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Importance: Increasing numbers of people with multiple sclerosis (MS) use disease-modifying therapy (DMT). Long-term stable disease while taking such medications provides a rationale for considering DMT discontinuation given patient burden, costs, and potential adverse effects of immunomodulating therapy., Objective: To investigate whether first-line DMT can be safely discontinued in patients with long-term stable MS., Design, Setting, and Participants: This multicenter, rater-blinded, noninferiority randomized clinical trial was conducted between July 1, 2020, and March 20, 2023, at 14 Dutch centers. Data analysis was performed between July 2023 and January 2024. Key inclusion criteria were relapse-onset MS, aged 18 years or older, without relapses, and without substantial magnetic resonance imaging (MRI) activity in the previous 5 years under first-line DMT. Participants were randomized 1:1 to discontinue or continue first-line DMT., Intervention: Discontinuation of first-line DMT., Main Outcome and Measure: The primary outcome was significant inflammatory disease activity, defined as relapse and/or 3 or more new T2 lesions or 2 or more contrast-enhancing lesions on brain MRI., Results: Of 163 potentially eligible participants, 89 participants were included in the trial at the moment of early termination. Forty-four participants (49.4%) were assigned to the continue group and 45 participants (50.6%) were assigned to the discontinue group. Median (IQR) age was 54.0 (49.0-59.0) years, and 60 participants (67.4%) were female. Two participants in the continue group were lost to follow-up. After a median (IQR) follow-up time of 15.3 (11.4-23.9) months, the trial was prematurely terminated because of inflammatory disease activity recurrence above the predefined limit. In total, 8 of 45 participants in the discontinue group (17.8%) vs 0 of 44 participants in the continue group reached the primary end point and had recurrent, mostly radiological inflammation. Two of these 8 participants had a clinical relapse. Median (IQR) time to disease activity was 12.0 (6.0-12.0) months., Conclusions and Relevance: In this randomized clinical trial, even in patients with long-term MS stable for over 5 years, first-line DMT discontinuation can lead to recurrence of inflammatory disease activity. Although this study cohort was relatively small, the recurrence of inflammation in the discontinue group was significantly higher than in the continue group and also higher than in the previously published DISCOMS trial, which only included individuals aged 55 years or older. This study provides additional data, especially in a younger population and including longitudinal biomarker measurements, for informed decision-making in cases when treatment discontinuation is considered., Trial Registration: ClinicalTrials.gov Identifier: NCT04260711.

Background and Objectives: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID., Methods: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated., Results: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms., Discussion: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations., Competing Interests: Declaration of competing interest A.A. Toorop: nothing to disclose. M.H.J. Wessels: nothing to disclose. L.M.Y. Gelissen: nothing to disclose. E. Hoitsma: has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche, and Sanofi Genzyme. E.M.P.E. Zeinstra: reports advisory boards/consultancy fees for Merck, Novartis, Genzyme and Roche. L.C. van Rooij: nothing to disclose. C.E.P. van Munster: nothing to disclose. A. Vennegoor: nothing to disclose. J.P. Mostert: nothing to disclose. B.H.A. Wokke: nothing to disclose. N.F. Kalkers: nothing to disclose. E.L.J. Hoogervorst: nothing to disclose. J.J.J. van Eijk: reports honoraria for advisory boards and/or speakers fee from Merck Serono, Biogen Idec, Sanofi Genzyme, Roche and Novartis. C.M. Roosendaal: nothing to disclose. J.J. Kragt: nothing to disclose. M. Eurelings: nothing to disclose. J. Nielsen: nothing to disclose. J. van Genugten: nothing to disclose. L.G.F. Sinnige: nothing to disclose. M.E. Kloosterziel: nothing to disclose. E.P.J. Arnoldus: nothing to disclose. G.W. van Dijk: nothing to disclose. W.H. Bouvy: nothing to disclose. E.M.M. Strijbis: nothing to disclose. B.W. van Oosten: nothing to disclose. B.A. de Jong: nothing to disclose. B.I. Lissenberg-Witte: nothing to disclose. T. Rispens received funding for research from Genmab and consultancy fees from Novartis. B.M.J. Uitdehaag: reports research support and/or consultancy fees from Genzyme, Biogen Idec, Novartis, Teva Pharmaceutical Industries, Merck Serono, Roche, and Immunic Therapeutics. J. Killestein: received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche Ltd., Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd., Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only). Z.L.E. van Kempen: nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP , PLK1 , MECP2 , MTMR7 , TOX3 , CPT1A , SORCS1 , TRIM66 , ITPR3 , TTC28 , CACNA1F , and PRAM1 . Of these, three genes ( MBP , MECP2 , and CPT1A ) have been previously reported as carrying MS-related rare variants. Six additional genes ( MTMR7 , TOX3 , SORCS1 , ITPR3 , TTC28 , and PRAM1 ) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.

