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Background: Potential supplemental disease-modifying and neuroprotective treatment strategies are warranted in multiple sclerosis (MS). Exercise is a promising non-pharmacological approach, and an uninvestigated ‘window of opportunity’ exists early in the disease course. Objective: To investigate the effect of early exercise on relapse rate, global brain atrophy and secondary magnetic resonance imaging (MRI) outcomes. Methods: This randomized controlled trial ( n = 84, disease duration Results: No between-group differences were observed for primary outcomes, relapse rate (incidence-rate-ratio exercise relative to control: (0.49 (0.15; 1.66), p = 0.25) and global brain atrophy rate (−0.04 (−0.48; 0.40)%, p = 0.87), or secondary measures of lesion load. Aerobic fitness increased in favour of the exercise group. Microstructural integrity was higher in four of eight a priori defined motor-related tracts and nuclei in the exercise group compared with the control (thalamus, corticospinal tract, globus pallidus, cingulate gyrus) at 48 weeks. Conclusion: Early supervised aerobic exercise did not reduce relapse rate or global brain atrophy, but does positively affect the microstructural integrity of important motor-related tracts and nuclei.

Background Exercise positively affects multiple sclerosis (MS) symptoms, physiological systems, and potentially cognition. However, an uninvestigated “window of opportunity” exists for exercise therapy early in the disease. Objective This study presents secondary analyses from the Early Multiple Sclerosis Exercise Study, and aims to investigate the efficacy of exercise on physical function, cognition, and patient-reported measures of disease and fatigue impact early in the disease course of MS. Methods This randomized controlled trial (n = 84, time since diagnosis Results Following early exercise aerobic fitness showed superior between-group physiological adaptations (4.0 [1.7; 6.3] ml O2/min/kg; large effect size [ES = 0.90]). No other outcomes showed significant between-group differences, yet all measures of walking and upper-limb function showed small-to-medium effect sizes in favor of exercise (ES = 0.19−0.58). Overall disability status as well as cognition were unaffected by exercise, whereas perception of disease and fatigue impact were reduced in both groups. Conclusion In early MS, 48 weeks of supervised aerobic exercise seem to positively modify physical function, but not cognitive function. Perception of disease and fatigue impact may be modifiable by exercise in early MS. Trial registration: Clinicaltrials.gov (identifier: NCT03322761).

Purpose: This article examines how issues of control, certainty, and uncertainty are experienced and managed in everyday life with multiple sclerosis (MS) and explores the ways in which people living with MS make sense of these experiences. Materials and methods: Qualitative interviews with 23 women and men diagnosed with MS and four relatives were carried out in Denmark. Drawing on the notion of “phenomenological uncertainty,” a thematic approach was used to analyse the interview data. Results: Three themes characterise participants’ experience of uncertainty: the body and issues of control; symptom fluctuations and disease progression; understanding and interpreting embodied MS experiences. Shared, between the themes, is a focus on the body and multi-faceted bodily aspects of uncertainty across diverse temporalities. Conclusion: Phenomenological uncertainty shapes and pervades the everyday lived experience of MS in the present and future. Gaining a sense of control and certainty in the face of daily uncertainty demands ongoing self-surveillance, and the evaluation and reconciliation of fluctuating MS symptom expressions and disease progression with personal needs, abilities, and management strategies.IMPLICATIONS FOR REHABILITATION Rehabilitation professionals and physicians should consider the lived experience of uncertainty in everyday life with MS in all their contacts with people living with MS. The multi-faceted uncertainties experienced by people living with MS should be actively acknowledged and incorporated in discussions of MS rehabilitation options and when integrating MS guideline content into activities-of-daily-living advice. Discussions of MS medical treatment options should actively consider and integrate the multi-faceted uncertainties experienced by people living with MS.

Background: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM). Objectives: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers. Methods: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring. Results: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35–3.75, n = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49–2.16), n = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78–2.54), n = 11). Conclusion: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.

A systematic review of the literature was conducted comparing neurophysiological outcomes in persons with multiple sclerosis (PwMS) to healthy controls (HC), in studies of the central nervous system (CNS) function comprising motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) and in studies of the peripheral nervous system (PNS) function comprising electroneuronography (ENG) outcomes elicited by peripheral nerve stimulation. Studies comparing neuromuscular function, assessed during maximal voluntary contraction (MVC) of muscle, were included if they reported muscle strength along with muscle activation by use of electromyography (EMG) and/or interpolated twitch technique (ITT). Studies investigating CNS function showed prolonged central motor conduction times, asymmetry of nerve conduction motor pathways, and prolonged latencies in PwMS when compared to HC. Resting motor threshold, amplitude, and cortical silent periods showed conflicting results. CNS findings generally correlated with disabilities. Studies of PNS function showed near significant prolongation in motor latency of the median nerve, reduced nerve conduction velocities in the tibial and peroneal nerves, and decreased compound muscle action potential amplitudes of the tibial nerve in PwMS. ENG findings did not correlate with clinical severity of disabilities. Studies of neuromuscular function showed lower voluntary muscle activation and increased central fatigue in PwMS, whereas EMG showed divergent muscle activation (ie, EMG amplitude) during MVC. When comparing the existing literature on neurophysiological motor examinations in PwMS and HC, consistent and substantial impairments of CNS function were seen in PwMS, whereas impairments of the PNS were less pronounced and inconsistent. In addition, impairments in muscle activation were observed in PwMS.

