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Keywords:

  • Plasmodium falciparum;
  • malaria;
  • cognition;
  • systematic review
  • Plasmodium falciparum;
  • malaria;
  • cognition;
  • revue systématique
  • Plasmodium falciparum;
  • malaria;
  • cognición;
  • revisión sistemática

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Review methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Objective  Systematic review to investigate the relationship between Plasmodium falciparum infection and cognitive function.

Method  We searched MEDLINE, EMBASE and PsycINFO, and hand-searched journals and PhD theses. The inclusion criteria were (1) use of standardized tests for the specific populations and/or appropriate controls; (2) clear differentiation between children and adults. Eighteen studies were eligible, of which three gave information on all cognitive domains considered in the review.

Results  Deficits in attention, memory, visuo-spatial skills, language and executive functions may occur after malaria infection. These deficits are not only caused by cerebral falciparum malaria, but also appear to occur in less severe infections. P. falciparum seems to affect the brain globally, not in a localised fashion. Outcome depends on both biological and social risk factors.

Conclusion  Future research should seek to establish the extent of these cognitive deficits using culturally appropriate techniques and well-defined criteria of disease.

Objectif  Revue systématique pour investiguer la relation entre l'infection par le Plasmodium falciparum et les fonctions cognitives.

Méthodes  Nous avons effectué des recherches dans MEDLINE, EMBASE et PsycINFO et des recherches manuelles dans des journaux scientifiques et thèses de doctorat. Les critères d'inclusion étaient les suivants: 1) utilisation de tests standardisés pour les populations spécifiques et/ou des contrôles appropriés, 2) différentiation claire entre enfants et adultes. Dix huit études étaient éligibles dont 3 avec des informations sur tous les domaines cognitifs considérés dans la revue.

Résultats  des altérations dans l'attention, la mémoire, les aptitudes spatio-visuelles, le langage et les fonctions exécutives peuvent apparaître suite à une infection à la malaria. Ces altérations ne sont pas seulement causées par la malaria falciparum cérébrale mais peuvent également apparaître suite à des infections moins sévères. Plasmodium falciparum semble affecter l'entièreté du cerveau et pas seulement de façon localisée. L'issue dépend à la fois de facteurs biologiques et sociaux.

Conclusion  Les études futures devraient chercher àétablir l'amplitude de ces altérations cognitives en utilisant des techniques culturelles appropriées et des critères bien définis de la maladie.

Objetivo  Repaso sistemático para evaluar la relación entre la infección por Plasmodium falciparum y la función cognitiva.

Método  Realizamos búsquedas en MEDLINE, EMBASE and PsycINFO, y buscamos a mano en revistas y tesis de doctorado. Los criterios de inclusión fueron (1) el uso de pruebas estandarizadas para poblaciones específicas y/o controles apropiados; (2) diferencias claras entre niños y adultos. Dieciocho estudios fueron aptos, de los cuales tres daban información sobre todos los dominios cognitivos considerados en la revisión.

Resultados  Después de una malaria pueden ocurrir déficits de atención, memoria, destreza visuoespacial, funciones ejecutivas y del lenguaje. Estos déficits no están solamente causados por la malaria cerebral por falciparum, sino que parecen también ocurrir en infecciones menos severas. P. falciparum parece afectar el cerebro de manera global, y no de forma localizada. El resultado depende tanto de factores de riesgo biológicos como sociales.

Conclusión  Investigaciones futuras deberían buscar establecer el alcance de estos déficits cognitivos, utilizando las técnicas culturales apropiadas, así como criterios de enfermedad bien definidos.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Review methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Epidemiology of malaria

Plasmodium falciparum infects up to 500 million people worldwide and causes 2.7 million deaths every year (WHO 2000). It is one of the malaria species that infect humans and appears to have a propensity for the central nervous system (CNS) (Newton & Krishna 1998). Over 85% of cases of falciparum malaria occur in sub-Saharan Africa, most commonly in children under 5 years (The World Health Report 2002). Although P. falciparum is known to cause acute neurological complications, it is only in the last 15 years that neurological deficits following cerebral malaria (CM) have been fully described (Brewster et al. 1990; Bondi 1992; Carme et al. 1993; Meremikwu et al. 1997; Van Hensbroek et al. 1997; Carter et al. 2003). Persisting or subtle effects following severe falciparum malaria on cognition are increasingly recognized (Holding et al. 1999,2004; Boivin 2002; Carter et al. 2003,2005a,b), but the extent of the effects in less severe disease is unclear. A variety of risk factors coupled with differing criteria of classifying severity of disease have added to the complexity.

