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Keywords:

  • Africa;
  • falciparum malaria;
  • child development;
  • prevalence

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix

Objective  Neurological deficits are reported in children after cerebral malaria (CM) but little is known about the prevalence and characteristics of persisting neurocognitive consequences. The prevalence of developmental impairments following other complications of falciparum malaria, such as multiple, prolonged or focal seizures, is not known. Thus, our objective was to investigate the long-term developmental outcome of CM and malaria with complicated seizures (M/S).

Methods  We followed up a cohort of children previously exposed to CM or M/S and children unexposed to either condition. All children between 6 and 9 years of age, exposed to CM, and an equal number of children exposed to M/S were identified from databases of hospital admissions from 1991 to 1998. The unexposed group was randomly selected from a census database. The children's performance was measured using assessments of cognition, motor, speech and language, hearing and vision. A parental questionnaire was used to identify children with epilepsy.

Results  CM group scores were significantly lower than unexposed group scores on the assessments of higher level language (adjusted mean difference −1.63, 95% CI: −2.99 to −0.27), vocabulary (−0.02, 95% CI: −0.04 to −0.01), pragmatics (OR 2.81, 95% CI: 1.04–7.6) and non-verbal functioning (−0.33, 95% CI: −0.61 to −0.06). The areas of significantly reduced functioning for the M/S group were concentrated on phonology (OR 2.74, 95% CI: 1.26–5.95), pragmatics (OR 3.23, 95% CI: 1.2–8.71) and behaviour (OR 1.8, 95% CI: 1.0–3.23). The performance of the active epilepsy group was significantly poorer than that of the group without epilepsy on the tests of comprehension, syntax, pragmatics, word finding, memory, attention, behaviour and motor skills.

Conclusions  CM and M/S are associated with developmental impairments. If these impairments persist, this may have implications for least 250 000 children in Sub-Saharan Africa each year. Active epilepsy significantly increases the risk of cognitive and behavioural problems in children with a history of severe malaria.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix

Infectious diseases are the most important causes of mortality in infants and young children, causing more than 13 million deaths per year, one in every two deaths in resource-poor countries (WHO 2002). Malaria is one of six infectious diseases that account for half of all premature deaths; over 40% of the world's population from more than 90 countries live with the risk of the disease. The morbid consequences of infectious disease are often overlooked in the face of high mortality rates, particularly in resource-poor countries where means of detecting such problems may be limited. Neurological impairment subsequent to central nervous system infections may have a devastating impact on the development of the child and by the nature of cerebral impairments, the economic and structural development of countries.

Falciparum malaria produces a range of acute neurological manifestations, of which cerebral malaria (CM) is the severe end of the clinical spectrum. CM presents as a diffuse encephalopathy: alterations in level of consciousness, ranging from drowsiness to deep coma, are often precipitated by seizures, which are reported in the histories of 50–80% of children (Schmutzhard & Gerstenbrand 1984; Molyneux et al. 1989). Most survivors of severe falciparum malaria are reported to make a full neurological recovery, although neurological impairment has increasingly been associated with CM in reports over the past decade. Estimates of its prevalence vary according to the definition of the disease, length of follow-up and nature of the assessment techniques. In African children with CM, neurological deficits have been estimated to occur in 10.9% (95% CI: 8.3–13.5%) of survivors (Newton & Krishna 1998), although few comprehensive and detailed studies have been reported. Both prolonged coma and seizures (multiple or prolonged) are associated with neurological impairment following the disease (Brewster et al. 1990; Bondi 1992; van Hensbroek et al. 1997). However, little is known about the prevalence of persisting neurocognitive consequences of CM in children.

Other acute neurological manifestations of falciparum malaria such as multiple, prolonged, generalized or focal seizures with rapid recovery of consciousness after the seizure are more common than CM. The prevalence and characteristics of acquired neurological impairment following such manifestations are not known. In the UK and North America, complex febrile seizures have been associated with the subsequent development of epilepsy and neurological damage, particularly to the mesial temporal lobe (Annegers et al. 1987; Maher & McLachlan 1995) with associated deficits in episodic memory (Vargha-Khadem et al. 1997).

