Search

Background: There is limited information on interpretation of cognitive changes over time in multiple sclerosis (MS)., Objective: This study aimed to provide normative data for the assessment of statistically meaningful change in all tests of the Minimal Assessment of Cognitive Function in MS (MACFIMS)., Methods: We applied the reliable change methodology to a healthy Italian cohort, assessed with two alternate versions of the MACFIMS 1 year apart. We calculated confidence intervals of retest score variance using the reliable change index (RCI). Moreover, multivariable linear regression models adjusted for age, sex, education, and baseline score were built to calculate the regression-based change index (RB-CI)., Results: Overall, 200 healthy individuals were enrolled. Thresholds for interpreting change in each test were calculated. In the multivariable models, baseline score was associated with retest score in all tests ( B from 0.439 to 0.760; p < 0.001). RB-CI can be calculated with data of the multivariable models., Conclusion: We provide normative data for reliable cognitive change evaluation for all the tests of the MACFIMS, which includes the Symbol Digit Modalities Test and Brief International Cognitive Assessment in MS, two widely used tools for screening and monitoring cognition in MS. Our findings can significantly improve the interpretation of cognitive changes in MS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.P. received compensation for travel grants, participation in advisory board and speaking activities from Biogen, Merck Serono, Sanofi, Teva, Roche, BMS Celgene, Janssen, and Novartis, and served on the editorial board of Frontiers in Neurology and Brain Sciences. M.P.A. served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis, and serves on the editorial board of Multiple Sclerosis Journal and BMC Neurology. P.G., F.B., V.B., S.C., M.F., B.G., C.N., E.P., and R.G.V. declare that there is no conflict of interest.

Background and Objectives: Patients 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., Methods: The 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 cognitive z scores 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., Results: Thirty-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 the z score 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)., Discussion: The 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., (© 2022 American Academy of Neurology.)

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., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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 < .001), severe-executive/attention (mean [SD] age, 42.9 [11.7] years; mean [SD] disease duration, 12.2 [9.5] years; P < .001), and severe-multidomain (mean [SD] age, 44.0 [11.0] years; mean [SD] disease duration, 13.3 [10.2] years; P < .001) phenotypes. Severe cognitive phenotypes prevailed in patients with progressive MS. At MRI evaluation, compared with those with preserved cognition, patients with mild-verbal memory/semantic fluency exhibited decreased mean (SE) hippocampal volume (5.42 [0.68] mL vs 5.13 [0.68] mL; P = .04), patients with the mild-multidomain phenotype had decreased mean (SE) cortical gray matter volume (687.69 [35.40] mL vs 662.59 [35.48] mL; P = .02), patients with severe-executive/attention had higher mean (SE) T2-hyperintense lesion volume (51.33 [31.15] mL vs 99.69 [34.07] mL; P = .04), and patients with the severe-multidomain phenotype had extensive brain damage, with decreased volume in all the brain structures explored, except for nucleus pallidus, amygdala and caudate nucleus., Conclusions and Relevance: This study found that by defining homogeneous and clinically meaningful phenotypes, the limitations of the traditional dichotomous classification in MS can be overcome. These phenotypes can represent a more meaningful measure of the cognitive status of patients with MS and can help define clinical disability, support clinicians in treatment choices, and tailor cognitive rehabilitation strategies.

Background: A significant proportion of patients with multiple sclerosis (MS) show cognitive impairment., Objective: To evaluate the effect of 2-year treatment with oral dimethyl fumarate (DMF) on cognition in relapsing remitting MS (RRMS)., Methods: In this prospective single-arm study RRMS patients treated with DMF underwent a wide battery of tests, including an extensive neuropsychological evaluation, clinical and patient-reported outcomes (PROs) and quality of life (QoL). Primary endpoints were the proportion of patients with cognitive impairment at baseline and of patients with cognitive worsening over 2 years., Results: Overall, 217 patients (74.2% females, mean age 37.3 years) receiving DMF were recruited, and 156 (67.2%) completed the study. Of the 49 patients with cognitive impairment at baseline, 34 had 2-year data: 15 (44.1%) patients worsened and 19 (55.9%) did not. The cognitive impairment index improved in one third of patients at 2 years. Less than 20% of patients had relapses at 2 years (annualized relapse rate: 0.190). Few patients had disability progression. PROs (fatigue, depression, impairment in work/social activities), QoL, and most of neuropsychological tests significantly improved vs. baseline., Conclusion: The 2-year treatment with DMF was associated with slowing of cognitive impairment and with significant improvements in QoL and psychosocial function.