Probable pathways of neuro-cognitive impairment post P. falciparum disease

Infection with P. falciparum ranges from asymptomatic infection to fatal disease. There is a difference in the clinical presentation between people living in endemic areas and non-immunes such as travellers. The former are exposed to repeated malaria infections from birth and generally attain some immunity to disease in the first decade of life (Newton & Warrell 1998). In endemic areas, between 20% and 70% of the population have parasites in their blood but most do not appear to have symptoms of malaria (Snow et al. 2003). In these areas, children under 5 years bear the brunt of severe disease and death, although pregnant women are also susceptible. Individuals are infected many times before immunity is acquired.

Non-immunes are highly susceptible to the disease. The outcome of infection depends upon factors such as the use of chemoprophylaxis, exposure to mosquito bites and the genotype of the individual. The CNS complications of severe malaria include seizures, hallucinations and psychosis, with CM the most serious complication. In endemic areas, severe malaria is defined as children with impaired consciousness (Blantyre coma score of ≤4), respiratory distress and severe anaemia (Marsh et al. 1995). CM is defined as the presence of a peripheral asexual parasitaemia, inability to localise a painful stimulus (Blantyre coma score of ≤2) and the exclusion of other encephalopathies (Newton et al. 2000).

Neuro-cognitive impairment following malarial disease or parasitisation is important since this may affect the future cognitive development of children (Muntemdam et al. 1996; Dugbartey et al. 1998a,b; Holding et al. 1999, 2004; Boivin 2002; Carter et al. 2003, 2005a,b). In addition to severe disease, various risk factors have been identified including multiple seizures, depth of coma, hypoglycaemia (Holding et al. 1999, 2004), multiple infections (Fernando et al. 2003b), schooling, multiple clinical abnormalities or complications at discharge (Holding et al. 2004), malnutrition and social economic status (Boivin et al. 1993; Boivin 2002). The exact path that leads to cognitive impairment is obscure and is a result of many potentially interacting factors. We have, however, used available evidence to construct a simplified sketch of the probable pathways of neuro-cognitive impairment (Figure 1).

image

Figure 1. Probable pathways of neurocognitive impairment post P. falciparum.

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We conducted a systematic review of literature of the effects of P. falciparum on cognition to answer the following research questions:

  • What is the relationship between P. falciparum and cognitive function?
  • Are there any differences in neuro-cognitive impairments between children and adults?
  • Could the patterns of impairment provide insight into the mechanisms of brain damage caused by falciparum malaria?

Review methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Review methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Data sources and search strategy

Literature searches were carried out using three databases: MEDLINE® (1966–August 2005), EMBASE® (1980–August 2005) and PsycINFO (1887–August 2005) using a combined text word and MESH or subject heading to identify relevant papers (Table 1). Additional articles were identified by hand searching the bibliographies of these papers. In addition, relevant doctoral theses were reviewed.

Table 1.  Keywords used for literature search
Search elementMEDLINEEMBASEPsycINFO
ExposureThesaurus terms explodedThesaurus terms explodedThesaurus terms exploded
Plasmodium falciparum Plasmodium falciparum Malaria
Falciparum malariaFalciparum malaria 
Cerebral malariaCerebral malaria 
Brain diseasesBrain diseases 
Malaria meningitisMalaria 
KeywordsSequela* or outcome or morbidity or impairment or long term or cognit* or memory or learning
OutcomeThesaurus terms explodedThesaurus terms explodedThesaurus terms exploded
Learning disorderLearning disorderCognitive deficit
Mental deficiencyMental deficiencyCognitive processes
Memory disorder Learning disorder
Perceptual disorder Memory disorder
Mental retardation  
Language disorders  
PopulationChild*or adultChild*or adultChild*or adult
LanguageAnyAnyAny

The strategy was developed by breaking the review question into its elemental facets, as recommended by the National Health Service Centre for Reviews and Dissemination (Khan et al. 2001). These facets include exposure, outcome, population, keywords and publication language (Table 1). Publication language was left open to ascertain how many studies were available in languages other than English.

