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Objectives: To study the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB) in patients with multiple sclerosis (MS).Methods: 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests.Results: Median change in BOD was 287 mm(3) in the placebo group and 83 mm(3) in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19-82) nmol/l to 110 (range 67-163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate.Conclusion: Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS.Trial Registration Number: EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676. [ABSTRACT FROM AUTHOR]

Background and Purpose: Multiple sclerosis (MS) is associated with excess mortality. The use of disease-modifying treatments (DMTs) has recently been associated with survival benefits., Methods: A regional MS database was linked with national registries. People with MS (pwMS) diagnosed in 1971-2010 were included and followed up until the end of the year 2019. Five matched controls were acquired for every person with MS. DMTs included in the analyses were interferon and glatiramer acetate., Results: Median follow-up time of the 1795 pwMS was 20.0 years (range 0.1-48.7 years). Survival did not differ between decades of diagnosis (p = 0.20). Amongst pwMS, male sex (adjusted hazard ratio [aHR] 1.70; 95% confidence interval [CI] 1.41-2.06), higher age at diagnosis (aHR 1.83; 95% CI 1.65-2.03 per 10-year increment) and primary progressive disease course (aHR 1.29; 95% CI 1.04-1.60) were independently associated with poorer survival. DMT use was associated with better survival (p < 0.0001) and better survival during follow-up (aHR 0.56; 95% CI 0.38-0.81). Compared to matched controls, median life expectancy was 8-9 years shorter in pwMS with survival diverging from controls during the first decade after diagnosis, more clearly in men than women., Conclusion: Despite DMT use being associated with better survival, relative life expectancy of pwMS did not change over five decades in Western Finland. Male sex was an independent risk factor for death amongst pwMS, but excess mortality was higher in women. More work and methods are needed to improve survival in pwMS., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: The Chordate System administers kinetic oscillation stimulation (K.O.S) into the nasal cavity thereby potentially modulating the activity of trigemino-autonomic reflex. Modulation of this reflex has been proposed as a potential therapeutic target in migraine. The aim of this clinical trial was to evaluate the efficacy of K.O.S for the preventive treatment of chronic migraine (CM)., Methods: In this randomized, double-blind, sham-controlled, multicenter clinical trial, patients with CM were treated with K.O.S once per week over a period of 6 weeks. The primary performance endpoint was the mean change in monthly headache days with moderate to severe intensity (MHDs) from the 28-day pretreatment baseline period to the performance assessment period (days 14-42 of treatment). Mean change from baseline in monthly migraine days (MMDs), proportion of participants with 30% and 50% or greater reduction in moderate to severe headache days compared with baseline, and change in the use of abortive medications from baseline were also assessed during the performance assessment period. Headache-related disability and quality-of-life measures were evaluated up to 70-day posttreatment., Results: The primary endpoint showed a significantly larger reduction of MHD across the performance assessment period with active treatment (-3.5 days, n = 67) compared with sham (-1.2 days, n = 65) ( p = 0.0132). Compared with sham, active treatment consistently also led to significant reduction of MHD during the follow-up period (-2.7 [-4.3; -1.0, p = 0.0014]) as well as of mean MMDs during the assessment (-2.4 [-4.1; -0.7, p = 0.0048]) and follow-up (-2.9 [-4.5; -1.2, p = 0.0008]) periods. 61.8% of participants reported treatment-emergent adverse events (TEAEs) with similar incidences among treatment groups (63.2% [active], 60.3% [sham]), with nasopharyngitis (8.3%), dizziness (6.3%), and epistaxis (6.3%) being the most common TEAEs. Treatment-related serious adverse events were not observed., Discussion: The Chordate System provides significant benefits to patients with CM by reducing the number of MHDs. The nonpharmacologic nature of the treatment option positions K.O.S as a valuable addition to the current therapeutic portfolio for the management of CM., Trial Registration Information: The trial was registered on ClinicalTrials.gov (NCT03400059) on January 17, 2018. The first patient was enrolled on March 22, 2018, and the last patient completed the study on October 1, 2022. The trial registration initially described the timing of the secondary endpoints incorrectly due to clerical error, and this was corrected to match the protocol and analysis plan once discovered., Classification of Evidence: This study provides Class I evidence that weekly intranasal K.O.S is associated with a reduced number of headache days per month in patients with CM.

