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Background: Biomarkers of neuronal and axonal damage (serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP)) may provide insight into the aetiology of natalizumab wearing-off symptoms (WoSs)., Objectives: We investigated the longitudinal association between and predictive value of sNfL and sGFAP and the occurrence of WoS in MS patients treated with natalizumab., Methods: We performed longitudinal measurements of sNfL and sGFAP in NEXT-MS trial participants who completed a questionnaire about WoS., Results: A total of 364 participants were included. In total, 55.5% presented with WoS and 44.5% without WoS during natalizumab treatment. Longitudinal analyses showed no association between sNfL and sGFAP levels and WoS at any timepoint. Biomarker levels at baseline did not predict first-time WoS occurrence., Conclusion: Acute and chronic neuronal and axonal damage are most likely not the underlying cause of WoS., 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: A.A.T. has nothing to disclose. M.H.J.W. has nothing to disclose. L.B. has nothing to disclose. L.M.Y.G. has nothing to disclose. E.H. has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche and Sanofi Genzyme. E.M.P.E.Z. reports advisory boards/consultancy fees for Merck, Novartis, Genzyme and Roche. L.C.v.R. has nothing to disclose. C.E.P.v.M. has nothing to disclose. A.V. has nothing to disclose. J.P.M. has nothing to disclose. B.H.A.W. has nothing to disclose. N.F.K. has nothing to disclose. E.L.J.H. has nothing to disclose. J.J.J.v.E. reports honoraria for advisory boards and/or speakers fee from Merck Serono, Biogen Idec, Sanofi Genzyme, Roche and Novartis. C.M.R. has nothing to disclose. J.J.K. has nothing to disclose. M.E. has nothing to disclose. J.N. has nothing to disclose. J.v.G. has nothing to disclose. L.G.F.S. has nothing to disclose. M.E.K. has nothing to disclose. E.P.J.A. has nothing to disclose. G.W.v.D. has nothing to disclose. W.H.B. has nothing to disclose. E.M.M.S. has nothing to disclose. B.W.v.O. has nothing to disclose. B.A.d.J. has nothing to disclose. B.M.J.U. reports research support and/or consultancy fees from Genzyme, Biogen Idec, Novartis, Teva Pharmaceutical Industries, Merck Serono, Roche and Immunic Therapeutics. T.R. received funding for research from Genmab and consultancy fees from Novartis. J.K. 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) and adjudication committee of MS clinical trial of Immunic (payments to institution only). Z.L.E.v.K. has nothing to disclose. C.E.T. reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no. 831434); has a research contract with Celgene; serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology & Neuroinflammation and is editor of a Neuromethods book Springer.

Background: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals., Methods: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID)., Results: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy., Conclusions: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks., Trial Registration Number: NCT04225312., Competing Interests: Competing interests: EH: has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche and Sanofi Genzyme. EMPEZ: reports advisory boards/consultancy fees for Merck, Novartis, Genzyme and Roche. JvE: reports honoraria for advisory boards and/or speakers fee from Merck Serono, Biogen Idec, Sanofi Genzyme, Roche and Novartis. FB: Steering committee and iDMC for Biogen, Merck, Roche, EISAI. Consultant to Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Novartis, Merck, Biogen, GE, Roche. Co-founder of Queen Square Analytics. Funding by NIHR-UCLH-BRC, Novartis, GE, UKMSS, MAGNIMS-ECTRIMS, EC-H2020, EC-JU (IMI), EPSRC. Editorial board member for Brain, MSJ, Neurology, Radiology and Neuroradiology (section editor). CET: reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434); has a research contract with Celgene; serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology and Neuroinflammation, and is editor of a Neuromethods book Springer. TR received funding for research from Genmab and consultancy fees from Novartis. BMJU: reports research support and/or consultancy fees from Genzyme, Biogen Idec, Novartis, Teva Pharmaceutical Industries, Merck Serono, Roche, and Immunic Therapeutics. JK: 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, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only)., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To gain insight into current treatment and barriers to optimal treatment for high disease activity relapsing remitting multiple sclerosis (MS) in the Netherlands. Materials & methods: A two-round Delphi panel using an online questionnaire was conducted. Seven MS neurologists from diverse locations in the Netherlands were invited to participate. Result: Out of the seven MS neurologists, five completed both questionnaire rounds. Conclusion: Effectiveness and side effects along with patient's lesion load were the most important factors for choosing a disease modifying therapy (DMTs). Respondents felt restricted to optimally treat their patients due to reimbursement restrictions for certain disease modifying therapies, although agreed that satisfactory treatment options are currently available. The answers show consensus between the participating MS neurologists with high certainty of answers.

