Unprescribed cannabinoids and multiple sclerosis: a multicenter, cross-sectional, epidemiological study in Lombardy, Italy.

INTRODUCTION: Cannabinoids are approved for spasticity and pain in multiple sclerosis (MS). In 2017 the prevalence of current users in the Italian general population was 10.2%, while data on Italian MS patients are limited. METHODS: From March 2022 to February 2023, we conducted a multicenter, cross-sectional study. Adult MS patients completed an anonymous online survey. The primary outcome was the estimated prevalence of unprescribed cannabis current use. Cannabis use patterns and associations with clinical and socio-demographical variables were investigated. The binomial method was used to estimate 95% confidence interval (95% CI) for primary outcome. RESULTS: 5620 patients were invited and 2024 (36.0%) were included (mean age 45.2 years, females 64.5%). Relapsing remitting form was the most frequent (77.3%). Median expanded disability status scale (EDSS) was 2.0. The proportion of current users was 15.5% (95% CI 13.9-17.1) and 36.4% of them disclosed to their physician their unprescribed cannabis use. 15.0% patients were former users while 69.5% never used cannabis. Current users more frequently reported a medical use (i.e., current medical users) compared to former users (p < 0.001). 41.1% of never users would use cannabis if it was legal. Young age, being male, and a free marital status were associated with current use. Current medical users had higher disability, spasticity and pain, reduced quality of life, concomitant neurological/psychiatric drugs and analgesics use. Unprescribed cannabis appeared relatively safe, with limited addiction risk, and reported clinical benefits, including concomitant medications reduction. CONCLUSION: Unprescribed cannabis use is common in patients with MS in Italy, with observed prevalence seemingly superior to the general population, often intended for medical use and without the disclosure to the treating physician, although with potential clinical benefits.

Prospective observational study to evaluate treatment satisfaction and effectiveness in patients with relapsing multiple sclerosis starting cladribine tablets (CLADREAL) in Italy.

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one first-line disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient's experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022.

Fast but not furious: Rapid ocrelizumab infusion as a strategy to optimize multiple sclerosis patients' management.

OBJECTIVES: Multiple sclerosis clinicians are continuously challenged to be innovative in delivering therapies and there is ongoing pressure to maximize day-hospital vacancies. We describe our single-center experience with ocrelizumab (OCR) rapid infusion (OCR-RI) in patients with MS (pwMS). METHODS: For pwMS with prior exposure to OCR standard infusion (OCR-SI) for at least one year/two cycles, infusion time was reduced from 3.5 to 2.0 h. A comparative analysis between OCR-RI vs OCR-SI patients was conducted. RESULTS: 283 (76.7%) out of 369 OCR-treated pwMS performed OCR-RI; 86 subjects did not start OCR-RI due to infusion-related reactions (IRR) occurring with OCR-SI (n = 13) or OCR-treatment duration shorter than one year (n = 73). Disease duration was longer in OCR-RI (p < 0.001). Median numbers of overall-OCR and OCR-RI cycles were 7 (IQR = 5-8) and 4 (IQR = 2-5) (p < 0.001). Overall, 38 (10.3%) IRR were reported, 25 (8.8%) in OCR-RI and 13 (15.1%) in OCR-SI group. IRR frequency did not differ between the two groups (p = 0.106). IRR included throat irritation, rash, hypotension, fever and gastrointestinal symptoms. IRR severity was mild (81.6%) or moderate (18.4%), all resolved and did not differ in distribution between the two groups. When IRR occurred, infusions were temporarily stopped, hydration and/or symptomatic medications were given and infusions were subsequently resumed at standard velocity. OCR-RI was not a risk factor for IRR (OR 0.55, 95% CI: 0.27-1.13, p = 0.096). CONCLUSIONS: In our cohort, IRR frequency, severity and management were comparable to literature. No severe IRR were observed. RI protocols represent a strategy to optimize patients' management in the clinic.

Intravenous or subcutaneous natalizumab in patients with relapsing-remitting multiple sclerosis: investigation on efficiency and savings-the EASIER study.

