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Background: The precise relationships among quality of life, depression, fatigue and cognitive impairment in multiple sclerosis (MS) are complex and poorly understood. Objective: To assess the effects of subcutaneous interferon beta-1a on quality of life, depression and fatigue over 3 years in the COGIMUS study, and to examine the relationship between these outcomes and baseline cognitive status. Methods: COGIMUS was an observational 3-year trial assessing cognitive function in 459 patients with relapsing–remitting MS treated with subcutaneous interferon beta-1a. Results: In total, 331 patients completed the study (168 received interferon beta-1a, 44 µg subcutaneously three times weekly, and 163 received interferon beta-1a, 22 µg subcutaneously three times weekly). Mean MS Quality of Life-54 (MSQoL-54) composite scores did not change over time. There were no significant differences between groups in MSQoL-54 composite scores when patients were grouped by treatment dose and baseline cognitive status. Mean (standard deviation) Hamilton Depression Rating Scale score decreased from 6.8 (4.9) at baseline to 5.8 (5.9) at year 3. Mean total Fatigue Impact Scale scores were low ( Conclusion: Quality of life, depression and fatigue remained largely stable over 3 years; no effects of treatment dose or baseline cognitive status were found.

The role of cognitive impairment in multiple sclerosis is now widely recognized. However, there is a dearth of research on variability and practice effects of neuropsychological measures when repeated over time. The objective was to assess reliability and practice effects for Rao’s Brief Repeatable Battery of neurophysiological tests and the Stroop Test, and to provide data for correction for variability and practice effects in serial assessments.In 54 healthy controls (34 women, mean age 38.3 ± 9.1 years, mean education 12.9 ± 3.3 years), the Brief Repeatable Battery and Stroop Test were administered 3 times with an 18-month interval. Reliability was assessed by intraclass correlation coefficient and practice effects by an analysis of variance with Bonferroni’s correction for repeated measures. Test—retest reliability was from adequate to good on the Symbol Digit Modalities Test, the Stroop Test, and the Paced Auditory Serial Addition Test. The great majority of tests showed at least a moderate practice effects. Data for calculation of an individual’s change in cognitive performance for each test of the Brief Repeatable Battery and the Stroop Test were provided. Our results provide relevant information for planning and interpreting longitudinal studies on cognition and cognitive rehabilitation in multiple sclerosis.

ObjectiveTo assess the effects of subcutaneous (sc) interferon (IFN) -1a on cognition over 5 years in mildly disabled patients with relapsing-remitting multiple sclerosis (RRMS).MethodsPatients aged 18-50 years with RRMS (Expanded Disability Status Scale score ≤4.0) who had completed the 3-year COGIMUS study underwent standardized magnetic resonance imaging, neurological examination, and neuropsychological testing at years 4 and 5. Predictors of cognitive impairment at year 5 were identified using multivariate analysis.ResultsOf 331 patients who completed the 3-year COGIMUS study, 265 participated in the 2-year extension study, 201 of whom (75.8%; sc IFN β-1a three times weekly: 44 µg, n = 108; 22 µg, n = 93) completed 5 years' follow-up. The proportion of patients with cognitive impairment in the study population overall remained stable between baseline (18.0%) and year 5 (22.6%). The proportion of patients with cognitive impairment also remained stable in both treatment groups between baseline and year 5, and between year 3 and year 5. However, a significantly higher proportion of men than women had cognitive impairment at year 5 (26.5% vs 14.4%, p = 0.046). Treatment with the 22 versus 44 µg dose was predictive of cognitive impairment at year 5 (hazard ratio 0.68; 95% confidence interval 0.48-0.97).ConclusionsThis study suggests that sc IFN β-1a dose-dependently stabilizes or delays cognitive impairment over a 5-year period in most patients with mild RRMS. Women seem to be more protected against developing cognitive impairment, which may indicate greater response to therapy or the inherently better prognosis associated with female sex in MS.