Cognitive impairment is common in multiple sclerosis (MS), and research has emphasized the crucial role of cognitive assessment in disease monitoring. The minimal neuropsychological assessment of MS (MACFIMS) represents one of the neuropsychological batteries most widely used throughout the world. To date, a complete validation, as well as normative values of an alternative form, is lacking in the Italian population, limiting the use of this tool in longitudinal assessment. A total of 200 healthy subjects (127 females and 73 males) were recruited from the community in 8 Italian cities and were evaluated with the MACFIMS at baseline and reassessed with an alternate form of the same battery after 12 months. Regression-based norms that account for demographic influences on test performance were calculated at each time point (baseline and follow-up). The study provides, for the first time, normative values of two forms of the MACFIMS battery for the Italian population. Data application allows clinicians to monitor the performance of cognitive functions over time and to better understand the efficacy of both pharmacological and non-pharmacological interventions in clinical practice and research.

Background: Many potentially modifiable risk factors for MS are investigated. It is not known, however, if these factors also apply to MS-related cognitive impairment (CI), a frequent consequence of MS., Objective: The aim of our study was to assess risk factors for CI in MS patients, focusing on environmental exposures, lifestyle and comorbidities., Methods: We included MS patients referring to MS Centers in Florence and Barletta between 2014 and 2017. Neuropsychological performance was assessed through the Rao's battery and Stroop test, cognitive reserve (premorbid intelligence quotient-IQ) was evaluated using the National Adult Reading Test (NART). Potential risk factors were investigated through a semi-structured questionnaire., Results: 150 patients were included. CI was detected in 45 (30%) subjects and was associated with older age (p<0.005), older age at MS onset (p = 0.016), higher EDSS score (p<0.005), progressive disease course (p = 0.048) and lower premorbid IQ score (p<0.005). As for risk factors, CI was related with lower physical activity in childhood-adolescence (p<0.005). In women, hormonal therapy resulted to be protective against CI (p = 0.041). However, in the multivariable analysis, the only significant predictors of CI were older age (p<0.05; OR 1.06, 95% CI 1.02-1.10) and lower premorbid IQ (p<0.05; OR 0.93, 95% CI: 0.88-0.98). Removing IQ from the model, CI was associated with higher EDSS (p = 0.030; OR 1.25, 95% CI 1.02-1.53) and, marginally, previous physical activity (p = 0.066; OR 0.49, 95% CI: 0.23-1.05)., Conclusions: Our findings suggest that physical activity in childhood-adolescence could be a contributor to cognitive reserve building, thus representing a potential protective factors for MS-related CI susceptible to preventive strategies., Competing Interests: The authors have declared that no competing interests exist.

Background: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group., Objective: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients., Methods: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains., Results: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70)., Conclusion: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders.

Background: Definition of benign multiple sclerosis (BMS) remains controversial. Moreover, a sizeable proportion of classically defined BMS patients may be no longer benign (NLB) when re-assessed in the long-term. In a previous work, we found that after a five-year follow-up, a clinical score was able to identify patients at risk of losing their benign status., Objectives: In this 12-year reappraisal of the same cohort, we aimed at assessing the predictive value of the same score in the long-term., Methods: After a mean follow-up of 12.6 + 0.4 years, patients still having an EDSS score <3.0 were classified as "still benign" (SB), whereas patients having an EDSS score ≥3.5 were defined as NLB. The predictive value of the mentioned score was re-assessed using survival analysis., Results: By the end of the follow-up, 20 (32.8%) were classified as NLB. Patients were grouped on the basis of the above mentioned score. Patients with score 2-3 were at higher risk of NLB status at the follow-up (HR = 3.5; 95%CI 1.5-8.6; p = 0.005, accuracy = 70.5%)., Conclusions: In patients with established BMS, prognostic prediction of longer-term disease course remains of critical value. In this study, a clinical score was able to predict disease evolution in the long term., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., 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.

The aim of this consensus paper was to define the state of the art on cognitive assessment of persons with multiple sclerosis (PwMS), with the purpose of providing recommendations for the Italian centers involved in MS management. While there are no formal guidelines published regarding the assessment of cognitive function in MS, on the basis of an expert opinion meeting, held in Milan (Italy) on July 4, 2016, we report the recommendations of a panel of Italian experts including MS neurologists and neuropsychologists for the assessment and follow-up of cognitive function in adult MS subjects.

