Ruel, T., Boivin, M., Boal, H., Bangirana, P., Charlebois, E., Havlir, D. V.,
Rosenthal, P. J., Dorsey, G., Achan, J., Akello, C., Kamya, M. R., &
Wong, J. K. (2012). Neurocognitive and motor deficits in HIV-infected
Ugandan children with high CD4 cell counts. Clinical Infectious Diseases.
BACKGROUND: Human immunodeficiency virus (HIV) infection causes neurocognitive or motor function deficits in children with advanced disease, but it is unclear whether children with CD4 cell measures above the World Health Organization (WHO) thresholds for antiretroviral therapy (ART) initiation suffer significant impairment.
METHODS: The neurocognitive and motor functions of HIV-infected ART-naive Ugandan children aged 6–12 years with CD4 cell counts of >350 cells/μL and CD4 cell percentage of >15% were compared with those of HIV-uninfected children, using the Test of Variables of Attention (TOVA), the Kaufman Assessment Battery for Children, second edition (KABC-2), and the Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2).
RESULTS: Ninety-three HIV-infected children (median CD4 cell count, 655 cells/μL; plasma HIV RNA level, 4.7 log10 copies/mL) were compared to 106 HIV-uninfected children. HIV-infected children performed worse on TOVA visual reaction times (multivariate analysis of covariance; P = .006); KABC-2 sequential processing (P = .005), simultaneous processing (P = .039), planning/reasoning (P = .023), and global performance (P = .024); and BOT-2 total motor proficiency (P = .003). High plasma HIV RNA level was associated with worse performance in 10 cognitive measures and 3 motor measures. In analysis of only WHO clinical stage 1 or 2 HIV-infected children (n = 68), significant differences between the HIV-infected and HIV-uninfected groups (P < .05) remained for KABC-2 sequential processing, KABC-2 planning/reasoning, and BOT-2 motor proficiency.
CONCLUSIONS: 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.
Bangirana, P., Allebeck, P., Boivin, M. J., John, C. C., Page, C., Ehnvall, A., &
Musisi, S. (2011). Cognition, behaviour and academic skills after cognitive
rehabilitation in Ugandan children surviving severe malaria: a randomised
trial. BMC Neurology, 11, 96.
BACKGROUND: Infection with severe malaria in African children is associated with not only a high mortality but also a high risk of cognitive deficits. There is evidence that interventions done a few years after the illness are effective but nothing is known about those done immediately after the illness. We designed a study in which children who had suffered from severe malaria three months earlier were enrolled into a cognitive intervention program and assessed for the immediate benefit in cognitive, academic and behavioral outcomes.
METHODS: This parallel group randomised study was carried out in Kampala City, Uganda between February 2008 and October 2010. Sixty-one Ugandan children aged 5 to 12 years with severe malaria were assessed for cognition (using the Kaufman Assessment Battery for Children, second edition and the Test of Variables of Attention), academic skills (Wide Range Achievement Test, third edition) and psychopathologic behaviour (Child Behaviour Checklist) three months after an episode of severe malaria. Twenty-eight were randomised to sixteen sessions of computerised cognitive rehabilitation training lasting eight weeks and 33 to a non-treatment group. Post-intervention assessments were done a month after conclusion of the intervention. Analysis of covariance was used to detect any differences between the two groups after post-intervention assessment, adjusting for age, sex, weight for age z score, quality of the home environment, time between admission and post-intervention testing and pre-intervention score. The primary outcome was improvement in attention scores for the intervention group. The trial is registered with Current Controlled Trials, number ISRCTN53183087.
RESULTS: Significant intervention effects were observed in the intervention group for learning mean score (SE), [93.89 (4.00) vs 106.38 (4.32), P = 0.04] but for working memory the intervention group performed poorly [27.42 (0.66) vs 25.34 (0.73), P = 0.04]. No effect was observed in the other cognitive outcomes or in any of the academic or behavioural measures.
CONCLUSIONS: In this pilot study, our computerised cognitive training program three months after severe malaria had an immediate effect on cognitive outcomes but did not affect academic skills or behaviour. Larger trials with follow-up after a few years are needed to investigate whether the observed benefits are sustained.