© 2021 European Academy of Neurology, Background and purpose: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system with an undetermined etiology. Retinoids may have immunomodulatory effects that favorably influence MS progression. We aimed to explore the yet unknown relationship between exposure to retinoids and the risk of acquiring MS. Methods: We performed a nationwide cohort study in the Danish population in the period 1998-2016, comparing MS incidence in three groups: users of systemic retinoids; users of topical retinoids (negative control group); and users of non-retinoid acne drugs (control group). We used data from the Danish Multiple Sclerosis Registry (DMSR), the Danish National Prescription Registry and the Danish National Patient Registry. Linkage was obtained through the personal identification number (CPR number). We addressed confounding by three-way propensity score (PS)-matching weights. Additionally, to evaluate a cumulative dose-response effect for systemic retinoids on MS incidence, we conducted a case-control study, nested within the cohort. Results: A total of 257,193 users of non-retinoid acne drugs, 130,560 users of topical retinoids, and 75,610 users of systemic retinoids were included. Systemic retinoid use was not associated with a reduced risk of MS compared to non-retinoid acne drug use in crude (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61 to 1.05]) and weighted analyses (HR 0.89, 95% CI 0.67 to 1.20). There was no evidence of a cumulative dose-response association between systemic retinoids and MS incidence. Conclusions: Use of systemic retinoids was not associated with a reduced incidence of MS compared to use of non-retinoid acne drugs in this study., A stipend to F.C.F. was paid by Fundação para a Ciência e Tecnologia (reference PD/BD/114122/2015), and K.B.K. was funded by the Independent Research Fund Denmark (grant 8020-00176B) and the Research Fund of the Region of Southern Denmark (grant 17/33580).

Objectives: Fatigue and walking impairment are disabling symptoms of multiple sclerosis (MS). We investigated the effects of progressive aerobic exercise (PAE) on fatigue, walking, cardiorespiratory fitness (VO2max), and quality of life in people with MS (pwMS). Materials & Methods: Randomized controlled trial (1:1 ratio, stratified by sex) with a 24-week crossover follow-up and intention-to-treat analysis. Allocation to an exercise (24 weeks of PAE followed by self-guided physical activity) and a waitlist (24 weeks of habitual lifestyle followed by PAE) group. PAE comprised two supervised sessions per week; 30–60 min, 65–95% of maximum heart rate. Fatigue impact (Modified Fatigue Impact Scale; MFIS) and severity (Fatigue Severity Scale; FSS), walking ability (12-item MS Walking Scale; MSWS-12) and capacity (Six-Minute Walk Test; 6MWT, Six Spot Step Test; SSST), quality of life (Short Form 36 health survey; SF-36), and VO2max were measured at baseline, 24 weeks, and 48 weeks. Results: Eighty-six pwMS were enrolled. Following PAE between-group differences showed reductions in MFIStotal (−5.3 [95% CI: −10.9;0.4], point estimate >clinical relevance), MFISphysical subscore (−2.8 [−5.6;-0.1]), and MFISpsychosocial subscore (−0.9 [−1.6;-0.2]), and an increase in VO2max (+3.5 ml O2/min/kg [2.0;5.1]). MSWS-12 (−5.9 [−11.9; 0.2]) and 6MWT (+14 m [−5;33]) differences suggested potential small walking improvements. No changes observed in FSS, SSST, or SF-36. Conclusions: In a representative sample of pwMS, PAE induced a clinically relevant reduction in fatigue impact, whereas small and no effects were seen for walking and quality of life, respectively. The results need confirmation in a future trial due to the study limitations.

Background Cognitive impairment is highly prevalent in multiple sclerosis (MS). Progressive aerobic exercise (PAE) represents a promising approach toward preservation or even improvement of cognitive performance in people with MS (pwMS). Objective To investigate the effects of PAE on the cognitive domains of information processing, learning and memory, and verbal fluency in pwMS. Methods This randomized controlled trial included an exercise ( n = 43, 24 weeks of supervised PAE, followed by self-guided physical activity) and a waitlist group ( n = 43, 24 weeks of habitual lifestyle, followed by supervised PAE). Assessments included the Brief Repeatable Battery of Neuropsychological tests (BRB-N), self-reported mood, and cardiorespiratory fitness. Published reference data were used to compute Z-scores for BRB-N scores. Cognitive impairment was defined as one or more Z-scores ⩽ –1.5 SD. Results No between-group changes in the total group were observed in BRB-N scores following PAE. In the cognitively impaired subgroup (43% of the total group) the between-group point estimate suggested a potential clinical relevant improvement in the Symbol Digit Modalities Test (95% CI overlapping zero). Cardiorespiratory fitness increased in the total group and the cognitively impaired subgroup. Conclusion In the present representative MS group, 24 weeks of supervised PAE had no effect on any cognitive domain in the total group but potentially improved processing speed in the cognitively impaired subgroup.

