Clara Chisari

Lesion Load May Predict Long-Term Cognitive Dysfunction in Multiple Sclerosis Patients

Background Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS). Objectives To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term CIm in a cohort of MS patients. Methods 303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors. Results AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.12–1.97 p = 0.006), PASAT (OR 1.43, CI 1.14–1.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.35–2.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.28–2.03 p<0.001), MCST-category (OR 1.52, CI 1.2–1.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.2–1.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.02–1.55 p = 0.032). Conclusion In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome.

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

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

Eye Movement Abnormalities in Multiple Sclerosis: Pathogenesis, Modeling, and Treatment

Multiple sclerosis (MS) commonly causes eye movement abnormalities that may have a significant impact on patients’ disability. Inflammatory demyelinating lesions, especially occurring in the posterior fossa, result in a wide range of disorders, spanning from acquired pendular nystagmus (APN) to internuclear ophthalmoplegia (INO), among the most common. As the control of eye movements is well understood in terms of anatomical substrate and underlying physiological network, studying ocular motor abnormalities in MS provides a unique opportunity to gain insights into mechanisms of disease. Quantitative measurement and modeling of eye movement disorders, such as INO, may lead to a better understanding of common symptoms encountered in MS, such as Uhthoff’s phenomenon and fatigue. In turn, the pathophysiology of a range of eye movement abnormalities, such as APN, has been clarified based on correlation of experimental model with lesion localization by neuroimaging in MS. Eye movement disorders have the potential of being utilized as structural and functional biomarkers of early cognitive deficit, and possibly help in assessing disease status and progression, and to serve as platform and functional outcome to test novel therapeutic agents for MS. Knowledge of neuropharmacology applied to eye movement dysfunction has guided testing and use of a number of pharmacological agents to treat some eye movement disorders found in MS, such as APN and other forms of central nystagmus.

Effectiveness and safety of Rituximab in demyelinating diseases spectrum: an Italian experience

BACKGROUND Rituximab (RTX), a monoclonal antibody targeting the CD20+ B lymphocytes, deserves major attention as therapeutic option in the treatment of demyelinating disorders of the central nervous system (DDCNS). We reported our clinical experience with the use of RTX in terms of efficacy and safety in persons suffering from DDCNS. METHODS An Italian single-center observational analysis of patients who underwent RTX treatment between 2011 and 2017 was performed at MS center of Catania, Italy. No evidence of disease activity (NEDA) was applied to evaluate the response to RTX. CD19+ and CD20+ counts were collected along therapy. RTX-related adverse events were recorded. RESULTS Eleven patients with MS, four with NMOSD and two with NMO were enrolled. Out of them, 4/17 were naïve to previous treatments. According to NEDA status, 11/17 got NEDA3 status at the follow-up. Six patients had relapses (two had a single relapse and four had multiple relapses). One patient with primary progressive MS and one with relapsing remitting MS stopped RTX, the last one for severe lymphopenia. CONCLUSIONS RTX showed efficacy to impact DDCNS worsening with an acceptable safety profile.

eMSQOL-29: Prospective validation of the abbreviated, electronic version of MSQOL-54

Background: We recently devised a shortened version of the 54-item Multiple Sclerosis Quality of Life (MSQOL-54) in paper (MSQOL-29, consisting of 25 items forming 7 subscales and 4 single items, and one filter question for 3 ‘sexual function’ items) and electronic format (eMSQOL-29). Objectives: To prospectively assess eMSQOL-29 psychometric properties, acceptability/equivalence versus MSQOL-29. Methods: Multiple sclerosis (MS) patients (n = 623; Expanded Disability Status Scale (EDSS) range 0.0–9.0) completed eMSQOL-29, Hospital Anxiety and Depression Scale, Functional Assessment of MS (FAMS), European Quality of life Five Dimensions-3L, and received EDSS and Symbol Digit Modalities Test (SDMT). Equivalence versus MSQOL-29 was assessed in 242 patients (randomized cross-over design). Results: ‘Sexual function’ items were filtered out by 273 patients (47%). No multi-item scale had floor effect, while five had ceiling effect. Cronbach’s alpha range was 0.88–0.90. Confirmatory factor analysis showed good overall fit and the two-factor solution for composite scores was confirmed. Criterion validity was sub-optimal for ‘cognitive function’ (vs SDMT, r = 0.25) and ‘social function’ (vs FAMS social function, r = 0.38). eMSQOL-29 equivalence was confirmed and its acceptability was good. Conclusion: eMSQOL-29 showed good internal consistency, factor structure and no floor effect, while most subscales had some ceiling effect. Criterion validity was sub-optimal for two subscales. Equivalence and acceptability were good.