INTRODUCTION: EASIER is a multicenter, observational, cross-sectional study investigating the consumption of healthcare resources, including healthcare professional (HCP) active working time, the costs associated with the current natalizumab intravenous (IV) administration, and the potential impact of the adoption of subcutaneous (SC) route. METHODS: The EASIER study has three parts: (1) time and motion study to measure healthcare resources and working time needed for natalizumab IV administration using a digital data collection tool operated directly by HCPs; (2) HCP structured questionnaire-based estimation of the potential impact of natalizumab SC vs. IV administration; and (3) patient survey on the burden of natalizumab administration. RESULTS: Nine Italian multiple sclerosis (MS) centers measured 404 IV natalizumab administration procedures and administered 26 HCP questionnaires and 297 patient questionnaires. Patients had a mean of 52 (range 1-176) previous IV administrations and spent a mean (median, IQR) of 152 (130, 94-184) minutes in the center per each IV procedure, with IV infusion covering 50% of the total. Including patient travel time, an average of 5 h was dedicated to each IV administration. Active working time by HCP amounted to 29 min per IV administration procedure, 70% of which by nursing staff. With adoption of the SC route, HCPs estimated a 50% reduction in patient procedure time and 55% lower HCP active working time. This translated into a 63% cost reduction for the MS center per natalizumab administration procedure. CONCLUSIONS: SC natalizumab administration will consistently reduce consumption of patient and HCP times per procedure and associated costs.

Perspectives on Neuromyelitis Optica Spectrum Disorders, the Narrative Medicine contribution to care.

BACKGROUND: This research aimed to investigate the experience of Neuromyelitis Optica Spectrum Disorders (NMOSD) by integrating the perspectives of patients, caregivers and clinicians through narrative-based medicine to provide new insights to improve care relationships. METHODS: The research was conducted in the second half of 2022 and involved six Italian centres treating NMOSD and targeted adult patients, their caregivers and healthcare providers to collect the three points of view of living with or caring for this rare disease, still difficult to treat despite the pharmacological options. Narratives followed a structured outline according to the time: yesterday-today-tomorrow, to capture all disease phases. RESULTS: Twenty-five patients diagnosed with NMOSD, ten caregivers and 13 healthcare providers participated in the research. Patients reported symptoms limiting their daily activities and strongly impacting their social dimension. We noticed improvements across disease duration, whilst the persistence of limitations was recurrent in patients with longer diagnoses. Caregivers' narratives mainly share experiences of their daily life changes, the burden of the caregiving role and the solutions identified, if any. Healthcare providers defined their role as a guide. CONCLUSION: Limitations in activities are prominent in the lives of people with NMOSD, along with fatigue. Family members are the weakest link in the chain and need information and support. Healthcare professionals are attentive to the helping dimension.

COVID-19 has no impact on disease activity, progression and cognitive performance in people with multiple sclerosis: a 2-year study.

BACKGROUND: Sequelae of COVID-19 in people with multiple sclerosis (PwMS) have not been characterised. We explored whether COVID-19 is associated with an increased risk of disease activity, disability worsening, neuropsychological distress and cognitive dysfunction during the 18-24 months following SARS-COV-2 infection. METHODS: We enrolled 174 PwMS with history of COVID-19 (MS-COVID) between March 2020 and March 2021 and compared them to an age, sex, disease duration, Expanded Disability Status Scale (EDSS), and a line of treatment-matched group of 348 PwMS with no history of COVID-19 in the same period (MS-NCOVID). We collected clinical, MRI data and SARS-CoV2 immune response in the 18-24 months following COVID-19 or baseline evaluation. At follow-up, PwMS also underwent a complete neuropsychological assessment with brief repeatable battery of neuropsychological tests and optimised scales for fatigue, anxiety, depression and post-traumatic stress symptoms. RESULTS: 136 MS-COVID and 186 MS-NCOVID accepted the complete longitudinal evaluation. The two groups had similar rate of EDSS worsening (15% vs 11%, p=1.00), number of relapses (6% vs 5%, p=1.00), disease-modifying therapy change (7% vs 4%, p=0.81), patients with new T2-lesions (9% vs 11%, p=1.00) and gadolinium-enhancing lesions (7% vs 4%, p=1.00) on brain MRI. 22% of MS-COVID and 23% MS-NCOVID were cognitively impaired at 18-24 months evaluation, with similar prevalence of cognitive impairment (p=1.00). The z-scores of global and domain-specific cognitive functions and the prevalence of neuropsychiatric manifestations were also similar. No difference was detected in terms of SARS-CoV2 cellular immune response. CONCLUSIONS: In PwMS, COVID-19 has no impact on disease activity, course and cognitive performance 18-24 months after infection.