Background: Varied responses to acute migraine medications have been observed, with over one-third (34.5%) of patients reporting insufficient headache relief. Sumatriptan-naproxen sodium, a single, fixed-dose combination tablet comprising sumatriptan 85 mg and naproxen sodium 500 mg, was developed with the rationale of targeting multiple putative mechanisms involved in the pathogenesis of migraine to optimise acute migraine care., Methods: A narrative review of clinical trials investigating sumatriptan-naproxen sodium for both adults and adolescents was performed in March 2024., Results: Across a total of 14 clinical trials in nine publications, sumatriptan-naproxen sodium offered greater efficacy for 2-h pain freedom (14/14) and sustained pain-free response up to 24 h (13/14) compared with monotherapy and/or placebo for both adult and adolescent study participants with an acceptable and well-tolerated adverse effect profile. Clinical trial data also demonstrates the effectiveness of sumatriptan-naproxen sodium in participants with allodynia, probable migraine, menstrual-related migraine and those with poor responses to acute, non-specific, migraine medication., Conclusions: Multi-mechanistic therapeutic agents offer an opportunity to optimise acute medications by targeting multiple mediators involved in the pathogenesis of migraine. Sumatriptan-naproxen sodium resulted in greater initial and sustained pain freedom, compared with either sumatriptan, naproxen-sodium and/or placebo, for the treatment of single or multiple attacks of migraine across both adult and adolescent study populations., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Cognitive impairment can considerably impact the work life of people who have multiple sclerosis (MS). Cognitive symptoms are associated with an increased likelihood of unemployment, changes in employment and decreased working hours. This qualitative interview-based study aims to gather real-word experiences and perspectives from both people living with MS and healthcare professionals, to explore how cognitive symptoms are experienced in the workplace, how their impact is addressed, and what can be done to support people in managing and minimizing this impact on employment., Methods: Semi-structured, one-to-one interviews were conducted with people living with MS who experience cognitive symptoms, and with healthcare professionals working in MS care. Participants were recruited from a healthcare market research agency based in the United States. The data obtained from the interviews were subsequently analysed using a Grounded Theory method, in order to identify the core themes that form the basis of this paper., Results: A total of 20 participants (n = 10 people living with MS; n = 10 healthcare professionals) from the United States were interviewed. Overall, 9 themes were identified from the raw data, which were grouped into three core themes describing the perspectives and experiences reported by both people living with MS and healthcare professionals: (1) The implications of cognitive symptoms on work; (2) Challenges in addressing cognitive impairment and its impact on work in MS care; (3) Strategies and support for managing the impact of cognitive symptoms., Conclusion: The real-world insights of PwMS and HCPs gained from this qualitative study show that a multi-faceted approach to addressing cognitive impairment and its impact on the employment of PwMS is required. Workplace adjustments can range from self-implemented changes to changes put in place by employers to accommodate the various ways in which cognitive symptoms may impact a person's work. This study provides valuable information on how people living with MS can be affected by cognitive symptoms in the context of their employment; furthermore, that preparing early when possible and maintaining a proactive approach to managing their impacts on work are important for maintaining a good quality of life., Competing Interests: Declaration of competing interest Sarah A Morrow has served as an advisory board member or received consulting fees from Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche, Sanofi Genzyme and Teva Neurosciences; has participated in a speaker's bureau for Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche and Sanofi Genzyme; has received research support from Biogen Idec, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche and Sanofi Genzyme; and has participated as a site investigator in clinical trials sponsored by Bristol Myers Squibb/Celgene, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche and Sanofi Genzyme. Nektaria Alexandri is an employee of Merck Healthcare KGaA, Darmstadt, Germany. David Yeandle is a member of the MS in the 21st Century Steering Group, Southampton, UK. Maija Pontāga has received honoraria or personal fees from Merck KGaA, Darmstadt, Germany. Marja-Liisa Sumelahti has received honoria or personal fees from Merck KGaA, Darmstadt, Germany, Novartis, Pfizer, Teva, Novartis, Lundbeck, Abbvie and Eli Lilly for lecturing or participating in advisory boards. She is also principal investigator for trials sponsored by Roche, Lundbeck, Novartis and Teva., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis (MS) progression coincides temporally with menopause. However, it remains unclear whether the changes in disease course are related to the changes in reproductive hormone concentrations. We assessed the association of menopausal hormonal levels with progression-related biomarkers of MS and evaluated the changes in serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels during menopausal hormone therapy (MHT) in a prospective baseline-controlled design., Methods: The baseline serum estradiol, follicle stimulating hormone, and luteinizing hormone levels were measured from menopausal women with MS (n = 16) and healthy controls (HC, n = 15). SNfL and sGFAP were measured by single-molecule array. The associations of hormone levels with sNfL and sGFAP, and with Expanded Disability Status Scale (EDSS) and lesion load and whole brain volumes (WBV) in MRI were analyzed with Spearman's rank correlation and age-adjusted linear regression model. Changes in sNfL and sGFAP during one-year treatment with estradiol hemihydrate combined with cyclic dydrogesterone were assessed with Wilcoxon Signed Ranks Test., Results: In MS group, baseline estradiol had a positive correlation with WBV in MRI and an inverse correlation with lesion load, sNfL and sGFAP, but no correlation with EDSS. The associations of low estradiol with high sGFAP and low WBV were independent of age. During MHT, there was no significant change in sNfL and sGFAP levels in MS group while in HC, sGFAP slightly decreased at three months but returned to baseline at 12 months., Conclusion: Our preliminary findings suggest that low estradiol in menopausal women with MS has an age-independent association with more pronounced brain atrophy and higher sGFAP and thus advanced astrogliosis which could partially explain the more rapid progression of MS after menopause. One year of MHT did not alter the sGFAP or sNfL levels in women with MS., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Nurses work at headache centres throughout Europe, and their care for migraine patients is acknowledged. However, the specific roles and tasks of nursing vary, and a unified understanding is lacking, posing challenges to knowledge sharing and research., Objectives: Using an e-Delphi study method, the objective is to obtain healthcare professional headache experts' opinions on nursing-specific roles and tasks and combine this into consensus statements for nurse recommendations for migraine treatment., Methods: A three-round questionnaire study was conducted with nurses and neurologists from 18 specialised headache centres in 10 countries. In round 1, statements were compiled from a systematic examination of existing literature and expert opinions. In rounds 2 and 3, the experts rated the importance of statements (from round 1) on a 5-point Likert scale. Statements were analysed using a content analysis method, and the consensus of pre-defined statements was evaluated with gradually increased predetermined criteria using descriptive statistics., Results: Twenty-one experts, representing all 10 countries, participated. The predetermined consensus of ≥70% agreement was reached for 42 out of the initial 63 statements. These statements formed the final recommendations within two themes: "The nurses' roles and tasks in the clinical setting" and "The nurses' roles and tasks in educating patients and colleagues." The consensus level of statements was strong, with 40% receiving unanimous agreement (100%) and 97% achieving relatively high agreement (>80%)., Conclusion: Nursing plays a vital role with diverse tasks in migraine care. This study offers practical recommendations and a framework for nurses, equipping them with a clinical tool to enhance care and promote a coordinated approach to migraine treatment., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.V.R. has received honoraria from Lundbeck and Eli Lilly for Advisory Boards and written compendium; R.H.J. has received honoraria for lectures and patient leaflets from MSD, Berlin-Chemie Menarini, ATI, and Pfizer and participated in medical advisory boards for ATI and Electrocore and conducted clinical trials for Eli-Lilly and ATI; A.G. has received honoraria for lectures or consulting from AbbVie, Almirall, Biogen, BioMed, Curatis, EliLilly, Lundbeck, Neurolite, Novartis, TEVA/Mepha; S.L. received fees for attending advisory meetings, presentations and preparing presentation materials from AbbVie, TEVA, Eli Lilly, Tillots Pharma, Salvia and Novartis; M.S.M. is chair of the medical advisory board of the CSF Leak Association, serves on the advisory board for Abbott, AbbVie, Eli Lilly, Salvia, Lundbeck, Pfizer and TEVA, has received payment for the development of educational presentations from AbbVie, Eli Lilly, Lundbeck, TEVA and Pfizer; S.B.M. has received travel grants from Lundbeck, TEVA, AbbVie and for Advisory board for AbbVie, Lundbeck, Novartis, TEVA; M.H. received funding for travel and/or speaker honoraria from TEVA, Lundbeck and compensation for advisory service or producing educational material from TEVA, Lundbeck and Novartis; All other authors have declared no conflict of interests.