Lateral switch to IFN beta-1a 44 mcg may be effective as escalation switch to fingolimod in selected persons with relapsing remitting multiple sclerosis: a real-world setting experience

ABSTRACT Background: The efficacy of lateral and escalation switch is a challenge in MS. We compared in a real-world setting the efficacy of switching to IFN beta-1a 44 mcg or to fingolimod in persons with relapsing remitting MS (pwRRMS) who failed with others injectable IFNs or glatiramer acetate. Research design and methods: retrospective analysis of 24 months prospectively-collected data at the MS center of the University of Catania, Italy was performed. Patients who were switched to IFN-beta 1a 44 mcg or fingolimod were analyzed using propensity-score covariate adjustment model within demographic (e.g. age and gender) and disease (e.g. timing of pre-switch relapse) characteristics. Switching-time was considered the starting-time of the observation. Results: 43 pwRRMS on IFN beta-1a 44 mcg and 49 pwRRMS on fingolimod were included. Baseline characteristics differed for EDSS score and number of T2 lesions (higher in group on fingolimod). At 24 months of follow up, both groups showed no differences in the survival curves of reaching a first new relapse, new T2 and Gd+ MRI brain lesions, even corrected for the propensity score covariate adjustment. Conclusions: lateral switch to IFN beta-1a 44 mcg and escalation switch to fingolimod showed same ability in influencing RRMS disease activity at 24 months.

Pharmacokinetic drug evaluation of daclizumab for the treatment of relapsing-remitting multiple sclerosis

ABSTRACT Introduction: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Despite the availability of several disease-modifying therapies for relapsing MS, there is a need for highly efficacious targeted therapy with a favorable benefit–risk profile and a high level of treatment adherence. Daclizumab is a humanized monoclonal antibody directed against CD25, the α subunit of the high-affinity interleukin 2 (IL-2) receptor, that reversibly modulates IL-2 signaling. Areas covered: Daclizumab blocks the activation and expansion of autoreactive T cells that plays a role in the immune pathogenesis of MS. As its modulatory effects on the immune system, daclizumab’s potential for use in MS was tested extensively showing a high efficacy in reducing relapse rate, disability progression and the number and volume of gadolinium-enhancing lesions on brain magnetic resonance imaging. Moreover, phase II and III trials showed a favorable pharmacokinetic (PK) profile with slow clearance, linear pharmacokinetics at doses above 100 mg and high subcutaneous bioavailability, not influenced by age, sex or other clinical parameters. Expert opinion: Among the new emerging drugs for MS, daclizumab also, thanks to a favorable PK profile, may represent an interesting and promising therapeutic option in the wide MS therapies armamentarium.

Late-onset and young-onset relapsing-remitting multiple sclerosis: evidence from a retrospective long-term follow-up study

Late‐onset multiple sclerosis (MS) has a prevalence of about 10–20% in natural history MS studies. Few data have been published about the long‐term disease trajectory in the cohort of late‐onset relapsing‐remitting MS (LORRMS). The aim of this study was to identify the risk factors for reaching an Expanded Disability Status Scale (EDSS) score of 6.0 in LORRMS (onset at >40 years of age) and young‐onset relapsing‐remitting MS (YORRMS) (onset between 18 and 40 years of age).

Neurorehabilitation in Persons with Multiple Sclerosis: Scientific Basis and Options of Treatment

Introduction: Multiple Sclerosis is the leading cause of no traumatic disability in young people. Nowadays, neurorehabilitation is commonly prescribed in patients with MS, but there are still some issues to be explored further. In this review, we discuss the following topics: 1) the neuroscientific basis of neurorehabilitation in multiple sclerosis; 2) what would be the ideal set of rehabilitative treatment: inpatients, outpatient or home-based therapy? Methods: A systematic search was made, using combination of the following terms: rehabilitation, multiple sclerosis, disability, plasticity, motor learning, cognitive rehabilitation, quality of life. Results: A growing amount of evidence suggest that motor and cognitive rehabilitation may enhance functional and structural brain plasticity in patients with multiple sclerosis. Improvement of function seems to be correlated with functional Magnetic Resonance Imaging changes in brain. Moreover, several studies show the effectiveness of cognitive rehabilitation to improve some domains of neuropsychological functions, such as attention, information processing and executive functions. Regarding the rehabilitative setting, it should be chosen taking into account the personal needs of each patient. All the studies, performed in different setting, demonstrated the effectiveness of rehabilitation in Persons affected by multiple sclerosis. Conclusion: Rehabilitation is effective in mitigating disability and improving QoL in persons with MS. Setting for rehabilitation treatment should be chosen taking into account many personal needs and desires of each patient.