Ocrelizumab extended-interval dosing in multiple sclerosis during SARS-CoV-2 pandemic: a real-world experience.

BACKGROUND AND PURPOSE: During the COVID-19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed. METHODS: Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended-interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B-cell counts were also retrospectively collected and analysed. RESULTS: A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow-up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%, p = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%, p = 0.374) or disability progression (11.3% vs. 18.4%, p = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19-positive relative (r = 0.530, p < 0.001) and absolute (r = 0.491, p < 0.001) cell counts, without implications on disease activity. CONCLUSIONS: Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended-interval regimens.

Effectiveness and safety profile of cladribine in an Italian real-life cohort of relapsing-remitting multiple sclerosis patients: a monocentric longitudinal observational study.

INTRODUCTION: Cladribine is approved for the treatment of active relapsing MS (RRMS), but its positioning in MS therapeutic scenario still needs to be fully elucidated. METHODS: This is a monocentric, observational, real-world study on RRMS patients treated with cladribine. Relapses, magnetic resonance imaging (MRI) activity, disability worsening, and loss of no-evidence-of-disease-activity-3 (NEDA-3) status were assessed as outcomes. White blood cell, lymphocyte counts and side effects were also evaluated. Patients were analyzed overall and in subgroups according to the last treatment before cladribine. The relationship between baseline characteristics and outcomes was tested to identify predictors of response. RESULTS: Among the 114 patients included, 74.9% were NEDA-3 at 24 months. We observed a reduction of relapses and MRI activity, along with a stabilization of disability. A higher number of gadolinium-enhancing lesions at baseline was the only risk factor for loss of NEDA-3 during follow-up. Cladribine was more efficacious in switchers from first-line therapies or naïves. Grade I lymphopenia was more frequent at month 3 and 15. No grade IV lymphopenia cases were observed. Independent predictors of grade III lymphopenia were a lower baseline lymphocyte count and a higher number of previous treatments. Sixty-two patients presented at least one side effect and globally 111 adverse events were recorded, none of them was serious. CONCLUSIONS: Our study confirms previous data on cladribine effectiveness and safety. Cladribine is more effective when placed early in the treatment algorithm. Real-world data on larger populations with longer follow-up are needed to confirm our findings.

Modifiable risk factors of COVID-19 in patients with multiple sclerosis: a single-centre case-control study.

BACKGROUND: Disease and treatment-associated immune system abnormalities may confer higher risk of Coronavirus disease 2019 (COVID-19) to people with multiple sclerosis (PwMS). We assessed modifiable risk factors associated with COVID-19 in PwMS. METHODS: Among patients referring to our MS Center, we retrospectively collected epidemiological, clinical and laboratory data of PwMS with confirmed COVID-19 between March 2020 and March 2021 (MS-COVID, n = 149). We pursued a 1:2 matching of a control group by collecting data of PwMS without history of previous COVID-19 (MS-NCOVID, n = 292). MS-COVID and MS-NCOVID were matched for age, expanded disability status scale (EDSS) and line of treatment. We compared neurological examination, premorbid vitamin D levels, anthropometric variables, life-style habits, working activity, and living environment between the two groups. Logistic regression and Bayesian network analyses were used to evaluate the association with COVID-19. RESULTS: MS-COVID and MS-NCOVID were similar in terms of age, sex, disease duration, EDSS, clinical phenotype and treatment. At multiple logistic regression, higher levels of vitamin D (OR 0.93, p < 0.0001) and active smoking status (OR 0.27, p < 0.0001) emerged as protective factors against COVID-19. In contrast, higher number of cohabitants (OR 1.26, p = 0.02) and works requiring direct external contact (OR 2.61, p = 0.0002) or in the healthcare sector (OR 3.73, p = 0.0019) resulted risk factors for COVID-19. Bayesian network analysis showed that patients working in the healthcare sector, and therefore exposed to increased risk of COVID-19, were usually non-smokers, possibly explaining the protective association between active smoking and COVID-19. CONCLUSIONS: Higher Vitamin D levels and teleworking may prevent unnecessary risk of infection in PwMS.