Background: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment., Methods: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported., Results: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported., Conclusion: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MA reports personal fees and PI in clinical trials for AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; and research grants from Lundbeck Foundation, Novo Nordisk Foundation, and Novartis. DDM has received honoraria, research, and travel grants from Allergan/Abbvie, Amgen, Biogen, Cefaly, Genesis Pharma, Electrocore, Eli Lilly, Lundbeck, Merk-Serono, Mertz, Novartis, Roche, Sanofi, Specifar, and Teva Pharmaceuticals; participated in clinical trials for Amgen, Cefaly, Electrocore, Eli Lilly, Genesis Pharma, Lundbeck, Mertz, Novartis, Specifar, and Teva Pharmaceuticals as principal investigator; and is President of the board of the Hellenic Headache Society and Co-chairman of the management group of the Headache Panel at the European Academy of Neurology. FMA reports lectures, advisory boards, and/or PI in clinical trials for Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals. PK, VRC, and AHA are employees and/or shareholders of Teva Pharmaceuticals. LL is a former employee of Teva Pharmaceuticals. CJS reports consulting, advisory boards, presentations, and travel support from Novartis, Eli Lilly, Teva Pharmaceuticals, AbbVie, Allergan, Almirall, Amgen, Lundbeck, MindMed, and Grünenthal; is a part-time employee of Zynnon; and reports research support from the Swiss Heart Foundation, Eye on Vision Foundation, Baasch-Medicus Foundation, and German Migraine and Headache Society. GS reports advisory boards and/or PI in clinical trials for AbbVie, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; and research support from Vinnova (Sweden’s innovation agency), Lund University, and the Swedish Neurological Association. PPR reports grant/research support from AbbVie, AGAUR, EraNet NEURON, Instituto Investigación Carlos III, MINECO, Novartis, RIS3CAT FEDER, and Teva Pharmaceuticals; and consultancy or education for AbbVie, Amgen, Biohaven, Chiesi, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals. PJD reports educational meetings and/or collaboration in clinical trials for Allergan/AbbVie, electroCore, Novartis, Teva Pharmaceuticals, and Lundbeck. TN reports consulting, speaking fees, and travel grants from Eli Lilly, Glenmark, Lundbeck, Novartis, Pfizer, St. Jude Medical, Teva Pharmaceuticals, and UCB; and advisory boards or PI in clinical trials for AbbVie, Amgen, Eli Lilly, Lundbeck, Neurocrine, Novartis, Teva Pharmaceuticals, and UCB. ACP reports lectures, advisory boards, and/or PI in clinical trials for Allergan, AbbVie, Pfizer, Teva Pharmaceuticals, Novartis, Lundbeck, Eli Lilly, and Roche. IPM reports lectures, advisory boards, and/or PI in clinical trials for Allergan-AbbVie, Teva Pharmaceuticals, Novartis, Lundbeck, and Eli Lilly. MLS reports lectures, advisory boards, and/or PI in clinical trials for Pfizer, Teva Pharmaceuticals, Novartis, Lundbeck, AbbVie, and Eli Lilly. CT reports personal fees for the participation in advisory boards or symposia for AbbVie, Dompé, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; she reports institutional fees for conducting clinical trials for AbbVie, Dompé, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; she received funding for research projects from the European Commission, the Italian Ministry of Health, the Migraine Research Foundation, and the Italian Multiple Sclerosis Foundation.

Background: Circulating microRNAs (miRNA) are suggested to be a promising biomarker for multiple sclerosis (MS). Previously, miR-128-3p, miR-24-3p, miR-191-5p and miR-223-3p have been reported to associate with MS pathology. However, their longitudinal changes and association with the disease activity have not been studied., Objectives: To evaluate the serum temporal variability of miR-128-3p, miR-191-5p, miR-24-3p, and miR-223-3p and their association with disability and disease activity in MS., Methods: The expression of four miRNAs in serum was studied in 57 MS patients, 18 clinically isolated syndrome patients, and 32 healthy controls over the four-year follow-up., Results: At the baseline, miR-191-5p was overexpressed in RRMS in comparison to controls, and its levels correlated positively with EDSS and progression index (PI) in RRMS. Increased levels of miR-128-3p were detected in PPMS in comparison to controls, and increased levels correlated with EDSS and PI in RRMS. The expression of miR-24-3p and miR-223-3p did not differ between the subtypes, but miR-223-3p correlated negatively with T1 lesions volumes in SPMS and PPMS. Over the four-years follow-up period, the expression of miR-128-3p and miR-24-3p was stable longitudinally, while temporal changes of miR-191-5p and miR-223-3p were observed in MS. Temporal changes in miR-191-5p were observed to be associated with an increase of EDSS or MRI activity, while the variability of miR-223-3p was associated with relapses., Conclusion: Temporal variability of miR-191-5p and miR-223-3p are associated with changes in disability accumulation and disease activity. While, miR-128-3p was stably expressed and associated with the PPMS subtype and correlated with disability accumulation., Competing Interests: Declaration of Competing Interest The authors report no conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Depression, sleep disturbances, and cognitive difficulties impair the quality of life in people with multiple sclerosis (MS). Similar symptoms are also frequent during the menopausal transition. In clinical practice, it is important to consider the multifactorial causes of these overlapping symptoms and the potential benefits of menopausal hormone therapy (MHT). The objective of this study was to evaluate vasomotor symptoms (VMS), mood, sleep, and cognition of menopausal women with and without MS at baseline and during one year of MHT., Methods: In this prospective baseline-controlled study, peri- and early postmenopausal participants with (n=14) and without (n=13) MS received MHT containing 1 or 2 mg of estradiol and cyclical 10 mg dydrogesterone for one year. VMS frequency, depressive symptoms (measured by Beck Depression Inventory), insomnia severity (Insomnia Severity Index), and cognitive performance (Paced Auditory Serial Addition Test; PASAT, Symbol Digit Modalities Test; SDMT) were evaluated at baseline and at 3 and 12 months of treatment. Differences in the outcome measures between groups at baseline were assessed using the Mann-Whitney U test. Changes during follow-up compared to baseline within groups were evaluated by Wilcoxon Signed Ranks Test. P < 0.05 was considered for statistical significance. MS activity was monitored by clinical assessment and brain MRI at baseline and at 12 months., Results: Depressive symptoms were more common in MS group, while vasomotor and insomnia symptoms were equally common. During follow-up with MHT, VMS frequency decreased in both groups. Depressive symptoms decreased at 3 months (p = 0.031 with MS; p = 0.024 without MS) and the reduction was sustained at 12 months (p = 0.017; p = 0.042, respectively). Alleviation in insomnia symptoms was seen in participants without MS at 3 months (p = 0.029) and in those participants with MS suffering insomnia at baseline (p = 0.016 at 3 months; p = 0.047 at 12 months). Both groups improved their performance in PASAT, but no significant change was observed in SDMT. MS activity at baseline was mainly stable, and no increase in activity was detected during MHT., Conclusion: Improvements in vasomotor, depressive, and insomnia symptoms observed during one year of MHT are encouraging and suggest that larger placebo-controlled studies of MHT in women with MS are warranted. Cognitive implications were inconclusive because the findings in PASAT likely result from practice effect. MHT did not show any adverse effect on MS activity and increasing safety data will hopefully facilitate patient recruitment for future studies., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Migraine is diagnosed using the extensively field-tested International Classification of Headache Disorders (ICHD-3) consensus criteria derived by the International Headache Society. To evaluate the criteria in respect to a measurable biomarker, we studied the relationship between the main ICHD-3 criteria and the polygenic risk score, a measure of common variant burden in migraine., Methods: We used linear mixed models to study the correlation of ICHD-3 diagnostic criteria, underlying symptoms, and main diagnoses with the polygenic risk score of migraine in a cohort of 8602 individuals from the Finnish Migraine Genome Project., Results: Main diagnostic categories and all underlying diagnostic criteria formed a consistent continuum along the increasing polygenic burden. Polygenic risk was associated with the heterogeneous clinical picture starting from the non-migraine headache (mean 0.07; 95% CI 0.02-0.12; p  = 0.008 compared to the non-headache group), to probable migraine (mean 0.13; 95% CI 0.08-0.18; p  < 0.001), migraine headache (mean 0.17; 95% CI 0.14-0.21; p  < 0.001) and migraine with typical visual aura (mean 0.29; 95% CI 0.26-0.33; p  < 0.001), all the way to the hemiplegic aura (mean 0.37; 95% CI 0.31-0.43; p  < 0.001). All individual ICHD-3 symptoms and the total number of reported symptoms, a surrogate of migraine complexity, demonstrated a clear inclination with an increasing polygenic risk., Conclusions: The complex migraine phenotype progressively follows the polygenic burden from individuals with no headache to non-migrainous headache and up to patients with attacks manifesting all the features of the ICHD-3 headache and aura. Results provide further biological support for the ICHD-3 diagnostic criteria.

