Visuospatial processing deficits are typically associated with damage to the right hemisphere. However, deficits on spatial working memory have been reported among some individuals with focal left hemisphere damage (LHD). It has been suggested that the left hemisphere may play a role in such non-verbal working memory tasks due to the use of subvocal, verbally-mediated strategies. The current study investigated the role of the left hemisphere in spatial working memory by testing spatial span performance, both forward and backward, in a large group of individuals with a history of left hemisphere stroke. Our first aim was to establish whether individuals with LHD are indeed impaired on spatial span tasks using standardized span tasks with published normative data. Our second aim was to identify the role that language plays in supporting spatial working memory by comparing LHD individuals with and without aphasia, and by relating spatial span performance to performance on a series of language measures. Our third aim was to identify left hemisphere brain regions that contribute to spatial working memory using voxel-based lesion symptom mapping (VLSM), a whole-brain statistical approach that identifies regions critical to a particular behavior on a voxel-by-voxel basis. We found that 28% of individuals with LHD performed in the clinically-impaired range on forward spatial span and 16% performed in the clinically-impaired range on backward spatial span. There were no significant differences in performance between individuals with and without aphasia, and there were no correlations between spatial span performance and language functions such as repetition and comprehension. The VLSM analysis showed that backward spatial span was associated with a left fronto-parietal network consisting of somatosensory cortex, the supramarginal gyrus, lateral prefrontal cortex, and the frontal eye fields. Regions identified in the VLSM analysis of forward spatial span did not reach the conservative statistical threshold for significance. Overall, these results suggest that spatial working memory, as measured by spatial span, can be significantly disrupted in a subset of individuals with LHD whose lesions infringe on a network of regions in the left hemisphere that have been implicated in domain-general working memory and attentional control mechanisms.

Background

Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM.

Methods

TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL).

Results

Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01).

Conclusions

In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial.

Clinical trials registration

NCT02958709.