Impact of immunotherapies on COVID-19 outcomes in multiple sclerosis patients.

INTRODUCTION: SARS-CoV-2 pandemic has led the scientific community to maximize efforts to prevent infections and disease severity in patients with multiple sclerosis (pwMS). We analyze the impact of immunotherapies on COVID-19 outcomes in pwMS, providing our interpretation of data. AREAS COVERED: Infections, hospitalizations, intensive care unit admissions, and death rates in COVID-19 pwMS are comparable to the general population. Severity of disability, MS clinical phenotype, age, and comorbidities, along with the use of intravenous methylprednisolone and anti-CD20 treatments, are risk factors for COVID-19 severity. Disease-modifying treatments (DMTs) can be safely started and continued during the pandemic. Benefit-risk evaluation is mandatory when managing second-line therapies to balance risk of worse COVID-19 outcomes and MS reactivation. COVID-19 vaccination is safe in MS, and its efficacy could be reduced in fingolimod- and ocrelizumab-treated patients. EXPERT OPINION: The rate of (re)-infection and outcomes with SARS-CoV-2 variants in pwMS and antiviral properties of DMTs need to be further explored. Data on COVID-19 in pregnant MS women, children, and elderly pwMS are limited. Evidence on long-term effects of infection is needed. Impact of emerging DMTs on COVID-19 should be investigated. More data and longer follow-up are needed to characterize long-term efficacy and safety profile of vaccinations in pwMS.

Fingolimod as an effective therapeutic strategy for pediatric relapsing-remitting multiple sclerosis: two case reports.

Approximately 3-10% of patients with multiple sclerosis (MS) have onset during childhood. Pediatric MS is characterized by a relapsing-remitting course and a high relapse rate. In 2010, fingolimod (Gilenya®) was approved in the USA for the treatment of relapsing-remitting MS in adults. In 2018, both the United States Food and Drug Administration and the European Medicines Agency expanded the approved indications of fingolimod to include its use in children with relapsing MS, and the drug was approved in Italy for this indication in September 2020. We describe two cases of children with relapsing-remitting MS who were treated with fingolimod at IRCCS Ospedale San Raffaele Multiple Sclerosis Center (Milan, Italy) for more than 2 years. Our real-world data confirm that fingolimod is an effective therapeutic strategy for children with relapsing MS, and its use could be considered in pediatric patients with active disease.

Early Predictors of 9-Year Disability in Pediatric Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to assess early predictors of 9-year disability in pediatric patients with multiple sclerosis. METHODS: Clinical and magnetic resonance imaging (MRI) assessments of 123 pediatric patients with multiple sclerosis were obtained at disease onset and after 1 and 2 years. A 9-year clinical follow-up was also performed. Cox proportional hazard and multivariable regression models were used to assess independent predictors of time to first relapse and 9-year outcomes. RESULTS: Time to first relapse was predicted by optic nerve lesions (hazard ratio [HR] = 2.10, p = 0.02) and high-efficacy treatment exposure (HR = 0.31, p = 0.005). Predictors of annualized relapse rate were: at baseline, presence of cerebellar (ß = -0.15, p < 0.001), cervical cord lesions (ß = 0.16, p = 0.003), and high-efficacy treatment exposure (ß = -0.14, p = 0.01); considering also 1-year variables, number of relapses (ß = 0.14, p = 0.002), and the previous baseline predictors; considering 2-year variables, time to first relapse (2-year: ß = -0.12, p = 0.01) entered, whereas high-efficacy treatment exposure exited the model. Predictors of 9-year disability worsening were: at baseline, presence of optic nerve lesions (odds ratio [OR] = 6.45, p = 0.01); considering 1-year and 2-year variables, Expanded Disability Status Scale (EDSS) changes (1-year: OR = 26.05, p < 0.001; 2-year: OR = 16.38, p = 0.02), and ≥ 2 new T2-lesions in 2 years (2-year: OR = 4.91, p = 0.02). Predictors of higher 9-year EDSS score were: at baseline, EDSS score (ß = 0.58, p < 0.001), presence of brainstem lesions (ß = 0.31, p = 0.04), and number of cervical cord lesions (ß = 0.22, p = 0.05); considering 1-year and 2-year variables, EDSS changes (1-year: ß = 0.79, p < 0.001; 2-year: ß = 0.55, p < 0.001), and ≥ 2 new T2-lesions (1-year: ß = 0.28, p = 0.03; 2-year: ß = 0.35, p = 0.01). INTERPRETATION: A complete baseline MRI assessment and an accurate clinical and MRI monitoring during the first 2 years of disease contribute to predict 9-year prognosis in pediatric patients with multiple sclerosis. ANN NEUROL 2021;89:1011-1022.