Study selection

The online abstracts of studies identified from the database search were reviewed and reprints of potentially eligible studies obtained. All reports were reviewed by at least the first author (MK) and one of the other authors (JC or CN). Studies meeting the following criteria were chosen for more detailed review:

  • the use of tests of cognitive function standardised for the population and/or appropriate controls;.
  • taking into account age of subjects, with at least a differentiation between children and adults;
  • in studies of severe falciparum malaria, follow-up at least 6 months after exposure to disease to exclude transient impairments and include later-developing deficits.

Data extraction

Data were extracted twice by the first author (MK) and results compared to resolve discrepancies. The elements of cognition to be examined in this review were divided into five categories, namely attention, memory, language, visual-spatial skills and reasoning (executive function) (Croisile 2004).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Review methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

The electronic search produced 34 references. A review of the abstracts showed that 15 were potentially relevant, all English language reports, despite the fact that we had not limited the language of publication. A hand search of the bibliographies identified a further nine papers. The full text of each of the 25 papers was evaluated and 10 were excluded because the studies did not meet the review criteria: they described effects of anti-malarial drug use on cognition (n = 3), they were review articles (n = 2), they did not include cognitive tests (n = 2), they lacked proper controls (n = 1), they had reported results from the same study (n = 1) or did not do at least 6 months follow-up (n = 1). In addition, four theses that met the inclusion criteria were identified, two of which contained unpublished data.

Results of literature extraction

Eight (44%) of the studies that fulfilled the inclusion criteria evaluated impairments following CM, four (22%) investigated the effects of severe malaria (which included some cases of CM), five (27%) studies reported the effects of non-severe malaria and one (5%) examined cognitive performance in participants with asymptomatic parasitaemia.

Fifteen (83%) of the studies were carried out with children and the remainder were with adults (i.e. none examined both children and adults). Eleven (61%) of the studies were performed in Africa, five (27%) in Asia and two (10%) in North America. Seventeen (94%) of the studies had a comparison group and one (5%) (Grote et al. 1997) used standardized tests only without a comparison group.

We summarized the results of the literature search according to different infection levels of P. falciparum and their reported effects on cognition, from asymptomatic infections to the effects post-CM.

Effect of parasitaemia on cognitive function

We identified only one study that fulfilled the criteria and that examined the effect of asymptomatic parasitaemia on cognition (Al Serouri et al. 2000). In a study of Yemeni children, 445 asymptomatic parasitaemic boys were compared with 142 non-parasitaemic boys matched for age and schooling status (Al Serouri et al. 2000). Two weeks later, 150 children who remained parasitaemic and 150 children who were no longer parasitaemic were assessed using a battery of cognitive tests. Impairment was defined as two standard deviations (SD) below the control mean. The investigators found no significant differences in cognitive test scores between those who became non-parasitaemic and those who remained parasitaemic, although those with parasitaemia had impaired fine motor skills.

Cognitive function during falciparum illness

Fernando (2001a,b) reported that the academic performance of 293 children experiencing an acute attack of uncomplicated malaria was poorer than that of 162 children experiencing an acute attack of non-malarial fever or that of 305 healthy controls. Impairment was defined as two SD lower than the control mean. Although the performance of the children with malaria improved 2 weeks after treatment, it was still significantly lower than that of the healthy controls. This study was unable to examine whether poor performance was due to malaria per se, or the absenteeism from school caused by having an illness.

The same investigators also conducted a randomised double-blind placebo controlled study of anti-malarial prophylaxis with school-age Sri Lankan children, in which they measured academic performance using school tests of language and mathematics (Fernando 2001a,b). About 295 children received chloroquine while another 292 children received placebo. They found an improvement in academic performance in those on prophylaxis for a 9-month period. However, the placebo group also had significantly higher rates of absenteeism. A multivariate model identified absenteeism due to malaria and chloroquine prophylaxis as significant predictors of school performance.

Cognitive function post-severe malaria

We identified three studies investigating the effects of severe malaria on cognitive function following exposure to severe malaria, which also included children who fulfilled the definition of CM (Holding et al. 1999,2004; Carter et al. 2003,2005a,b). Each of these studies investigated Kenyan children from the same area.