Impairments across multiple domains are a disabling consequence of multiple sclerosis (MS). Originating from preventive medical strategies, the “time matters”-perspective has become a focal point when treating MS. In particular, early detection of physical and cognitive deficits, along with deficits in patient-reported outcomes seems crucial to further optimize both pharmacological and non-pharmacological MS treatment strategies. Therefore, this topical review investigates the level of impairments across multiple domains (physical function, cognitive function, and patient-reported outcomes) in the early stage of MS (⩽5 years since diagnosis, including clinically isolated syndrome (CIS)), when compared to matched healthy controls. Even at early disease stages, studies show impairments corresponding to 8%–34% and small-to-large numerical effect sizes (0.35–2.85) in MS/CIS patients across domains. This evidence call for early screening programs along with early interventions targeting the multiple impaired domains. This further highlights the importance of preventive initiatives preserving and/or restoring physical and cognitive reserve capacity if possible.

Purpose The purpose of this paper is to understand how the hospital staff (nurses and physicians) at two hospital wards have coped with everyday work having leaders in conflict or longer periods without one or the other leader and whether the way the staff handled the challenges was resilient. Design/methodology/approach Through semi-structured interviews with the staff at the two wards, the authors analysed how the staff were working, if they had cooperation and interdisciplinary cooperation, how they would handle uncertainties and how they coped with the absence of their leaders. Findings The staff at both wards were handling the everyday work in a resilient way. The authors argue that to increase the resilience in an organisation, leaders should acknowledge the need to establish strong emotional ties among staff and at the same time ensure role structures that make sense in the everyday work. Originality/value This study reports on original work and shows what decision makers could do to increase resilience in an organisation. This paper shows that the organisational context is important for the staff to act resiliently. As leaders come and go, it can be important for the stability of the organisation to promote the staff in acting resiliently independent of the leader situation.

Background Population-based clinical studies in neuromyelitis optica spectrum disorder (NMOSD) and epidemiological and clinical comparisons of White ethnicities are missing. In a large population-based international cohort, we extensively characterized aquaporin-4 antibody seropositive (AQP4-Ab+) NMOSD, and also compared the clinical, radiological and epidemiological features between two European populations residing in different areas. Methods Between self-reported Danish and Hungarian ethnicities, we compared the population-based clinical features, disability outcomes, and death of 134 AQP4-Ab+ NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis (IPND) criteria. For precise comparison of epidemiology, we conducted a population-based head-to-head comparative study of the age-standardized prevalence (January 1, 2014) and incidence (2007–2013) of AQP4-Ab+ NMO/NMOSD among adults (≥16 years) in Denmark (4.6 million) and Hungary (6.4 million) by applying 2015 IPND (NMOSD) criteria and 2006 Wingerchuk (NMO). Results Danes were more likely to present with transverse myelitis and were more affected by spinal cord damage on long-term disability. Hungarians presented most often with optic neuritis, although visual outcome was similar in the groups. No differences were observed in sex, disease course, relapse rate, autoimmune comorbidity, mortality, brain MRI, and treatment strategies. The age-standardized prevalence estimates of AQP4-Ab+ NMOSD (2015 IPND criteria) in Denmark vs. Hungary were 0.66 vs. 1.43 (/100,000) while incidence rates were 0.04 vs. 0.11 (/100,000 person-years); similar differences were found based on the 2006 NMO criteria. Conclusions This head-to-head comparative study indicates different disease characteristics and epidemiology among White populations in Europe, and substantiates the need for population-based genetic and environmental studies in NMOSD.

Background. Motor fatigability (i.e. contraction-induced reduction in muscle strength) from a concentric task associatestronger to walking and perception of fatigue in persons with multiple sclerosis (pwMS), compared with an isometric task.However, the central and peripheral contributions of motor fatigability between these tasks have not been investigated.Objective. Compare the central and peripheral contributions of motor fatigability in the knee extensors in a sustainedisometric fatigability protocol versus a concentric fatigability protocol and in pwMS versus healthy controls (HCs).Methods. Participants (n=31 pwMS; n=15 HCs) underwent neuromuscular testing before and immediately after twoknee extensor fatigability tasks (sustained isometric and concentric) in an isokinetic dynamometer. Neuromuscular testingof fatigability consisted of maximal voluntary contraction, voluntary activation (central/neural contributor), and restingtwitch (peripheral/muscular contributor) determined by the interpolated twitch technique. Results. Sustained isometricand concentric fatigability protocols resulted in motor fatigability for both pwMS and HCs, with no between-protocolsdifferences for either group. Regression analysis showed that motor fatigability variance in pwMS was mainly attributedto central fatigability in the sustained isometric protocol and to both central and peripheral fatigability in the concentricprotocol. In HCs, the variance in sustained isometric and concentric fatigability were attributed to both peripheral andcentral fatigability. Conclusion. Central and peripheral contributions of motor fatigability differed between sustainedisometric and concentric protocols as well as between pwMS and HCs. These between-protocol differences in pwMSprovide a neuromuscular dimension to the reported difference in the strength of associations of concentric and isometrictasks to walking and perception of fatigue in pwMS. BACKGROUND: Motor fatigability (i.e. contraction-induced reduction in muscle strength) from a concentric task associate stronger to walking and perception of fatigue in persons with multiple sclerosis (pwMS), compared with an isometric task. However, the central and peripheral contributions of motor fatigability between these tasks have not been investigated.OBJECTIVE: Compare the central and peripheral contributions of motor fatigability in the knee extensors in a sustained isometric fatigability protocol versus a concentric fatigability protocol and in pwMS versus healthy controls (HCs).METHODS: Participants (n=31 pwMS; n=15 HCs) underwent neuromuscular testing before and immediately after two knee extensor fatigability tasks (sustained isometric and concentric) in an isokinetic dynamometer. Neuromuscular testing of fatigability consisted of maximal voluntary contraction, voluntary activation (central/neural contributor), and resting twitch (peripheral/muscular contributor) determined by the interpolated twitch technique.RESULTS: Sustained isometric and concentric fatigability protocols resulted in motor fatigability for both pwMS and HCs, with no between-protocols differences for either group. Regression analysis showed that motor fatigability variance in pwMS was mainly attributed to central fatigability in the sustained isometric protocol and to both central and peripheral fatigability in the concentric protocol. In HCs, the variance in sustained isometric and concentric fatigability were attributed to both peripheral and central fatigability.CONCLUSION: Central and peripheral contributions of motor fatigability differed between sustained isometric and concentric protocols as well as between pwMS and HCs. These between-protocol differences in pwMS provide a neuromuscular dimension to the reported difference in the strength of associations of concentric and isometric tasks to walking and perception of fatigue in pwMS.

