
endemicity and clinical burden of Plasmodium vivax, 2000-17: a spatial and temporal modelling study.
Lancet.2019;394:332–43.
4. Gething PW, Casey DC, Weiss DJ, Bisanzio D, Bhatt S, Cameron E, et al.Mapping Plasmodium
falciparum mortality in Africa between 1990 and 2015. N Engl J Med. 2016;375:2435–45.
5.
References continued...