Children born preterm or small for gestational age to mothers with multiple sclerosis: Do these children have an increased risk of infections in early life?

BACKGROUND: Mothers with multiple sclerosis are at increased risk of preterm birth and small for gestational age infants. Both conditions pose a risk of morbidity, including early-life infections. OBJECTIVE: This study aimed to assess the risk of infections in the first 3 years of life among children born preterm or small for gestational age to mothers with multiple sclerosis. METHODS: We used Danish national health registers to establish the study cohort of all births by women with MS born from 1995 to 2023. In Cox regression models, we estimated hazard ratios (HRs) of infections in preterm or small for gestational age children. RESULTS: Preterm children had an adjusted HR of 1.49 (95% confidence interval (95% CI) 1.15-1.93) for hospital-diagnosed infection and 0.88 (95% CI 0.72-1.06) for antibiotic prescriptions. Small for gestational age children had an adjusted HR of 0.81 (95% CI 0.54-1.22) for hospital-diagnosed infection and 1.07 (95% CI 0.82-1.38) for antibiotic prescriptions. CONCLUSION: Children born preterm to mothers with multiple sclerosis had an increased risk of hospital-diagnosed infections in the first 3 years of life, but not of mild-to-moderate infections evaluated on prescriptions. Children born small for gestational age did not have an increased risk of infections.

Smoking during pregnancy and risk of multiple sclerosis in offspring and mother: A Danish nationwide register-based cohort study.

BACKGROUND: The association between intra-uterine exposure to maternal smoking and risk of multiple sclerosis (MS) has been little studied and with conflicting results. OBJECTIVE: To examine the risk of MS in offspring exposed intra-uterine to maternal smoking. In addition, to re-examine prior observations of an elevated risk of MS among smokers, assuming that self-reported smoking during pregnancy reflects the woman's general smoking habits. METHODS: The study cohort included all Danish women, pregnant in the period 1991-2018, (n = 789,299) and singletons from these pregnancies (n = 879,135). Nationwide information on maternal smoking during pregnancy and MS cases in the study cohort were obtained from the Medical Birth Register and the National Patient Register. Cox regression analysis was used to estimate hazard ratios (HRs) for the association between smoking and MS risk. RESULTS: Women who smoked during pregnancy had a 42% increased risk of developing MS compared with non-smoking women (HR = 1.42 (1.32-1.52), n = 1,296). The risk of MS among singletons of women who smoked during pregnancy was 38% higher than that among singletons born to non-smoking women (HR = 1.38 (1.08-1.76), n = 110). CONCLUSION: Our observations add further to the evidence implicating smoking in the development of MS and suggest that intra-uterine exposure to tobacco smoke may increase MS risk.

Expert opinion on the use of contraception in people with multiple sclerosis.

BACKGROUND: Current guidance on the selection of appropriate contraception for people with multiple sclerosis (PwMS) is lacking. OBJECTIVE: To address this gap, an expert-led consensus program developed recommendations to support clinicians in discussing family planning and contraception with women and men with multiple sclerosis (MS). METHODS: A multidisciplinary steering committee (SC) of 13 international clinical experts led the program, supported by an extended faculty of 32 experts representing 18 countries. A modified Delphi methodology was used for decision-making and consensus-building. The SC drafted 15 clinical questions focused on patient-centered care, selection of contraception, and timing of stopping/starting contraception and disease-modifying therapies (DMTs). Statements addressing each question were drafted based on evaluation of published evidence and the experts' clinical experience. Consensus was reached if ⩾75% of respondents agreed (scoring 7-9 on a 9-point scale) with each recommendation. RESULTS: Consensus was reached on 24 of 25 proposed recommendations, including how and when to discuss contraception, types and safety of contraceptives, and how to evaluate the most appropriate contraceptive options for specific patient groups, including those with significant disability or being treated with DMTs. CONCLUSION: These expert recommendations provide the first practical, relevant, and comprehensive guidance for clinicians on the selection of contraception in PwMS.

Investigating the potential disease-modifying and neuroprotective efficacy of exercise therapy early in the disease course of multiple sclerosis: The Early Multiple Sclerosis Exercise Study (EMSES).

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 <2 years) included 48 weeks of supervised aerobic exercise or control condition. Population-based control data (Danish MS Registry) was included (n = 850, disease duration <2 years). Relapse rates were obtained from medical records, and patients underwent structural and diffusion-kurtosis MRI at baseline, 24 and 48 weeks. 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.

Retinoids are not linked to risk of multiple sclerosis: A Danish nationwide cohort study.

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.