Bangirana, P., Musisi, S., Boivin, M. J., Ehnvall, A., John, C. C., Bergemann,
T. L., & Allebeck, P. (2011). Malaria with neurological involvement in
Ugandan children: effect on cognitive ability, academic achievement
and behaviour. Malaria Journal, 10: 334. doi: 10.1186/1475-2875-10-334
BACKGROUND: Malaria is a leading cause of ill health and neuro-disability in children in sub-Saharan Africa. Impaired cognition is a common outcome of malaria with neurological involvement. There is also a possibility that academic achievement may be affected by malaria with neurological involvement given the association between cognitive ability and academic achievement. This study investigated the effect of malaria with neurological involvement on cognitive ability, behaviour and academic achievement.
METHODS: This prospective case-control study was carried out in Kampala City, Uganda between February 2008 and October 2010. Sixty-two children with a history of malaria with neurological involvement were followed up and given assessments for cognitive ability (working memory, reasoning, learning, visual spatial skills and attention), behaviour (internalizing and externalizing problems) and academic achievement (arithmetic, spelling and reading) three months after the illness. Sixty-one community controls recruited from the homes or neighbouring families of the cases were also given the same assessments. Tests scores of the two groups were compared using analysis of covariance with age, sex, level of education, nutritional status and quality of the home environment as covariates. This study was approved by the relevant ethical bodies and informed consent sought from the caregivers.
RESULTS: Children in the malaria group had more behavioural problems than the community controls for internalizing problems (estimated mean difference = -3.71, 95% confidence interval (CI), = -6.34 to -1.08, p = 0.007). There was marginal evidence of lower attention scores (0.40, CI = -0.05 to 0.86, p = 0.09). However, excluding one child from the analyses who was unable to perform the tests affected the attention scores to borderline significance (0.32, CI, = 0.01 to 0.62, p = 0.05). No significant differences were observed in other cognitive abilities or in academic achievement scores.
CONCLUSION: Malaria with neurological involvement affects behaviour, with a minimal effect on attention but no detectable effect on academic achievement at three months post discharge. This study provides evidence that development of cognitive deficits after malaria with neurological involvement could be gradual with less effect observed in the short term compared to the long term.
Full Text: Bangirana et al., 2011.pdf
Boivin, M. J., Ruel, T. D., Boal, H. E., Bangirana, P., Cao, H., Eller, L. A.,
Charlebois, E., Havlir, D. V., Kamya, M. R., Achan, J., Akello, C., &
Wong, J. K. (2010). HIV-subtype A is associated with poorer
neuropsychological performance compared with subtype D in
antiretroviral therapy-naive Ugandan children. Aids, 24(8), 1163-1170.
BACKGROUND: HIV-subtype D is associated with more rapid disease progression and higher rates of dementia in Ugandan adults compared with HIV-subtype A. There are no data comparing neuropsychological function by HIV subtype in Ugandan children.
DESIGN: One hundred and two HIV-infected antiretroviral therapy (ART) naive Ugandan children 6-12 years old (mean 8.9) completed the Kaufman Assessment Battery for Children, second edition (KABC-2), the Test of Variables of Attention (TOVA), and the Bruininks-Oseretsky Test for Motor Proficiency, second edition (BOT-2). Using a PCR-based multiregion assay with probe hybridization in five different regions (gag, pol, vpu, env, gp-41), HIV subtype was defined by hybridization in env and by total using two or more regions. Analysis of covariance was used for multivariate coparison.
RESULTS: The env subtype was determined in 54 (37 A, 16 D, 1 C) children. Subtype A and D groups were comparable by demographics, CD4 status, and WHO stage. Subtype A infections had higher log viral loads (median 5.0 vs. 4.6, P = 0.02). Children with A performed more poorly than those with D on all measures, especially on KABC-2 Sequential Processing (memory) (P = 0.01), Simultaneous Processing (visual-spatial analysis) (P = 0.005), Learning (P = 0.02), and TOVA visual attention (P = 0.04). When adjusted for viral load, Sequential and Simultaneous Processing remained significantly different. Results were similar comparing by total HIV subtype.