Background: Mortality risk and causes of death have been widely studied in MS. Surveys on conditions related to approaching death have not been conducted before in Finland., Objective: Our aim was to sort out the possible needs for end of life (EOL) care in MS by examining causes, place of death and level of hospitalization by age and MS related disability before approaching death., Materials: Data included information for MS patients diagnosed from 1981 to 2010 in a Finnish university hospital district. Information on place and causes of death and care prior to death was based on death certificates from Statistics Finland. Decedents initial disease course, disease modifying treatment (DMT) use and MS related disability status by using EDSS were achieved from hospital records., Results: Data included 113 decedents. Level of disability showed EDSS 6.0 or higher in 54% of the patients. In relapsing onset MS (N 93, 80%) DMTs were used in 11%. Infections, respiratory or other, were the main immediate cause of death (51.3%, n 58) among cases with varying disability. Central or university hospital (42.5%) or community hospital ward (28.3%) were places of death in majority of cases and nursing home (13.3%), home (9.7%) or hospice (3.7%) less often. Place of death did not significantly differ between age-groups (Chi square p = 0.86). Mean age at death was 57 years (range 28-90, SD 13.86). Cardiovascular causes of death were reported mainly in age group 60 years or more and suicide in age group younger than 50 years., Conclusion: The level of hospitalization was high at end of life in all age-groups. High MS related disability and immobility among decedents likely relates to infections as the most common cause of death. Along with our and earlier surveys in this field, we showed that places of death and level of disability before death share similarities in both younger and older age groups highlighting the need of palliative care and end of life care plans in all MS patients with triggers of poor survival. The recently published consensus definition featuring palliative care guideline in MS is aimed at improving end of life care in MS. Our results point at need for future studies in order to assess the impact of palliative care treatment guidelines in MS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The aim of our study was to evaluate the risk for comorbid cardio- and cerebrovascular diseases in the working-aged migraine population of Finland., Methods: A total of 1505 cases who reported diagnosed migraine and 3010 controls from a cohort of 11,596 cases in the Finnish Health and Social Support Study were included. The study material was linked with two registers. ICD diagnoses I63 for ischemic stroke (IS), I21 - I22 for acute myocardial infarction (AMI), and G43 for transient ischemic attack (TIA) among study participants were drawn from the national Finnish Care Register for Health Care at the follow-up in 2012. Reimbursed triptan prescriptions were drawn from the national Social Security Institution (SII) data. The self-reported vascular risk factors were hypertension, high cholesterol values, any diabetes, myocardial infarction, stroke, and TIA. Odds Ratios (OR) with 95% confidence (95% CI) intervals were assessed for diagnosed stroke, myocardial infarction, and TIA., Results: Migraineurs were mostly female (82%) and ≥ 54 years old (62%). Triptans were reimbursed among 34.7% of migraineurs. A self-reported hypertension (21%), high serum cholesterol (38%), and any diabetes (7%) were more common among migraineurs vs controls (p < 0.05). There was no risk for AMI. The risk for TIA (OR 3.20, 95% CI 1.45-7.05) and IS (2.57, 95% CI 1.28-5.17) among migraineurs vs controls remained high after adjustment for self-reported hypertension, obesity, and smoking. The risk was higher among women in two groups ≥54 years (3.25, 95% CI 1.35-7.84 and 5.0, 95% CI 1.94-12.89, respectively). The average age for IS in migraine was 57.5 years and for TIA 58.2 years among women, and 52.8 years and 50.3 years among men, respectively., Conclusion: Cardiovascular risk should be screened in the aging migraine population, and hormonal and other migraine-related risk factors should be considered, especially among women. Efficacious attack treatment with triptans should be offered to migraine patients who do not show contraindications.

Background: A global My Migraine Voice survey was conducted in 31 countries among 11,266 adults who suffered from ≥4 monthly migraine days (MMD). The aim of this retrospective observational survey-based study was to analyse the country specific results in Finland in order to understand the impact of migraine based on disease severity., Methods: The included participants (3%, n = 338/11,266) were stratified by mean MMDs into 4 ≤ MMD < 8 (n = 133), 8 ≤ MMD < 15 (n = 139) and MMD ≥ 15 (n = 66) subgroups. Comorbidities, migraine-related emotional burden and impact on daily living and work productivity and activity impairment (WPAI) were assessed. Subgroup analysis on healthcare resource utilization (HCRU) due to migraine was assessed by visits to healthcare practitioners (HCPs) during the past 6 months and by hospitalizations and emergency room (ER) visits during the past 12 months. The group difference was tested using the one-way ANOVA and for categorical variables using the Chi-squared test. The association between HCRU and MMD and number of comorbidities was assessed using negative binomial regression analysis., Results: Mean age was 44 years, 93% were women and 67% (n = 227) were employed. Chronic migraine (CM, MMD ≥ 15) was reported in 19.5% of the respondents. The negative impact on daily functioning and emotional burden increased significantly by migraine frequency. Mean number of comorbidities was 2.4, and mean number of HCP visits during the previous 6 months was 5.9. Increase in migraine frequency and comorbidities was associated with higher HCRU. Eighty-eight percent of the respondents reported negative impact on working life and 52% experienced overall work productivity impairment. Over previous month, the mean number of missed working days for all respondents was 2.8 days of which 54% were paid sick leave days, and in CM up to 6.0 days and 30%, respectively. Both absenteeism and presenteeism were higher in the CM group., Conclusions: The emotional and functional burden was high, and the societal burden increased by frequency and severity of migraine, as shown by higher HCRU and reduced work productivity. There is a need to improve quality of care in migraine and improve migraine management related issues in both healthcare and society in Finland.

