OBJECTIVE-Cerebral malaria affects >785 000 African children every year. We previously documented an increased frequency of cognitive impairment in children with cerebral malaria 6 months after their initial malaria episode. This study was conducted to determine the long-term effects of cerebral malaria on the cognitive function of these children.METHODS-Children who were 5 to 12 years of age and presented to Mulago Hospital, Kampala, Uganda, with cerebral malaria (n = 44) or uncomplicated malaria (n = 54), along with healthy, asymptomatic community children (n = 89), were enrolled in a prospective cohort study of cognition. Cognitive testing was performed at enrollment and 2 years later. The primary outcome was presence of a deficit in ≥1 of 3 cognitive areas tested.RESULTS-At 2-year follow-up testing, 26.3% of children with cerebral malaria and 12.5% with uncomplicated malaria had cognitive deficits in ≥1 area, as compared with 7.6% of community children. Deficits in children with cerebral malaria were primarily in the area of attention (cerebral malaria, 18.4%, vs community children, 2.5%). After adjustment for age, gender, nutrition, home environment, and school level, children with cerebral malaria had a 3.67-fold increased risk for a cognitive deficit compared with community children. Cognitive impairment at 2-year follow-up was associated with hyporeflexia on admission and neurologic deficits 3 months after discharge.CONCLUSIONS-Cerebral malaria is associated with long-term cognitive impairments in 1 of 4 child survivors. Future studies should investigate the mechanisms involved so as to develop interventions aimed at prevention and rehabilitation. NIH Public Access Author ManuscriptPediatrics. Author manuscript; available in PMC 2009 July 1. Published in final edited form as:Pediatrics. What's Known on This SubjectRetrospective studies have suggested that cerebral malaria in children is associated with long-term cognitive deficits. What This Study AddsThis is the first prospective study to document long-term cognitive impairment in children with cerebral malaria. We document that deficits found early persist long-term, whereas additional new deficits are discovered on long-term follow-up.Cerebral Malaria (CM), which is estimated to affect 785 000 children who are younger than 9 years in sub-Saharan Africa every year, 1 is among the deadliest forms of malaria, with an average mortality rate estimated at 18.6%. 2 Gross neurologic deficits are frequent at the time of discharge but generally resolve within 6 months of discharge. 3 A number of retrospective studies have suggested that CM is associated with higher frequencies of more subtle cognitive deficits as long as 3 to 9 years after the episode of CM, 4-8 but, to date, no long-term prospective studies of cognitive impairment after CM have been performed. In retrospective studies, the effects of variables such as home environment or nutrition, which may be important in cognitive development and which may change over time, cannot be assessed in c...

OBJECTIVE-This study was conducted to assess prospectively the frequency of cognitive deficits in children with cerebral malaria.METHODS-Cognitive testing in the areas of working memory, attention, and learning was performed for Ugandan children 5 to 12 years of age with cerebral malaria (n = 44), children with uncomplicated malaria (n = 54), and healthy community children (n = 89) at admission and 3 and 6 months later.RESULTS-Six months after discharge, 21.4% of children with cerebral malaria had cognitive deficits, compared with 5.8% of community children. Deficits were seen in the areas of working memory (11.9% vs 2.3%) and attention (16.7% vs 2.3%). Children with cerebral malaria had a 3.7-fold increased risk of a cognitive deficit, compared with community children, after adjustment for age, gender, nutritional status, school level, and home environment. Among children with cerebral malaria, those with a cognitive deficit had more seizures before admission (mean: 4.1 vs 2.2) and a longer duration of coma (43.6 vs 30.5 hours), compared with those without a deficit. Children with uncomplicated malaria did not have an increased frequency of cognitive deficits.CONCLUSIONS-Cerebral malaria may be a major cause of cognitive impairment in children in sub-Saharan Africa. Cognitive deficits in children with cerebral malaria are more likely for those who have multiple seizures before effective treatment for cerebral malaria. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIt has been estimated that each year 575 000 children suffer from cerebral malaria (CM) in sub-Saharan Africa. 1 CM is among the deadliest complications of malaria, with an estimated mortality rate in sub-Saharan Africa of 18.6% among hospitalized children. 2 Neurologic deficits are seen frequently at the time of hospital discharge for children with CM, but most resolve within 6 months after discharge. 3 However, several retrospective studies suggested that cognitive deficits in children with CM are more frequent (occurring in 11%-28% of children with CM) and persist for a far longer time (3-9 years after the CM episode) than neurologic deficits. [4][5][6][7][8] The data from those studies were strong and generally consistent, but one study found no evidence of increased cognitive deficits. 9 Furthermore, the original clinical and social assessments of those children were performed as part of studies investigating other aspects of CM and not as part of a study designed specifically to address the question of cognitive deficits in children with CM. Initial cognitive testing was performed for case and control subjects several years after the episode of CM. History, physical examination, and laboratory data were limited to those collected from medical charts, and data on potential confounding risk factors for cognitive deficits, such as home environment and level of schooling at the time of enrollment, either were not collected or were collected through questionnaires and therefore were subject to significant recall bia...

