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Abstract

Nociplastic pain has been introduced by the IASP as a third category of pain, distinct from nociceptive and neuropathic pain. Pathogenetically, it is considered to be a continuum of these two types of pain after becoming chronic. Repetitive peripheral painful stimulation causes a central sensitization with hypersensitivity of the corresponding spinal metamer or brain region. Therefore, signs of altered nociception, such as allodynia, may be found on the tissues of the related dermatome, myotome and sclerotome, and characterize nociplastic pain. This kind of pain was found in over 20% of people with multiple sclerosis (pwMS), a demyelinating autoimmune disease that affects the central nervous system. Nociplastic pain may be an amplifier of spasticity, the main pyramidal symptom that affects about 80% of pwMS. This article details the case of a 36-year-old woman with multiple sclerosis who was affected by spasticity and non-specific pain of the lower limbs, disabling on walking. Previous analgesic and muscle relaxant treatment had no benefits. The diagnosis of nociplastic pain on the cutaneous tissue of the anterolateral region of the left thigh and its treatment with intradermal normal saline injection on the painful skin area showed immediate and lasting effects on pain and spasticity, improving significantly the patient's balance and walking, as assessed by a 3D motion analysis and rating scales.

Keywords: gait analysis; infiltrative treatment; multiple sclerosis; nociplastic pain; spasticity.

Abstract

Objective: Despite cognitive tests have been validated in multiple sclerosis (MS), a neuropsychological evaluation is not implemented in the Expanded Disability Status Scale (EDSS) scoring.

Methods: We used the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and orientation tests (OTs) to measure the cerebral functional system (CFS) score and to evaluate its impact on the EDSS. We compared EDSS calculated as usual (Native-EDSS) and after the use of the BICAMS and OT (NPS-EDSS).

Results: We tested 604 MS patients with BICAMS, OTs, and EDSS. In all, 384 patients (63.6%) had at least one altered test at the BICAMS. Older age, lower education, higher Native-EDSS, and male gender were independently associated with at least one impaired BICAMS test. Native-EDSS was different from NPS-EDSS (-0.112; p < 0.001) in 99 patients (16%). When considering patients with a Native-EDSS ⩽ 4.0, the proportion of miscalculated EDSS was 25%.

Conclusion: The use of brief neuropsychological tests leads to a more accurate CFS assessment in two-thirds of MS patients, and a more accurate EDSS calculation in 25% of patients with a score ⩽4.0. This may help clinicians to better recognize cognitive impairment in everyday clinical practice, especially in the case of isolated cognitive worsening.

Keywords: BICAMS; EDSS; cerebral functional score; cognitive.

Abstract

Aim: Complaints about Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®; GW Pharma Ltd, Salisbury, UK) in the management of multiple sclerosis spasticity include unpleasant taste and oral mucosal anomalies. This pilot study assessed the use of sugar-free chewing gum and/or a refrigerated bottle of THC:CBD oromucosal spray to mitigate these effects.

Materials & methods: Patients with multiple sclerosis spasticity (n = 52) at six sites in Italy who were receiving THC:CBD oromucosal spray and had associated oral mucosal effects were randomized into Group A (chewing gum; n = 15); Group B (cold bottle; n = 20); and Group C (cold bottle + chewing gum; n = 17).

Results: Taste perception in patients receiving chewing gum ± cold bottle intervention (Groups A and C combined) was significantly (p = 0.0001) improved from baseline to week 4 while maintaining spasticity control.

Conclusion: Patient comfort, satisfaction and treatment adherence may benefit from these interventions.

Keywords: Sativex; THC:CBD; multiple sclerosis; oral cavity complaints; oromucosal spray; spasticity; taste perception.

Abstract

Background: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort.

Methods: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab.

Results: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076).

Conclusion: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age.

Keywords: Determinants first therapy; Immunomodulatory therapy; Multiple sclerosis; Naive; Relapsing-remitting.