Finland is a high-risk region for multiple sclerosis (MS) with several epidemiological studies on the subject published since 1964, but these have not been comprehensively scrutinized. The objective of this study was to review previous studies of Finnish MS epidemiology, introduce new data on MS prevalence in western parts of Finland and do further analyses on data from previous studies. We performed a systematic search on articles regarding MS epidemiology in Finland in PubMed database, and all relevant articles were included in this review. MS prevalences in the western hospital districts of Vaasa, South Ostrobothnia and Pirkanmaa were calculated in 1980-2007 by using previously unpublished data obtained from a retrospective search from hospital administrative registries. To enhance comparability of the epidemiological figures, we calculated age-standardized prevalence of MS from the new data from western hospital districts and previous data from North Ostrobothnia, Southwest Finland and North Karelia. Marked regional differences in MS epidemiology were confirmed with concentration of the disease in the western and south-western parts of the country. The highest regional age-standardized MS prevalence of 288/100 000 was reported in South Ostrobothnia in 2007. A clear and stable increase in MS prevalence was observed through the decades, but the only marked increase in incidence happened in 1990s. Methodological differences hampered direct comparisons of different studies, highlighting the importance of common principles of reporting and standardizing the epidemiological figures. More comprehensive studies on MS epidemiology are still warranted to yield important information concerning the aetiology of the disease., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Objective: To study ten-year change in MS prevalence in the Province of Western Finland in Tampere University Hospital District located in 62.7°N, 23.7°E., Methods: Age-standardized prevalence/10 5 by using direct standardization in European Standard Population (ESP2013) and crude prevalence/10 5 with 95% confidence interval (95% CI) were assessed among resident MS cases fulfilling Poser criteria by sex and disease course in 31.12.2000 and 31.12.2010. MS-related disability and disease-modifying treatment (DMT) use were estimated in 31.12.2010., Results: Crude prevalence increased 49% from 129/10 5 (95% CI 121-137) in 2000 (N 1080) to 196/10 5 (187-203) in 2010 (N 1666). Age-standardized prevalence increased 45% from 133/10 5 (127-140) to 192/10 5 (184-200) and peaked in 40- to 49-year age-group. Age-standardized prevalence increased 58% among women from 176/10 5 (171-176) to 277/10 5 (270-284) and 31% among men from 91/10 5 (87-95) to 119/10 5 (115-124). Increase in RRMS was 61% from 111/10 5 (105-117) to 179/10 5 (171-186), and decrease in PPMS was 14% from 21/10 5 (19-24) to 18/10 5 (15-21).  In 2010 among the 52% RRMS cases on DMT, MS-related disability was mild in 50%. In total, cohort disability was mild in 46%, moderate to severe in 47%, and information was not available in 14%., Conclusion: A significant increase in prevalence was observed in Western Finland. Increase was higher among women and in relapsing-remitting onset MS. Disability showed age- and disease course-specific variation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Cost assessment modelling (CAM) of treatments in highly active relapsing multiple sclerosis was conducted., Methods: The CAM was developed using the R programming language. The PICOSTEPS health technology assessment framework was applied in the CAM. Modelled patients were 280 adults with highly active relapsing multiple sclerosis eligible for disease-modifying treatment. Intervention was cladribine tablets, a new and reimbursed oral treatment for highly active relapsing multiple sclerosis in Finland. Comparators included fingolimod, the most used oral reimbursed treatment for the highly active disease, and natalizumab, the most used intravenous treatment, and a treatment mix (80% use fingolimod, 20% use natalizumab) in Finland. Outcomes presented expected annual and cumulative drug-associated costs in the overall population and per patient. Setting was modelled public specialist care in Finland. Time was set to 4 years, without discounting. Effects covered expected drug-associated costs (screening, acquisition, administration, monitoring, adverse events, travelling, productivity). Perspective was a limited societal perspective. Sensitivity analyses regarding all PICOSTEPS components were conducted., Results: Cladribine tablets were projected to be cost saving in comparison to fingolimod, natalizumab and treatment mix. The respective modelled savings were €4,598,742, €16,249,701 and €6,928,934 in the overall population, and €16,424, €58,035 and €24,746 per patient, respectively, during the 4 years. The most important cost driver was drug costs, representing 96.3%, 96.0% and 83.4% of modelled costs associated with cladribine tablets, fingolimod and natalizumab, respectively. Cladribine tablets sustained their affordability in the sensitivity analyses. From the perspective of health care payer, cladribine tablets' savings were projected to be €4,514,509, €15,145,366 and €6,640,680 in the overall population, and €16,123, €54,091 and €23,717 per patient in comparison to fingolimod, natalizumab and treatment mix, respectively., Conclusion: Based on the CAM, cladribine tablets were projected to robustly save modelled drug-associated costs in comparison to fingolimod, natalizumab and their mix in Finland.

Prognostic factors and long-term treatment response of interferon β-1a s.c tiw has not been studied in a real-life clinical cohort in Finland. The aim of the paper was to evaluate long-term treatment response, prognostic clinical factors and adherence among interferon β-1a s.c tiw treated patients in Finland. A retrospective review of medical records was performed. Confirmed relapsing multiple sclerosis patients treated with interferon β-1a s.c tiw 22μg or 44μg as their first treatment, from 1996 to 2010 in Western Finland, were included. Longitudinal generalized linear regression models were applied to assess risk of disability progression, using Expanded Disability Status Scale (EDSS), during the treatment period. Odd's ratios with 95% confidence intervals (95% CI) were calculated for risk factors: gender, age at diagnosis, treatment delay, dose, baseline EDSS and EDSS change in one year. Kaplan-Meier was applied to study median time to discontinuation. Mean duration of treatment in 293 cases was 2.9 years (min 0.04, max 13.5). EDSS increase vs. no increase in one-year carried a significant risk for long-term disability progression (1.20, 1.08-1.33). Older age, defined by a 10-year increase in age at diagnosis (1.43, 1.07-1.91) and one-year delay to treatment start showed an increased risk for disability progression (1.05, 0.99-1.11), but gender (0.66, 0.38-1.15) or initial dose (1.00, 0.45-2.25) showed no risk. Treatment was stopped in 37% due to disease activation at median of 1.7 years, and in 25% due to side effects at 9.3 months. Our results show that young age, a short delay to treatment start and slower disability progression were identified as factors for better outcome among cases with interferon β-1a s.c tiw as their first disease modifying treatment., Competing Interests: Conflict of interest: EJ is an employee of Merck Finland, an affiliate of Merck KGaA, Darmstadt, Germany., (©Copyright: the Author(s), 2019.)