Background: Since decision making about treatment with disease-modifying drugs (DMDs) for multiple sclerosis (MS) is preference sensitive, shared decision making between patient and healthcare professional should take place. Patient decision aids could support this shared decision making process by providing information about the disease and the treatment options, to elicit the patient's preference and to support patients and healthcare professionals in discussing these preferences and matching them with a treatment. Therefore, a prototype of a patient decision aid for MS patients in the Netherlands-based on the principles of multi-criteria decision analysis (MCDA) -was developed, following the recommendations of the International Patient Decision Aid Standards. MCDA was chosen as it might reduce cognitive burden of considering treatment options and matching patient preferences with the treatment options., Results: After determining the scope to include DMDs labelled for relapsing-remitting MS and clinically isolated syndrome, users' informational needs were assessed using focus groups (N = 19 patients) and best-worst scaling surveys with patients (N = 185), neurologists and nurses (N = 60) to determine which information about DMDs should be included in the patient decision aid. Next, an online format and computer-based delivery of the patient decision aid was chosen to enable embedding of MCDA. A literature review was conducting to collect evidence on the effectiveness and burden of use of the DMDs. A prototype was developed next, and alpha testing to evaluate its comprehensibility and usability with in total thirteen patients and four healthcare professionals identified several issues regarding content and framing, methods for weighting importance of criteria in the MCDA structure, and the presentation of the conclusions of the patient decision aid ranking the treatment options according to the patient's preferences. Adaptations were made accordingly, but verification of the rankings provided, validation of the patient decision aid, evaluation of the feasibility of implementation and assessing its value for supporting shared decision making should be addressed in further development of the patient decision aid., Conclusion: This paper aimed to provide more transparency regarding the developmental process of an MCDA-based patient decision aid for treatment decisions for MS and the challenges faced during this process. Issues identified in the prototype were resolved as much as possible, though some issues remain. Further development is needed to overcome these issues before beta pilot testing with patients and healthcare professionals at the point of clinical decision-making can take place to ultimately enable making conclusions about the value of the MCDA-based patient decision aid for MS patients, healthcare professionals and the quality of care.

Objective: To determine whether natalizumab efficacy is maintained when switching to personalized extended interval dosing based on individual natalizumab trough concentrations in patients with relapsing-remitting multiple sclerosis (RRMS)., Methods: This was a prospective multicenter single-arm trial with 1 year follow-up and a 1-year extension phase. Participants were adult persons with RRMS treated with natalizumab without disease activity in the year prior to enrollment. The natalizumab treatment interval was based on longitudinal natalizumab trough concentrations. Patients received 3 monthly MRI scans, relapse assessments, and disability scoring during follow-up. The primary endpoint was the occurrence of gadolinium-enhancing lesions on MRI. Secondary endpoints were new/enlarging T2 lesions on MRI and relapses and progression on the Expanded Disability Status Scale (EDSS) during follow-up and extension phase., Results: Sixty-one patients were included. Eighty-four percent extended the interval from a 4-week interval to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI] 0%-7.4%) during follow-up. No new/enlarging T2 lesions (95% CI 0%-7.4%) or relapses (95% CI 0%-7.4%) were reported during follow-up and in the extension phase. Median EDSS was comparable at baseline (3.0, interquartile range [IQR] 2.0-5.0) and after follow-up (3.0, IQR 2.0-5.0)., Conclusion: Personalized extended interval dosing did not induce recurrence of MS disease activity. Natalizumab efficacy was maintained in stable patients with RRMS receiving personalized extended interval dosing based on individual natalizumab concentrations., Classification of Evidence: This study provides Class IV evidence that personalized extended interval dosing of natalizumab does not result in recurrence of disease activity in stable patients with RRMS., (© 2020 American Academy of Neurology.)