We examined the long-term outcome of two complications of severe malaria – CM and malaria with complicated seizures (M/S) – specifically in cognition, language, behaviour and special senses. We also investigated the influence of active epilepsy on developmental outcome.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix

Participants were recruited from a study area on the coast of Kenya. Children were between 6.0 and 9.11 years of age when they were assessed, as cognition and speech and language can be assessed more reliably over the age of 6 years. All children admitted with CM, born between 1991 and 1995 and living in the study area, were identified from databases of admissions to Kilifi District Hospital (KDH). A similar number of children admitted with M/S were identified from this database. A random sample of children unexposed to severe malaria was drawn from a census database of children living in the study area, recognizing that exposure to mild malaria is almost universal in this area. All children spoke a Mijikenda language as their first language and fulfilled one of the following group criteria:

  • 1
    Children who had been admitted to KDH with CM (defined as a Blantyre coma score of ≤2 for 4 or more hours, a peripheral parasitaemia and the exclusion of other causes of encephalopathy) (Newton et al. 1997).
  • 2
    Children who had been admitted with a primary diagnosis of M/S (>2 seizures within 24 h or focal or prolonged >30 min) but who did not develop coma (i.e. able to localize a painful stimulus within 1 h of the seizure).
  • 3
    Children who had not previously been admitted to KDH with either complication of severe falciparum malaria (CM or M/S).

Children in groups 1 and 2 were treated with quinine and/or chloroquine or pyrimethamine/sulphadoxine; none received mefloquine. Children were excluded if they refused verbal informed consent or their parents refused written informed consent. Ethical permission for the study was obtained in Kenya (KEMRI) and the UK (Institute of Child Health).

Each child underwent a battery of assessments: cognition, motor, speech and language, hearing and vision. The cognitive assessment focussed on temporal lobe function and included tests of memory based on the Rivermead Behavioural Memory Test for Children (RBMTC) (Wilson et al. 1991), non-verbal functioning (construction task), attention (visual search) and parental rating of behaviour problems (Holding et al. 1999). The speech and language assessment covered all major areas of language (see Appendix 1): comprehension, syntax/morphology, semantics (vocabulary, divided into function and content words), pragmatics, higher level language, word finding and phonology (Carter et al. 2003). The motor skills assessment was based on a system for classifying motor function in children with cerebral palsy (Palisano et al. 1997). Hearing was tested with a Kamplex screening audiometer (P.C. Werth, London, UK), and vision using a Sonksen-Silver chart (Salt et al. 1995).

The prevalence of epilepsy in the cohort was estimated using a parental questionnaire based on questionnaires used to carry out surveys in other resource-poor countries (Feksi et al. 1991; Placencia et al. 1992; Pal et al. 1998). Children were classified as having ‘active epilepsy’ (two or more seizures unrelated to fever in those 6 years or under, with at least one in the previous 12 months) or ‘inactive epilepsy’ (defined as previous, except no seizures in the previous 12 months).

All speech, language and cognitive tests were based on standardized UK assessments but were extensively altered in content and format to make them culturally appropriate. We followed a four-stage process to develop the assessments: developing a theoretical framework, adapting assessments using the principles of content validation, piloting and making alterations and refinements (J.A. Carter, G. Murira, J. Gona, J. Tumaini, J.A. Lees, B.G.R. Neville, C.R.J.C. Newton, in preparation). Reliability and validity testing supported their use in this context (Carter 2002). A team of assessors trained in the theoretical and practical aspects of assessment and fluent in the Mijikenda languages carried out the cognitive and speech and language assessments. One group of assessors travelled to the child's home on day 1 to perform the speech and language assessment and to administer the behaviour, pragmatics and socioeconomic questionnaires to the parent. On day 2, the child and parent attended KDH, where the cognitive, neurological, hearing and vision assessments were performed. All assessors, with the exception of the clinicians taking the epilepsy history, were blinded to the group status of each child.

To investigate children with particularly poor performance in the context of average group performance, an ‘impairment’ group was defined. On assessments that did not indicate ‘impairment’ levels, ‘impairment’ was defined as an estimate of more than 2SDs below the age-specific unexposed group mean or below the 2.0 centile of the unexposed group results for normally distributed and skewed data respectively (Lezak 1995).

Standardized weight/height, height/age and weight/age z-scores were calculated as proxy measures for nutritional status using the NutStat program in EpiInfo 2000 (CDC, Atlanta, GA, USA). This uses reference data from the American National Centre for Health Statistics, which we employed based on the premise of the equal growth potential of all children (Richter & Griesel 1994). Weight and height were measured using standardized scales by the two clinicians responsible for the motor skills examination. Data were collected on a series of indicators of socioeconomic status. Mother's level of education was selected as a covariate for analysis, as it is often regarded as a predictor of child health and development in resource-poor countries (Kvalsvig & Connolly 1994; Coreil 1997). Father's occupation was also selected, as it has been found to be associated with income level in previous studies on the Kenyan coast (Hoorweg et al. 1995).