ObjectiveTo determine whether 24 weeks of high-intensity progressive aerobic exercise (PAE) affects brain MRI measures in people with multiple sclerosis (MS).MethodsWe conducted a randomized, controlled, phase 2 trial (with a crossover follow-up) including an exercise group (supervised PAE followed by self-guided physical activity) and a waitlist group (habitual lifestyle followed by supervised PAE). Mildly to severely impaired patients with MS aged 18–65 years were randomized (1:1). The primary outcome was percentage brain volume change (PBVC) after 24 weeks, analyzed using the intention-to-treat principle.ResultsEighty-six participants were recruited. PBVC did not change over the intervention period (mean between-group change +0.12%, 95% confidence interval [CI] −0.27 to 0.51, p = 0.55). In contrast, cardiorespiratory fitness (+3.5 mL O2/min/kg, 2.0 to 5.1, p < 0.01) and annualized relapse rate (0.00, 0.00–0.07 vs +0.45, 0.28 to 0.61, p < 0.01) improved in the exercise group.ConclusionThese findings do not support a neuroprotective effect of PAE in terms of total brain atrophy in people with MS and it did not lead to a statistically significant difference in gray matter parenchymal fraction. PAE led to improvements in cardiorespiratory fitness and a lower relapse rate. While these exploratory findings cautiously support PAE as a potential adjunct disease-modifying treatment in MS, further investigations are warranted.Clinicaltrials.gov identifierNCT02661555.Classification of evidenceThis study provides Level I evidence that 24 weeks of high-intensity PAE did not elicit disease-modifying effects in PBVC in people with MS. Exploratory analyses showed that PAE may reduce relapse rate.

The association between somatic disorders and suicidal behaviour has been examined in many studies. Despite large variation in quality and study design, recent studies have improved our knowledge substantially, not only regarding the extent of risk but also factors influencing the risk. Most studies have been conducted in European countries, the US, Australia, Japan, and South Korea. A series of studies have examined suicide risk in relation to somatic disorders of older persons, while others addressed somatic disorders and attempted suicide in children and youth. Physical conditions may play an important role in medical settings, regardless of whether mental disorders are present or not, though especially when mental disorders are present. This chapter presents a review of present knowledge on suicide and suicidal behaviour in selected somatic disorders and pain syndromes, with a focus on studies from different parts of the world.

OBJECTIVE: To compare baseline physical and cognitive performance, neurophysiological, and magnetic resonance imaging (MRI) outcomes and examinetheir interrelationship inparticipants with Multiple Sclerosis (MS), already established aseither responder or non-responder to Fampridine treatment, andto examine associationswiththe expanded disability status scale (EDSS) and 12-item MS walking scale (MSWS-12).METHODS: Baseline data from an explorative longitudinal observational study were analyzed. Participants underwent the Timed 25-Foot Walk Test (T25FW), Six Spot Step Test (SSST), Nine-Hole Peg Test, Five Times Sit-to-Stand Test, Symbol Digit Modalities Test (SDMT), neurophysiological testing, including central motor conduction time (CMCT), peripheral motor conduction time (PMCT), motor evoked potential (MEP) amplitudesand electroneuronographyof the lower extremities, and brain MRI (brain volume, number and volume of T2-weighted lesions and lesion load normalized to brain volume).RESULTS: 41 responders and 8 non-responders were examined. There were no intergroup differences inphysical performance, cognitive, neurophysiological, andMRI outcomes (p > 0.05).CMCT was associated withT25FW, SSST, EDSS, and MSWS-12,(p < 0.05). SDMT was associated with the number and volume of T2-weighted lesions, and lesion load normalized to brain volume (p < 0.05).CONCLUSION: No differences were identified between responders and non-responders to Fampridine treatment regarding physical and cognitive performance, neurophysiological or MRI outcomes. The results call for cautious interpretation and further large-scale studies are needed to expand ourunderstanding of underlying mechanisms discriminating Fampridine responders and non-responders.CMCT may be used as a marker of disability and walking impairment, while SDMT was associated with white matter lesions estimated by MRI. ClinicalTrials.gov identifier: NCT03401307.