Background Conventional magnetic resonance imaging (MRI) has improved the diagnosis and monitoring of multiple sclerosis (MS). In clinical trials, MRI has been found to detect treatment effects with greater sensitivity than clinical measures; however, clinical and MRI outcomes tend to correlate poorly. Methods In this observational study, patients (n = 550; 18-50 years; relapsing-remitting MS [Expanded Disability Status Scale score ≤4.0]) receiving interferon (IFN) β-1a therapy (44 or 22 µg subcutaneously [sc] three times weekly [tiw]) underwent standardized MRI, neuropsychological and quality-of-life (QoL) assessments over 3 years. In this post hoc analysis, MRI outcomes and correlations between MRI parameters and clinical and functional outcomes were analysed. Results MRI data over 3 years were available for 164 patients. T2 lesion and T1 gadolinium-enhancing (Gd+) lesion volumes, but not black hole (BH) volumes, decreased significantly from baseline to Year 3 (P < 0.0001). Percentage decreases (baseline to Year 3) were greater with the 44 μg dose than with the 22 μg dose for T2 lesion volume (-10.2% vs -4.5%, P = 0.025) and T1 BH volumes (-7.8% vs +10.3%, P = 0.002). A decrease in T2 lesion volume over 3 years predicted stable QoL over the same time period. Treatment with IFN β-1a, 44 μg sc tiw, predicted an absence of cognitive impairment at Year 3. Conclusion Subcutaneous IFN β-1a significantly decreased MRI measures of disease, with a significant benefit shown for the 44 µg over the 22 µg dose; higher-dose treatment also predicted better cognitive outcomes over 3 years.

Background A critical problem with neuropsychological assessment in children and adolescents with multiple sclerosis (MS) is the absence of a standardized, well-validated neuropsychological battery specifically tailored for detecting disease-related cognitive problems in this age range. Objective To develop a Brief Neuropsychological Battery for Children (BNBC) with MS. Methods We assessed cognitive functions in 61 patients with childhood and juvenile MS and 58 demographically matched healthy controls through an extensive neuropsychological battery. Results In MS patients, we found a proportion of cognitive impairment of 41%. In the BNBC, we included the tests with higher discriminating ability (the Selective Reminding Test, the Symbol Digit Modalities Test, the Trail Making Test, and the Vocabulary test from the Wechsler Intelligence Scale for children). The BNBC yielded a sensitivity of 96% and a specificity of 76%. Conclusion Our findings provide preliminary evidence of the usefulness of the BNBC as a screening tool for detecting cognitive impairment in childhood and juvenile MS cases.

Background Cognitive impairment is a common symptom of multiple sclerosis (MS), but the association between cognitive impairment and magnetic resonance imaging (MRI) disease measures in patients with relapsing–remitting (RR) MS is unclear. Objectives To study the prevalence of cognitive impairment and its relation with MRI disease measures in mildly disabled patients with RRMS. Methods Patients aged 18–50 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score ≤4.0, who were enrolled in the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study, underwent baseline standardized MRI complete neurological examination and neuropsychological testing. Results A total of 550 patients were enrolled, 327 of whom underwent MRI assessments. Cognitive impairment (impaired performance in ≥3 cognitive tests) was present in approximately 20% of all patients and in the subgroup who underwent MRI. T2 hyperintense and T1 hypointense lesion volumes were significantly higher in patients with cognitive impairment (defined as impaired performance on at least three tests of the Rao’s battery) than those without. EDSS score was also significantly higher in cognitively impaired than in cognitively preserved patients. Disease duration, depression, and years in formal education did not differ significantly between cognitively impaired and cognitively preserved patients. T2 lesion volume, performance intelligence quotient, and age were significant predictors of cognitive impairment in this population. Weak correlations were found between performance on individual cognitive tests and specific MRI measures, with T1 and T2 lesion volumes correlating with performance on most cognitive tests. Conclusions Cognitive impairment occurs in approximately one-fifth of mildly disabled patients with MS and is associated with specific MRI disease measures. Assessment of cognitive function at diagnosis could facilitate the identification of patients who may benefit from therapeutic intervention with disease-modifying therapies to prevent further lesion development.

Objective: The aim of the study was to perform a third cognitive assessment in our pediatric-onset multiple sclerosis (MS) patient cohort and determine predictors of the individual cognitive outcome. Methods: After 4.7 ± 0.7 years from baseline evaluation, 48 of 63 patients in the original cohort were reassessed on an extensive neuropsychological battery and compared with 46 healthy controls. Two alternate versions of the tests were used at different assessment points. Cognitive impairment was defined as the failure of ≥3 tests; individual change in the cognitive impairment index was measured. Results: At year 5, 38% of the subjects with MS fulfilled our criterion for impairment. Between years 2 and 5, regarding individual cognitive impairment index change, 66.7% of the patients improved. However, comparing baseline and 5-year testing (when the same versions of the tests were used), cognitive impairment index deterioration was observed in 56% of the patients, improvement in 25%, and stability in 18.8%. A deteriorating performance was related to male sex, younger age and age at MS onset, and lower education. None of these variables, however, was retained in the multivariate analysis. Conclusions: Cognitive outcome in pediatric-onset MS can be heterogeneous. Progression of cognitive problems in a few subjects and potential for compensation and improvement in others call for systematic cognitive screening in this population and development of effective treatment strategies.