Holding and colleagues (1999) compared 87 children with a history of severe malaria with impaired consciousness (defined as a Blantyre score of ≤4, Molyneux et al. 1989) with community controls on tasks measuring information processing, language and behaviour based on the K-ABC (Kaufman & Kaufman 1993) and other locally established tests. Impairment was defined as ≥2SD below the mean of the control group. The results on information processing skills showed no impairment in performance for the majority of children, although a significantly greater number of cases showed impaired performance. There were deficits in measures of language and attention/planning in which significant differences were found between cases and controls.

In a re-analysis of their previously reported data (Holding et al. 1999), Holding and colleagues (2004) divided children with a history of severe malaria into medium- and high-risk groups based on the severity of the disease. Seventeen children were considered high-risk and the rest medium-risk (Holding et al. 2004). These children were then compared to controls (low-risk group) matched for age, gender and socio-economic status. Impairment was defined as >2SD below the mean for the low-risk group. The results revealed that unschooled high-risk children performed significantly poorer than unschooled children in the other two groups.

Carter and colleagues (2003) compared 25 children previously admitted to hospital with CM or severe malaria (defined as malaria prostration, multiple seizures or severe anaemia) and 27 children unexposed to either condition and found that language performance was poorer in the children exposed to either CM or severe malaria up to 6 years post-insult. Assessments of comprehension, syntax, lexical semantics, higher-level language abilities, pragmatics and phonology were administered to each child. The investigators found that children with a history of CM or severe malaria performed significantly poorer in tests of comprehension, syntax and lexical semantics than the unexposed group. There was no evidence of a difference between the scores of children who had suffered CM and those who had severe malaria, although this may have been due to the small numbers.

Another study by Carter and her colleagues compared 156 children exposed to malaria with complicated seizures (M/S) (defined as >2 seizures within 24 h or focal or prolonged for >30 min but without coma) with children unexposed to severe malaria (Carter et al. 2005a,b). The exposed children belonged to a cohort that had been under investigation over a period of over 2 years post-discharge. The results indicate that M/S is associated with significantly increased odds of impairment (defined as 2SD or less than 2% of the normative data from the controls) in two aspects of speech and language (pragmatics and phonology) relative to unexposed children (Carter et al. 2005a). There was no evidence of a difference in performance on tests of memory, attention or other aspects of language.

Cognitive function post-cerebral malaria

Many studies have reported neuro-cognitive deficits associated with severe malaria, particularly CM. In a Ghanaian study 20 children with a history of CM (defined using the WHO criteria) aged 7–16 years were compared with 20 age-, sex- and education-matched controls on a standardised neuropsychological battery (Dugbartey 1995; Dugbartey & Spellacy 1997; Dugbartey et al. 1998a,b). Children with a history of CM performed significantly poorer than controls in bimanual tactile discrimination, accuracy of visual scanning, visual memory, perceptual abstraction and rule learning skill, right ear auditory information processing, and dominant-hand motor speed. The study found no significant differences between those with a history of CM and controls in non-verbal reasoning, visual-spatial processing, auditory attention and verbal fluency (Dugbartey 1995).

In Senegal, 29 children aged 5–12 years with a history of CM (defined using WHO criteria but with coma duration adjusted to 12 h) were compared with 29 age- and education-matched controls (mild-malaria). Those with a history of CM performed significantly poorer on the simultaneous processing (spatial memory, photo series), mental processing, and sequential processing (hand movements, word order) tasks of the K-ABC and the attention capacity task from Test of Attention Variables (TOVA) than matched controls (Boivin 2002). Impairment was defined as a score more than 2SD lower than the control mean. The study found a significant correlation between coma duration and attention capacity for the CM group emphasising the importance coma duration on outcome.

In Kenya, 152 children aged 6–9 years previously exposed to CM (defined as a Blantyre coma score of ≤2 for 4 or more hours, peripheral parasitaemia and the exclusion of other causes of encephalopathy) (Newton et al. 2000) were compared to 179 children unexposed to severe malaria (Carter et al. 2005a,b). Impairment was defined as 2SD lower than the mean. The performance of children previously exposed to CM was poorer than unexposed children on all the cognitive assessments administered: speech and language battery, attention, memory and non-verbal functioning. There were significant differences in higher-level language abilities, lexical semantics, pragmatics and non-verbal functioning (construction task).