Elena Didenko Pedersen,1,2 Egon Stenager,3,4 JL Vadgaard,5 MB Jensen,6 R Schmid,7 N Meland,8 G Magnussen,9 Jette L Frederiksen10,11 1Akershus University Hospital, Department of Neurology, Loerenskog, Norway; 2Sandvika Nevrosenter, Sandvika, Norway; 3MS Clinic of Southern Jutland, Department of Neurology, Hospital of Southern Denmark, Odense, Denmark; 4Institute of Regional Research, University of Southern Denmark, Odense, Denmark; 5Department of Neurology, Sjællands University Hospital, Roskilde NeuroCenter, Roskilde, Denmark; 6Department of Neurology, Nordsjaellands Hospital, Hilleroed, Denmark; 7MS Clinic, Department of Neurology, Vejle Hospital, Vejle, Denmark; 8Smerud Medical Research, Oslo, Norway; 9Merck Norway, An Affiliate of Merck AB (Merck AB NUF), Oslo, Norway; 10Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Science, Glostrup, Denmark; 11Institute of Clinical Medicine, Copenhagen University, Copenhagen, Denmark Background: Disease modifying drugs help control the course of relapsing remitting multiple sclerosis (RRMS); however, good adherence is needed for long-term outcomes.Objective: To evaluate patient adherence to treatment with subcutaneous interferon beta-1a using RebiSmart® and assess injection-site reactions and treatment satisfaction.Methods: This prospective, single-arm, open-label, noninterventional multicenter Phase IV trial included disease modifying drug-experienced mobile patients with RRMS. Adherence was measured over 12 weeks. Items 13–23, 35, 37, and 38 of the Multiple Sclerosis Treatment Concerns Questionnaire (injection-site reactions and treatment satisfaction) were recorded at 12 weeks.Results: Sixty patients were recruited (mean age 43.7 [±SD 7.9] years; 83% female; mean years since multiple sclerosis diagnosis 6.7 [SD 4.5]). Adherence data were obtained in 54 patients only due to technical problems with six devices. Over 12 weeks, 89% (n=48) of patients had ≥90% adherence to treatment. Most patients experienced mild influenza-like symptoms and injection-site reactions, and global side effects were minimal. Most patients (78%) rated the convenience as the most important aspect of the device, and most experienced no or mild pain.Conclusion: RRMS patients treated with subcutaneous interferon beta-1a, administered with RebiSmart, demonstrated generally good adherence, and the treatment was generally well tolerated. Keywords: adherence, multiple sclerosis, relapsing remitting MS, subcutaneous interferon beta-1a, RebiSmart, trial

This paper explores the moral implications of treatment of young people with functional somatic symptoms. Based on an ethnographic field study at a Danish pain clinic for youngsters (age 8 to 18), the paper seeks to unearth the cultural, moral values that clinical practice steers by and upholds, and the implications this has for the assessment and management of ill body-selves. Through an exposition of the general practice of the clinic and an investigation of two specific cases of youngsters, it is found that the assessment of symptoms and selves and the goals of treatment are informed by cultural ideals of 'the good self' and 'the good life' in which agency and work ethic - both pertaining to the notion of individual responsibility - figure as prevalent virtues. The study underpins the findings of other researchers who have found that ideals of individual autonomy and responsibility for own life and health permeate the Western health care system and the discourses of ill individuals. The contribution of this article is to portray in ethnographic detail how such a cultural ethics manifests in practice and what implications this have for the treatment of young people with functional symptoms at a specific location and in specific cases. The two cases illustrate that the underlying norms and values can give rise to very different moral assessments of symptoms and selves within the same diagnostic category.

BACKGROUND: The severity of walking impairment in persons with multiple sclerosis (pwMS) at different levels on the expanded disability status scale (EDSS) is unclear. Furthermore, it is unclear if the EDSS is differently related to performed- and perceived walking capacity tests.AIMS: To quantify walking impairment and perceived impact of MS on walking according to EDSS scores and to examine the relations between these parameters in pwMS.METHODS: EDSS was collected by neurologists and walking was assessed by the timed 25ft walk test (T25FWT), two minute walk test (2MWT), six minute walk test (6MWT) and the 12-item MS walking scale (MSWS-12) in 474 PwMS with mild (EDSS 1-4: n=200) to moderate (EDSS 4.5-6.5: n=274) MS. Magnitude of walking impairment was calculated and related to EDSS.RESULTS: Compared to predicted values in healthy controls, walking speed was reduced by 41.5±25.8% in the 6MWT for the total MS group and by 21.8±20.2% and 55.8±19.1% in the mild and moderate MS subgroups, respectively. The EDSS score showed the strongest relationship to the 2MWT and the 6MWT in the total MS group (r=-0.76, pCONCLUSION: In pwMS (EDSS scores 1-6.5), walking speed is on average reduced by ~40% when compared to predicted values in healthy controls, and impairments are already present at early disease stages, suggesting early initiation of rehabilitation. The 2MWT and 6MWT show the strongest relationship to EDSS, but the MSWS-12 identify impairments more gradually at low EDSS scores.

