A Randomized Computer-Assisted Rehabilitation Trial of Attention in Pediatric Multiple Sclerosis: A Post Hoc Analysis

Cognitive impairment (CI) is a remarkable feature in pediatric-onset multiple sclerosis (POMS). The Symbol Digit Modalities Test (SDMT) is increasingly used to explore CI in MS. Recently, a four-point worsening on the SDMT score has been demonstrated to correlate with a clinically meaningful cognitive worsening in adult MS. We conducted a post hoc analysis of a randomized computer-assisted rehabilitation trial for attention impairment in POMS to test the clinical meaningfulness of the changes in SDMT scores at the end of the trial (delta SDMT). A four-point SDMT cut-off was applied. POMS patients exposed to specific computer training (ST) and non-specific training (nST) were compared. Data of 16 POMS (9 females, age 15.75 +/- 1.74 years) patients were analyzed. At the end of the trial, 25% of patients reported no clinically significant changes (-3 to 3), 12.5% a clinically significant worsening (<=-4) and 62.5% a clinically significant improvement (>= 4) in the delta SDMT. The proportion of patients reporting a clinically meaningful improvement was significantly (p = 0.008) higher (100%) in patients exposed to ST in comparison to those (25%) exposed to nST. The use of the four-point SDMT cut-off may be useful to assess the clinical meaningfulness of results from cognitive rehabilitation trials

Impact of Natalizumab on Cognitive Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label, Two Years Observational Study

Background and Objectives: Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years. Methods: Cognitive performances were examined by the Rao’s Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient’s selfreported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively. Results: After 1 year of treatment the percentage of CI patients decreased from 29 % (29/100) at baseline to 19 % (19/100) (p = 0.031) and the mean baseline values of CII (13.5266.85) and FSS (4.0161.63) scores were significantly reduced (10.4867.12, p,0.0001 and 3.6161.56, p = 0.008). These significant effects were confirmed in the subgroup of patients treated up to two years. Conclusions: These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performance

Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: an Italian collaborative study

Background: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. Objective: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). Methods: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. Results: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p < 0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS (p = 0.03) compared with AOMS patients.The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was in part financed through an FISM (Italian Federation of Multiple Sclerosis) research grant

Applying multidimensional computerized adaptive testing to the MSQOL-54: a simulation study

Background: The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is one of the most commonly-used MS-specific health-related quality of life (HRQOL) measures. It is a multidimensional, MS-specific HRQOL inventory, which includes the generic SF-36 core items, supplemented with 18 MS-targeted items. Availability of an adaptive short version providing immediate item scoring may improve instrument usability and validity. However, multidimensional computerized adaptive testing (MCAT) has not been previously applied to MSQOL-54 items. We thus aimed to apply MCAT to the MSQOL-54 and assess its performance. Methods: Responses from a large international sample of 3669 MS patients were assessed. We calibrated 52 (of the 54) items using bifactor graded response model (10 group factors and one general HRQOL factor). Then, eight simulations were run with different termination criteria: standard errors (SE) for the general factor and group factors set to different values, and change in factor estimates from one item to the next set at &lt; 0.01 for both the general and the group factors. Performance of the MCAT was assessed by the number of administered items, root mean square difference (RMSD), and correlation. Results: Eight items were removed due to local dependency. The simulation with SE set to 0.32 (general factor), and no SE thresholds (group factors) provided satisfactory performance: the median number of administered items was 24, RMSD was 0.32, and correlation was 0.94. Conclusions: Compared to the full-length MSQOL-54, the simulated MCAT required fewer items without losing precision for the general HRQOL factor. Further work is needed to add/integrate/revise MSQOL-54 items in order to make the calibration and MCAT performance efficient also on group factors, so that the MCAT version may be used in clinical practice and research

Viability of a MSQOL-54 general health-related quality of life score using bifactor model

