Cognition, behaviour and academic skills after cognitive rehabilitation in Ugandan children surviving severe malaria: a randomised trial

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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. This trial is registered with Current Controlled Trials, number ISRCTN53183087.</p> <p>Results</p> <p>Significant intervention effects were observed in the intervention group for learning mean score (SE), [93.89 (4.00) vs 106.38 (4.32), <it>P </it>= 0.04] but for working memory the intervention group performed poorly [27.42 (0.66) vs 25.34 (0.73), <it>P </it>= 0.04]. No effect was observed in the other cognitive outcomes or in any of the academic or behavioural measures.</p> <p>Conclusions</p> <p>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.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN53183087">ISRCTN53183087</a></p

Grand Challenges: Improving HIV Treatment Outcomes by Integrating Interventions for Co-Morbid Mental Illness.

In the fourth article of a five-part series providing a global perspective on integrating mental health, Sylvia Kaaya and colleagues discuss the importance of integrating mental health interventions into HIV prevention and treatment platforms. Please see later in the article for the Editors' Summary

Reliability of the Luganda version of the Child Behaviour Checklist in measuring behavioural problems after cerebral malaria

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Socioeconomic Predictors of Cognition in Ugandan Children: Implications for Community Interventions

Background: Several interventions to improve cognition in at risk children have been suggested. Identification of key variables predicting cognition is necessary to guide these interventions. This study was conducted to identify these variables in Ugandan children and guide such interventions. Methods: A cohort of 89 healthy children (45 females) aged 5 to 12 years old were followed over 24 months and had cognitive tests measuring visual spatial processing, memory, attention and spatial learning administered at baseline, 6 months and 24 months. Nutritional status, child’s educational level, maternal education, socioeconomic status and quality of the home environment were also measured at baseline. A multivariate, longitudinal model was then used to identify predictors of cognition over the 24 months. Results: A higher child’s education level was associated with better memory (p = 0.03), attention (p = 0.005) and spatial learning scores over the 24 months (p = 0.05); higher nutrition scores predicted better visual spatial processing (p = 0.002) and spatial learning scores (p = 0.008); and a higher home environment score predicted a better memory score (p = 0.03). Conclusion: Cognition in Ugandan children is predicted by child’s education, nutritional status and the home environment

Differentially expressed microRNAs in experimental cerebral malaria and their involvement in endocytosis, adherens junctions, FoxO and TGF-β signalling pathways

Cerebral malaria (CM) is the most severe manifestation of infection with Plasmodium, however its pathogenesis is still not completely understood. microRNA (miRNA) have been an area of focus in infectious disease research, due to their ability to affect normal biological processes, and have been shown to play roles in various viral, bacterial and parasitic infections, including malaria. The expression of miRNA was studied following infection of CBA mice with either Plasmodium berghei ANKA (causing CM), or Plasmodium yoelii (causing severe but non-cerebral malaria (NCM)). Using microarray analysis, miRNA expression was compared in the brains of non-infected (NI), NCM and CM mice. Six miRNA were significantly dysregulated between NCM and CM mice, and four of these, miR-19a-3p, miR-19b-3p, miR-142-3p and miR-223-3p, were further validated by qPCR assays. These miRNA are significantly involved in several pathways relevant to CM, including the TGF-β and endocytosis pathways. Dysregulation of these miRNA during CM specifically compared with NCM suggests that these miRNA, through their regulation of downstream targets, may be vitally involved in the neurological syndrome. Our data implies that, at least in the mouse model, miRNA may play a regulatory role in CM pathogenesis.This work was funded by the National Health and Medical Research Council (#1099920 for GEG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan children

BACKGROUND: Asymptomatic falciparum malaria is associated with poorer cognitive performance in African schoolchildren and intermittent preventive treatment of malaria improves cognitive outcomes. However, the developmental benefits of chemoprevention in early childhood are unknown. Early child development was evaluated as a major outcome in an open-label, randomized, clinical trial of anti-malarial chemoprevention in an area of intense, year-round transmission in Uganda. METHODS: Infants were randomized to one of four treatment arms: no chemoprevention, daily trimethoprim–sulfamethoxazole, monthly sulfadoxine–pyrimethamine, or monthly dihydroartemisinin–piperaquine (DP), to be given between enrollment (4–6 mos) and 24 months of age. Number of malaria episodes, anaemia (Hb < 10) and neurodevelopment [Mullen Scales of Early Learning (MSEL)] were assessed at 2 years (N = 469) and at 3 years of age (N = 453); at enrollment 70 % were HIV-unexposed uninfected (HUU) and 30 % were HIV-exposed uninfected (HEU). RESULTS: DP was highly protective against malaria and anaemia, although trial arm was not associated with MSEL outcomes. Across all treatment arms, episodes of malarial illness were negatively predictive of MSEL cognitive performance both at 2 and 3 years of age (P = 0.02). This relationship was mediated by episodes of anaemia. This regression model was stronger for the HEU than for the HUU cohort. Compared to HUU, HEU was significantly poorer on MSEL receptive language development irrespective of malaria and anaemia (P = 0.01). CONCLUSIONS: Malaria with anaemia and HIV exposure are significant risk factors for poor early childhood neurodevelopment in malaria-endemic areas in rural Africa. Because of this, comprehensive and cost/effective intervention is needed for malaria prevention in very young children in these settings

Longitudinal Visuomotor Development in a Malaria Endemic Area: Cerebral Malaria and Beyond

Paediatric cerebral malaria is the most serious complication of Plasmodium falciparum infection. While the majority recover, long-term cognitive impairment has been highlighted as a significant and neglected problem. Persistent or serious deficits in processes such as attention or behavioural inhibition should be manifest in changes to performance on oculomotor tasks. Therefore we investigated the impact of cerebral malaria on the development of reflexive pro-saccades and antisaccades. In a longitudinal study, 47 children previously admitted with retinopathy-confirmed cerebral malaria (mean age at admission 54 months), were compared with 37 local healthy controls (mean ages at first study visit 117 and 110 months respectively). In each of three or four test sessions, over a period of up to 32 months, participants completed 100 prosaccade tasks and 100 antisaccade tasks. Eye movements were recorded using infrared reflectance oculography; prosaccade, correct antisaccade and error prosaccade latency, and antisaccade directional error rate were calculated. Hierarchical linear modelling was used to investigate the effect of age and the influence of cerebral malaria on these parameters. Data were also collected from an independent, older group (mean age 183 months) of 37 local healthy participants in a separate cross-sectional study. Longitudinal data exhibited the expected decrease in latency with age for all saccade types, and a decrease in the antisaccade directional error rate. Hierarchical linear modelling confirmed that age had a statistically significant effect on all parameters (p< = 0.001). However, there were no statistically significant differences between the cerebral malaria and control groups. Combining groups, comparison with the literature demonstrated that antisaccade directional error rate for the Malawi sample was significantly higher than expected, while latencies for all saccade types were indistinguishable from published. The high directional error rate was also confirmed in the older, healthy Malawian participants from the cross sectional study. Our observation of similar oculomotor performance in cerebral malaria and control groups at long follow-up periods suggests that cerebral malaria survivors are not at a generally increased risk of persistent cognitive deficits. Our data raise questions about the prevailing hypothesis that cerebral malaria has gross impacts on the development of processes such as attention and behavioural inhibition. More importantly, our novel finding of a clear difference in antisaccade performance between all of the Malawi participants and published data suggests that the Malawian paediatric population as a whole faces serious challenges to cognitive development beyond cerebral malaria