In children <5 years of age, SMA is associated with long-term impairment in cognitive ability, whereas CM is associated with additional impairment in the areas of attention and associative memory. SMA may be a major contributor to long-term neurocognitive impairment in children in sub-Saharan Africa.

Fourteen asymptomatic HIV-infected Zairian children under 2 years of age displayed social and motor developmental deficits on the Denver Developmental Screening Test when compared with 20 HIV-negative cohorts born to HIV-infected mothers and 16 control children. In a second study, 11 infected children over 2 years of age had sequential motor and visual-spatial memory deficits on the Kaufman Assessment Battery for Children and motor development deficits on the Early Childhood Screening Profiles. HIV infection affects central nervous system structures mediating motor and spatial memory development, even in seemingly asymptomatic children. Furthermore, maternal HIV infection compromises the labor-intensive provision of care in the African milieu and undermines global cognitive development in even uninfected children.

Significant motor and cognitive deficits were found in HIV-infected ART-naive Ugandan children with CD4 cell counts of ∼350 cells/μL and percentages of >15%. Study of whether early initiation of ART could prevent or reverse such deficits is needed.

Twenty-nine Senegalese children with a history of cerebral malaria (CM) performed more poorly on the Kaufman Assessment Battery for Children (K-ABC) Simultaneous Processing domain and on the Test of Variables of Attention (TOVA) attention capacity indicators in comparison with a matched control group. Thus, CM can disrupt neuropsychological integration during critical developmental periods, impacting on global neurological integrity, attentional vigilance, perceptual acuity, and subsequent development of visual-spatial processing and memory foundational to global cognitive ability. A subsequent structural equation model confirmed that rural children are at greater risk for CM, subsequent attention deficits, and other developmental risk factors in addition to the CM impact on K-ABC performance. We document CM as one of a host of developmental risk factors within the complex web of poverty in sub-Saharan Africa, which limit children's ability to achieve their full intellectual potential and, thus, extend the human cost of the disease beyond general measures of mortality and morbidity.

These children seem to represent a significant subgroup of HIV-infected child survivors for whom the progress of the disease is less aggressive throughout early life. Given the fact that many infants, especially in developing countries, continue to be born without the benefit of perinatal ARVT, there will likely continue to be many older HIV-infected children in the same situation as those described in this follow-up study. They will not have been recognized as being HIV-infected. It is important that such children be identified and offered access to ARVT and other appropriate support services.

Cerebrospinal fluid (CSF) and serum levels of 12 cytokines or chemokines important in central nervous system (CNS) infections were measured in 76 Ugandan children with cerebral malaria (CM) and 8 control children. As compared with control children, children with cerebral malaria had higher cerebrospinal fluid levels of interleukin (IL)-6, CXCL-8/IL-8, granulocyte-colony stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-alpha), and IL-1 receptor antagonist. There was no correlation between cerebrospinal and serum cytokine levels for any cytokine except G-CSF. Elevated cerebrospinal fluid but not serum TNF-alpha levels on admission were associated with an increased risk of neurologic deficits 3 months later (odds ratio 1.55, 95% CI: 1.10, 2.18, P = 0.01) and correlated negatively with age-adjusted scores for attention (Spearman rho, -0.34, P = 0.04) and working memory (Spearman rho, -0.32, P = 0.06) 6 months later. In children with cerebral malaria, central nervous system TNF-alpha production is associated with subsequent neurologic and cognitive morbidity.