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS), most probably autoimmune in origin, usually occurring in young adults with a female/male prevalence of approximately 3:1. Women with MS in the reproductive age may face challenging issues in reconciling the desire for parenthood with their condition, owing to the possible influence both on the ongoing or planned treatment with the possible consequences on the disease course and on the potential negative effects of treatments on foetal and pregnancy outcomes. At MS diagnosis, timely counselling should promote informed parenthood, while disease evolution should be assessed before making therapeutic decisions. Current guidelines advise the discontinuation of any treatment during pregnancy, with possible exceptions for some treatments in patients with very active disease. Relapses decline during pregnancy but are more frequent during puerperium, when MS therapy should be promptly resumed in most of the cases. First-line immunomodulatory agents, such as interferon-β (IFN-β) and glatiramer acetate (GA), significantly reduce the post-partum risk of relapse. Due to substantial evidence of safety with the use of GA during pregnancy, a recent change in European marketing authorization removed the pregnancy contraindication for GA. This paper reports a consensus of Italian experts involved in MS management, including neurologists, gynaecologists and psychologists. This consensus, based on a review of the available scientific evidence, promoted an interdisciplinary approach to the management of pregnancy in MS women.

Processing speed is a frequently affected cognitive domain in pediatric multiple sclerosis (MS) and is commonly assessed using the Symbol Digit Modalities Test (SDMT). The objective of this study was to determine maturational trajectories in SDMT performance and baseline factors affecting trajectories in a sample of 82 pediatric MS individuals. Performance on the SDMT increased with age in patients with pediatric MS followed by a subsequent decline. Furthermore, patients who were older at disease onset and had a higher IQ showed greater gains with age, suggesting that these factors may be protective with respect to cognitive maturation in pediatric MS.

Background: The study of cognitive reserve (CR) in relationship with cognitive impairment (CI) in pediatric-onset multiple sclerosis (POMS) may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies., Objectives: To assess the potential impact of CR on cognition in a cohort of POMS patients., Methods: In all, 48 POMS patients were followed up for 4.7 ± 0.4 years. CI was defined as the failure of ⩾3 tests on an extensive neuropsychological battery. Change of neuropsychological performance was assessed through the Reliable Change Index (RCI) method. At baseline, CR was estimated by measuring the intelligence quotient (IQ). The relationships were assessed through multivariable regression analyses., Results: At baseline, CI was detected in 14/48 (29.2%) patients. Two out of 57 healthy control (HC; 3.5%) met the same criteria of CI (p < 0.001). A deteriorating cognitive performance using the RCI method was observed in 18/48 patients (37.6%). Among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (odds ratio (OR) = 1.11; 95% confidence interval (CI): 1.03-1.20; p = 0.006)., Conclusion: Our results suggest that higher CR in POMS patients may protect from CI, particularly in subjects with initial cognitive preservation, providing relevant implications for counseling and rehabilitation strategies., (© The Author(s), 2016.)

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: Recently, a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been developed as an international and standardized brief cognitive test, which is easily performed in everyday clinical practice for neuropsychological assessment in multiple sclerosis (MS). However, we need to gather more information about this tool compared to other neuropsychological batteries. The aim of our study is to compare the performance of BICAMS and Brief Repeatable Battery (BRB) in MS subjects., Methods: Tests of the BRB and BICAMS were administered to MS patients recruited from 11 Italian MS centres. Cognitive impairment (CI) was defined as the failure on at least two tests (scores below the fifth percentile) on the BRB and as the failure on at least one test of the BICAMS. The agreement between the performances on the two batteries was assessed through Cohen's K statistic. Finally we calculated the effects sizes for each test of the two batteries using Cohen's d., Results: The two batteries were administered to 192 MS patients (142 women, 50 men; mean age 41.4 ± 10.8 years, mean education 12.3 ± 3.5 years). Mean scores of patients were lower compared to those of healthy subjects in all the cognitive measures examined. Forty-six MS patients were identified as impaired and 48 as unimpaired on both of the batteries, when the Symbol Digit Modalities Test (SDMT) was included in the analysis. Cohen's K statistic was 0.46 which corresponds to a moderate accord. If the SDMT was excluded from the BRB, 37 MS patients were identified as impaired and 57 as unimpaired on both of the batteries. Cohen's K statistic was 0.3 which corresponds to a poor accord. The SDMT, the Paced Auditory Serial Addition Test (PASAT) 3 and 2 yielded higher d values (SDMT 0.83, PASAT 3 0.65, PASAT 2 0.84)., Conclusions: This study confirms the feasibility of BICAMS in everyday clinical practice for the identification of CI and highlights the good psychometric properties of the SDMT.

