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Background: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes., Objectives: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection., Methods: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders., Results: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations., Conclusion: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes., 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: S.S. has received honoraria or consultancy fees for participating to advisory boards, giving educational lectures and/or travel and registration coverage for attending scientific congresses or symposia from F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, Merck Serono, Novartis, Teva, and Biogen Idec/Gen Pharma. R.K. has received honoraria for giving educational lectures, consultancy fees for participating advisory boards, and travel grants for attending scientific congresses or symposia from Roche, Sanofi-Genzyme, Merck Serono, Novartis, Teva, Biogen Idec/Gen Pharma of Turkey, Abdi İbrahim İlac, Deva, and ARIS. A.S. has received honoraria or consultancy fees for participating to advisory boards, giving educational lectures and/or travel and registration coverage for attending scientific congresses or symposia from F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, Merck Serono, Novartis, Teva, Biogen Idec/Gen Pharma of Turkey, and Abdi İbrahim İlac. E.P. received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis and serves 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. M.P.S. received consulting fees from Roche, Biogen, Merck, Novartis, Sanofi, Celgene, Immunic, Geneuro, GSK, and MedDay; received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche, Biogen Merck, Novartis, Sanofi, and Celgene; and participated on a Data Safety Monitoring Board or Advisory Board for Roche, Sanofi, Novartis, and Merck. I.S. received consulting fees from Hippocrates Research, NovaNeuro, Sakura Italia, ADL Farmaceutici, and Associazione Commissione Difesa Vista Onlus. C.C. received grants or contracts from Roche, Novartis, Merck Serono, Biogen, and Celgene and received consulting fees from Biogen. L.M. received compensation for consulting services, travel grants, and/or speaking activities from Biogen, Serono, Sanofi, Teva, Roche, and Novartis. E.S. received personal compensation from Almirall, Biogen, Sanofi, Novartis, Roche, Horizon, Alexion, Merck, Mylan, and Teva for traveling and advisory boards. S.D.B. received personal compensation from Alexion, Almirall, Biogen, Merck Novartis, Roche, and Sanofi for traveling and advisory boards. M.B. received honoraria for speaking, advisory board, consulting from Teva, Genzyme, Biogen, Bristol MS, Merck, and Novartis. M.C. received personal compensations from Novartis, Genzyme, and Teva and consulting fees from Zambon. R.F. received honoraria for advisory boards and consulting from Bristol MS, Roche, Merck, and Novartis. P.C. received honoraria as speaker or travel grants to attend national and international conferences or consultation for advisory boards from Alexion, Almirall, Bayer Schering, Biogen, Cellgene-BMS, Janssen, Merck Serono, Teva, Roche, Novartis, Sandoz, and Sanofi-Genzyme. S.T. received travel grants or personal compensations from Biogen, Novartis, Sanofi-Genzyme, Roche, Janssen, Teva, and Almirall. The remaining authors have nothing to report.