Background: The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) has been developed to assess upper extremity function of patients with multiple sclerosis (MS). A minimal clinically important difference (MCID) value has not been determined yet., Objective: The objective of this study is to determine an MCID for AMSQ., Methods: We used the sensitivity- and specificity-based approach with dichotomized global perceived effect as an anchor., Results: The receiver operating characteristic (ROC) curve yielded an optimal threshold value of 14.5 (sensitivity 0.68 and specificity 0.79). The area under the ROC curve value was 0.77., Conclusion: We identified an MCID of 15 points for the AMSQ (range 31-186).

Background: Accurate clinical assessment in multiple sclerosis (MS) is challenging. The Assess MS system is being developed to automatically quantify motor dysfunction in MS, including upper extremity function (UEF) and mobility., Objective: To determine to what extent combinations of standardized movements included in the Assess MS system explain accepted measures of UEF and mobility., Methods: MS patients were recruited at four European MS centres. Eight movements were selected, including tasks of activities of daily living (ADL) and classical neurological tests. Movements were recorded on video and rated by experienced neurologists ( n  = 5). Subsequently, multivariate linear regression models were performed to explain the variance of the Nine-Hole Peg Test (9HPT), Arm Function in Multiple Sclerosis Questionnaire (AMSQ) and Timed-25 Foot Walk test (T25WT)., Results: In total, 257 patients were included. The movements explained 62.9% to 80.1% of the variance of the 9HPT models, 43.3% and 44.3% of the AMSQ models and 70.8% of the T25WT. In all models, tasks of ADL contributed most to the variance., Conclusion: Combinations of movements are valuable to assess UEF and mobility. Incorporating ADL tasks into daily clinical practice and clinical trials may be more valuable than the classical neurological examination of UEF and mobility.

Personalized treatment is highly desirable in multiple sclerosis (MS). We believe that multidisciplinary measurements including clinical, functional and patient-reported outcome measures in combination with extensive patient profiling can enhance personalized treatment and rehabilitation strategies. We elaborate on four reasons behind this statement: (1) MS disease activity and progression are complex and multidimensional concepts in nature and thereby defy a one-size-fits-all description, (2) functioning, progression, treatment, and rehabilitation effects are interdependent and should be investigated together, (3) personalized healthcare is based on the dynamics of system biology and on technology that confirms a patient's fundamental biology and (4) inclusion of patient-reported outcome measures can facilitate patient-relevant healthcare. We discuss currently available multidisciplinary MS data initiatives and introduce joint actions to further increase the overall success. With this topical review, we hope to drive the MS community to invest in expanding towards more multidisciplinary and longitudinal data collection.

Motor dysfunction, particularly ataxia, is one of the predominant clinical manifestations in patients with multiple sclerosis (MS). Assessment of motor dysfunction suffers from a high variability. We investigated whether the clinical rating of ataxia can be improved through the use of reference videos, covering the spectrum of severity degrees as defined in the Neurostatus-Expanded Disability Status Scale. Twenty-five neurologists participated. The variability of their assessments was significantly lower when reference videos were used (SD = 0.12; range = 0.40 vs SD = 0.26; range = 0.88 without reference videos; p  = 0.013). Reference videos reduced the variability of clinical assessments and may be useful tools to improve the precision and consistency in the clinical assessment of motor functions in MS.

Due to the heterogeneous nature of the disease, it is a challenge to capture disease activity of multiple sclerosis (MS) in a reliable and valid way. Therefore, it can be difficult to assess the true efficacy of interventions in clinical trials. In phase III trials in MS, the traditionally used primary clinical outcome measures are the Expanded Disability Status Scale and the relapse rate. Secondary outcome measures in these trials are the number or volume of T2 hyperintense lesions and gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) of the brain. These secondary outcome measures are often primary outcome measures in phase II trials in MS. Despite several limitations, the traditional clinical measures are still the mainstay for assessing treatment efficacy. Newer and potentially valuable outcome measures increasingly used or explored in MS trials are, clinically, the MS Functional Composite and patient-reported outcome measures, and on MRI, brain atrophy and the formation of persisting black holes. Several limitations of these measures have been addressed and further improvements will probably be proposed. Major improvements are the coverage of additional functional domains such as cognitive functioning and assessment of the ability to carry out activities of daily living. The development of multidimensional measures is promising because these measures have the potential to cover the full extent of MS activity and progression. In this review, we provide an overview of the historical background and recent developments of outcome measures in MS trials. We discuss the advantages and limitations of various measures, including newer assessments such as optical coherence tomography, biomarkers in body fluids and the concept of 'no evidence of disease activity'.