TL1A/DR3/DcR3 pathway is an important mediator of inflammatory responses and contributes to the pathogenesis of several chronic inflammatory diseases. Therefore, we analysed PBMC gene expression of these molecules in 30 relapsing-remitting multiple sclerosis (RRMS) patients, 8 secondary progressive MS (SPMS), 9 primary progressive MS (PPMS), 11 clinically isolated syndrome (CIS) patients, and 16 healthy controls (HCs), to evaluate their biomarker potential in MS. The results showed significant decrease in TL1A expression in RRMS compared to other study groups. TL1A as a marker of inflammation, we found its higher expression among treatment näive RRMS patients as compared to HCs and among patients who were treated with DMTs. Moreover, TL1A expression was found to be associated with the clinical and MRI findings of MS patients suggesting its possible involvement in the establishment or preservation of immune system homeostasis or in the regulation of inflammatory activity. Taken together, these findings suggest the TL1A should be evaluated further for its potential as a candidate biomarker of inflammatory activity and the marker of therapeutic response to immunomodulatory treatments in MS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Most studies that have investigated the association between multiple sclerosis (MS) and cancer have suggested a reduced overall cancer risk and no effect of long-term exposure to the immunomodulatory disease modifying treatments (DMTs). Some studies have suggested an increased cancer risk among MS patients treated with immunosuppressive (IS) therapies. Cancer risk among Finnish MS patients has previously been studied from an incidence cohort from 1964 to 1993 followed until year 1999. The objective of this nested case-control study was to assess the cancer risk among Finnish MS patients in a hospital district cohort from southwest Finland during the DMT era., Methods: Patients with MS and cancer comorbidity were identified from the hospital administrative data at the Hospital District of Southwest Finland during a period from 1.1.2004 to 31.12.2012. Case ascertainment for MS diagnosis by the McDonald criteria was performed by review of medical records. During the follow-up 1074 confirmed MS cases were treated in the hospital district, including the deceased cases after 1.1.2004 (5.9%, n = 70). The randomly chosen 10-fold control population was matched by birth year and gender to calculate the coincident risks (odds ratio, OR) with 95% confidence intervals (95% CI) for each cancer diagnosis. Another separate control population from the same patient pool was used to verify the stability of the results. The Kaplan-Meier analysis and ANOVA test log rank test was applied to study cumulative index proportion and age (years) at breast cancer diagnosis in the MS and in the control group., Results: A total of 61 (5,7%) of the MS patients and 757 (7,0%) of the controls were diagnosed with cancer during the study period. The overall risk of cancer in the MS cohort did not significantly differ form the controls (OR 0.80, 95% CI 0.6-1.0, p = 0.092). The age at breast cancer diagnosis in the MS cohort was statistically significantly higher in comparison to the control cohort (61,7 vs. 55.7 years, ANOVA test p-value 0.010). However, the risk for breast cancer did not statistically significantly differ between MS patients and controls (OR 0.9, 95% CI 0.5-1.4, p-value 0.566). In the MS cohort we observed an increased risk of oral cavity cancers (OR 10, CI 1.1-94.2, p-value 0.04), colon cancer (OR 2.3, 95% CI 1.1-5.2, p-value 0.037), lung cancer (OR 4.4, CI 1.5-13.0, p-value 0.007), renal cancer (OR 3.6, CI 1.2-10.6, p-value 0.018), brain cancer (OR 5, 95% CI 1.1-23.0, p-value 0.039) and thyroid cancer (OR 3.6, 95% CI 1.2-10.6, p-value 0.018), and a decreased risk for prostate cancer (OR 0.2, 95% CI 0.1-0.8, p-value 0.026), although for these cancer subtypes the patient numbers were small., Conclusions: Overall risk of cancer in our MS cohort did not significantly differ from the controls. However, the age at diagnosis of breast cancer was statistically significantly higher among the MS patients in comparison with a control population from the same patient pool. Further population-based larger studies spanning longer follow-up periods and longer exposure to emerging MS therapies are needed to evaluate cancer risk related to MS treatments and breast cancer risk in particular., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Diffusion tensor imaging (DTI) is sensitive technique to detect widespread changes in water diffusivity in the normal-appearing white matter (NAWM) that appears unaffected in conventional magnetic resonance imaging. We aimed to investigate the prognostic value and stability of DTI indices in the NAWM of the brain in an assessment of disability progression in patients with a relapsing-onset multiple sclerosis (MS)., Methods: Forty-six MS patients were studied for DTI indices (fractional anisotropy (FA), mean diffusivity (MD), radial (RD), and axial (AD) diffusivity) in the NAWM of the corpus callosum (CC) and the internal capsule at baseline and at 1 year after. DTI analysis for 10 healthy controls was also performed at baseline. Simultaneously, focal brain lesion volume and atrophy measurements were done at baseline for MS patients. Associations between DTI indices, volumetric measurements, and disability progression over 4 years were studied by multivariate logistic regression analysis., Results: At baseline, most DTI metrics differed significantly between MS patients and healthy controls. There was tendency for associations between baseline DTI indices in the CC and disability progression (p < 0.05). Changes in DTI indices over 1 year were observed only in the CC (p < 0.008), and those changes were not found to predict clinical worsening over 4 years. Clear-cut association with disability progression was not detected for baseline volumetric measurements., Conclusion: Aberrant diffusivity measures in the NAWM of the CC may provide additional information for individual disability progression over 4 years in MS with the relapsing-onset disease. CC may be a good target for DTI measurements in monitoring disease activity in MS, and more studies are needed to assess the related prognostic potential., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.

Background: Biomarkers that could be used in early diagnosis of multiple sclerosis (MS), segregation of disease subtypes, and discrimination of the aggressive disease course from the benign one are urgently needed., Objective: The aim of this study was to investigate the specificity of circulating microRNAs: miR-191-5p, miR-128-3p, miR-24-3p, and miR-376c-3p in MS and evaluate their association with disease activity and disability progression., Methods: The expressions of circulating miRNAs were studied in serum of 100 subjects (53 relapsing-remitting (RRMS), 20 primary progressive (PPMS), and 27 controls), using miScript serum miRNA RT-PCR assay techniques., Results: In comparison with controls, miR-191-5p and miR-24-3p were overexpressed in RRMS and PPMS, with no differences between the subtypes. miR-24-3p correlated positively with the disability progression index in the combined group of all patients with MS. miR-128-3p showed tendency toward the predominant expression in PPMS and correlated positively with the annual relapse rate in RRMS. miR-376c-3p expression levels did not differ between the groups, and no associations were found to clinical parameters., Conclusion: This study highlighted the connection of circulating miRNAs to MS. miR-24-3p and miR-128-3p showed a tendency of association with disability accumulation and disease activity, respectively. Further studies should evaluate their suitability for clinical use., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Musculoskeletal disorders and depression are common among migraineurs. The aim of our study was to evaluate the occurrence of these disorders among working aged migraineurs., Material and Methods: The risk for fibromyalgia, rheumatoid arthritis (RA), osteoarthrosis (OA), sciatic syndrome, and the occurrence of depression was studied among cases who reported about these conditions and migraine in working aged Finnish population in The Health and Social Support Study (HeSSup) based on postal questionnaire in 2012. Group differences were tested by chi-square test. Odds ratios (ORs with 95% CI) adjusted for age, gender, education level and depression were calculated with logistic regression analysis., Results: Total of 1505 migraineurs (13%) and 8092 controls were included among the 11 596 responders in 2012. Age and gender adjusted ORs, 2.37 (95% CI 1.81-3.09) for fibromyalgia, 1.46 (1.10-1.95) for RA, 1.58 (1.38-1.80) for OA, and 2.09 (1.84-2.37) for sciatic syndrome, were significant. At least moderate depression was more common among migraineurs (7.3%) than among controls (3.4%) (P < .001)., Conclusion: Recognition of comorbid musculoskeletal disorders and mood disorders among migraineurs needs targeted outreach in working aged population. The acute and preventive treatments to control for neuronal sensitization in migraine and comorbid pain disorders may benefit of individual treatment plan and tailored use of antidepressants., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Survival in MS has increased during the era of disease modifying therapies, but life expectancy in MS patients is still reduced by several years. Increased risk for common comorbidities related to brain health, such as risk for circulatory diseases have been reported in MS and could affect survival. In this paper, we studied age- and gender adjusted risks for circulatory diseases and related disorders, and their impact on overall MS survival in population of Southwest Finland., Materials and Methods: The ICD-10 codes for hospital visits were searched from the administrative data pool from 1.1.2004 up to 31.12.2012 for the resident MS and control cases at the Hospital District of Southwest Finland. The MS population under study consisted of prevalent cases in 1.1.2004 and new cases from 1.1.2004 followed up to death or 31.12.2012. Patient documents were scrutinized to confirm the MS diagnosis (G 35) by the McDonald´s criteria and to confirm the diagnoses and causes of death for the cerebro- and cardiovascular diagnoses under study. The randomly chosen 10-fold control population was matched by birth year and gender to calculate the coincident risks (odds ratio, OR) with 95% confidence intervals (95% CI) and another separate control population from the same patient pool was used to verify the stability of the results. P-values were calculated using Pearson's χ2 test. The Kaplan- Meier analysis log rank test was applied to study survival., Results: During the follow-up 1074 confirmed MS cases were treated in the hospital district, including the deceased cases after 1.1.2004 (5.9%). The probability of survival was 82.4 years among MS and 85.6 years among the control cases, log rank p < 0.001. The survival disadvantage within MS was associated with comorbidity for circulatory disease codes in ICD -10: I06-I71, log rank p < 0.001. The specific risk for ischemic and haemorrhagic stroke was significant with high OR of 1.49 (95% CI 1.03- 2.35) and 2.5 (1.24-5.06) respectively. The two-fold risk for type 1 diabetes in MS was significant, OR 2.1 (1.3-3.36). The main causes of death among the MS cases were infections and the coincident high risk for several infections was significant. There was no difference in the risk for acute myocardial infarct, transient ischemic attack, atrial fibrillation, hypertension, or obesity in comparison with the control cases., Conclusions: Given the high risk for stroke in this MS population and the observed complexity among the coincident common risk factors for circulatory diseases, the high risk for type 1 diabetes and common infections raise a need to recognize patients at risk with these conditions and with the other known risk factors such as metabolic syndrome and smoking. The survival disadvantage related to circulatory diseases observed in general population is true also in MS and should be recognized to reduce the burden of disease and premature mortality in MS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Increased risk of osteoporotic fractures in multiple sclerosis (MS) patients compared with general population has been reported. The purpose of this study was to assess the risk of osteoporotic and other low-energy fractures in an MS cohort from a large hospital district in southwest Finland. Age-adjusted total and gender-specific prevalence for definite MS per 100 000 in a population of 472 139 was calculated as a point prevalence in December 31, 2012., Materials and Methods: Patients with MS and comorbid fractures were identified by searching for ICD-9 and ICD-10 codes during a period from 2004 to 2012 from hospital administrative data in Turku University Hospital (TYKS) in southwest Finland Case ascertainment was performed by review of medical records. Osteoporotic fracture was defined as a low-energy fracture of the pelvis, hip, femur, tibia, humerus, collar bone, ulna/radius, vertebrae, or rib. The control population was a 10-fold age- and gender-matched population., Results: The point prevalence (N 1004) of MS was 212.6/10 5 (CI 199.5-225.8) in December 31, 2012. A total of 100 (9.9%) of 1004 confirmed MS cases experienced at least one fracture during the study period. Relative risks (RRs) for all fractures (1.33, 95% CI 1.10-1.60) and osteoporotic fractures (1.50, 95% CI 1.18-1.90) were significantly increased in patients with MS compared with controls. In particular, RRs for hip fractures (5.00, 95% CI 2.96-8.43) and fractures of humerus (2.36, 95% CI 1.32-4.42) were elevated in patients with MS vs controls., Conclusions: We observed high prevalence of MS in southwest Finland and confirmed increased age-adjusted comorbid risk for osteoporotic fractures and other low-energy fractures compared with individually matched controls., (© 2016 John Wiley & Sons A/S.Published by John Wiley & Sons Ltd.)