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.

Background: A defective emotional enhancement of verbal memory (VM) performances has been reported in different neurological diseases., Objectives: To assess the emotional enhancement of VM in 22 Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis (MS) and 49 Relapsing (RR) MS patients in comparison to 32 Healthy Controls (HC)., Methods: Immediate and delayed recall of VM was assessed using the Selective Reminding Test (SRT). A list of 12 emotionally significant words was used to evaluate the Emotional (E) variants of the SRT. Depressive symptoms were assessed by the Beck Depression Inventory., Results: The prevalence of depression did not differ between RRMS and CIS patients. Both patient groups showed poorer (p<0.01) VM performances in comparison to HC in all the SRT tasks, but no difference was found between the two patient groups. Emotionally salient words were more (p<0.0001) recalled than neutral words in HC and CIS, but not in RRMS patients, while performing the immediate recall tasks. Delayed recall was not affected by emotional stimuli in both CIS and RR MS groups. The presence of depressive symptoms did not influence the VM performances., Conclusions: Our results demonstrate a defective emotional enhancement of VM in definite MS and, although to a lesser extent, in CIS patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate the impact of anxiety on the cognitive performance of a clinical sample of relapsing-remitting (RR) MS patients. One hundred ninety patients (140 females) were included in the study and assessed through the beck depression inventory, the state-trait anxiety inventory and the Rao's brief repeatable battery which assesses cognitive domains most frequently impaired in MS. As for neuropsychological performance, a total of 76 (40%) subjects fulfilled our criterion for cognitive impairment. Tests most frequently failed by cognitive impairment (CI) patients were those assessing complex attention and information processing speed [Simbol Digit Modalities Test (SDMT), Paced Auditory Serial Auditory Test (PASAT) 3 and 2] and verbal memory. In the univariate analysis, state anxiety was related to failure on the SDMT (p = 0.042), and marginally, to failure on the PASAT-3 (p = 0.068), and to the presence of CI (p = 0.082). Moderate/severe depression was detected in 38 (20%) patients and fatigue in 109 (57%). Higher depression scores were related to impairment on the ST (OR = 1.05; 95% CI 1.01-1.10; p = 0.029).

Background: Studies on emotional distress and health-related quality of life (HRQOL) broadened the traditional bio-medical focus in MS research, but little attention was paid to general well-being indicators., Objective: To investigate for the first time both ill-being and well-being dimensions in persons with MS (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 (Short Form-36), psychological well-being (Psychological Well-Being Scales), optimal experience (Flow Questionnaire), life satisfaction (Satisfaction with Life Scale), hedonic balance (Positive Affect and Negative Affect Schedule). Demographic and clinical information was also gathered., Results: Overall, 71 PwMSs, 71 caregivers and 26 professionals were enrolled (N=168). Compared to healthy populations, PwMSs reported higher depression, lower HRQOL and lower general well-being; caregivers presented higher depression and lower general well-being; professionals reported the best ill- and well-being profiles. However, after controlling for demographic differences in age and education, hierarchical regressions highlighted that, though PwMSs reported higher depression and lower HRQOL than caregivers and professionals, their general well-being substantially leveled off., Conclusions: Well-being coexists with ill-being. It can counterbalance the negative effects of disease or caregiving, and its measurement could complement and support medical intervention., (Copyright © 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.

Approximately, 3-10% of patients with multiple sclerosis (MS) present a disease onset before the age of 18 years. Although growing attention is dedicated to cognitive impairment and its functional consequences in paediatric MS, so far no study has explored possible neurophysiologic correlates. The study's aim was to describe event-related potentials in relationship with cognitive performance in children and adolescents with MS compared with demographically matched healthy controls (HC), providing two-year follow-up data. Six MS subjects aged between 9 and 17 years were assessed through an extensive neuropsychological battery at two time points. Event-related potentials with an odd-ball acoustic paradigm were also recorded in the patients and in nine HC. At baseline, four out of six patients failed three or more cognitive tasks and were classified as cognitively impaired. In all the cognitively impaired patients, we found abnormal latencies and amplitudes of the P300. After 2 years, five patients exhibited a deteriorating cognitive performance and a corresponding deterioration of the P300 parameters. In our group of children and adolescents with MS, changes in P300 parameters proceeded in parallel with deteriorating cognitive performance. P300 might represent an objective parameter to monitor cognitive changes in paediatric MS.