Statistical analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix

Analysis was carried out using stata version 6. We estimated the difference between exposed and unexposed group scores and the difference between epilepsy and non-epilepsy group scores using multiple regression for normally distributed outcomes. Binary variables were analysed using logistic regression. An a priori decision was made to adjust all estimates for age, sex, schooling status, nutritional status and socioeconomic status, as variables for which there is evidence of an effect on child development. There were a limited number of comparisons between groups, all of which were defined a priori and were unlikely to be independent outcomes; therefore the P-values were not adjusted for multiple comparisons.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix

A total of 244 children with a history of CM and 231 with a history of M/S were identified from the KDH admissions databases, and 273 children unexposed to either condition were identified from the census database. Of these, 25 were found to be under/overage on age confirmation (six CM, seven M/S), 211 were no longer at the same address (72 CM, 63 M/S) and 25 had subsequently died (14 CM, five M/S). Verbal autopsies indicated that most children died from syndromes of malaria or meningitis or from acute respiratory tract infections (Carter et al. 2005). Thus, 487 children were recruited to the study, 152 children who had previously been hospitalized with CM, 156 with previous M/S and 179 unexposed to either condition. The median time from admission to assessment in the CM group was 64 months (inter-quartile range; IQR 40–78 months) compared with 71 months (IQR 55–85 months) in the M/S group. The minimum time since admission in either group was 20 months and the maximum was 112 months. Fourteen (9%) of the CM group, 18 (12%) of the M/S group and four (2%) of the unexposed group were reported to have epilepsy. The epilepsy was ‘active’ in seven (5%) survivors of CM, 10 (6%) survivors of M/S and two (1%) children unexposed to either condition. The distribution of children between the age and sex groups was similar (Table 1).

Table 1.  Demographic characteristics of the study groups
 Unexposed (%) (n = 179)CM (%) (n = 152)M/S (%) (n = 156)
  1. * Year 1 of formal schooling.

  2. † Years 2–4 of formal schooling.

  3. CM, cerebral malaria; M/S, Malaria with complicated seizures.

Male93 (52)77 (51)72 (46)
Age (years)
 642 (23)43 (28)45 (29)
 737 (21)43 (28)45 (29)
 848 (27)34 (22)28 (18)
 952 (29)32 (21)38 (24)
No schooling55 (31)74 (49)67 (43)
Nursery62 (35)47 (31)54 (35)
Standard 1*39 (22)19 (13)24 (15)
Standard 2–4†23 (13)12 (8)11 (7)

The direction of the association with CM suggested a poorer group performance relative to the unexposed group on all of the assessments, with the exception of the comprehension and syntax assessments from the language battery (Table 2). These differences were significant on the assessments of higher level language, vocabulary (content words), pragmatics and non-verbal functioning (construction task). There was no evidence of a difference in performance between the M/S group and the unexposed group on many of the assessments, although their performance on the tests of vocabulary, pragmatics, phonology, non-verbal functioning, behaviour and motor skills was poorer than that of the unexposed group (Table 3). The areas of significantly reduced functioning for the M/S group were concentrated on phonology, pragmatics and behaviour. Analysis of subsections of the RBMTC did not suggest specific hippocampal damage in the M/S group, although the scores of the CM group were significantly poorer than those of the unexposed group on several subtests linked to hippocampal functioning. Neither the CM nor M/S groups had an increased prevalence of visual or hearing problems.

Table 2.  Estimated mean differences between children exposed to CM and children from the unexposed group
BatteryAssessmentEstimated mean difference* (95% CI)P-value
Speech and languageComprehension0.25 (−0.64–1.14)0.59
Syntax0.07 (−1.16–1.3)0.91
Higher level language−1.63 (−2.99 to −0.27)0.02
Vocabulary (function words)−0.01 (−0.02–0.003)0.2
Vocabulary (content words)−0.02 (−0.04 to −0.01)0.002
CognitionAttention (time taken)0.04 (−0.19–0.27)0.75
Non-verbal functioning−0.33 (−0.61 to −0.06)0.02
  1. * Adjusted for age, sex and epilepsy, schooling, nutritional and socioeconomic status.