Efficacy of high-intensity aerobic exercise on common multiple sclerosis symptoms.

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 (VO2 max), 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 VO2 max 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 VO2 max (+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.

Maternal diabetes and risk of multiple sclerosis in the offspring: A Danish nationwide register-based cohort study.

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.

Efficacy of high-intensity aerobic exercise on cognitive performance in people with multiple sclerosis: A randomized controlled trial.

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 ⩽ -1.5SD. 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.

Neurophysiological impairments in multiple sclerosis-Central and peripheral motor pathways.

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.

Multiple sclerosis among first- and second-generation immigrants in Denmark: a population-based cohort study.

Multiple sclerosis is a disease with a highly variable incidence worldwide. While knowledge about multiple sclerosis risk factors has grown over the years, the aetiology of multiple sclerosis has still not been fully established. We examined multiple sclerosis incidence rates among first-generation immigrants in Denmark, a high-incidence country, and their Danish-born children (second-generation immigrants), to evaluate the importance and timing of exposure to environmental factors in the aetiology of multiple sclerosis. By means of the Danish Civil Registration System we identified 9 121 187 individuals living in Denmark between 1968 and 2015, including 1 176 419 first-generation and 184 282 second-generation immigrants. Study participants were followed for multiple sclerosis in the Danish Multiple Sclerosis Registry from 1968 to 2015. The relative risk (RR) of multiple sclerosis according to immigration status was estimated by means of multiple sclerosis incidence rate ratios obtained in log-linear Poisson regression analysis. Altogether, 16 905 cases of multiple sclerosis were identified in the study cohort, 578 among first-generation and 106 among second-generation immigrants. Multiple sclerosis risk among first-generation immigrants whose parents were born in low, intermediate and high multiple sclerosis risk areas were 21% (RR = 0.21; 95% CI: 0.16-0.28), 43% (RR = 0.43; 95% CI: 0.36-0.50) and 75% (RR = 0.75; 95% CI: 0.67-0.83), respectively, of that among ethnic Danes (test for trend P < 0.0001). First-generation immigrants arriving in Denmark before age 15 years had a multiple sclerosis risk higher than that in their country of birth but lower than that in Denmark, reaching on average 69% of the multiple sclerosis risk among ethnic Danes (RR = 0.69; 95% CI: 0.55-0.87). Multiple sclerosis risk among individuals who came to Denmark at a later age remained closer to that of their country of birth, corresponding to 45% of the multiple sclerosis risk among ethnic Danes (RR = 0.45; 95% CI: 0.41-0.49). Our study supports the idea that environmental factors exerting their role in childhood or adolescence may be of aetiological relevance in multiple sclerosis.

Intake of dietary fibre, red and processed meat and risk of late-onset Chronic Inflammatory Diseases: A prospective Danish study on the "diet, cancer and health" cohort.

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.

Association Between Neurological Disorders and Death by Suicide in Denmark.

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 = 7 300 395). 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 = 1 248 252). 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 161 935 233 person-years (49.1% males), 35 483 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 100 000 person-years compared with 20.1 per 100 000 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 < .001). Compared with those who were not diagnosed with a neurological disorder, those with dementia had a lower overall adjusted IRR of 0.8 (95% CI, 0.7-0.9), which was elevated during the first month after diagnosis to 3.0 (95% CI, 1.9-4.6; P < .001). The absolute risk of suicide for people with Huntington disease was 1.6% (95% CI, 1.0%-2.5%). Conclusions and Relevance: In Denmark from 1980 through 2016, there was a significantly higher rate of suicide among those with a diagnosed neurological disorder than persons not diagnosed with a neurological disorder. However, the absolute risk difference was small.

Can we trust self-reported walking distance when determining EDSS scores in patients with multiple sclerosis? The Danish MS hospitals rehabilitation study.

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 < 0.05) and in patients with primary progressive MS (69%, p < 0.05). Misclassification of walking distance corresponded to incorrect EDSS scores (EDSSself-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.

Exercise as Medicine in Multiple Sclerosis-Time for a Paradigm Shift: Preventive, Symptomatic, and Disease-Modifying Aspects and Perspectives.

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). 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.

Distribution of disease courses in familial vs sporadic multiple sclerosis.

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.

Morality in clinical space: treatment of youngsters with functional somatic symptoms in a Western clinical context.

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.

Is there an overlooked "window of opportunity" in MS exercise therapy? Perspectives for early MS rehabilitation.