There was one study that did not detect any differences between CM (defined as a Blantyre coma score of ≤2) and controls. This case-control study focused on the measurement of non-verbal functioning in 36 pairs of Gambian children who were discharged from hospital without any neurological deficits. Impairment was defined as 1SD lower than the control group mean. The results showed no significant impairments in children after an average follow-up of 3.4 years (Muntemdam et al. 1996). An interesting finding from the study, though not statistically significant, was that the CM children performed better on all tests of intellectual development than the controls. A group difference of borderline significance was detected on a test of balance (sensori-motor development), with poorer performance among children exposed to CM.

Effect of Age at exposure on cognitive function

Age is a potentially important variable that may influence recovery from neuro-cognitive impairment. We found no published literature describing the effects of falciparum malaria on the cognitive performance of both children and adults. Three studies documented the effects of falciparum malaria on the cognitive performance of adults (Grote et al. 1997; Richardson et al. 1997; Dugbartey et al. 1998a,b). Kastl and his colleagues (1968) had reported that CM patients made complete recovery with no residual deficits. Such negative findings were obtained by Dugbartey et al. (1998a,b) on Ghanaian adults with non-severe malaria. The other studies have found neuro-cognitive sequelae many years post-CM (Grote et al. 1997; Richardson et al. 1997). However, none of these studies tested all the five facets of cognition making it difficult to identify patterns of neuro-cognitive impairment.

Children exposed to acute falciparum malaria may have deficits in the cognitive dimensions studied, such as attention (Holding et al. 1999,2004; Boivin 2002), memory (Holding et al. 2004; Boivin 2002; Dugbartey et al. 1998a, 1995), language (Holding et al. 1999; Carter et al. 2003,2005a,b; Fernando et al. 2003a,b), visual-spatial skills (Dugbartey & Spellacy 1997; Boivin 2002; Fernando et al. 2003a,b) and executive function (Dugbartey et al. 1998a, 1995; Holding et al. 2004; Carter et al. 2005a,b).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Review methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Summary of the main results

The results of this review indicate that falciparum malaria affects neuro-cognitive performance both in the short- and long-term. The hypothesis that falciparum malaria affects a specific brain location seems unlikely given the wide variety of neuropsychological outcomes post-infection. However, there are still few data on which to assess the degree and extent of the impairments.

In children (Table 2a), most studies reported that increased severity of malaria is associated with greater degrees of neurological and cognitive impairment (Dugbartey 1995, Dugbartey & Spellacy 1997; Dugbartey et al. 1998a; Holding et al. 1999, 2004; Boivin 2002; Carter et al. 2003, 2005a,b), while only one suggests that there is complete recovery with no significant reduction in their cognitive abilities (Muntemdam et al. 1996). This discrepancy could be accounted for by the fact that the one latter study was small, and possibly did not have enough power to show the effect. Further, the test battery may have lacked sensitivity to detect subtle differences. The exclusion of children with neurological deficits at discharge could have excluded the very children who are most vulnerable to neuro-cognitive sequelae.

Table 2.  Studies examining cognitive function following falciparum malaria
 CountryPopulation (years)Clinical descriptionCriteriaNo. casesControlsFollow-up length (years)Study designAttentionMemoryLanguageVisual spatial skillsExecutive functions
  1. NT, not tested; CM, cerebral malaria.