Background: Cladribine tablets are a highly effective option for the treatment of relapsingremitting multiple sclerosis (RRMS)., Objective: The study aims to evaluate the effectiveness of cladribine in a real-world setting., Methods: This prospective real-world study consecutively screened all RRMS patients from seven different MS centers in Sicily (Italy) who completed the 2-year treatment course of cladribine tablets in the period between 11 th March 2019 and 31 st October 2021. Data about Expanded Disability Status Scale (EDSS), relapses, previous treatments, adverse events (AEs) and magnetic resonance imaging (MRI) were collected. Patients who were previously treated with other DMTs were further stratified into moderately active treatment (MAT) and highly active treatment (HAT) patients., Results: A total of 217 patients (70% women, with a mean age of 38.4 ± 11.3 years) were enrolled. Fifty patients (23.0%) were naïve to treatment and 167 (77%) switched from other disease modifying therapies. After the second year of treatment, about 80% were EDSS progression free, 88% remained relapse-free at T24, and 48% of patients were MRI activity-free. Kaplan Meier analyses showed significant differences between MT and HAT in terms of time to first clinical relapse (HR: 2.43, IC 1.02- 5.76; p = 0.04), time to the first new T1-gadolinium enhancing lesion (HR: 3.43, IC 1.35-8.70; p = 0.009) and time to MRI worsening (HR: 2.42, IC 1.15-5.09; p = 0.02)., Conclusion: This study confirmed that cladribine is an effective treatment for MS, particularly in naïve patients and those who have switched from MATs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Previous studies attempted to define the best threshold for κ free light chains (κFLC) index, confirming higher sensitivity (Se) but less specificity (Sp) compared with IgG oligoclonal bands (OCB) for the diagnosis of MS., Objective: To evaluate the diagnostic accuracy of different κFLC index intervals in a miscellaneous cohort of neurological patients, proposing a procedural flowchart for MS diagnosis., Methods: We analyzed data from 607 patients diagnosed with MS (179), CIS (116), other inflammatory (94) or non-inflammatory neurological diseases (218). Measures of diagnostic accuracy were reported for different potential thresholds of κFLC index, and for IgG OCB and IgG index. Binary logistic regression was to used to calculate the odds of being diagnosed with MS based on each increase of κFLC index., Results: CSF IgG OCB showed 72.2% Se (CI 95% 68.4-75.7) and 95.2% Sp (CI 95% 93.1-96.7) in discriminating between MS/CIS and controls, with an AUC of 0.84 (CI 95% 0.80-0.87). The highest diagnostic accuracy was reported for κFLC index cut-off of 5.0 (Se = 85.4%, Sp = 90.4%, AUC = 0.88), while a threshold of 11.0 exhibited higher Sp (95.5%, 95% CI 93.1-97.1) than IgG OCB. AUCs for all thresholds between 4.25 and 6.6 were not significantly different from each other, but were significantly higher than the AUC of IgG OCB (p < 0.05). The odds of being diagnosed with MS/CIS increased by 17.1% for each unit increase of κFLC index (OR = 1.17; 95% CI 1.12-1.23; p < 0.001)., Conclusion: κFLC index performed better than CSF IgG OCB in supporting the diagnosis of MS/CIS, with the advantage of being a cost-effective and quantitative analysis., (© 2023. The Author(s).)

Ocrelizumab is a recombinant humanized monoclonal antibody selectively targeting CD20-expressing B cells. The effect of ocrelizumab on primary progressive multiple sclerosis (PPMS) has been evaluated during phase 3 trials that enrolled patients under 55 years with a maximum Expanded Disability Status Scale (EDSS) of 6.5. However, little is known on older disabled patients with longer disease duration. We aimed to assess the clinical effectiveness of ocrelizumab in PPMS patients out of the ORATORIO eligibility criteria. This multicenter retrospective study collected data about the effectiveness of ocrelizumab in PPMS patients who received treatment between May 2017 and June 2022 in the Italian MS centers contributing to the Italian MS Registry who adhered to the Compassionate Use Program. The confirmed EDSS worsening (CEW) (defined as either a ≥ 1-point or ≥ 2-point increase in EDSS score from baseline that was confirmed at T12 and T24) was calculated. At the date of data extraction, out of 887 PPMS patients who had received ocrelizumab, 589 (mean age 49.7 ± 10.7 years, 242 (41.1%) females) were enrolled. The mean follow-up period was 41.3 ± 12.3 months. A total of 149 (25.3%) received ocrelizumab according to the ORATORIO criteria (ORATORIO group) and 440 (74.7%) outside the ORATORIO criteria (non-ORATORIO group). No differences in terms of cumulative probabilities of 12 and 24 months of CEW of ≤ 1 point were found between ORATORIO and non-ORATORIO groups. Cox regression analyses showed that age older than 65 years (HR 2.51, 25% CI 1.07-3.65; p = 0.01) was associated with higher risk of CEW at 24 months. Patients not responding to ORATORIO criteria for reimbursability may benefit from ocrelizumab treatment, as disease activity, disease duration, and EDSS seem to not impact the disability outcome. Our results may suggest to extend the possible use of this powerful agent in selected patients under the age of 65 years., (© 2023. The Author(s).)