Importance: Neurological disorders have been linked to suicide, but the risk across a broad spectrum of neurological disorders remains to be assessed. Objectives: To examine whether people with neurological disorders die by suicide more often than other people and to assess for temporal associations. Design, Setting, and Participants: Nationwide, retrospective cohort study on all persons 15 years or older living in Denmark, from 1980 through 2016 (N = 7300395). Exposures: Medical contact for head injury, stroke, epilepsy, polyneuropathy, diseases of myoneural junction, Parkinson disease, multiple sclerosis, central nervous system infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington disease, dementia, intellectual disability, and other brain diseases from 1977 through 2016 (n = 1248252). Main Outcomes and Measures: Death by suicide during 1980-2016. Adjusted incidence rate ratio (IRRs) were estimated using Poisson regressions, adjusted for sociodemographics, comorbidity, psychiatric diagnoses, and self-harm. Results: Of the more than 7.3 million individuals observed over 161935233 person-years (49.1% males), 35483 died by suicide (median duration of follow-up, 23.6 years; interquartile range, 10.0-37.0 years; mean age, 51.9 years; SD, 17.9 years). Of those, 77.4% were males, and 14.7% (n = 5141) were diagnosed with a neurological disorder, equivalent to a suicide rate of 44.0 per 100000 person-years compared with 20.1 per 100000 person-years among individuals not diagnosed with a neurological disorder. People diagnosed with a neurological disorder had an adjusted IRR of 1.8 (95% CI, 1.7-1.8) compared with those not diagnosed. The excess adjusted IRRs were 4.9 (95% CI, 3.5-6.9) for amyotrophic lateral sclerosis, 4.9 (95% CI, 3.1-7.7) for Huntington disease, 2.2 (95% CI, 1.9-2.6) for multiple sclerosis, 1.7 (95% CI, 1.6-1.7) for head injury, 1.3 (95% CI, 1.2-1.3) for stroke, and 1.7 (95% CI, 1.6-1.8) for epilepsy. The association varied according to time since diagnosis with an adjusted IRR for 1 to 3 months of 3.1 (95% CI, 2.7-3.6) and for 10 or more years, 1.5 (95% CI, 1.4 to 1.6, P

Background: Human and animal studies support the involvement of diet in the development of CID -chronic inflammatory diseases such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, psoriatic arthritis, and multiple sclerosis. Objective: This cohort study aimed to investigate the association between intake of fibre, red and processed meat, and occurrence of late-onset CID (50+ years of age) in the DCH: Danish Diet, Cancer and Health cohort. We hypothesised that risk of late-onset CID would be lower among those with high intake of fibre and/or low intake of meat compared to individuals with low fibre and/or high meat intake. Methods: The DCH recruited 56,468 individuals, aged 50-64 years, between 1993 and 1997. At recruitment, diet intake was registered using food frequency questionnaires as well as lifestyle factors in 56,075 persons. Exposure variables were generated as sex-adjusted tertiles of fibre and meat (g/day). Development of CIDs was identified in national registries. Hazard ratios (HR) of late-onset CIDs (adjusted for age, sex, energy intake, alcohol, smoking, education, comorbidity, and civil status) were estimated for all three exposure variables. Results: During follow-up of 1,123,754 years (median (Interquartile range) = 22.2 (20.1-23.1)), 1,758 (3.1%) participants developed at least one CID. The adjusted HRs for developing CID (low fibre 1.04 [0.89-1.22] and medium fibre 1.04 [0.91-1.18] (high fibre as reference), and medium meat 0.96 [0.86-1.09] and high meat 0.94 [0.82-1.07] (low meat as reference)) or the individual diseases were not statistically significant. Conclusion: This large study did not support that a high intake of fibre and/or a low intake of meat had a high impact on the risk of late-onset CID.

Persistent postural-perceptual dizziness (PPPD) is a new diagnosis for functional chronic dizziness and included in the new International Classification of Diseases (ICD)-11. The new criteria are positive, specific and make it easier to identify and study functional chronic dizziness. PPPD is a condition triggered by vestibular-, neurological- or psychological conditions. This review examines the symptoms, pathophysiology and treatment of PPPD.

Purpose of Review: For many years, exercise was controversial in multiple sclerosis (MS) and thought to exacerbate symptoms and fatigue. However, having been found to be safe and effective, exercise has become a cornerstone of MS rehabilitation and may have even more fundamental benefits in MS, with the potential to change clinical practice again. The aim of this review is to summarize the existing knowledge of the effects of exercise as primary, secondary, and tertiary prevention in MS. Recent Findings: Initial studies established exercise as an effective symptomatic treatment (i.e., tertiary prevention), but recent studies have evaluated the disease-modifying effects (i.e., secondary prevention) of exercise as well as the impact on the risk of developing MS (i.e., primary prevention). Summary: Based on recent evidence, a new paradigm shift is proposed, in which exercise at an early stage should be individually prescribed and tailored as “medicine” to persons with MS, alongside conventional medical treatment.

The authors1 agree that Flanagan et al.2 may have achieved a more complete coverage of patients with neuromyelitis optica spectrum disorder, but identified a very low number of patients.