Children
Carter et al. (2005a,b) Kenya6–10CMUsed Blantyre Coma Score of ≤2152179>2Cohort studyNot significantNot significantPerformed significantly poorer (P < 0.05)NTPerformed significantly poorer (P < 0.05)
Carter et al. (2005b) Kenya6–10M/SUsed Blantyre Coma Score of ≤2156179>2Cohort studyNot significantNot significantPerformed significantly poorer (P < 0.05)NTNot significant
Holding et al. (2004) Kenya6M/SUsed Blantyre Coma Score of ≤417873.5–6Matched case– controlPerformed significantly poorer (P < 0.05)Performed significantly poorer (P < 0.05)Not significantPerformed significantly poorer (P < 0.05)Performed significantly poorer (P < 0.01)
Carter et al. (2003) Kenya8–9CM & Severe MalariaUsed Blantyre Coma Score of <2 (W.H.O criteria)2527>2Cohort studyNTNTPerformed significantly poorer (P = 0.004)NTNT
Fernando et al. (2003a,b) Sri Lanka5–6MalariaN/A1711541Cross- sectionalNot significantNot significantBorderline performance (P = 0.093)NTNT
Fernando et al. (2003a,b) Sri Lanka6–14MalariaN/A3852131–6ProspectiveNTNTPerformed significantly poorer (P < 0.001)NTNT
Boivin (2002) Senegal5–12CMUsed W.H.O. criteria for CM2929avg 3.4Matched case– controlPerformed significantly poorer (P < 0.05)Performed significantly poorer (P < 0.05)NTPerformed significance poorer (P < 0.05)Borderline significantly (P = 0.07)
Fernando (2001) Sri Lanka5–12MalariaN/A3433051–2ProspectiveNTNTPerformed significantly poorer P < 0.001)NTNT
Fernando (2001) Sri Lanka6–12MalariaN/A295292N/ARandomized control studyNTNTPerformed significantly poorer (P < 0.001)NTNT
Al Serouri et al. (2000) Yemen11–13AsymptomaticN/A445142N/AMatched case– controlNot significantNot significantNTNTNot significant
Holding et al. (1999) Kenya6–10Severe malariaUsed Blantyre Coma Score of ≤487873.5–6Matched case– controlPerformed significantly poorer (P < 0.05)Not significantPerformed significantly poorer (P = 0.02)Not significantBorderline performance (P = 0.06)
Dugbartey et al. (1998a) Ghana7–16CMUsed WHO criteria for CM2020avg 3.9Matched case– controlNot significantPerformed significantly poorer (P < 0.01)Not significantNot significantPerformed significantly poorer (P < 0.01)
Dugbartey and Spellacy (1997) Ghana7–16CMUsed WHO criteria for CM2020avg 3.9Matched case– controlNTNTNTPerformed significantly poorer (P < 0.01)NT
Muntemdam et al. (1996) Gambia5–9CMUsed Blantyre Coma Score of ≤23636avg 3.4Matched case– controlNTNot significantNot significantNot significantNot significant
Dugbartey (1995) Ghana7–16CMUsed WHO criteria for CM2020avg 3.9Matched case– controlNot significantperformed significantly poorer (P < 0.01)Not significantNot significantPerformed significantly poorer (P < 0.01)
Adults
Dugbartey et al. (1998b) Ghana18–68MalariaN/A14230>1 yearCase– controlNot significantNTNot significantNTNot significant
Grote et al. (1997) USA38CMCriteria not given1010Case studyNo ImpairmentDelayed memory impairmentNTNo impairmentNT
Richardson et al. (1997) USA35–55CMUsed medical records (criteria not given)4040>20RetrospectivePerformed significantly poorer (P < 0.05)Performed significantly poorer (P < 0.001)Performed significantly poorer (P < 0.001)NTNT

In adults (Table 2b), the results are more difficult to interpret. First, there are few studies, then definition of CM was not based on any standard criterion and finally they have methodological differences. However, cognitive deficits were found in attention, memory and language while none were present in visual-spatial skills and executive functions.

Some studies conclude that cognitive impairment also occurs after non-severe malarial disease (Fernando 2001a,b; Fernando et al. 2003a,b). The Sri Lankan study (Fernando 2001a,b) shows that the children who had non-severe malarial infection still performed significantly poorer in scholastic tasks two weeks post-acute infection compared to controls. 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 (Fernando 2001a,b; Fernando et al. 2003b). The trial performed in Sri Lanka aimed to differentiate the effects of malarial infection from school absence on school performance. However, the group that received the placebo was absent from school significantly more times than the group receiving chloroquine. It remains difficult to ascertain whether it was the malaria per se or influence of other risk factors that affected academic performance.

Studies that examined asymptomatic children did not detect any appreciable differences between when they were parasitaemic and when non-parasitaemic (Boivin et al. 1993; Al Serouri et al. 2000), perhaps because of very low parasitaemia. Furthermore, the two-week duration in the Yemeni study, used on follow-up may be too short to detect appreciable differences.

Limitations of the studies

One of the difficulties of attributing effects of P. falciparum, particularly in malaria endemic areas, is the exclusion of other causes. In a recent study of Malawian children who fulfilled the WHO criteria of CM, 23% were found to have other causes of death at post-mortem (Taylor et al. 2004). The lack of specificity of the diagnosis affects all the studies of severe malaria reported from Africa and may influence the interpretation of results of these studies.