Cognitive dysfunction involves 40-65% of multiple sclerosis patients and can have a great functional impact. It can be detected in all the disease phenotypes since the early stages of the disease, and tends to progress over time. Memory, complex attention, information-processing speed and executive functions are most commonly involved. The relationship between cognitive changes and magnetic resonance imaging (MRI) findings may involve changes in different areas, including white matter lesions, cortical and deep grey matter and normal appearing brain tissue on conventional MRI. The search for effective therapeutic strategies is a major undertaking, involving the use of both pharmacologic and rehabilitative approaches. Early treatment with disease-modifying drugs that can contain the disease burden in the brain seems to be highly advisable in order to prevent or delay the development of cognitive impairment.

Cognitive impairment has been recently recognized in patients with pediatric multiple sclerosis in more than 30% of cases. Altered functions with variable frequency are: attention, language (receptive, verbal fluency, naming), visual-spatial and motor functions, spatial memory, executive functions and abstract reasoning. Fatigue and affective disorders are associated, but not correlated with cognitive impairment. The frequency and severity of cognitive impairment increase with time. Cognitive impairment has a negative impact on patient's life limiting social, academic and recreational activities.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system typically affecting young adults. Psychological coping has proved to be crucially important for adjusting to the adaptive demands of chronic diseases, and in the last few years it has received growing interest in MS. A common finding in the literature is that MS patients tend to adopt dysfunctional avoiding strategies and to rely less on task-oriented and positive attitude strategies, which represent a better adjustment to disease-related challenges. Moreover, the studies show higher psychoticism in MS subjects compared with the general population, and higher levels of depression and anxiety that can contribute to lower QoL perception. In our study including 63 MS patients cognitive functioning did not seem to influence the type of coping. However, subjects with impairment on tasks that assess sustained attention and some aspects of executive function were less prone to adopt positive coping strategies. Cognitive and emotional problems should be carefully monitored, providing prompt diagnosis and treatment as appropriate.

Cognitive impairment can be detected in a sizeable proportion of pediatric multiple sclerosis (MS) patients. It involves memory, complex attention, information processing speed, executive functions, linguistic abilities, and intelligent quotient. It has a great impact on school, everyday and social activities, and significantly progresses overtime in the great majority of the subjects. These findings highlight the importance of a comprehensive and systematic assessment of MS-related cognitive difficulties in pediatric cases. Moreover, despite the acknowledged relevance of cognitive impairment in this age range, specific interventions for pediatric MS are lacking. As for rehabilitative strategies, there is some evidence of efficacy in other diseases, in particular brain trauma, tumor, and stroke. The development of effective rehabilitative strategies tailored to the needs of young MS patients is a priority for future research in the field.

Objective: To assess the evolution of cognitive and psychosocial functioning in a cohort of childhood and juvenile multiple sclerosis (MS) cases after a mean period of 2 years had elapsed since baseline evaluation., Methods: In this cohort study, we used the same extensive neuropsychological battery with alternative versions of the tests assessing 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. The cognitive performance of the patients was compared with that of demographically matched healthy controls (HC)., Results: Fifty-six patients and 50 HC were assessed. At follow-up, criteria for cognitive impairment (failure on at least 3 tests) were fulfilled in 39 patients (70%) and 75% of the cases were classified as having a deteriorating cognitive performance. Changes were prominent in tests of verbal memory, complex attention, verbal fluency, and receptive language. In the regression analysis, the only significant predictor of cognitive deterioration was older age of the subject (odds ratio 1.9, 95% confidence interval 1.2-2.9, p = 0.003). Psychiatric disorders, most frequently depression, were diagnosed in 12 patients (30.5%). Fatigue was reported by 21% of the patients. MS negatively affected school and everyday activities in 30% to 40% of the subjects., Conclusions: Our findings confirm the importance of systematic assessment of cognitive and psychosocial issues in children and teens with MS. The progressive nature of the cognitive difficulties emphasizes the need for developing 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.

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.