Background: Recently, ocrelizumab (Ocrevus®) was approved for the treatment of primary progressive multiple sclerosis (PPMS) based on data from the ORATORIO clinical trial. Real-world data about the clinical effectiveness of ocrelizumab has yet to be gathered., Objective: The aim of this study was to provide data about the clinical effectiveness of ocrelizumab for patients diagnosed with PPMS in a real-world setting., Methods: We conducted a retrospective cohort study of all patients with PPMS who started ocrelizumab treatment ( n = 21) in St. Antonius Hospital (Utrecht/Nieuwegein, the Netherlands) between April 2018 and December 31, 2018. Primary outcome was pre- versus post-ocrelizumab disability worsening rate (from 96 weeks prior to first ocrelizumab administration up to 24 weeks post first ocrelizumab administration)., Results: Disability worsening rate while on treatment significantly differed (lower) from disability worsening rate in pre-treatment period ( Z = -2.81, p ≤ .01). Three out of 17 patients showed a clinically relevant improvement in disability status after treatment start., Conclusion: Ocrelizumab can stabilize disability progression in patients with PPMS. Some patients even showed a clinically relevant improvement in disability status. Further research should help to identify which patients benefit most from ocrelizumab., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 K. Daniels et al.)

Dizziness is a frequently reported symptom following head trauma. Although often ascribed to concussion, post-traumatic benign paroxysmal positional vertigo (BPPV) must be included in the differential diagnosis. In this article, three patients who attended a neurology outpatient clinic with persistent dizziness following head trauma were ultimately diagnosed with post-traumatic BPPV. Dizziness lessened substantially once a canalith repositional manoeuvre was performed. Patients with post-traumatic BPPV are generally younger, report more severe symptoms and have a higher rate of relapse. Diagnosing post-traumatic BPPV can be challenging due to the presence of more urgent injuries in the initial phase and the habitual attribution of symptoms to concussion. A timely diagnosis is crucial, however, since treatment is easy to perform, non-invasive and effective.

Approximately 34-65% of patients with multiple sclerosis (MS) are confronted with cognitive problems sooner or later. These include problems with the speed of information processing, memory, attention and executive functioning. Cognitive problems in patients with MS are currently often not examined on a routine basis and therefore remain unrecognised, or are not recognised in time. This may have a negative impact on their work and lead to social problems. In this article, we talk about the importance of early recognition of cognitive problems in patients with MS. Routine questioning about cognitive problems and the use of a short screening test are first steps in the right direction.

Background: In multiple sclerosis patients, the persistence of, and adherence to, disease-modifying treatment are often insufficient. The degree of persistence and adherence may relate to the care received from various disciplines., Methods: In an observational study of 203 patients treated with glatiramer acetate 20 mg subcutaneous daily, we assess the persistence and adherence in relation to the amount of care received in various disciplines. The frequencies and durations of care per discipline were reported by patients online, as were missed doses and eventual treatment discontinuation. The associations between the care provided by neurologists, nurses, psychologists, pharmacists, and rehabilitative doctors and persistence and adherence were the primary outcomes; the associations between care received from general practitioners, occupational therapists, physiotherapists, social workers, dieticians, home caregivers, informal caregivers, other medical specialists, and other caregivers and persistence and adherence were secondary outcomes., Results: It was found that the 12-month persistence rate was 62% and that 85% of the persistent patients were 95% adherent (missed <5% of doses). Patients who discontinued treatment in the fourth quarter (Q) had received less-frequent and shorter psychological care in Q3 than persistent patients (P=0.0018 and P=0.0022). Adherent patients had received more frequent home care and informal care than nonadherent patients (P=0.0074 and P=0.0198), as well as longer home care and informal care (P=0.0074 and P=0.0318). Associations between care in other disciplines and persistence or adherence were not observed. As to the relationship between adherence and persistence, nonadherence in Q2 was related to discontinuation after Q2 (P=0.0001)., Conclusion: We obtained no evidence that, in multiple sclerosis patients, persistence of and adherence to disease-modifying treatment are associated with the amount of neurological, nursing, pharmaceutical, or rehabilitative care. However, findings suggest that the treatment of psychological problems in Q3 may relate to persistence and that home care and informal care may relate to adherence.