Rehabilitative of COVID-19 patients with acute lower extremity Ischemia and amputation.

OBJECTIVE: To evaluate the clinical characteristics and rehabilitation management of patients who undergo amputation for COVID-19-associated coagulopathy. METHODS: Clinical and laboratory data for 3 patients were analysed and their rehabilitative management discussed. RESULTS: The medical records of 3 patients who had undergone amputation due to acute lower extremity ischaemia and who were provided with rehabilitation in our COVID-19 unit were reviewed. CONCLUSION: Coagulation changes related to SARS-CoV-2 may complicate recovery from this devastating disease. The rehabilitation management of amputated patients for COVID-19 acute lower extremity ischaemia is based on a multilevel approach for clinical, functional, nutritional and neuropsychological needs. Based on this limited experience, a dedicated programme for this specific group of patients seems advantageous to warrant the best functional outcome and quality of life.

Therapeutic applications of the cell-penetrating HIV-1 Tat peptide.

Over the past decades, many new therapeutic approaches have been developed for several conditions, including neurodegenerative diseases. However, efficient biodistribution and delivery at biological target sites are hampered by the presence of cell and tissue barriers, and a clinical therapy is prevented by the requirement of invasive administration routes. Candidate drug conjugation to cell-penetrating peptides, which are able to cross cellular membranes and reach biological targets even when administered systemically, represents a promising tool to overcome this issue. Here, we review the biology, classification and mechanisms of internalization of cell-penetrating peptides. We focus our attention on the cell-penetrating peptide: HIV-derived Tat peptide, and discuss its efficient but controversial use in basic, preclinical and clinical research from its discovery to the present day.

Pluripotent stem cell-based models of spinal muscular atrophy.

Motor neuron diseases, as the vast majority of neurodegenerative disorders in humans, are incurable conditions that are challenging to study in vitro, owing to the obstacles in obtaining the cell types majorly involved in the pathogenesis. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, have opened up the possibility of generating a substantial amount of disease-specific neuronal cells, including motor neurons and glial cells. The present review analyzes the practical implications of iPSCs, generated from fibroblasts of patients affected by spinal muscular atrophy (SMA), and discusses the challenges in the development and optimization of in vitro disease models. Research on patient-derived disease-specific cells may shed light on the pathological processes behind neuronal dysfunction and death in SMA, thus providing new insights for the development of novel effective therapies.

The wide spectrum of clinical phenotypes of spinal muscular atrophy with respiratory distress type 1: a systematic review.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1), also known as distal spinal-muscular atrophy 1 (DSMA10), is an autosomal recessive type of spinal muscular atrophy that is related to mutations in the IGHMBP2 gene, which encodes for the immunoglobulin µ-binding protein. SMARD1 patients usually present low birth weight, diaphragmatic palsy and distal muscular atrophy. Clinical features are still the most important factor that leads to the diagnosis of SMARD1, due to the fact that IGHMBP2 gene mutations are characterized by significant phenotypic heterogeneity. In the present review, we will systematically discuss the genetic, clinical and neuropathological features of SMARD1 in order to provide a complete overview of SMARD1 variable clinical presentations and of the most important diagnostic tools which can be used to identify and properly manage affected individuals. This background is crucial also in the perspective of the development of novel therapeutic strategies for this still orphan disorder.