Objectives: To assess the impact of cognitive impairment (CI) on coping strategies in multiple sclerosis (MS)., Materials and Methods: Sixty-three patients (40 women, 55 relapsing-remitting and 8 secondary progressive, age 42.6+/-10.1 years, Expanded Disability Status Scale 2.2+/-1.7) were assessed using the Coping Orientation for Problem Experiences-New Italian version Inventory, the Beck Depression Inventory and the Rao's Brief Repeatable Battery., Results: MS patients were less likely to use positive and problem-focused strategies, whereas avoiding strategies were adopted more frequently. Twenty-three (36.5%) cases were CI. We found no differences in the type of coping between CI and cognitively preserved patients. Scores on the Stroop test (beta=-0.91, p=0.04) and on the Word List Generation (beta=1.15, p=0.04) were associated with poorer coping strategies., Conclusions: Our study suggests that cognitive functioning (in particular on sustained attention and aspects of executive function) must be considered in a comprehensive account of the factors contributing to successful coping in MS patients., (2009 Elsevier B.V. All rights reserved.)

Significant cognitive impairment has been found in 20-30% of patients with clinically isolated syndromes suggestive of multiple sclerosis. In this study we aimed to assess the prognostic value of the presence of cognitive impairment for the conversion to multiple sclerosis in patients with clinically isolated syndromes. All patients with clinically isolated syndromes consecutively referred to our centre since 2002 and who had been followed-up for at least one year underwent cognitive assessment through the Rao's Battery and the Stroop test. Possible predictors of conversion to clinically definite multiple sclerosis were evaluated through the Kaplan Meier curves and Cox regression analysis. A total of 56 patients (41 women; age 33.2 +/- 8.5 years; expanded disability scale score 1.2 +/- 0.7) were recruited. At baseline, 32 patients (57%) fulfilled McDonald's criteria for dissemination in space. During the follow-up (3.5 +/- 2.3 years), 26 patients (46%) converted to a diagnosis of multiple sclerosis. In particular, 64% of patients failing >or= 2 tests and 88% of patients failing >or= 3 tests converted to multiple sclerosis. In the Cox regression model, the failure of at least three tests (HR 3.3; 95% CI 1.4-8.1; p = 0.003) and the presence of McDonald's dissemination in space at baseline (HR 3.8; 95% CI 1.5-9.7; p = 0.005), were found to be predictors for conversion to multiple sclerosis. We conclude that cognitive impairment is detectable in a sizable proportion of patients with clinically isolated syndromes. In these subjects cognitive impairment has a prognostic value in predicting conversion to multiple sclerosis and may therefore play a role in therapeutic decision making.

Background: No study has assessed the association between apolipoproteinE (APOE) and multiple sclerosis (MS) forms grouped by also taking into account cognitive performance., Aims of the Study: To assess the relationship between APOE and disease course, particularly focusing on benign MS (BMS), defined as also including cognitive preservation., Methods: In 173 consecutive patients, we assessed the association between APOE and MS course and severity., Results: Twenty-nine APOE-epsilon4 carriers were identified. The epsilon4 allele was not associated with BMS. Moreover, it was associated neither with other disease courses nor with the time to reach disability milestones and secondary progression., Conclusion: Although plausible, the association between APOE and MS course (particularly with BMS defined by including cognitive preservation) and disease severity remains controversial.

Objective: To assess whether neuropsychological tests and MRI measures could be used as predictors of short-term disease evolution in a population of patients with benign multiple sclerosis (B-MS)., Background: The definition of B-MS is controversial. Recent data suggest that neuropsychological tests and MRI measures can provide valuable information for a more correct definition and interpretation of B-MS., Methods: Sixty-three patients with B-MS (Expanded Disability Status Scale [EDSS] < or =3.0 and disease duration > or =15 years) underwent neuropsychological assessment using the Rao's Brief Repeatable Neuropsychological Battery and the Stroop Test. At that time, conventional brain MRI and magnetization transfer (MT) imaging was performed. White matter lesion load, global and regional brain volumes, and MT ratio in lesions and normal-appearing brain were measured. After a mean follow-up of 5 years, patients still having an EDSS score < or =3.5 were classified as still benign, whereas patients who had developed a secondary progressive course or who had an EDSS score > or =4.0 were defined as no longer benign (NLB)., Results: At end of follow-up, 29% of patients were classified as NLB. Male gender (hazard ratio [HR] = 2.9; 95% confidence interval [CI] 1.2-7.5; p = 0.02), number of neuropsychological tests failed (HR = 1.4; 95% CI 1.1-1.7; p = 0.003), and T1-weighted lesions (HR = 1.3; 95% CI 1.1-1.5; p = 0.002) were related to NLB status. In a model including these 3 variables, the NLB status was predicted with an accuracy of 82%., Conclusions: Cognitive assessment and MRI metrics can predict short-term disease evolution in benign multiple sclerosis (B-MS). This information can be useful to correctly identify patients with B-MS.