In adult-onset multiple sclerosis (MS) cases, major depression, fatigue and psychological distress are common, whereas there is little information on these issues in children with the disease. The aim of this study was to assess psychosocial disorders in an Italian cohort of children and adolescent with MS. We evaluated 56 patients through self-assessment scales of depression (Children Depression Inventory) and fatigue (Fatigue Severity Scale), a psychiatric interview [Kiddie-SADS-Present and Lifetime Version (K-SADS-PL)] and an interview on school and everyday activities. Significant fatigue was found in 11 patients (20%). Twelve of the 39 patients who underwent the K-SADS-PL received a formal diagnosis of an affective disorder. Moreover, MS affected school activities in 28% of cases, daily living activities in 41% and social relationships in 28%. Our study confirms the critical role of psychosocial difficulties in children and adolescents with MS and provides a few cues to clinical management.

To assess the impact of multiple sclerosis (MS) on cognitive and psychosocial functioning in childhood and juvenile cases.We used an extensive neuropsychological battery assessing IQ, memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. Performance of cases was compared with that of demographically matched healthy controls.Sixty-three patients and 57 healthy controls were assessed. Five patients (8%) exhibited a particularly low IQ (70). Criteria for cognitive impairment (failure on at least three tests) were fulfilled in 19 patients (31%), whereas 32 patients (53%) failed at least two tests. Beyond deficits in memory, complex attention, and executive functions, the profile of deficits was characterized by involvement of linguistic abilities. In the regression analysis, the only significant predictor of cognitive impairment was an IQ score lower than 90 (odds ratio [OR] 18.2, 95% CI 4.6-71.7, p0.001). Considering the IQ score as a dependent variable, the only significant predictor was represented by younger age at onset (OR 0.7, 95% CI 0.5-0.9, p = 0.009). Depressive symptoms were reported by 6% of the cases, and fatigue was reported by 73% of the cases. MS negatively affected school and everyday activities in 56% of the subjects.In childhood and juvenile cases, multiple sclerosis (MS) is associated with cognitive impairment and low IQ scores, the latter related to younger age at onset. These aspects are of critical importance in helping children and adolescents with MS to manage their difficulties and psychosocial challenges.

Background and ObjectivesPatients with pediatric-onset multiple sclerosis (MS) can be especially vulnerable to cognitive impairment (CI) due to the onset of MS during a critical period for CNS development and maturation. The objective of this longitudinal study was to assess long-term cognitive functioning and socioprofessional attainment in the Italian pediatric MS cohort, previously assessed at baseline and 2 and 5 years.MethodsThe 48 patients evaluated at the 5-year assessment were screened for inclusion. All participants were assessed with a cognitive test battery exploring 4 different cognitive abilities. Depression, fatigue, and socioprofessional attainment were also assessed. Mean cognitivezscores were calculated for the whole cohort, and their evolution over time was analyzed with an analysis of variance for repeated measurements test. Predictors of cognitive worsening or improvement were assessed with a linear mixed-model analysis.ResultsThirty-three participants were included (mean follow-up 12.8 ± 0.8 years). The global cognitive performance worsened at year 2 and improved at year 5, although thezscore remained significantly lower than at baseline (−0.9 ± 1.2 vs −0.3 ± 0.9,p= 0.002). There was no significant variation between years 5 and 12 (−0.7 ± 1.1,p= 0.452). Higher IQ (>90) at baseline (effect 0.3, 95% CI 0.1–0.5,p= 0.017) and lower number of relapses in the 2 years before baseline (effect −0.1, 95% CI −0.1 to 0.1,p= 0.025) predicted better cognitive performances. Eighteen (54.5%) patients failed at least 2 tests compared with healthy controls and were defined as cognitively impaired. The presence of CI predicted worse socioprofessional attainment (β = 4.8, 95% CI 1.4–8.2,p= 0.008).DiscussionThe longitudinal cognitive trajectory in pediatric-onset MS has a heterogeneous course over time, with a decline in the first years followed by a partial recovery over the long term. However, at the last follow-up evaluation, the proportion of impaired patients was more than double compared with baseline, with a negative impact on the individual’s socioprofessional attainment in adulthood. This study underscores how cognitive reserve may partially mitigate the negative effects of brain damage, highlighting the critical importance of intellectual enrichment early during the disease course.