Background: There is a need to develop effective educational experience in neurology to improve the students' skills in diagnosing and managing patients with neurological symptoms or disease. The aim of this study was to investigate the medical students' attitudes and emotions towards neurology before and after the four week clinical course at two Finnish Universities in order to find elements to improve effective learning by decreasing the emotional stress in medical studies., Methods: In this two-stage study, 58 medical students participated in an internet survey with open-ended questions after completing a clinical neurology course. In the content analysis of this survey 20 students (35%) were identified with negative anticipation towards neurology before undertaking the clinical neurology course. In the second phase of the study, the narrative analysis method was used to analyse the face-to-face interviews. Two of these interviews are described in this paper and represent cases who expressed negative emotions in both online survey and narrative interview., Results: According to the content analysis, the principal emotions that were experienced at the beginning of the clinical neurology course were insecurity about personal performance (n = 19, 95%) anxiety (n = 9, 45%) and fear (n = 6, 30%). During the course the combined negative emotions (insecurity, anxiety, and fear) decreased in 80% of students (16/20 cases), remained unchanged in 15% (3/20) and could not be evaluated in 1 (5%) case. The main reasons for the observed negative anticipation were the complexity of neurology and challenges in the interpretation of clinical findings. Based on content analysis and narratives, elements that were evaluated as the most significant contributors in reducing this included small group teaching with real patients, teachers' expertise and the increase in self-confidence., Conclusion: Teaching with appropriate didactic methodology and feedback, and plenty of practical training can improve effective learning in neurology. We suggest that the pedagogic competence of the clinical teacher influences a student's motivation and proficiency and reduce stress in neurology-related learning tasks.

Purpose: This study evaluated the cost-effectiveness of first-line treatments of relapsing-remitting multiple sclerosis (RRMS) (dimethyl fumarate [DMF] 240 mg PO BID, teriflunomide 14 mg once daily, glatiramer acetate 20 mg SC once daily, interferon [IFN]-β1a 44 µg TIW, IFN-β1b 250 µg EOD, and IFN-β1a 30 µg IM QW) and best supportive care (BSC) in the health care payer setting in Finland., Methods: The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained, 3%/y discounting). Markov cohort modeling with a 15-year time horizon was employed. During each 1-year modeling cycle, patients either maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS) or showed EDSS progression in SPMS, experienced relapse with/without hospitalization, experienced an adverse event (AE), or died. Patients׳ characteristics, RRMS progression probabilities, and standardized mortality ratios were derived from a registry of patients with MS in Finland. A mixed-treatment comparison (MTC) informed the treatment effects. Finnish EuroQol Five-Dimensional Questionnaire, Three-Level Version quality-of-life and direct-cost estimates associated with EDSS scores, relapses, and AEs were applied. Four approaches were used to assess the outcomes: cost-effectiveness plane and efficiency frontiers (relative value of efficient treatments); cost-effectiveness acceptability frontier, which demonstrated optimal treatment to maximize net benefit; Bayesian treatment ranking (BTR); and an impact investment assessment (IIA; a cost-benefit assessment), which increased the clinical interpretation and appeal of modeled outcomes in terms of absolute benefit gained with fixed drug-related budget. Robustness of results was tested extensively with sensitivity analyses., Findings: Based on the modeled results, teriflunomide was less costly, with greater QALYs, versus glatiramer acetate and the IFNs. Teriflunomide had the lowest ICER (24,081) versus BSC. DMF brought marginally more QALYs (0.089) than did teriflunomide, with greater costs over the 15 years. The ICER for DMF versus teriflunomide was 75,431. Teriflunomide had >50% cost-effectiveness probabilities with a willingness-to-pay threshold of <€77,416/QALY gained. According to BTR, teriflunomide was first-best among the disease-modifying therapies, with potential willingness-to-pay thresholds of up to €68,000/QALY gained. In the IIA, teriflunomide was associated with the longest incremental quality-adjusted survival and time without cane use. Generally, primary outcomes results were robust, based on the sensitivity analyses. The results were sensitive only to large changes in analysis perspective or mixed-treatment comparison., Implications: The results were sensitive only to large changes in analysis perspective or MTC. Based on the analyses, teriflunomide was cost-effective versus BSC or DMF with the common threshold values, was dominant versus other first-line RRMS treatments, and provided the greatest impact on investment. Teriflunomide is potentially the most cost-effective option among first-line treatments of RRMS in Finland., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to assess long-term use, adherence and efficacy of injectable disease modifying agents (DMAs). Multiple Sclerosis (MS) patients diagnosed during 2002-2010 with early treatment start and at least one year in first choice medication were included in a large university district in Finland. Annualized relapse rates (ARR) during each treatment period were studied, and number of switches by medication evaluated. Use of health care facilities during 2002-2010 was assessed. In the study were included 113 MS patients; 15 (13%) switched medication. The mean duration of treatment period (128) was 3.8 years. In 77% (98/128) the treatment continued with the first DMA for (mean) 3.8 years, in 19% (25/128) with the second for 3.5 years and in 4% (5/128) with the third for 4.8 years. Mean ARR was 0.26, with 54% (69/128) of the periods relapse free. Mean ARR during the treatment periods with product switch was 0.41 before, and 0.28 after the switch, showing a trend towards better efficacy with the second DMA. The usage of health care resources remained within the guidelines. Long-term adherence to first choice DMA was observed, and a switch of product within the DMAs showed continuous adherence and efficacy. The efforts to seek a clinically effective and well tolerated agent within the first-line DMAs is warranted, leading to continued adherence and increased clinical effectiveness., Competing Interests: Conflict of interest: Markus Holmberg has no conflict of interest. Elina Järvinen is an employee of Merck Finland, an affiliate of Merck KGaA Darmstadt, Germany. Marja-Liisa Sumelahti has received honoraria for consulting and as a speaker from Novartis, and received grants for congress trips and participation from Novartis, TEVA, Biogen Idec, Bayer, Merck-Serono and Sanofiaventis.