There is no universally accepted system for defining impairment on non-standardized neuropsychological assessments. Many studies used different definitions for impairment, making cross-study comparisons difficult. Further, studies had different criterion of defining their cases and controls complicating the comparison process even more. A variety of risk factors were identified in some studies e.g. effects of duration of coma, hypoglycaemia, socio-economic status, malnutrition but they were not treated the same across studies. Some studies had very small sample sizes (Muntemdam et al. 1996; Dugbartey et al. 1998a), which may have affected their results. It is also possible that malaria parasitaemia may affect cognitive function but the instruments may not be sensitive enough to detect subtle deficits. In the Fernando et al. (2003a) study, they did not account for age at entry of school, the fact that 13% children did not have pre-school education and depended on parental/guardian reports for frequency of malarial attacks.

Several studies (Muntemdam et al. 1996; Dugbartey et al. 1998a,b; Boivin 2002; Carter et al. 2003, 2005a,b) used tests that were developed in other cultures and their psychometric properties in local populations were not reported. The use of adapted neuropsychological or cognitive assessment tests, rather than tests developed for local populations, makes interpretation difficult since no assumptions can be made that the same neuropsychological/cognitive function is being measured (Greenfield 1997). Lack of culturally appropriate tools that can be used over a wide range of ages has further complicated comparability between ages, particularly between children and adults.

Other studies did not adequately define the expected outcome measures. The Sri Lankan studies (Fernando 2001a,b; Fernando et al. 2003a,b) used mathematics and language tests as measures of impairment. These tests may not be an adequate assessment of cognition, which could have helped identify possible brain regions that are affected by malaria infection.

Mechanisms of neuro-cognitive impairment

The exact mechanisms by which P. falciparum causes neuro-cognitive impairment remain unknown. Malaria infection can indirectly affect cognition through nutrition, school attendance or psychosocial development, all of which may contribute to delay or sub-optimal cognitive development (Holding & Kitsao-Wekulo, 2004; Figure 1). For example, children with malaria are reported to have poorer nutritional status than non-malarial children (Shiff et al. 1996; McGregor 1988; Fernando et al. 2003a). Although malnutrition is associated with poorer cognitive development (Bryan et al. 2004), it is unclear if this is a direct effect of malaria itself. The impact of malaria-induced anaemia remains unstudied, but iron deficiency anaemia, which often occurs in children with malaria impairs school performance (Lozoff et al. 1991; Grantham-McGregor & Ani 2001). There is strong evidence that CM causes neuro-cognitive impairment as a result of direct brain damage. Specific impairments such as hippocampal dysfunction and damage to sub-cortical white matter may lead to impairments of memory and language function (Richardson et al. 1994; Grote et al. 1997; Varney et al. 1997). The study by Richardson and her colleagues (1994) on a dichotic listening task by Vietnam veterans with a history of CM showed that adults may have inefficiencies in processing auditory information many years post-infection. This finding further points to the possibility that CM affects the brain's white matter structure. Also, it has been suggested that neurotoxins released from infected red blood cells may damage the cortical areas of the brain, affecting cognitive performance (Fernando 2001a,b). Language comprehension, learning and reasoning are mediated via the brain's working memory (Young 2000) thus it is also possible that malaria infections affect neuro-cognitive performance through the working memory of the brain.

This review identified only two published studies that performed tests on the whole spectrum of cognitive domains under review (Dugbartey et al. 1998a; Holding et al. 1999,2004). This makes it difficult to draw firm conclusions about patterns of impairment. Further, in all the studies reviewed, there was no particular facet of cognition that was consistently impaired in either children or adults following exposure to falciparum malaria.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Review methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

These results indicate that P. falciparum is associated with neuro-cognitive impairment both during infection and following severe disease. There are many risk factors other than malarial disease that seem to affect cognitive outcome, and these need to be studied in a more systematic manner. There may be a difference in impairment patterns between children and adults, although this needs to be explored further. The age of exposure to severe disease may prove an important variable, as well as the total number repeated infections. The impairment appears diffuse, with children having cognitive impairment in all categories of cognition, while adults seem relatively unaffected in visual-spatial skills and executive function. Further research is required to determine the pernicious effects of P. falciparum infection: as it infects over 500 million people per year, it is potentially one of the most important causes of cognitive impairment worldwide.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Review methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

This paper was published with the permission of the Director of the Kenya Medical Research Institute, KEMRI. CRJC Newton (070114) is supported by The Welcome Trust, UK.

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  3. Introduction
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  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References
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