Main target in palliative care (PC) is burden care of patients and their families, with the aim to reduce suffering through the management of symptoms, rehabilitation, psychosocial issues, and spiritual well-being, using a multidisciplinary approach. Multiple sclerosis (MS) is a chronic disease which induces physical and psychosocial symptoms, with a significant impact on the quality of life. As a consequence, despite advances in research in disease-modifying drugs, MS remains a life-limiting disease with symptoms negatively impacting the lives of MS patients and their families. PC has been developed for end-of-life treatment in oncology, being little used in MS. Specific issues in MS, like pain due to spasticity, requires a different approach respect to cancer pain management. Moreover, it is difficult to anticipate life expectancy in people with severe MS, who often need palliative care for a long extended period. PC teams are trained to keep open full and competent lines of communication about symptoms and disease progression, advanced care planning, and end-of-life issues and wishes. Many studies investigated the effects of home-based PC in advanced MS, showing weak evidences about the efficacy of PC versus usual care in MS. However, current evidence does not support or refute the routine use of PC interventions for people with MS., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Evidence of the cost-effectiveness of telemedicine (TM) for the management of Multiple Sclerosis (MS) has been provided recently. However, some doubts persist about the accuracy of neurological examinations performed remotely., Objectives: This study investigated the reliability of neurological evaluations performed through TM in mild MS patients as compared with standard in-person visits., Methods: In total, 76 patients with relapsing-remitting MS and Expanded Disability Status Scale (EDSS) ≤ 3.5 were consecutively recruited. Of them, 40 patients (52.6%) accepted to undergo both in-person and TM evaluations with independent examiners within 48 h. We alternatively asked patients to assure or not the presence of a caregiver during TM visits. A satisfaction questionnaire was administered to all participants., Results: The inter-rater agreement attributed by two independent neurologists during TM visit was high (κ > 0.80) for EDSS and Functional Systems (FS) scores. Moderate agreement between TM and in-person evaluations emerged for pyramidal (κ = 0.57; p < 0.001), brainstem (κ = 0.57; p < 0.001), bowel and bladder (κ = 0.54; p < 0.001) and sensory (κ = 0.51; p < 0.001) FS scores, higher in patients providing the support of a caregiver. A good reliability was reported for EDSS scores computed during remote and in-person visits (ICC = 0.83; 95% CI 0.70-0.91; p < 0.001)., Conclusions: Despite the complexity of neurological examination, TM could be useful in monitoring MS patients with low disability., (© 2022. The Author(s).)

Background and Objectives: Several studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR)., Methods: A case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score-matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered., Results: A total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls). In all 3 models, comorbidities, female sex, and a younger age were significantly associated ( p < 0.02) with a higher risk of contracting COVID-19. Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66-3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16-2.13], p = 0.003) were at significantly higher COVID-19 risk. Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34-2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home., Discussion: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS., Classification of Evidence: This study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19. Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated with natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease-modifying therapies (DMTs) on the JCV index have not been fully explored., Objective: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs., Methods: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1)., Results: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index <0.90 was found to be significantly increased in the ALM group (16.7 % versus 66.7 %, p = 0.05), while the percentage of patients with JCV index >1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index <0.90 was also found (23.5 % versus 1.4 %, p = 0.0006). The mean JCV index was reduced in the RTX/OCR and ALM groups, while a significant increase was observed in the FTY group., Conclusion: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

On 11 March 2020, the World Health Organization declared the coronavirus disease 19 (COVID-19) outbreak a pandemic. In this context, several studies and clinical trials have been conducted since then, and many are currently ongoing, leading to the development of several COVID-19 vaccines with different mechanisms of action. People affected by multiple sclerosis (MS) have been considered high-risk subjects in most countries and prioritized for COVID-19 vaccination. However, the management of MS during the COVID-19 pandemic has represented a new challenge for MS specialists, particularly because of the initial lack of guidelines and differing recommendations. Despite an initial hesitation in prescribing disease-modifying drugs (DMDs) in naïve and already treated patients with MS, most national neurology associations and organizations agree on not stopping treatment. However, care is needed especially for patients treated with immune-depleting drugs, which also require some attentions in programming vaccine administration. Many discoveries and new research results have accumulated in a short time on COVID-19, resulting in a need for summarizing the existing evidence on this topic. In this review, we describe the latest research results on the immunological aspects of SARS-CoV-2 infection speculating about their impact on COVID-19 vaccines' mechanisms of action and focused on the management of MS during the COVID pandemic according to the most recent guidelines and recommendations. Finally, the efficacy of COVID-19 and other well-known vaccines against infectious disease in patients with MS on DMDs is discussed., (© 2021. The Author(s).)