While early medical treatment has proven effective in MS, early-phase MS rehabilitation has not gained much attention in MS research and clinical practice. Exercise therapy is one of the most promising treatment strategies in MS rehabilitation. Here, we provide a topical review investigating when exercise therapy is initiated in existing MS studies, showing that exercise is initiated at a rather late disease stage, where it predominantly serves as a symptomatic treatment. Recent findings in MS suggest that exercise may have neuroprotective and disease-modifying effects. Such findings along with the findings from medical trials that an early-stage "window of opportunity" exists leads to the proposal that early exercise therapy should be an increased focus in research and clinical practice for persons with MS. A further perspective relates to other rehabilitation interventions that are also initiated at a later disease stage, as these may also take advantage of an early-phase approach.

Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis?

BACKGROUND: Multiple sclerosis (MS) is characterised by accelerated brain atrophy, which relates to disease progression. Previous research shows that progressive resistance training (PRT) can counteract brain atrophy in other populations. OBJECTIVE: To evaluate the effects of PRT by magnetic resonance imaging (MRI) and clinical measures of disease progression in people with MS. METHODS: This study was a 24-week randomised controlled cross-over trial, including a Training ( n = 18, 24 weeks of PRT followed by self-guided physical activity) and Waitlist group ( n = 17, 24 weeks of habitual lifestyle followed by PRT). Assessments included disability measures and MRI (lesion load, global brain volume, percentage brain volume change (PBVC) and cortical thickness). RESULTS: While the MS Functional Composite score improved, Expanded Disability Status Scale, lesion load and global brain volumes did not differ between groups. PBVC tended to differ between groups and higher absolute cortical thickness values were observed in 19 of 74 investigated cortical regions after PRT. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups for four areas: anterior cingulate gyrus, temporal pole, orbital sulcus and inferior temporal sulcus. CONCLUSION: PRT seem to induce an increase in cortical thickness, indicating that PRT have a neuroprotective or even neuroregenerative effect in relapsing-remitting MS.

Cerebrospinal fluid levels of catecholamines and its metabolites in Parkinson's disease: effect of l-DOPA treatment and changes in levodopa-induced dyskinesia.

Levodopa (l-DOPA, l-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to l-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily l-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here, we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID [PD-LID, n = 8)] as compared to non-dyskinetic PD patients receiving l-DOPA (PD-L, n = 6), or not receiving l-DOPA (PD-N, n = 7) as well as non-PD controls (n = 16). PD patients were clinically assessed using the Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale and CSF was collected after overnight fasting and 1-2 h after oral intake of l-DOPA or other anti-Parkinson medication. CSF catecholamines and its metabolites were analyzed by HPLC with electrochemical detection. We observed (i) decreased levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid in PD patients not receiving l-DOPA (ii) higher dopamine (DA) levels in PD-LID as compared to controls (iii) higher DA/l-DOPA and lower DOPAC/DA ratio's in PD-LID as compared to PD-L and (iv) an age-dependent increase of DA and decrease of DOPAC/DA ratio in controls. These results suggest increased DA release from non-DA cells and deficient DA re-uptake in PD-LID. Monitoring DA and DOPAC in CSF of l-DOPA-treated PD patients may help identify patients at risk of developing LID.

Changes in kynurenine pathway metabolism in Parkinson patients with L-DOPA-induced dyskinesia.

L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective drug in the symptomatic treatment of Parkinson's disease, but chronic use is associated with L-DOPA-induced dyskinesia in more than half the patients after 10 years of treatment. L-DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L-DOPA-induced dyskinesia. In this study, we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients and controls. Parkinson patients (n = 26) were clinically assessed for severity of motor symptoms (UPDRS) and L-DOPA-induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1-2 h after intake of L-DOPA or other anti-Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid of controls (n = 14), Parkinson patients receiving no L-DOPA (n = 8), patients treated with L-DOPA without dyskinesia (n = 8), and patients with L-DOPA-induced dyskinesia (n = 10) using liquid chromatography-mass spectrometry. We observed approximately fourfold increase in the 3-hydroxykynurenine/kynurenic acid ratio in plasma of Parkinson's patients with L-DOPA-induced dyskinesia. Anthranilic acid levels were decreased in plasma and cerebrospinal fluid of this patient group. 5-Hydroxytryptophan levels were twofold increased in all L-DOPA-treated Parkinson's patients. We conclude that a higher 3-hydroxykynurenine/kynurenic acid ratio in plasma may serve as a biomarker for L-DOPA-induced dyskinesia. Longitudinal studies including larger patients cohorts are needed to verify whether the changes observed here may serve as a prognostic marker for L-DOPA-induced dyskinesia.