Association between Plasmodium falciparum malaria and the mental health of children between five years and nineteen years in sub-Saharan Africa: A systematic review.

Background Plasmodium falciparum (P. falciparum) malaria is the most common parasitic infection of the central nervous system. Every year, over two billion people are infected globally, and over a million children, mostly less than five years die.1, 2 Children living in sub-Saharan Africa bear the brunt of the disease and its common neurological complications, since over 85% of global malaria cases occur in this region of the world.1,2 In terms of geographical context, sub-Saharan Africa consists of 47 countries which lie south of the Sahara desert, with countries like Mauritania, Mali, Niger, Chad and Sudan serving as the northern boundaries of the sub-region.2, 3Figure 1. The Spatial Distribution of P. falciparum Malaria P. falciparum Parasite Rates.: 2Light red = Low riskMedium red = Intermediate riskDark red = High riskNearly a century ago, Anderson described detailed accounts of the links between malaria and two mental disorders: psychosis and neurosis3 P. falciparum is one of the malaria species that infect humans and appears to have a propensity for the central nervous system. 4 From the 1980s, the association between malaria and mental health took centre-stage, and many studies corroborated Anderson's findings, and linked malaria with many mental and neurological disorders - such as neurotic behaviour, psychosis, impaired executive functioning and epilepsy. 6, 7,8 These diverse deficits can only occur in different brain areas, and not in any specific part of the brain. The earlier hypothesis that falciparum malaria affects only a specific brain location seems unlikely, given the wide variety of neuropsychological outcomes that are exhibited after infection. 8 These studies have indicated that P. falciparum seems to affect the brain globally, not in a localised fashion. Cerebral malaria complications have been shown to be caused by the sequestration of infected erythrocytes within cerebral blood vessels. This seems to an essential component of the pathogenesis, even though other factors such as convulsions, acidosis or hypoglycaemia can cause cognitive deficits and impair consciousness.9 Cerebral malaria has been regarded as the most severe neurological complication of Plasmodium falciparum malaria, and it is relatively common in children living in sub-Saharan Africa. 2, 5, 10 It has become increasingly recognised that cerebral malaria may cause persistent neurological and cognitive deficits that span a wide range of cognitive functions long after the infection has been successfully treated with antimalarial drugs, even in asymptomatic individuals. 9 It is estimated that between 10%-28% of children who survive an episode of cerebral malaria develop neurological and psychiatric sequelae. 10 Acute psychiatric complications that have been described in cerebral malaria include schizophrenic and manic syndromes, typical and atypical depression, anxiety attacks, acute confusional states, possession or trance-like states, delirium, amnesia, irritability, violence, impaired memory, and acute personality changes. 11 In addition to acute conditions, studies have also reported persistent deficiencies including attentional memory, learning and language impairments, visuospatial and motor deficits, and psychiatric disorders. 10, 9, 8 In another study that focused on mental disorders in cerebral malaria, Thiam and his colleagues listed mental confusion, delirium, visual hallucinations and motor agitation as some of the mental disorders diagnosed among in-patients of a psychiatric facility in Senegal. 12 Cerebral malaria can disrupt neuropsychological integration during critical developmental periods, impacting negatively on global neurological integrity, attentional vigilance, perceptual acuity, and subsequent development of visual-spatial processing and memory that is foundational to global cognitive ability. Severe malaria and mental health Severe malaria has also been found to lead to persistent neuropsychiatric impairments and deficits among children. For example, Carter and his colleagues found neurocognitive impairments associated with severe falciparum malaria in Kenyan children who survived severe malaria.8 This study also found evidence of acquired childhood language disorder, persistent neurocognitive deficits and developmental impairments among child survivors of severe malaria. Some studies have shown mental health deficits are not only associated with cerebral and severe malaria, but they also appear to occur in patients who have suffered repetitive uncomplicated malarial infections. The impairment of fine motor skills which affect psychomotor coordination in later life has also been found as sequelae in asymptomatic Plasmodium falciparum infection. 8, 10 A study examining the mental health effects of uncomplicated malaria showed that children who had non-severe malarial infection still performed significantly poorer in scholastic tasks two weeks post-acute infection compared to controls. 12 Further findings have also pointed to the possibility that repeated non-severe malaria attacks have a significant negative effect on cognitive performance, manifesting as impairment in school performance. 12, 13 These studies controlled for the effect of absence from school, so that the students used for the study had a non-significant difference in the number of days spent at school. Taken together, the deficits suffered by children who survive severe malaria, cerebral malaria, repetitive uncomplicated malaria and asymptomatic malaria include deficits in attention, memory, visuo-spatial skills, language, memory and general school performance. Other studies have associated malaria with schizophrenic and manic syndromes, typical and atypical depression, anxiety attacks, mental confusion, amnesia, irritability, violence and acute personality changes. Other negative sequelae that have followed episodes of malaria include visual hallucinations, motor agitation and an effect on the executive functions of the victims. 