Importance: Cognitive impairment is a common and disabling feature of multiple sclerosis (MS), but a precise characterization of cognitive phenotypes in patients with MS is lacking. Objectives: To identify cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and magnetic resonance imaging (MRI) features. Design, Setting, and Participants: This multicenter cross-sectional study consecutively screened clinically stable patients with MS and healthy control individuals at 8 MS centers in Italy from January 1, 2010, to October 31, 2019. Patients with MS and healthy control individuals who were not using psychoactive drugs and had no history of other neurological or medical disorders, learning disability, severe head trauma, and alcohol or drug abuse were enrolled. Main Outcomes and Measures: Participants underwent a neurological examination and a cognitive evaluation with the Rao Brief Repeatable Battery and Stroop Color and Word Test. A subgroup of participants also underwent a brain MRI examination. Latent profile analysis was used on cognitive test z scores to identify cognitive phenotypes. Linear regression and mixed-effects models were used to define clinical and MRI features of each phenotype. Results: A total of 1212 patients with MS (mean [SD] age, 41.1 [11.1] years; 784 women [64.7%]) and 196 healthy control individuals (mean [SD] age, 40.4 [8.6] years; 130 women [66.3%]) were analyzed in this study. Five cognitive phenotypes were identified: Preserved cognition (n = 235 patients [19.4%]), mild-verbal memory/semantic fluency (n = 362 patients [29.9%]), mild-multidomain (n = 236 patients [19.5%]), severe-executive/attention (n = 167 patients [13.8%]), and severe-multidomain (n = 212 patients [17.5%]) involvement. Patients with preserved cognition and mild-verbal memory/semantic fluency were younger (mean [SD] age, 36.5 [9.8] years and 38.2 [11.1] years) and had shorter disease duration (mean [SD] 8.0 [7.3] years and 8.3 [7.6] years) compared with patients with mild-multidomain (mean [SD] age, 42.6 [11.2] years; mean [SD] disease duration, 12.8 [9.6] years; P

This study jointly examined illness beliefs held by persons with multiple sclerosis (PwMS) and caregivers in relation to well-being. A group of 68 PwMS and their caregivers completed the Revised Illness Perception Questionnaire, Psychological Well-being Scales, Satisfaction with Life Scale and Positive Affect and Negative Affect Schedule. Findings revealed that PwMS’ well-being was primarily predicted by their own illness beliefs, and that also caregivers’ well-being was primarily predicted by their own beliefs. Across the two groups, well-being was positively associated with their belief that they understood the disease, and inversely associated with their representations of negative emotions. In addition, among PwMS, well-being was inversely associated with the number of symptoms they specifically attributed to their illness, while among caregivers, well-being was positively associated with beliefs that treatment could control the disease. Based on the study findings, psychoeducational and cognitive-behavioral strategies are suggested to promote well-being among PwMS and caregivers.

Background BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) has been recently developed as brief, practical and universal assessment tool for cognitive impairment in MS subjects. It includes the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2) and the Brief Visuospatial Memory Test–Revised (BVMT-R) . In this study we aimed at gathering regression based normative data for the BICAMS battery in the Italian population. Methods Healthy subjects were consecutively recruited among patient friends and relatives. Corrections for demographics were calculated using multivariable linear regression models. Test-retest reliability was assessed using the Pearson correlation coefficient. Results The BICAMS battery was administered to 273 healthy subjects (180 women, mean age 38.9 ± 13.0 years, mean education 14.9 ± 3.0 years). Test-retest reliability was good for all the tests. Conclusions The study provided normative data of the BICAMS for the Italian population confirming good test-retest reliability which can facilitate the use of the battery in clinical practice, also for longitudinal patient assessments.