Background MSQOL-54 is a multidimensional, widely-used, health-related quality of life (HRQOL) instrument specific for multiple sclerosis (MS). Findings from the validation study suggested that the two MSQOL-54 composite scores are correlated. Given this correlation, it could be assumed that a unique total score of HRQOL may be calculated, with the advantage to provide key stakeholders with a single overall HRQOL score. We aimed to assess how well the bifactor model could account for the MSQOL-54 structure, in order to verify whether a total HRQOL score can be calculated. Methods A large international database (3669 MS patients) was used. By means of confirmatory factor analysis, we estimated a bifactor model in which every item loads onto both a general factor and a group factor. Fit of the bifactor model was compared to that of single and two second-order factor models by means of Akaike information and Bayesian information criteria reduction. Reliability of the total and subscale scores was evaluated with Mc Donald's coefficients (omega, and omega hierarchical). Results The bifactor model outperformed the two second-order factor models in all the statistics. All items loaded satisfactorily (&gt;= 0.40) on the general HRQOL factor, except the sexual function items. Omega coefficients for total score were very satisfactory (0.98 and 0.87). Omega hierarchical for subscales ranged between 0.22 to 0.57, except for the sexual function (0.70). Conclusions The bifactor model is particularly useful when it is intended to acknowledge multidimensionality and at the same time take account of a single general construct, as the HRQOL related to MS. The total raw score can be used as an estimate of the general HRQOL latent score

Natalizumab discontinuation is associated with a rebound of cognitive impairment in multiple sclerosis patients

Natalizumab discontinuation is associated with a disease reactivation in multiple sclerosis (MS) patients. Whether this reactivation involves also cognitive functions is not known to date. To assess the persistence of the effect of natalizumab on cognitive functions 1&nbsp;year after its discontinuation, we compared the longitudinal changes of cognitive performances in two groups of patients. The interrupters, 30 MS patients, have stopped natalizumab due to PML concern, and the continuers, 28 MS patients, continued the treatment. The cognitive impairment index (CII) was used as main outcome measure. As expected, during the natalizumab treatment, we observed a significant reduction of the relapse rate and the number of gadolinium-enhancing lesions along with a reduction of the CII. After 1&nbsp;year of discontinuation, the beneficial effect on cognitive functions was lost in the interrupters group, as the mean CII increased in comparison with the mean at the end of natalizumab treatment (12.2&nbsp;±&nbsp;7.9 vs 9.3&nbsp;±&nbsp;8.1, p&nbsp;&lt;&nbsp;0.0001). As opposite, in the continuers group, the CII further decreased after an additional year of treatment (8.4&nbsp;±&nbsp;5.1 vs 9.8&nbsp;±&nbsp;4.6, p&nbsp;=&nbsp;0.007). A multivariate logistic regression model revealed as predictors of cognitive worsening male sex, disease duration, and the treatment discontinuation. The worsening of cognitive functions after natalizumab discontinuation goes in parallel with the clinical/radiological disease reactivation. Our data reinforce the hypothesis that, in the short-term, natalizumab exerts its positive impact on cognitive functions by means of its anti-inflammatory properties

Computer-assisted rehabilitation of attention in pediatric multiple sclerosis and ADHD patients: a pilot trial

Abstract Background The treatment of cognitive deficits is challenging in pediatric onset multiple sclerosis (POMS) and in patients with attention deficit hyperactivity disorder (ADHD). We performed a pilot double-blind RCT to evaluate the efficacy of a home-based computerized-program for retraining attention in two cohorts of POMS and ADHD patients. Methods POMS and ADHD patients failing in at least 2/4 attention tests on a neuropsychological battery were randomized to specific or nonspecific computerized training (ST, nST), performed in one-hour sessions, twice/week for 3 months. The primary outcome was the effect of the training on global neuropsychological performances measured by the cognitive impairment index (CII). The efficacy of the intervention was evaluated in each disease group by using repeated measures ANOVA. Results Sixteen POMS (9 females, age 15.75 ± 1.74 years) and 20 ADHD (2 females, age 11.19 ± 2.49 years) patients were enrolled. In POMS patients the ST exposure was associated to a significantly more pronounced improvement of the CII (p < 0.0001) and on cognitive test exploring attention, concentration, planning strategies and visuo-spatial memory performances in comparison to nST exposure. In ADHD patients the difference between the ST and nST on the CII was not statistical significant (p = 0.06), but a greater effect of the ST was found only on cognitive test exploring attention and delayed recall of visuo-spatial memory performances. Conclusions Our data suggest that a cognitive rehabilitation program that targets attention is a suitable tool for improving global cognitive functioning in POMS patients, whereas it has a less pronounced transfer effect in ADHD patients. Trial Registration ClinicalTrials.gov; NCT03190902; registration date: June 15, 2017; retrospectively registered

Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: An Italian collaborative study

Background: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. Objective: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). Methods: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. Results: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR)=1.71; p= 0.02) and for impairment in information processing speed (OR=1.86; p&lt;0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS (p= 0.03) compared with AOMS patients. Conclusion: Patients with a history of POMS appear to be at higher risk of physical and cognitive disability than AOMS patients, after correcting for age effects, with particular involvement of information processing speed