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

Participant characteristics.

<p>Participant characteristics.</p

Analysis of data from the longitudinal study comparing cerebral malaria and control groups.

<p>Analysis of data from the longitudinal study comparing cerebral malaria and control groups.</p

Comparison of cross-sectional and longitudinal data.

<p>Cross-sectional data from the participants from the BRINK cohort (C) is compared to data from participants aged >144 months in the longitudinal study (L). In each plot individual participants’ data is shown, with the mean±95% CI. A. Prosaccade latency. B. Antisaccade directional error rate (DER). C. Correct antisaccade latency. D. Error prosaccade latency from the antisaccade task. Note different axis scales between A and C, D.</p

Effect of age on antisaccade directional error rate (DER).

<p>Presented calculated as a percentage for control (A) and cerebral malairia (B) groups. Plotting conventions as for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164885#pone.0164885.g001" target="_blank">Fig 1</a>.</p

Effect of age on DER in combined Malawi group, and comparrision with data from the literature.

<p>A. Combined analysis of data from cerebral malaria (blue) and control (red) groups in the longitudinal study. Both hierarchical linear model (solid lines) and LOESS fits (dotted lines), ±95% CI are shown. B. Comparison of hierarchical linear model (solid lines) from longitudinal Malawi dataset, with a weighted mixed-effect linear model constructed from data extracted from four published studies in which a synchronous antisaccade task was used (dashed lines). Central estimates ±95% CI shown.</p

Comparison data from the literature.

<p>Comparison data from the literature.</p

The latency of different types of saccade and their relationships.

<p>A. Intersubject mean (95% CI–upper or lower error bars plotted for clarity) averaged across each testing session. CM: Data plotted in red. CON: Data plotted in blue. ● correct antisaccades (CorAS); ■ error prosaccades (ErrPS). B. Plot of the difference between mean correct antisaccade latency (averaged over testing sessions) and mean error prosaccade latency for each participant against their age (calculated as the mean age over testing sessions). CM: red, CON: blue as in A. C. Correlation between prosaccade (ProSac) latency and error prosaccade (ErrPS) latency for all participants and sessions. CM: red, CON: blue as in A. Parameters of least-squares linear regression functions and correlation coefficients are shown.</p