CONCLUSION: HIV subtype A children demonstrated poorer neurocognitive performance than those with HIV subtype D. Subtype-specific neurocognitive deficits may reflect age-related differences in the neuropathogenesis of HIV. This may have important implications for when to initiate ART and the selection of drugs with greater central nervous system penetration.
Boivin, M. J., Busman, R. A., Parikh, S. M., Bangirana, P., Page, C. F.,
Opoka, R. O., & Giordani, B. (2010). A pilot study of the
neuropsychological benefits of computerized cognitive rehabilitation
in Ugandan children with HIV. Neuropsychology, 24(5), 667-673.
OBJECTIVE: 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.
METHOD: 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.
RESULTS: 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.
CONCLUSIONS: 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).
Boivin, M. J., Bangirana, P., & Smith, R. C. (2010). The relationship between
visual-spatial and auditory- verbal- working memory span in Senegalese
and Ugandan children. PloS ONE, 5(1), 1-6.
BACKGROUND: Using the Kaufman Assessment Battery for Children (K-ABC) Conant et al. (1999) observed that visual and auditory working memory (WM) span were independent in both younger and older children from DR Congo, but related in older American children and in Lao children . The present study evaluated whether visual and auditory WM span were independent in Ugandan and Senegalese children.
METHOD: In a linear regression analysis we used visual (Spatial Memory, Hand Movements) and auditory (Number Recall) WM along with education and physical development (weight/height) as predictors. The predicted variable in this analysis was Word Order, which is a verbal memory task that has both visual and auditory memory components.
RESULTS: Both the younger (<8.5 yrs) and older (>8.5 yrs) Ugandan children had auditory memory span (Number Recall) that was strongly predictive of Word Order performance. For both the younger and older groups of Senegalese children, only visual WM span (Spatial Memory) was strongly predictive of Word Order. Number Recall was not significantly predictive of Word Order in either age group.
CONCLUSIONS: It is possible that greater literacy from more schooling for the Ugandan age groups mediated their greater degree of interdependence between auditory and verbal WM. Our findings support those of Conant et al., who observed in their cross-cultural comparisons that stronger education seemed to enhance the dominance of the phonological-auditory processing loop for WM.
Bangirana, P., Seggane-Musisi, Allebeck, P., Giordani, B., Chandy, C. J.,
Opoka, O. R., Byarugaba, J., Ehnvall, A., & Boivin, M. J. (2009). A
preliminary examination of the construct validity of the KABC-II in
Ugandan children with a history of cerebral malaria. African Health
Sciences, 9(3), 186-192.
BACKGROUND: Several diseases and adverse conditions affect the cognitive development of children in Sub-Saharan African. There is need to assess there children to determine which abilities are affected and the severity of the damage so as to plan interventions accordingly. However most psychological tests developed in the West have not been validated in this region making it impossible to know whether they measure what they were intended to in African children.
OBJECTIVE: To examine the construct validity of the Kaufman Assessment Battery for Children, Second Edition (KABC-II) in Ugandan children.
METHODS: Sixty five Ugandan children aged 7 to 16 years (Mean=9.90, SD-2.46) were tested using the KABC-II 44.59 months (SD=2.82) after an episode of cerebral malaria. The KABC-II scales of Sequential Processing, Simultaneous Processing, Planning and Learning were administered. In order to identify which factors result from administering the KABC-II in these children, factor analysis using principal component analysis with Varimax rotation was applied to the subtests making up the above scales.
RESULTS: Five factors emerged after factor analysis comprising of subtests measuring Sequential Processing, Simultaneous Processing, Planning and Learning. The fifth scale comprised of subtests measuring immediate and delayed recall.
CONCLUSION: This preliminary study in Ugandan children shows the KABC-II to have good construct validity with subtests measuring similar abilities loading on the same factors. The KABC-II can be used in assessing Ugandan children after a few modifications. Further analysis of its psychometric properties in Ugandan children is required.
