Charvet, Leigh

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Objective To assess real‐world effectiveness of switching disease‐modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. Methods Of 2615 pediatric‐onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. Results A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety‐three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52–1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20–0.57; rate ratio: 0.38, 95% CI = 0.21–0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09–0.37; rate ratio: 0.21, 95% CI = 0.10–0.44) ( p < 0.001). Adjusted number needed to treat in person‐years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03–8.69) and infusion over injectable 1.43 (95% CI = 1.00–3.88). Interpretation Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long‐term safety data are required. ANN NEUROL 2026;99:715–729

Objective: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. Methods: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. Results: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery’s composite mean score or individual test scores ( ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite ( p = 0.03), Symbol Digit Modalities Test ( p = 0.02), Rey Auditory Verbal Learning Test ( p = 0.01), and Cogstate choice reaction time ( p < 0.001). Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Background: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS. Objective: To screen for cognitive impairment early in the course of POMS and analyze predictive factors. Methods: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free. Results: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing ( n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT. Conclusion: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

AbstractBackgroundWe previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory.MethodsPediatric MS cases (N = 290) and healthy controls (N = 442) were included as part of an ongoing case–control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk‐Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases.ResultsFine particulate matter (PM2.5), carbon monoxide (CO), sulfur dioxide (SO2), and lead air emissions were associated with increased odds for pediatric MS (P < 0.01) for those residing within 20 miles of an MS center. Most study participants (75%) resided within 5 miles of at least one TRI site; however, the mean total pounds of stack air releases was higher for sites near MS cases (81,000 tons) compared to those near healthy controls (35,000 tons, P = 0.002). Average RSEI scores did not differ significantly between cases and controls.ConclusionOut of several air pollutants examined, we show that fine particulate matter and three other criteria pollutants (SO2, CO, and lead) were statistically associated with higher odds for pediatric MS.