Article history:Received 2 September 2013Received in revised form 21 October 2013Accepted 12 November 2013Available online xxxxKeywords:Multiple sclerosisQuality of lifeDepressionWell-beingPatientsCaregiversHealth professionals Background: Studies on emotional distress and health-related quality of life (HRQOL) broadened the traditionalbio-medical focus in MS research, but little attention was paid to general well-being indicators.Objective:Toinvestigateforthefirsttimebothill-beingandwell-beingdimensionsinpersonswithMS(PwMSs),caregivers and health professionals, in relation to both health and life in general.Methods: A multi-center study assessed participants' depression (Beck Depression Inventory-II), HRQOL (ShortForm-36),psychologicalwell-being(PsychologicalWell-BeingScales),optimalexperience(FlowQuestionnaire),lifesatisfaction(SatisfactionwithLifeScale),hedonicbalance(PositiveAffectandNegativeAffectSchedule).De-mographic and clinical information was also gathered.Results: Overall, 71 PwMSs, 71 caregivers and 26 professionals were enrolled (N = 168). Compared to healthypopulations,PwMSsreportedhigherdepression,lowerHRQOLandlowergeneralwell-being;caregiverspresent-ed higher depression and lower general well-being; professionals reported the best ill- and well-being profiles.However,aftercontrollingfordemographicdifferencesinageandeducation,hierarchicalregressionshighlightedthat, though PwMSs reported higher depression and lower HRQOL than caregivers and professionals, their gen-eral well-being substantially leveled off.Conclusions:Well-beingcoexistswithill-being.Itcancounterbalancethenegativeeffectsofdiseaseorcaregiving,and its measurement could complement and support medical intervention.© 2013 Elsevier B.V. All rights reserved.

Background: There is limited information on fatigue and its clinical and psychosocial correlates in children and adolescents with multiple sclerosis (MS). Objective: To assess the relationships between fatigue, cognitive functioning and depression in paediatric MS. Methods: The study cohort consisted of patients with MS recruited for an Italian collaborative study on cognitive and psychosocial functioning in paediatric MS. The present assessment included evaluation of fatigue on the Pediatric Quality of Life Inventory-Multidimensional Fatigue Scale, cognitive functioning on an extensive neuropsychological battery and depression on the Children’s Depression Inventory (CDI). A psychiatric interview through the Kiddie-SADS-Present and Lifetime Version was also administered. Results: In total, 57 patients with relapsing–remitting MS were compared with 70 healthy controls. Percentages of fatigued patients ranged from 9% to 14% according to self-reports, and from 23% to 39% according to parent reports. Fatigue was significantly related with higher scores on the CDI ( p < 0.03). Higher levels of self-reported cognitive fatigue were associated with impaired performance on a problem-solving test, whereas higher levels of parent-reported cognitive fatigue were associated with impairment on tests of verbal learning, processing speed, complex attention and verbal comprehension. Conclusions: Our data show that fatigue can affect a sizeable proportion of paediatric MS patients, and confirm the association between fatigue and depressive symptoms in MS. They also highlight the difficulties of fatigue assessment in the paediatric population and provide a few clues to further research in the field.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was shown to strongly affect BDNF function, but its role in modulating gray matter damage in multiple sclerosis (MS) patients is still not clear. Given BDNF relevance on the hippocampus, we aimed to explore BDNF Val66Met polymorphism effect on hippocampal subfield volumes and its role in cognitive functioning in MS patients. Using a 3T scanner, we obtained dual-echo and 3DT1-weighted sequences from 50 MS patients and 15 healthy controls (HC) consecutively enrolled. MS patients also underwent genotype analysis of BDNF, neurological and neuropsychological evaluation. Hippocampal subfields were segmented by using Freesurfer. The BDNF Val66Met polymorphism was found in 22 MS patients (44%). Compared to HC, MS patients had lower volume in: bilateral hippocampus-amygdala transition area (HATA); cornus ammonis (CA)1, granule cell layer of dentate gyrus (GCL-DG), CA4 and CA3 of the left hippocampal head; molecular layer (ML) of the left hippocampal body; presubiculum of right hippocampal body and right fimbria. Compared to BDNF Val66Val, Val66Met MS patients had higher volume in bilateral hippocampal tail; CA1, ML, CA3, CA4, and GCL-DG of left hippocampal head; CA1, ML, and CA3 of the left hippocampal body; left HATA and presubiculum of the right hippocampal head. In MS patients, higher lesion burden was associated with lower volume of presubiculum of right hippocampal body; lower volume of left hippocampal tail was associated with worse visuospatial memory performance; lower volume of left hippocampal head with worse performance in semantic fluency. Our findings suggest the BNDF Val66Met polymorphism may have a protective role in MS patients against both hippocampal atrophy and cognitive impairment. BDNF genotype might be a potential biomarker for predicting cognitive prognosis, and an interesting target to study for neuroprotective strategies.