7, 8 Malaria and mental health Carter and his colleagues indicated that in addition to killing about one million children every year, falciparum malaria in children is now known to leave survivors with multiple cognitive, motor and many other mental health deficits. This is a matter of great concern, given the endemic nature of malaria in sub-Saharan Africa and the fact that the children who survive the episodes live with persistent negative sequelae. 8 Different studies have examined the mental health sequelae of falciparum malaria in a wide range of age groups of children - many of them in narrow age bands. This review therefore deemed it necessary to extend the age band from five to nineteen years so as to capture as many studies as possible. The broad age-band for this review is also aimed at looking at studies which looked at late-teen malaria survivors, so as to have an idea about how far the deficits can persist in childhood. The review focuses on sub-Saharan Africa as falciparum malaria is highly endemic in this region as compared to other regions of the world. 17 Malaria and mental health: the Ghanaian context Dugbartey and his colleagues conducted several studies about the neuropsychology of cerebral malaria in Ghana generally, and also about simple reaction time and cognitive information processing efficiency and somatosensory discrimination deficits after cerebral malaria in Ghanaian children.1, 2, 14, 15 Potential outcome for research and policy Even though there are efforts aimed at preventive strategies, most government policies on malaria in sub-Saharan Africa are focused on early treatment and the prevention of mortality due to malarial episodes. This systematic review therefore aims to draw together the studies that have documented the negative and persistent mental health sequelae of survivors of malaria, with the overall aim to shape policy towards malaria preventive strategies since the negative impacts of malaria have been shown to go far beyond successful treatment. A preliminary search of Joanna Briggs Institute Library of Systematic Reviews, Cochrane Library, PubMed and CINAHL has revealed no existing systematic review on the topic of interest for this systematic review. Review objectives The objective of this review is to identify and synthesise the best available evidence on the association of Plasmodium falciparum malaria and the short-term and long-term mental health deficiencies of children aged between 5 years and 19 years in sub-Saharan Africa. More specifically, the objectives are to identify the effects of malaria episodes on children's memory, attention, general school performance, schizophrenic and manic syndromes, typical and atypical depression, anxiety attacks, mental confusion, amnesia, irritability, violence and acute personality changes. In addition, this review will also consider studies that look at other negative sequelae such as visual hallucinations, motor agitation and those that report negative effects on the executive functions of the victims in sub-Saharan Africa. Inclusion criteria Type of participants This review will consider studies that include children aged between 5 years and 19 years, who reside in sub-Saharan Africa. Children below 5 years of age are prone to active bouts of falciparum malaria as compared to older children, 18 hence the lower age limit of 5 years to capture persons less prone to active malaria disease. The review focuses on children; the upper age limit of that group is 19 years. Phenomenon of interest/exposure This review will consider studies that examine the association between severe malaria, cerebral malaria, repetitive uncomplicated malaria or asymptomatic malaria and mental disorders. Type of outcomes The main outcome of interest is the association between malaria and mental health outcomes. This review will consider studies that include the following mental health outcome measures: cognitive deficits and impairments, acquired language disorder, school performance and psychomotor skills Types of study This review will consider epidemiological study designs including randomised controlled trials, non-randomised controlled trials, quasi-experimental, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies. Search strategy The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilised in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases as shown below. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in the English language from 1980, when the association between malaria and mental health was highlighted to 2012, will be considered for inclusion in this review. The search for unpublished studies will include: WHOLIS (World Health Organization Library Database) and Networked Digital Library of Theses and Dissertations (PROQUEST). Initial search words will include, but not limited to: Africa, malaria, mental health, psychosis, neurosis, cognitive deficits, executive functions, psychomotor skills and neurological deficits. Databases to be searched The databases to be searched include: Pubmed, CINAHL, PSYCNET, PsycARTICLES, PsycBITES, PsycINFO, Digital dissertations, Social Science Citation Index, Social Science abstracts, Sociological abstracts, Social Services Abstracts, World Bank, British Library for Development Studies, SCOPUS and MedNar. Assessment of methodological quality Quantitative papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardised critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. Data extraction Data will be extracted from papers included in the review using the standardised data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Data synthesis Quantitative papers will, where possible be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. Conflict of interest The authors of this review have no individual or joint conflict of interest. Acknowledgement The reviewers wish to acknowledge the JBI Affiliate Centre at the Kintampo Health Research Centre for their initial comprehensive training of the first three authors, and for their continued motivation.

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