Boivin, M. J. & Giordani, B. (2009). Neuropsychological assessment of
African children: Evidence for a universal brain/behavior omnibus
within a coconstructivist paradigm. Progress in Brain Research, 178,
ABSTRACT: Cross-cultural neuropsychology with African and American childrcn provides evidence of consistent deficit patterns in attention, working memory, and learning in children at risk from disease affecting brain function by means of similar pathophysiologic mechanisms (e.g., cerebral malaria (CM) and sickle-cell disease (SCD); HIV in African and American children). These brain―behavior disease processes arc also modified in a consistent manner cross-culturally by quality of developmental milieu and caregiving. We then present findings from the pioneering use of computerized cognitive rehabilitation therapy (CCRT) with Ugandan children surviving CM and with HIV. This neuropsychological evidence that CCRT enhances positive brain plasticity in a consistent manner across cultures supports the "coconstructive" paradigm (Li, 2003), since plasticity across the life span is the hallmark of this approach. Coconstructivism is a holistic multi-dimensional approach that emphasizes reciprocal biocultural influences across the life span. It also emphasizes the reciprocal interaction of culture and the genome in shaping brain/mind at multiple levels: neurobiological, cognitively, behavioral, and sociocultural (Li, 2003). Cross-cultural neuropsychology in healthy and diseased brains, brain imaging technologies, and genomic research can triangulate the manner in which a universal brain/behavior omnibus drives plasticity across the life span. As such, the further scientific characterization of the brain/behavior omnibus can provide the vital lynchpin between biology and culture in Li's coconstructive paradigm, revolutionizing our understanding of intelligence and culture.
John, C. C., Bangirana, P., Byarugaba, J., Opoka, R. O., Idro, R., Jurek,
A. M., Wu, B., & Boivin, M. J. (2008). Cerebral malaria in children
is associated with long-term cognitive impairment. Pediatrics.
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.
Full Text: John et al., 2008.pdf
John, C. C., Panoskaltsis-Mortari, A., Opoka, R. O., Park, G. S., Orchard,
P. J., Jurek, A. M., Idro, R., Byarugaba, J., & Boivin, M. J. (2008).
Cerebrospinal Fluid Cytokine levels and cognitive impairment in
cerebral malaria. The American Journal of Tropical Medicine and
Hygiene, 78(2), 198-205.
ABSTRACT: 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- (TNF- ), 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- 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- production is associated with subsequent neurologic and cognitive morbidity.
Boivin, M. J., Bangirana, P., Byarugaba, J., Opoka, R. O., Idro, R., Jurek,
A.M., & John, C. C. (2007). Cognitive impairment after cerebral malaria
in children: a prospective study. Pediatrics, 119(2), 360-366.
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.
Bagenda, D., Nassali, A., Kalyesubula, I., Sherman, B., Drotar, D., Boivin,
M. J., & Olness, K. (2006). Health, neurologic, and cognitive status of
HIV-infected, long-surviving, and antiretroviral-naive Ugandan children.
Pediatrics, 117(3), 729-740.
OBJECTIVE: The purpose of this study was to assess the health status and school-age neurodevelopmental progress of antiretroviral treatment (ARVT)-naive, HIV-infected Ugandan children who had been followed as part of cohorts of children born to HIV-infected and -noninfected mothers between 1989 and 1993.
METHODS: Twenty-eight children, aged 6 to 12 years, vertically infected with HIV-1 and never treated with ARVT were evaluated in terms of health status, neurologic, and psychometric testing. A randomly selected group of 42 seroreverters and 37 HIV-1 negative children who were age- and gender-matched and who had been followed in the sane cohorts were evaluated also. The families studied were homogenous in their socioeconomic status. None of the mothers or children had received ARVT or been exposed to illicit drugs.
RESULTS: The HIV-infected children showed significantly more evidence of acute malnutrition. They also had more illness, especially parotitis, otitis media, upper respiratory infections, and lymphadenopathy. However, they did not differ significantly in neurologic and cognitive assessments when compared with age- and gender-matched seroreverter and HIV-negative children. They were in the normal range with respect to neurologic and psychometric development measures.
CONCLUSIONS: 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.