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-α (TNF-α), 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-α 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-α production is associated with subsequent neurologic and cognitive morbidity.

Because antiretroviral treatment (ART) fails to improve neurocognitive impairment in children with HIV, we completed a pilot study evaluating the feasibility and cognitive benefit of computerized cognitive rehabilitation therapy (CCRT) in Ugandan children with HIV. Sixty Ugandan children with HIV (23 on ART) were randomly assigned to 10 sessions of Captain's Log CCRT (Sandford, 2007) training configured for attention and memory skills or no intervention. Kaufman Assessment Battery for Children (2nd ed., KABC-2; Kaufman & Kaufman, 2004) performance at baseline indicated pervasive neurocognitive impairment. Cognitive ability was assessed before and after training using the Cogstate computerized neuropsychological test (Darby, Maruff, Collie, & McStephen, 2002). Viral load along with CD4 and CD8 absolute and activation levels also were measured posttest. CCRT was well received with a 95% adherence rate to scheduled training sessions. CCRT intervention children showed greater improvement on a Cogstate card detection task of simple attention (p = .02), and speed of correct moves on a Groton Maze Learning Task (p < .001). These analyses were completed using an analysis of covariance model that adjusted Cogstate performance for the child's age, standardized weight for age, gender, socioeconomic status, school grade level, and baseline KABC-2 performance. ART treatment was not related to Cogstate performance or improvement as a result of CCRT. CD4 and CD8 activation levels were correlated with Cogstate improvement specifically for the CCRT group. CCRT was feasible with our study population and improved maze learning and attention on a detection task. This supports previous findings by our group with cerebral malaria survivors (Bangirana, Giordani, et al., 2009).

BackgroundIn children with cerebral malaria (CM), serum chemokine levels and associated morbidity and mortality have not been characterized MethodsSerum levels of the cytokines interleukin (IL)–1β, IL-6, IL-10, interferon (IFN)–γ, and tumor necrosis factor–α and the chemokines macrophage inflammatory protein (MIP)–1α, MIP-1β, and regulated upon activation, normal T cell expressed and secreted (RANTES) were measured in Ugandan children with CM, in children with uncomplicated malaria (UM), and in healthy children from the community, as control subjects (CCs) ResultsChildren with CM had lower levels of RANTES and higher levels of all other cytokines and chemokines than CCs (all P<.0001), and they had lower levels of RANTES (P=.004) and higher levels of IL-10 (P=.003), IFN-γ (P=.007), and IL-1β (P=.05) than children with UM. Children with CM who died had lower levels of RANTES (P=.006) and higher of levels of IL-6 (P=.006), IL-10 (P=.01), IFN-γ (P=.03), and MIP-1β (P=.008) than children who survived. After adjustment for other cytokine and chemokine levels, only low levels of RANTES were independently associated with mortality (P=.016). Levels of RANTES correlated with platelet count but were associated with mortality independently of platelet count ConclusionsThe serum cytokine and chemokine profile of children who die of CM is similar to that of individuals who die of sepsis. Levels of RANTES are significantly lower in children with CM, and very low levels of RANTES are associated with mortality, independently of other cytokine and chemokine levels

Objective and design: Children with HIV infection (HIV+) are at neuropsychological risk, but few studies have evaluated this at multiple sites in low-income and middle-income countries. We compared neuropsychological outcomes at enrollment (>5 years age) among HIV+, HIV perinatally exposed uninfected (HEU), and HIV unexposed uninfected (HUU) children from four sub-Saharan countries. Methods: IMPAACT P1060 compared nevirapine versus lopinavir/ritonavir-based antiretroviral treatment (ART) in HIV-infected children 6–35 months of age. The present study (P1104s) enrolled P1060 children at 5–11 years of age and evaluated their neuropsychological performance over 2 years using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II), Tests of Variables of Attention (TOVA), Bruininks–Oseretsky Test, 2nd edition (BOT-2), and parent-reported Behavior Rating Inventory of Executive Function (BRIEF). Cohorts were compared using generalized estimating equations least-squares means adjusted for site, child age and sex, and personal and social characteristics for child and caregiver. Results: Six hundred and eleven (246 HIV+, 183 HEU, 182 HUU) of the 615 enrolled at six sites [South Africa (three), Zimbabwe, Malawi, Uganda] were available for analysis. Mean age was 7.2 years, 48% male, 69% in school. Unadjusted and adjusted comparisons were consistent. HIV+ children performed significantly worse than HEU and HUU cohorts on all KABC-II cognitive performance domains and on BOT-2 total motor proficiency (P < 0.001), but not on the BRIEF Global Executive Indices. HUU and HEU cohorts were comparable on cognitive outcomes. HIV+ children initiated on ART before 1 year of age had significantly better BRIEF evaluations (lower scores - fewer behavior problems), compared with those started after (P = 0.03). Conclusion: Significant cognitive deficits were documented among HIV+ children at school age, even when started on ART at an early age. Earlier HIV treatment, neuropsychological monitoring, and rehabilitative interventions are all needed. Subsequent testing for 2 more years will help further evaluate how HIV infection and exposure affect the developmental trajectory.

Objective: Mediational intervention for sensitizing caregivers (MISC) is a structured program enabling caregivers to enhance their child’s cognitive and emotional development through daily interactions. The principal aim was to evaluate if a year-long MISC caregiver training program produced greater improvement in child cognitive and emotional development compared with a control program. Methods: One hundred and nineteen uninfected HIV-exposed preschool children and their caregivers were randomly assigned to 1 of 2 treatment arms: biweekly MISC training alternating between home and clinic for 1 year or a health and nutrition curriculum. All children were evaluated at baseline, 6 months, and 1 year with the Mullen Early Learning Scales, Color-Object Association Test for memory, and Achenbach Child Behavior Checklist for psychiatric symptoms. Caregivers were evaluated on the same schedule with the Hopkins Symptoms Checklist-25 for depression and anxiety. Results: The treatment arms were compared using repeated-measures analysis of covariance with child age, gender, weight, socioeconomic status, caregiving quality, caregiver anxiety, and caregiver education as covariates. The MISC children had significantly greater gains compared to controls on the Mullen Receptive and Expressive Language development, and on the Mullen composite score of cognitive ability. Color-Object Association Test total memory for MISC children was marginally better than controls. No Achenbach Child Behavior Checklist differences between the groups were noted. Caldwell Home Observation for Measurement of the Environment scores and observed mediational interaction scores from videotapes measuring caregiving quality also improved significantly more for the MISC group. Conclusions: The MISC enhanced cognitive performance, especially in language development. These benefits were possibly mediated by improved caregiving and positive emotional benefit to the caregiver.