Rao's Brief Repeatable Battery (BRB) is the most widely used instrument for cognitive evaluation in multiple sclerosis (MS). We assessed a short version of the BRB in 116 relapsing-remitting participants. We found that the administration of three tests, the Selective Reminding Test, the Paced Auditory Serial Addition Test-3 seconds and the Symbol Digit Modalities Test, was able to detect cognitive impairment with a sensitivity of 94%, a specificity of 84%, and an accuracy of 89%. On the basis of these results we developed a screening algorithm requiring 5 to 15 minutes, which may represent a highly sensitive and rapid tool to detect MS-associated cognitive impairment.

The aim of this study was to assess the impact of psychological features in the choice of coping strategies in multiple sclerosis (MS) patients, and their influence on quality of life (QoL). One hundred four patients (72 women, age 45.3 +/- 10.9 years, disease duration 17.9 +/- 13.2 years, Expanded Disability Status Scale 2.8 +/- 2.0) were assessed through the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Eysenck Personality Questionnaire, the Coping Orientation for Problem Experiences-New Italian version and the MSQoL-54. MS patients were less likely to use problem-focused strategies, whereas avoiding strategies were adopted more frequently. The use of positive strategies positively influenced both mental and overall QoL. Depression had a negative impact on all QoL domains and anxiety on mental domains. These data point out the importance of a comprehensive assessment of MS patients. Orienting therapeutic interventions, to oppose depression and anxiety and to favour more appropriate coping strategies can improve the patients' QoL.

Background: The definition of benign multiple sclerosis (B-MS) is still controversial. This mainly takes into account the subject's motor ability, with little or no relevance to other important features such as cognition. Moreover, no paraclinical markers are currently available to reliably identify patients who will remain benign in the long term., Objectives: To assess, by using quantitative magnetic resonance (MR) metrics, differences in tissue damage between B-MS patients after dividing them into two groups on the basis of their cognitive performance., Methods: Forty-seven B-MS patients (Expanded Disability Status Scale score /=15 years) underwent neuropsychological assessment through the Rao Brief Repeatable Battery and the Stroop Test. At that time, B-MS patients underwent conventional brain MR and magnetization transfer (MT) imaging. White matter lesion load, global and regional brain volumes, and MT ratio (MTr) in lesions and normal-appearing brain were measured. Quantitative MR measures were compared in cognitively impaired (CI-MS) and cognitively preserved (CP-MS) patients and in 24 demographically matched healthy controls. Test performance was correlated with MR changes in specific cortical regions., Results: Eleven patients were classified as CI-MS, and 36 were classified as CP-MS. Both T2-weighted and T1-weighted lesion loads were higher (p = 0.05 and 0.001) in CI-MS than in CP-MS patients. Furthermore, CI-MS patients were characterized by more pronounced decrease in neocortical volume (p = 0.005) and cortical MTr (p = 0.02) values than CP-MS patients. Finally, test performance correlated significantly with MR changes in relevant cortical regions., Conclusions: Cognitive assessment and quantitative magnetic resonance can help to reliably identify benign multiple sclerosis patients.