Background: Carotid sinus massage is a widely used method for diagnosis and treatment of supraventricular tachycardia and carotid sinus hypersensitivity. Complications, mostly neurological, can occur but are rare. Carotid stenosis is a risk factor for complications. Hearing a carotid bruit on auscultation indicates stenosis, and is a contraindication for performing carotid sinus massage. However, the sensitivity of auscultation is insufficient., Case Description: A 71-year-old man with a history of hypertension and hypercholesterolemia presented to the cardiology accident and emergency department with palpitations. A supraventricular tachycardia was found on examination, for which carotid sinus massage was performed. The patient developed severe aphasia and right-sided hemiparesis caused by an extensive stroke, and died a few days later., Conclusion: The chance of complications following carotid sinus massage is slight; however, this type of complication can have severe consequences. Safer alternative methods may be used for patients with supraventricular tachycardia. In older patients with vascular risk factors, more extensive diagnostic investigations for carotid stenosis should be considered in the diagnostic workup for carotid sinus hypersensitivity.

Traditionally, multiple sclerosis (MS) is considered to be a disease primarily affecting the white matter (WM). However, the development of some clinical symptoms such as cognitive impairment cannot be fully explained by the severity of WM pathology alone. During the past decades it became clear that gray matter (GM) damage of the brain is also of major importance in patients with MS. Thanks to improved magnetic resonance imaging techniques, the in vivo detection of GM pathology became possible, enabling a better understanding of the manifestation of various clinical symptoms, such as cognitive impairment. Using higher field strengths and specific sequences, detection of cortical lesions was increased. However, despite these improvements, visualization of cortical MS lesions remains difficult (only about 30-50% of histopathologically confirmed lesions can be detected at 7 Tesla magnetic resonance imaging (MRI)). Furthermore, more research is needed to understand the exact interplay of cortical lesions, GM atrophy and WM pathology in the development of clinical symptoms. In this review, we summarize the historical background that preceded current research and provide an overview of the current knowledge on clinical consequences of GM pathology in MS in terms of disability, cognitive impairment and other clinically important signs such as epileptic seizures., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

The aim of this work was to determine the value of stroking the lateral dorsal border of the foot, in addition to stroking the sole in patients with a suspected pyramidal tract lesion. In addition, we studied the differences in interpretation between neurologists, residents, and medical students. We included subjects who had weakness of at least one leg and in whom a pyramidal tract lesion was suspected. After testing muscle power, tone, reflexes, and foot tapping, a decision on the presence of a pyramidal syndrome had to be made by each observer. After stimulating the sole as well as the lateral border of the foot, observers made a decision about the presence of a pyramidal syndrome again. Twenty-two legs of 18 patients were examined. Testing the plantar reflex (according to both methods) led to a change of opinion on the presence of a pyramidal syndrome in 45 of 69 (65 %) observations. On analysis according to level of experience, a change of opinion occurred in 19 (86 %) observations by medical students, 15 (65 %) by residents, and 11 (46 %) by neurologists. On eight occasions, the change was prompted by stimulation of the lateral border; in five of these cases the examiner (three medical students and two residents) found a new pathological response. Consecutively stroking the sole and the lateral border may be of added value, especially for less-experienced physicians. It seems that more-experienced physicians need fewer tests in the physical examination in order to identify a pyramidal syndrome of the leg.

Background and Purpose: The high incidence of aneurysmal subarachnoid hemorrhage (aSAH) in Finland may be related to genetic or environmental factors, which may also influence patient and aneurysm characteristics. We compared these characteristics in 2 cohorts in Finland (Kuopio) and the Netherlands (Utrecht)., Methods: For aSAH patients in Kuopio (n=1786) and Utrecht (n=1788), we compared sex, age at onset, and the sites and number of aneurysms from 1986 to 2005. Five-year time trends were assessed with chi(2) tests (sex distribution and the sites and number of aneurysms) and with 1-way ANOVA (age)., Results: The proportion of men in Kuopio (46.1%; 95% CI, 43.8% to 48.4%) was higher than in Utrecht (33.6%, 95% CI, 31.4% to 35.8%) and declined in Kuopio from 50.9% (95% CI, 46.3% to 55.5%) in 1986-1990 to 42.8% (95% CI, 38.0% to 47.6%) in 2001-2005. Mean+/-SD age at onset was 52.4+/-13.3 years in Kuopio and 53.3+/-14.3 years in Utrecht. Both increased similarly over time. The most common aneurysm site in the Kuopio cohort was the middle cerebral artery (33.1%; 95% CI, 30.9% to 35.3%) and in the Utrecht cohort was the anterior communicating artery (38.0%; 95% CI, 35.5% to 40.5%). Multiple aneurysms were more frequent in Kuopio (27.8%; 95% CI, 25.1% to 29.2%) than in Utrecht (14.8%; 95% CI, 13.0% to 16.6%). Sites and proportions of multiple aneurysms did not change during 1986-2005., Conclusions: The cohorts of aSAH patients differed with respect to age at onset and the number and sites of aneurysms. The decline in the proportion of men in Kuopio coincided with increased smoking and alcohol use in women and decreased smoking in men. The differences in aneurysm characteristics remained stable, which suggests that these factors are less influenced by environmental factors.