Background: In multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) reflects disease severity. Although parts of the EDSS are dependent on actual walking distance, self-reported statements are often applied. Objectives: The purpose of the present study was, therefore, to compare self-reported walking distance to actual walking distance to outline how this influences EDSS scoring. Methods: MS patients with EDSS 4.0–7.5 ( n = 273) were included from the Danish MS hospitals rehabilitation study ( n = 427). All patients subjectively classified their maximal walking distance according to one of seven categories (>500; 300–499; 200–299; 100–199; 20–99; 5–19; 0–4 m). Subsequently, actual maximal walking distance was assessed and EDSS was determined from both self-reported walking distance (EDSSself-report) and actual walking distance (EDSSactual). Results: In 145 patients (53%), self-reported walking distance was misclassified when compared to the actual walking distance. Misclassification was more frequent in patients using walking aids (64% vs. 44%, p self-report vs EDSSactual) of ⩾0.5 point in 24%. Conclusion: In MS patients with EDSS 4.0–7.5, 53% misclassified their walking distance yielding incorrect EDSS scores in 24%. Therefore, correct EDSS determination must be based on measurement of actual walking distance.

Objectives: The overall distribution of disease courses in multiple sclerosis (MS) is well established, but little is known about the distribution among familial MS cases. We examine the frequency of the different MS courses among familial and sporadic MS cases and determine whether MS cases within the same family had the same age at diagnosis and have experienced the same disease course. Materials and methods: This is a nationwide register study, based on data from the Danish MS Registry, the Danish Civil Registration System, and the Danish National Patient Registry. The main variables are MS diagnosis, MS course, and first-degree relatives with MS The statistical analyses were carried out using logistic regression analysis, Kappa coefficient, and intraclass correlations coefficient. Results: In total, 7402 MS cases were included in the study, of which 531 have an affected first-degree relatives, and 6871 are sporadic. We found that relapsing-remitting MS including secondary progressive MS was more common among familial MS cases than among sporadic MS cases (Odds ratio = 1.64, 95% CI: 1.20-2.24, P = 0.002). We subsequently analyzed data on 133 MS families and found that MS courses correlate between the first and the second MS case diagnosed, while age at diagnosis does not. Conclusion: Familial MS cases are more likely to have relapsing-remitting MS than a progressive course compared to sporadic MS cases. Secondly, we find that within MS families, first-degree relatives are likely to have the same MS course, but we do not find that they are diagnosed at the same age.

Objective:As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS.Methods:We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1–2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models.Results:We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (Conclusion:Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health.

Background Flu-like symptoms (FLS) are common side effects of interferon beta (IFNs) treatment, and may affect the willingness to initiate therapy, the long-term acceptability, and the adherence to the treatment. Case reports suggest that aerobic exercise is able to markedly reduce FLS following IFNs-1a injections in persons with multiple sclerosis (PwMS). Objective To test the hypothesis that aerobic exercise can alleviate FLS following IFNs-1a injections in PwMS, and secondarily to examine whether or not fluctuations in circulating cytokines provide a mechanism that can explain a potential positive effect. Methods Seventeen PwMS who frequently experience FLS following IFNs-1a injections completed four days of testing. On two of the testing days they completed 35 min of aerobic exercise on a bicycle-ergometer following IFNs-1a injection. On the two other testing days, no intervention took place following the injection. FLS were assessed pre-injection and 3 h, 5 h, 12 h and 24 h post-injection. Blood samples were taken pre-injection and 1 h and 3 h post-injection to determine levels of circulating interleukin 6 and 17 and IFNγ. The primary study endpoint was the comparison of the change in FLS severity from pre-injection to 5 h post-injection between days with injection alone and days with injection followed by aerobic exercise. Results FLS severity change was significantly lower on days with exercise compared to days with rest. IL6 was significantly increased 3 h following IFNs-1a injection and exercise compared to 1 h post and pre and when compared to the resting condition. Participants reported no adverse events in addition to FLS during the study period. Conclusion Data from this study suggest that moderate intensity aerobic exercise following IFNs-1a injections is safe and can alleviate the FLS severity in PwMS. Based on these results, 35 min of aerobic exercise should be encouraged for PwMS who often experience FLS following IFNs-1a injections.

Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease modifying treatments. Developments in analytical chemistry allow the detection of large numbers of molecules in plasma or cerebrospinal fluid, associated with the pathophysiology or pathogenesis of PD. This systematic review includes cerebrospinal fluid biomarker studies focusing on different disease pathways: oxidative stress, neuroinflammation, lysosomal dysfunction and proteins involved in PD and other neurodegenerative disorders, focusing on four clinical domains: their ability to (1) distinguish PD from healthy subjects and other neurodegenerative disorders as well as their relation to (2) disease duration after initial diagnosis, (3) severity of disease (motor symptoms) and (4) cognitive dysfunction. Oligomeric alpha-synuclein might be helpful in the separation of PD from controls. Through metabolomics, changes in purine and tryptophan metabolism have been discovered in patients with PD. Neurofilament light chain (NfL) has a significant role in distinguishing PD from other neurodegenerative diseases. Several oxidative stress markers are related to disease severity, with the antioxidant urate also having a prognostic value in terms of disease severity. Increased levels of amyloid and tau-proteins correlate with cognitive decline and may have prognostic value for cognitive deficits in PD. In the future, larger longitudinal studies, corroborating previous research on viable biomarker candidates or using metabolomics identifying a vast amount of potential biomarkers, could be a good approach.