Background and Purpose: Subclinical multiple sclerosis (S-MS) can be defined as the discovery of characteristic lesions at magnetic resonance (MR) or at autopsy, in the absence of clinical evidence consistent with MS. To describe four cases of S-MS cases followed-up with clinical and MR examinations., Methods: The four patients were initially evaluated because of accidental MRI findings suggestive of MS that fulfilled the Barkhof criteria. At the moment of MR examination, patients were asymptomatic or complained of unspecific symptoms. The objective examinations as well as the clinical history were negative. An extensive diagnostic work-up excluded alternative diagnoses., Results: Case 1: 40-year woman undergoing MR examination due to trivial cervical trauma. The cerebrospinal fluid (CSF) analysis showed an IgG Index of 3.32 and presence of oligoclonal bands (OCB). New MR enhancing lesions were detected in the brain and cervical cord after 2 and 5 years. The patient remained clinically asymptomatic. Neuropsychological assessment (NPS) performed after 5 years revealed moderate deficits of attention/concentration and executive functions. Case 2: 35- year man, undergoing MR due to recent-onset headache. CSF analysis showed an IgG Index of 1.54 and presence of OCB. At baseline, NPS assessment revealed moderate deficit on complex attention tasks. New MR enhancing lesions were detected in the brain after 1 and 3 years. Four years after the first MR, the patient presented double vision with internuclear ophthalmoplegia. He fulfilled Polman's criteria for MS and he started interferon beta therapy. He remained stable at a 8-year follow-up. Case 3: 32-year man, undergoing MR due to brief loss of consciousness following neck hyperextension. CSF analysis showed absence of OCB and normal IgG Index. At baseline, NPS assessment revealed mild deficits of attention and executive functions. Over a 5-year follow-up the subject remained asymptomatic and MR was unchanged. Case 4: 40-year woman, sister of an MS patient. MR was required during a period of marked tiredness taking into account the family history. The patient did not present any relevant symptoms and MRI remained unchanged over a 6-year follow-up. NPS evaluation performed after 7 years showed moderate impairment of memory, attention and executive functions., Conclusion: With the increased use of MR, S-MS cases can be identified more often. In our series, despite the absence of any typical symptoms, an NPS assessment detected cognitive impairments consistent with those reported in MS.

Objective: To assess the impact of multiple sclerosis (MS) on cognitive and psychosocial functioning in childhood and juvenile cases., Methods: 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., Results: 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, p < 0.001). 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., Conclusions: 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.

Objectives: A study of cognitive, psychological and social aspects in benign multiple sclerosis (MS). Methods One hundred and sixty three patients with benign MS (defined as disease duration > or = 15 years and Expanded Disability Status Scale (EDSS) score < or = 3.0 ) underwent neuropsychological testing on the Rao's Brief Repeatable Battery (BRB) and the Stroop test, evaluation of depression on the Montgomery and Asberg Depression Rating Scale (MADRS), of fatigue on the Fatigue Severity Scale (FSS) and of handicap on the Environmental Status Scale (ESS). Patients' cognitive performance was compared with that of 111 demographically matched healthy controls. Cognitive impairment was defined as the failure in at least 3 tests, using the fifth percentile of controls' performance as the cut-off point. Clinical correlates of cognitive impairment were determined by multiple logistic regression analysis., Results: Cognitive assessment led to the identification of 74 subjects (45%) with cognitive impairment. Significant fatigue was found in 80 subjects (49%) and depression in 88 patients (54%). In comparison with cognitively preserved subjects, cognitively impaired patients exhibited higher handicap scores on the ESS (p = 0.005). In the regression analysis, only EDSS scores were significantly associated with cognitive impairment (OR 1.8, 95%CI 1.2-2.6)., Conclusion: Current definitions of benign MS may overestimate this entity, since they are mainly weighted for the patients' motor abilities and fail to capture relevant disease-related cognitive, psychological and social problems.

Fatigue, a common symptom of multiple sclerosis (MS), is associated with impairment in performing daily activities, poor quality of life and premature retirement from the workforce. There is little doubt that patients with MS can exhibit marked weakness and other objective signs of physical fatigue, but whether cognitive performance by patients declines more rapidly than that by controls as a function of time engaged in mental activity remains controversial. Krupp and Elkins (2000) reported more rapid deterioration of performance by MS patients on two of five cognitive measures when subjects performed 3 hr of continuously effortful tasks between baseline and posttest. Others, using shorter and less taxing interpolated tasks found similar changes in performance over time for patients and controls. In the present study participants completed a timed walk, fatigue ratings and four cognitive tests that emphasized processing novel information before they went to work and again after completing a normal workday. Patients with MS walked somewhat more slowly and performed more poorly on two of the cognitive tests, but they did not show more decline from baseline to posttest on any of these objective measures of cognitive fatigue. By contrast, subjective ratings of fatigue showed a greater increase over the day for patients than for controls. These results confirm other reports that patients' subjective ratings of their fatigue are not valid indicators of their actual performance on cognitive tests. Furthermore, laboratory studies that report "objective" cognitive fatigue in MS may utilize conditions that model the cognitive fatigue associated with the jobs patients actually perform rather poorly.