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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.

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.

This study investigated the possible existence of causal links between anxiety and language learning difficulties by using the Foreign Language Classroom Anxiety Scale (FLCAS) (Horwitz, Horwitz, & Cope, 1986) to examine anxiety and the Foreign Language Screening Instrument for Colleges (FLSI-C) (Ganschow & Sparks, 1991) to explore learning difficulty variables. Factor analysis, correlation analysis, and stepwise multiple regression analysis of data provided by 1,187 college students learning English as a foreign language (EFL) in Taiwan indicate that English learning difficulties account for 36.80% of variance in anxiety. The results show that some anxious students have a history of English learning problems, obtain low grades, suffer difficulties with classroom learning, and exhibit poor developmental skills. The findings are used to discuss both theoretical and practical implications for foreign language anxiety.

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.

The objective of this study was to assess the effects of subcutaneous (sc) interferon beta-1a (IFNβ-1a) on cognition in mildly disabled patients with relapsing—remitting multiple sclerosis (RRMS). Patients aged 18—50 years with RRMS (McDonald criteria; Expanded Disability Status Scale score ≤4.0) were assigned IFNβ therapy at the physician’s discretion and underwent standardized magnetic resonance imaging, neurological examination and neuropsychological testing at the baseline and regular intervals for up to three years. This analysis included 459 patients who received sc IFNβ-1a (44 mcg: n = 236; 22 mcg: n = 223; three-year follow up was available for 318 patients). The hazard ratio for cognitive impairment over three years (44 mcg versus 22 mcg) was 0.68 (95% confidence interval [CI]: 0.480—0.972), suggesting a 32% lower risk with the higher dose treatment. At year 3, the proportion of patients who were cognitively impaired increased slightly from 23.5% at the baseline to 24.8% in the IFNβ-1a 22 mcg treatment group, but remained stable at 15.2% in the IFNβ-1a 44 mcg treatment group. The proportion of patients with cognitive impairment at year 3 was significantly higher in the 22 mcg group than in the 44 mcg group (P = 0.03), although a trend was also seen at the baseline (P = 0.058). Multivariate logistic regression (corrected for baseline cognitive deficits) indicated that treatment with the higher dose of IFNβ-1a was predictive of lower cognitive impairment at three years (odds ratio: 0.51, 95% CI: 0.26—0.99) compared with the lower dose of IFNβ-1a. These findings suggest that sc IFNβ-1a may have dose-dependent cognitive benefits in mildly disabled patients with RRMS, and may support early initiation of high-dose IFNβ-1a treatment.

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.

The effect of interferon (IFN) beta-1a (44 and 22 mg subcutaneously [sc] three times weekly [tiw]) on cognition in mildly disabled patients with relapsing–remitting multiple sclerosis (McDonald criteria; Expanded Disability Status Scale 4.0) was assessed by validated neuropsychological testing at baseline and at regular intervals for up to 2 years in this ongoing open-label, 3-year study. Year-2 data were available for 356 patients (22 mg, n¼175; 44 mg, n¼181). The proportion of patients with impaired cognitive function was stable during the study: 21.4% at baseline and 21.6% at 2 years. At 2 years, the proportion of patients with 3 impaired cognitive tests was significantly lower in the 44 mg treatment group (17.0%) compared with the 22 mg group (26.5%; p¼0.034), although there was already a trend towards a higher proportion of patients with cognitive impairment in the 22 mg group at baseline. Factors associated with impairment in three cognitive tests after 2 years were age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.00–1.09), verbal intelligence quotient (OR: 0.95; 95% CI: 0.92–0.98), and having three impaired cognitive tests at baseline (OR: 11.60; 95% CI: 5.94–22.64). These interim results show that IFN beta-1a sc tiw may have beneficial effects on cognitive function as early as 2 years after treatment initiation, but the final 3-year data of the study are required to confirm these results.