Abstract

Introduction: During the COVID-19 pandemic, ocrelizumab (OCR) infusions for MS patients were often re-scheduled because of MS center's disruption and concerns regarding immunosuppression. The aim of the present study was to assess changes in OCR schedule during the first wave of pandemic in Italy and to evaluate the effect of delayed infusion on clinical/radiological endpoints.

Methods: Data were extracted from the Italian MS Register database. Standard interval dosing was defined as an infusion interval ≤ 30 weeks, while extended interval dosing was defined as an infusion interval > 30 weeks at the time of the observation period. Clinico-demographics variables were tested as potential predictors for treatment delay. Time to first relapse and time to first MRI event were evaluated. Cumulative hazard curves were reported along their 95% confidence intervals. A final sample of one-thousand two patients with MS from 65 centers was included in the analysis: 599 pwMS were selected to evaluate the modification of OCR infusion intervals, while 717 pwRMS were selected to analyze the effect of infusion delay on clinical/MRI activity.

Results: Mean interval between two OCR infusions was 28.1 weeks before pandemic compared to 30.8 weeks during the observation period, with a mean delay of 2.74 weeks (p < 0.001). No clinico-demographic factors emerged as predictors of infusion postponement, except for location of MS centers in the North of Italy. Clinical relapses (4 in SID, 0 in EID) and 17 MRI activity reports (4 in SID, 13 in EID) were recorded during follow-up period.

Discussion: Despite the significant extension of OCR infusion interval during the first wave of pandemic in Italy, a very small incidence of clinical/radiological events was observed, thus suggesting durable efficacy of OCR, as well as the absence of rebound after its short-term suspension.

Keywords: COVID-19 Pandemic; Extended interval dosing; MS (multiple sclerosis); Ocrelizumab.

Abstract

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences.

Objectives: To identify prognostic factors for early switch after first therapy choice.

Methods: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models.

Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047).

Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

Keywords: Switch; disease modifying therapies; naïve; persistence; real-life; relapsing–remitting.

Abstract

Background: Few studies examined the effects of combined motor and cognitive rehabilitation in patients with multiple sclerosis (MS). The present prospective, multicenter, observational study aimed to determine the efficacy of an integrated cognitive and neuromotor rehabilitation program versus a traditional neuromotor training on walking, balance, cognition and emotional functioning in MS patients. Methods: Sixty three MS patients were selected and assigned either to the Integrated Treatment Group (ITG; n = 32), receiving neuropsychological treatment (performed by ERICA software and paper-pencil tasks) complemented by conventional neuromotor rehabilitation, or to the Motor Treatment Group (n = 31) receiving neuromotor rehabilitation only. The intervention included two 60-min sessions per week for 24 weeks. At baseline and at end of the training all patients underwent a wide-range neuropsychological, psychological/emotional, and motor assessment. Results: At baseline the two groups did not differ for demographic, neuropsychological, psychological/emotional, and motor features significantly. After rehabilitation, only ITG group significantly (p-corrected for False Discovery Rate) improved on test tapping spatial memory, attention and cognitive flexibility, as well as on scales assessing depression and motor performance (balance and gait). A regression analysis showed that neuropsychological and motor improvement was not related to improvements in fatigue and depression. Conclusion: The present study demonstrated positive effects in emotional, motor, and cognitive aspects in MS patients who received an integrated cognitive and neuromotor training. Overall, results are supportive of interventions combining motor and cognitive training for MS.

Keywords: brain plasticity; cognitive motor interference; cognitive rehabilitation; multiple sclerosis; neuromotor rehabilitation.

Abstract

Background: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection.

Methods: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose.

Findings: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave.

Interpretation: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response.

Funding: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding.

Keywords: Breakthrough infections; COVID-19; Disease Modifying Treatments; Multiple Sclerosis.

Abstract

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p &lt; 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203-24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients.

Keywords: Disease activity; Extended interval dosing; MRI; Ocrelizumab; Standard interval dosing.