  Odds ratio* (95% CI) 
Speech and languagePragmatics2.81 (1.04–7.6)0.04
Word finding1.55 (0.87–2.78)0.14
Phonology2.03 (0.91–4.53)0.09
CognitionMemory (impaired)1.44 (0.57–3.62)0.43
Memory (borderline)1.33 (0.7–2.53)0.38
Attention (number of errors)1.31 (0.6–2.87)0.5
BehaviourBehaviour1.24 (0.67–2.3)0.49
NeurologyMotor skills2.17 (0.82–5.71)0.12
Table 3.  Estimated mean differences between children exposed to M/S and children from the unexposed group
BatteryAssessmentEstimated mean difference* (95% CI)P-value
Speech and languageComprehension0.87 (−0.01–1.76)0.06
Syntax1.26 (0.05–2.48)0.04
Higher level language0.37 (−0.98–1.71)0.59
Vocabulary (function words)−0.001 (−0.01–0.01)0.74
Vocabulary (content words)0.001 (−0.01–0.01)0.9
CognitionAttention (time taken)0.08 (−0.14–0.31)0.48
Non-verbal functioning−0.04 (−0.31–0.24)0.8
  1. * Adjusted for age, sex and epilepsy, schooling, nutritional and socioeconomic status.

  Odds ratio* (95% CI) 
Speech and languagePragmatics3.23 (1.2–8.71)0.02
Word finding0.88 (0.48–1.6)0.67
Phonology2.74 (1.26–5.95)0.01
CognitionMemory (impaired)0.97 (0.36–2.59)0.94
Memory (borderline)0.85 (0.43–1.68)0.64
Attention (number of errors)0.86 (0.37–1.99)0.72
BehaviourBehaviour1.8 (1.0–3.23)0.05
NeurologyMotor skills1.42 (0.5–3.99)0.51

The performance of the active epilepsy group was significantly poorer than that of the group without epilepsy on the tests of comprehension, syntax, pragmatics, word finding, ‘impaired’ memory, attention errors, behaviour and motor skills (Table 4). The results were in the direction of poorer performance on the remaining assessments, with the exception of the function word element of lexical semantics and the ‘borderline’ category of the memory test.

Table 4.  Estimated mean differences between children with active epilepsy and children without epilepsy
BatteryAssessmentEstimated mean difference* (95% CI)P-value
Speech and languageComprehension−3.34 (−5.23 to −1.45)0.001
Syntax−3.13 (−5.8 to −0.47)0.02
Higher level language−0.74 (−3.62–2.13)0.61
Vocabulary (function words)0.01 (−0.01–0.03)0.23
Vocabulary (content words)−0.01 (−0.04–0.02)0.49
CognitionAttention (time taken)0.25 (−0.25–0.76)0.32
Non-verbal functioning−0.17 (−0.78–0.44)0.58
  1. * Adjusted for age, sex and schooling, nutritional and socioeconomic status.

  Odds ratio* (95% CI) 
Speech and languagePragmatics3.74 (1.19–11.8)0.02
Word finding4.23 (1.27–14.07)0.02
Phonology1.32 (0.37–4.69)0.67
CognitionMemory (impaired)5.77 (1.74–19.11)0.004
Memory (borderline)0.23 (0.03–1.83)0.17
Attention (number of errors)5.55 (1.66–18.52)0.01
BehaviourBehaviour2.76 (1.0–7.56)0.05
NeurologyMotor skills9.22 (3.03–28.04)<0.001

Twenty-four per cent of the CM and M/S groups had at least one impairment on any of the major domains assessed in the study (motor skills, memory, behaviour, attention, non-verbal functioning, hearing, vision, speech and language), compared with 10% of the unexposed group (Table 5). Both CM (OR 2.15, 95% CI: 1.07–4.3, P = 0.03) and M/S (OR 2.46, 95% CI: 1.24–4.9, P = 0.01) were associated with significantly increased odds of an impairment-level score. Children with previous CM had more extensive impairments, with 10% attaining impairment-level scores in two or more domains compared with 7% of the M/S group.

Table 5.  Number of children with an ‘impairment level’ score
 Unexposed (n = 179)CM (n = 152)M/S (n = 156)
  1. Values are presented as n (%).

Any impairment18 (10.1)36 (23.7)37 (23.7)
Speech and language4 (2.2)18 (11.8)14 (9.0)
Non-verbal functioning1 (0.6)4 (2.6)2 (1.3)
Behaviour3 (1.7)4 (2.6)9 (5.8)
Memory5 (2.8)16 (10.5)10 (6.4)
Attention05 (3.3)3 (1.9)
Motor skills (neurological)5 (2.8)16 (10.5)12 (7.7)
Hearing/vision6 (3.4)4 (2.6)2 (1.3)

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix

Murphy and Breman (2001) estimate that each year in Africa, between 9000 and 19 000 children under 5 years experience neurological impairments following CM for more than 6 months after discharge from hospital. Our results suggest that the impact of malaria on child development is more persistent and wide-ranging: 24% of children exposed to CM or M/S displayed developmental impairments up to 9 years after discharge.

