Background
Malaria remains a public global health challenge that disproportionally affects children who already face multiple other risk factors for growth and development, such as poverty and malnutrition especially in low and middle-income countries (LMICs) [
1,
2]. Between 300-600 million people suffer from malaria each year, and 90% of these cases occur in young children in sub-Saharan Africa [
3]. Over 300,000 of children infected with malaria will die of the disease [
4,
5]. Those who survive often suffer multiple morbidities with severe and complicated outcomes including increased risks of neurological, cognitive, and behavioral deficits [
6‐
10]. With the high numbers of malaria infection worldwide, many children are at increased risk of cognitive and behavioral impairments. By not reaching their full developmental potential, these children are estimated to have a 20% deficit in their adult incomes, which affects families, communities, and countries [
11].
A review by Holding and Snow [
12] reported that the effect of malaria in childhood has subtle to profound effects on cognition and behavior linked to the negative brain injury consequences and the impact on performance exacerbated by chronic or recurrent malaria infection, anemia, and undernutrition [
12]. A systematic review by Kihara, Carter [
8] reported potential deficits in cognition: attention, memory, visuospatial skills, language, and executive functions after
Plasmodium falciparum infection. The review suggests there is strong evidence that direct brain damage during malaria episodes causes neuro-cognitive impairment [
8]. Additionally, a recent review by Fernando, Rodrigo [
10] showed that few studies have assessed the impact of malaria on cognitive functions. The review found significantly impaired cognitive abilities and school performance among malaria groups before and after treatment of acute illness [
10]. While these reviews brought attention to this critical issue, they were published over 10 years ago and lack differentiation regarding severity or different forms of malaria infection.
Furthermore, no reviews have evaluated the effects of
Plasmodium falciparum on behavior, although persisting immediate and long-term behavioral problems have also been recorded in children surviving malaria [
13‐
15]. A retrospective study conducted to assess the behavior problems in children aged 1-6½ years that had survived cerebral malaria with severe neurological sequelae who had suffered cerebral malaria at the ages of 5 months-4 years found them to have behavior problems that included inattention and impulsivity, aggression, ADHD with hyperactivity, destructibility, running away from home, autistic spectrum disorders, feeding difficulties and self-injurious behaviors [
15]. Moreover, in a Ugandan study, children less than 5 years who had cerebral malaria and severe malaria anemia were found to higher externalizing and internalizing problems compared to the control children [
13].
Important to note is that malaria is considered an independent causative factor for cognitive and behavioral impairment however the exact pathological mechanisms and the link between malaria and cognitive and behavior deficits remains unclearly defined [
10]. One possible explanation is that parasitic sequestration within cerebral circulation causes biochemical changes in the central nervous system [
10,
12]. This causes hypoxia, hypoglycemia, multiple, prolonged, generalized, or focal seizures; intracranial hypertension, severe metabolic derangement, and coma leading to damage of the frontal lobes, medial temporal lobes, and the hippocampal system [
10]. Another possible explanation is that malaria induces acute neurological complications as a result of vascular obstruction, brain hyper-inflammation, reduced cerebral blood flow, and disruption of the blood-brain barrier (BBB) with consequent axonal damage and demyelination responsible for behavioral, and cognitive impairment [
16]. These mechanisms have however been thought to be dependent on factors like the nature of parasite involved, the level of parasitization, infection, intensity, and the age of the host at infection [
12]. It is important to note that these mechanisms may not cut across the different malaria types and thus the possibility of different outcomes for different malaria types.
Limited literature currently exists regarding what specific domains of cognition and behavior may be negatively impacted by malaria infection and the extent of that impact. Furthermore, it is unclear how other potential factors, such as varying intensities of malaria infection, may impact cognition and behavior. While national malaria control programs and malarial campaigns aim to reduce the number of malaria-associated morbidity and mortality [
17,
18], many children surviving malaria in LMICs continue to present with cognitive and behavioral deficits. In recent years, cognitive and behavioral assessments are increasingly performed post-malaria infection, in both clinical and research settings. However, a succinct synthesis of these data has not been performed to describe the impact that various forms of malaria infection have on cognitive and behavioral outcomes in children, as well as other factors that may be contributing to cognitive and behavioral deficits in this population.
This systematic review is necessary to help find, appraise, and summarize the current evidence that malaria infection is associated with cognitive and behavioral performance and may provide evidence to inform clinical care, identify knowledge gaps, and highlight further areas for investigation. We focus on LMICs where malaria is still greatly endemic with moderate and high transmissions and malaria burden [
1,
2]. For example in 2018, nineteen countries in sub-Saharan Africa and India carried almost 85% of the global malaria burden with six countries (Uganda Mozambique, Nigeria, the Democratic Republic of the Congo, Côte d’Ivoire, and Niger) bearing more than half of all malaria cases worldwide [
2]. Additionally, quality of malaria care among children varies widely in endemic LMICs with fragile health systems creating major health and development challenges (1) as not all children with apparently the same brain insult have the same outcome. This is notwithstanding the fact that LMICs receive the highest percentage of international funding for malaria (85% for low income and 61% for lower-middle-income countries in 2018) (2) proposing the need for further exploration.
Objectives
The objective of this systematic review is to examine the association of malaria infection on cognition and behavior outcomes among children living in low- and middle-income countries (LMICs). We will achieve this objective by addressing the following research questions:
a.
Which cognitive and behavioral domains are negatively impacted by malaria infection?
b.
To what extent are these domains impacted?
c.
Which forms of malaria are associated with specific deficits in cognition and behavior?
Discussion and outcomes
The systematic review will provide meaningful insights on the association of malaria on cognitive and behavioral outcomes of children, including the adverse effects of post-malaria survival. Additionally, the review will inform strategies for the prevention and management of adverse outcomes associated with malaria among children in endemic LMICs. The findings may guide further research in addressing the current gaps in knowledge and limitations regarding cognitive and behavioral outcomes associated with malaria episodes.
This systematic review will be the first to examine a full range of both cognitive and behavioral outcomes in children in malaria-endemic and LMICs, as well as explore various forms of malaria infection may impact outcomes. Findings from this review may support clinicians, health experts, and policymakers develop guidelines to minimize deficits and impairment due to malaria infection; better inform policy; and develop interventions to improve outcomes for children surviving malaria.
Ethics and dissemination
We will not seek for ethical approval as this is a systematic review protocol. We will synthesize literature on the cognitive and behavioral outcomes of children surviving malaria. The findings of this review will be shared electronically and in-print through conference presentations and peer-reviewed publications to provide information to scientists when developing guidelines for managing the outcomes and understanding the burden of malaria in LMICs.
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