Background: The Coronavirus disease 2019 (COVID-19) caused by the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a pandemic, affecting the therapeutic management for Multiple Sclerosis (MS). Any decision regarding the discontinuation of high-potency agents for moderate and highly active MS should be carefully evaluated, taking into account the potential risk of rebound of the disease. In particular, no data about clinical outcome of patients with MS receiving Natalizumab (NTZ) during active COVID-19 infection have been reported yet., Cases Presentation: We reported on 6 patients treated with NTZ for relapsing MS during active COVID-19 infection, who recovered without reporting any worsening or new symptoms. Most of the patients were asymptomatic, with the exception of one patient who had a slight worst COVID-19 clinical course. No patients received O2-therapy or required intensive care. No neurological complications were observed., Conclusions: This paper reported the clinical outcome of patients with MS receiving NTZ during active COVID-19 infection. This case series suggests that treatment with NTZ during pandemic is relatively safe and might be continued in selected patients who are infected by COVID-19, thereby reducing the risk of MS disease rebound., (© 2021. The Author(s).)

Idiopathic intracranial hypertension is a neurological syndrome determined by a rise in intracranial pressure without a detectable cause. Course and prognosis may be changeable, requiring a multidisciplinary approach for its diagnosis and management. Although its precise pathogenesis is still unknown, many studies have been carried out to define the possible causal and associated factors, such as retinoids, steroid hormones, body mass index and recent weight gains, cytokines and adipokines levels. The clinical presentation can be variable including chronic headache, disturbance of vision, diplopia and tinnitus. Even if papilloedema is considered the most specific sign, it could not be observed in more than 5% of patients during the evaluation of the fundus oculi. Neuroradiological signs acquire greater importance in patients who do not present papilloedema and may suggest the diagnosis of idiopathic intracranial hypertension. Other assessments can be useful in the diagnostic process, such as optical coherence tomography, visual evoked potentials, ocular ultrasonography and fundus fluorescein angiography and autofluorescence. Nonetheless, cerebrospinal fluid pressure measurement is required to establish a definite diagnosis. Management may be different, since surgical procedures or lumbar punctures are often required when symptoms develop rapidly leading to a loss of visual function. Apart from these cases, patients can be treated with a pharmacological approach and low-calorie diet, but they also need to be monitored over time since relapses years later are not uncommon., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The prevalence of pain in Multiple Sclerosis (MS) is estimated to be between 29-86% depending on various stages of the disease. According to a recent mechanism-based classification, MS pain syndromes include ongoing extremity pain, trigeminal neuralgia, and Lhermitte's phenomenon, painful tonic spasms and spasticity pain, pain associated with optic neuritis, musculoskeletal pain, migraine, and treatment-induced pain., Area Covered: Pharmacological approaches for MS pain include anticonvulsants, antidepressants, botulinum toxin, cannabinoids, muscle relaxants, opioid analgesics, and intrathecally administered baclofen. It has been reported that pharmacological treatments have poor efficacy and alarming side effects. For these reasons, non-pharmacological interventions, either alone or in combination with pharmacological treatments are commonly used in clinical practice. Examples of these interventions include electrical or chemical neurostimulation therapy, exercise, and psychological approaches. This is discussed in more detail herein., Expert Opinion: The management of MS pain can be challenging due to the natural course of the disease and the lack of a definite cure. Recommendations based on rigorous scientific methods for MS pain treatment are unavailable. Thus, clinicians should consider available treatment regimens based on efficacy, safety, cost, and the clinical complexity of the patient. The use of therapeutic approaches combining pharmacological and non-pharmacological treatments may help to reduce the risk of overuse and mitigate the complaint of simultaneous and multiple therapies.

Introduction : Recently, the economic impact of multiple sclerosis (MS), which includes both direct and indirect costs, has been increasing. While direct costs comprise health-care costs, such as the cost of pharmaceuticals, additional treatments such as physiotherapy, and medical aids, indirect costs are triggered by the productivity loss of patients and caregivers. Although new drugs for MS have changed the therapeutic scenario, they have increased the direct costs of health-care services. Areas covered : This review describes the pharmacoeconomic aspects of synthetic therapies for MS. Additionally, it discusses the economic impact of the various classes of licensed disease-modifying treatments (DMTs) for relapsing forms of MS. Expert opinion : The emerging and more expensive DMTs for MS represent a considerable challenge for health-care systems and resource consumption. Future research should focus on the long-term efficacy of DMTs and the cost of treating MS in a real-life setting. Future biological and radiological biomarkers could help stratify patients at early stages of MS, helping physicians design a personalized therapeutic approach that could have a positive impact in economic terms.