We read the nationwide Swedish epidemiologic study of neuromyelitis optica spectrum disorder (NMOSD) published by Jonsson et al.1 with great interest. The study revealed similar prevalence (1.04 per 100,000 people [CI: 0.85–1.26]) and incidence (0.79 per 1,000,000 person-years [CI: 0.55–1.03]) of NMOSD to the prevalence (1.09 per 100,000 people [CI: 0.81–1.44]) and incidence (0.70 per 1,000,000 person-years [CI: 0.46–1.02]) estimates of the recent nationwide Danish study2 and also to the incidence study of NMOSD from the Region of Central Denmark (incidence: 0.12 per 1,000,000 person-years).3 These studies from Scandinavia showed similar data to each other and also to other white populations, and they contrast with the results of the study from the region of Southern Denmark,4 reporting the highest prevalence (4.4 per 100,000 people [CI: 3.1–5.7]) and incidence (4.0 per 1,000,000 person-years [CI: 3.0–5.4]) so far in a predominantly Caucasian population.

Purpose The purpose of the study is to determine whether one leader set-up is better than the others according to interdisciplinary cooperation and leader legitimacy. Design/methodology/approach The study is a qualitative study based on semi-structured interviews at three Danish hospitals. Findings The study found that the leadership set-up did not have any clear influence on interdisciplinary cooperation, as all wards had a high degree of interdisciplinary cooperation independent of which leadership set-up they had. Instead, the authors found a relation between leadership set-up and leader legitimacy. In cases where staff only referred to a leader from their own profession, that leader had legitimacy within the staff group. When there were two leaders from different professions, they only had legitimacy within the staff group from their own profession. Furthermore, clinical specialty also could influence legitimacy. Originality/value The study shows that leadership set-up is not the predominant factor that creates interdisciplinary cooperation; but rather, leader legitimacy also should be considered. Additionally, the study shows that leader legitimacy can be difficult to establish and that it cannot be taken for granted. This is something chief executive officers should bear in mind when they plan and implement new leadership structures. Therefore, it would also be useful to look more closely at how to achieve legitimacy in cases where the leader is from a different profession to the staff.

Background: Accelerated brain atrophy is a main determinant of the progressing disabilities clinically characterizing people with multiple sclerosis (MS). Preliminary data from animal studies and human phase 1 studies indicate a possible disease-modifying effect of physical exercise. We therefore assessed whether high-intensity progressive aerobic exercise (PAE) affects brain atrophy in MS. Methods: We conducted a 24-week randomized, controlled, cross-over, phase 2 trial, including an exercise group (24 weeks of supervised PAE followed by self-guided physical activity) and a waitlist group (24 weeks of habitual lifestyle followed by supervised PAE). Participants were recruited at four Danish hospitals. MS patients aged 18-65 years with an Expanded Disability Status Scale score of 0-6 willing to travel to the trial and training facility were randomly assigned (1:1) by the sealed envelope principle, stratified by sex. The primary outcome was percentage brain volume change (PBVC) after 24 weeks, analyzed using an intention-to-treat linear mixed effects model. Findings: A total of 86 participants were recruited from 28 April 2016 to 10 October 2017 (43 patients were assigned to each group). PBVC was -0·29% (SD 0·63) in the exercise group; -0·17% (0·99) in the placebo group (between-group change +0·12%, 95% CI -0·27-0·51; p=0·545). We observed higher grey matter parenchymal fraction (+1·13 percentage points, 0·00-2·26; p=0·05) and cardiorespiratory fitness (+3·5 mL O2/min/kg, 2·0-5·1; p

Introduction: Suicidal behavior is a relatively rare occurrence among patients with multiple sclerosis (MS). Nonetheless, it is important to identify and be aware of the constituting risk factors to prevent suicidal behavior among vulnerable patients.Areas covered: This scoped review will shortly outline well-known biological and psychosocial risk factors for suicidal behavior among MS patients and suggest preventive initiatives. The preventive strategies should include a close monitoring of MS pharmacotherapy to prevent progression, and awareness and early identification of psychosocial risk factors across a variety of heathcare and social instances the patient may encounter during their life with the disease. The staff in these instances should be educated in detecting the MS patients at increased risk and refer them to relevant healthcare instances, including the general practitioner, neurologists, psychiatrist, etc. In addition, referral to social instances to support educational, vocational, and home environment to the state of the disease is of utmost importance.Expert commentary: Enhancing quality of life for as long as possible by these means may be held to reduce the risk for psychosocial problems and hence suicidal behavior.

Infections in schizophrenia patients are associated with an increased premature mortality. However, our knowledge about the burden of infections in schizophrenia is scarce. The aims of this study were to (1) determine the prevalence of clinically important hospital registered infections in the period of five years prior to and five years after the diagnosis, (2) estimate the risk of infections before and after the schizophrenia diagnosis and, (3) evaluate the impact of comorbidity on the risk of infections in schizophrenia. Using combined data from Danish national registers, we sampled a cohort of all persons born in Denmark in the period 1975–1990 and obtained health-related records from 1995–2013. Occurrence patterns and the risk of infections were measured as annual incidence rates and incidence rates ratios, estimated using Poisson models. Medical conditions from the Charlson Index were considered as a measure of comorbidity. The analyses showed that schizophrenia patients had a significantly elevated risk of almost all types of hospital registered infections during the period of the study when compared to the controls. Comorbidity increased rates of infections by 176%. The results suggest that the risk of infections is elevated in the schizophrenia population and physical illness is an important risk factor.