Exposure to both CM and M/S is associated with neurocognitive impairments, although the patterns of impairment are different (Tables 3 and 4). Previous studies have found neurocognitive impairments following CM but have not examined the other complications of falciparum malaria. Our results suggest that M/S may be associated with a different pattern of deficits than CM, yet may still cause problems for children, particularly in the educational environment.

Cerebral malaria and M/S are frequent causes of admission to hospital in malaria-endemic areas. Our results are likely to be minimal estimates, as children with complex seizures who recover probably never attend hospital. The minimum community incidence of CM in stable endemic areas of Sub-Saharan Africa (excluding southern Africa) is 1.1/1000 per year (Snow et al. 2003) and that of complex seizures not associated with CM, 5.8/1000 per year (Waruiru et al. 1996). Thus, a minimum estimate of children in this area acquiring impairments associated with severe falciparum malaria [accounting for 36% of children with CM who have access to life-saving medical treatment, 17.5% inpatient mortality in CM (Snow et al. 2003) and 6.8% inpatient mortality in M/S (Marsh et al. 1995)] is approximately 250 000 children per year. This estimate does not include children with severe neurological impairments following CM, who often die within the first year after discharge.

These results suggest that both CM and M/S incur a significant risk of persisting developmental impairments, although further evidence on the prevalence of pre-existing deficits is required. The presence of long-term active epilepsy significantly increases the risk of cognitive and behavioural problems. These findings highlight the fact that neurocognitive impairment associated with falciparum malaria may represent a major public health problem in terms of education and development in malaria-endemic areas. This problem is likely to be compounded by the fact that the outcome of severe malaria is enmeshed with other health and development factors affecting children in resource-poor countries (Boivin 2002). Nutritional and socioeconomic indicators imply that the majority of children in this study live in conditions of economic deprivation: some of these indicators, particularly those of long-term nutritional status, are associated with poor performance on cognitive and speech and language assessments. Mild to moderate neurodevelopmental dysfunction exerts more negative influence in contexts of environmental turmoil or deprivation (Levine 1999), suggesting that similar levels of impairment may have more detrimental effects in this context compared with that of resource-rich settings. Alternatively, the prevalence of impairments associated with malaria may be even greater if factors such as poor nutrition were removed from all groups. Children such as those participating in the current study encounter more risks to normal development than their counterparts in richer countries, as evidenced by the fact that the prevalence of impairments in the unexposed group was higher than that usually reported in resource-rich countries.

Effective services for prevention and rehabilitation of impairment rarely coexist in situations in which there are few healthcare resources, therefore there are often few avenues of treatment for children with developmental impairments. Child health and survival is considered to be the most important public health issue in resource-poor countries. However, rehabilitation may be considered to be of equal importance to prevention because a reduction in the incidence of a disease only reduces the composition of disability in the short-term, rather than the numbers of children affected (Thorburn 1990). Mbise and Kysela (1990) describe the case of Tanzania, where preventive services in the forms of vaccinations and nutritional education were provided but were reduced in effectiveness due to lack of transportation, long travelling distances in rural areas, difficulties in communicating the benefits of vaccinations and prompt treatment, inadequate drug storage facilities and lack of trained personnel. In such situations, rehabilitative services will continue to be a necessary component of the healthcare system, although in many areas – including our own – such services are limited.

Lack of information is one of the reasons for the lack of services for children with developmental impairments in resource-poor countries (Thorburn 1990). Further research to provide information about the morbid consequences of common infectious diseases such as malaria is needed because despite the lack of immediate rehabilitative provision in many areas, the characterization of developmental impairments associated with malaria will both allow governmental and other agencies to address the issues of schooling and rehabilitation services and facilitate the development of appropriate remedial measures.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix

We thank Mr Joseph Gona, Ms Gladys Murira, Mr Kenneth Rimba, Ms Judy Tumaini and Mr Francis Yaah for carrying out assessments, Mr Douglas Konde for fieldwork and Ms Rachael Odhiambo for data entry. We would also like to thank Prof. Faraneh Vargha-Khadem for advice on memory assessment tools. J.A. Carter (059336) and C.R.J.C. Newton (050533) are supported by The Wellcome Trust, UK. This paper is published with the permission of the Director of KEMRI.

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  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix
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Appendix

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Appendix
Table Appendix1.  Glossary of assessment terms
Non-verbal functioning
Skills of visual-spatial perception, visual-motor co-ordination, simultaneous processing and reasoning
Syntax
Sentence structure (word order) and rules of grammar
Semantics
Vocabulary size and breadth
Pragmatics
Rules of language use and non-verbal communication
Higher level language
Use and understanding of language beyond its superficial meaning; the level at which the basic aspects of language integrate and interact
Phonology
The sound system