Treatment for relapsing-remitting multiple sclerosis (RRMS) is initiated upon fulfillment of new McDonald 2010 criteria for RRMS. In addition, lumbar puncture is an essential diagnostic method. Interferon-β, dimethyl fumarate, glatiramer acetate and teriflunomide are the first-line immunomodulating drugs (IMD) for RRMS. If the disease is active according to clinical or MRI evaluation during the first-line IMD treatment, alemtuzumab, fingolimod or natalizumab may be considered as second-line therapies. IMD treatment is discontinued upon the transition of RRMS to secondary progressive phase. Rehabilitation should be considered at every phase of the disease.

Object. Gender and disease course specific incidences were studied in high- and medium-risk regions of MS in Finland. Methods. Age- and gender-specific incidences with 95% CIs were calculated in 10-year periods from 1981 to 2010. Poser diagnostic criteria were used and compared with the McDonald criteria from 2001 to 2010. Association between age and diagnostic delay over time was assessed by using the Kruskal-Wallis test. Results. 1419 (89%) RRMS and 198 (11%) PPMS cases were included. RRMS incidence increased with the female to male ratio (F/M) from 4,2/10(5) (F/M 1.9) to 9,7 (2.3), while that of PPMS decreased from 1,2 (1.6) to 0,7 (1.2). The use of McDonald criteria did not change the conclusion. The decreasing diagnostic delay and age at diagnosis in RRMS were associated within the 10-year periods and contrasted those in PPMS. Increasing female risk in RRMS was observed in the high-risk region. Conclusion. Increasing RRMS incidence and high female ratios shown in each age group indicate gender-specific influences acting already from childhood. A more precise definition of the risk factors and their action in MS is needed to provide a better understanding of underlying pathological processes and a rationale for the development of new preventive and treatment strategies.

Background. MS incidence has increased among females, suggesting the presence of environmental effect. Object. Regional differences and temporal changes in gender-specific MS incidence were studied in Finland. Methods. Cases from Jan 1, 1981 to Dec 31, 2010 in Pirkanmaa, Seinäjoki and Vaasa districts were included. The standardized incidence rates (SIR), incidences per 10(5) person years with 95% confidence intervals (CI), and female-to-male ratios (F/M) were determined by district. Results. 1617 cases were included. Compared to Pirkanmaa, the MS risk was 1.9-fold (95% CI: 1.7-2.0) greater in Seinäjoki and 1.2-fold (95% CI: 1.1-1.4) in Vaasa, and the risk was high for both genders. The incidence trend stabilized in Seinäjoki and Vaasa, accompanied by an increase in the F/M ratio. A steady increase in Pirkanmaa was accompanied by a high F/M ratio. Conclusion. A high female preponderance accompanied a general increase in incidence since the 1990s, suggesting the influence of environmental factors. In high-risk districts, increased MS risk prevailed in both genders. High risk reflects both genetic and environmental effects. These effects may be shared with autoimmune diseases such as type 1 diabetes mellitus; the incidence of which follows MS in Finland. Population-based case-control studies are needed to identify these factor effects.

Migraine is a problem of young working-age women in particular, and may influence the choice of the method of contraception. Other conditions causing headache should be taken into account in the differential diagnosis of migraine with an onset during pregnancy. Effective drugs are available for acute treatment, but in some attacks the effect of the drugs is insufficient. In women, these attacks are frequently associated with menstrual migraine. Recognition of prolonged and intense attacks as menstrual migraine, their anticipation and medication of attacks according to instructions are means to improve the treatment outcome.

Background: Migraine is considered a common but under-diagnosed and untreated condition. Treatment patterns have pointed at frequent over-the-counter medication use and low use of preventive therapies. Studies exploring migraine prescription practice among doctors are few., Methods: A population-based study was carried out to examine the prescription practice in the use of acute and preventive migraine medications. The data covered 4864 working-age people reporting they have been diagnosed with migraine. Data on reimbursed prescription medicines from 1 January 1998 to 31 December 2006 were drawn from the registers of the Social Insurance Institute of Finland and compared with age- and sex-matched controls., Results: Anti-inflammatory analgesics were prescribed for 71% of female and 62% of male migraine patients vs. 56% and 50% of controls. Triptans were prescribed for 21% of female and 10% of male patients. Combinations of analgesics and muscle relaxants were offered to 37% of female and 29% of male patients vs. 26% and 21% of controls, and antidepressants to 19% of women and 14% of men vs. 13% and 9% of controls., Conclusion: Although use of preventive medication among migraineurs was high, the prescription patterns in acute treatments showed that NSAIDS were used more often than triptans. Assimilation of national guidelines to treat migraine published in 2002 in Finland was not reflected in the prescription patterns up to 2006.

Background: Several studies show a high mortality risk among patients with multiple sclerosis (MS)., Objectives: In this study, mortality and underlying causes of death were analysed among patients with MS diagnosed between 1964-1993 in Finland (n = 1595)., Methods: Standardized mortality ratios (SMRs) were calculated for both genders. The follow-up was based on linkage to the national computerized Cause-of-Death Register of Statistics Finland., Results: Altogether, 464 deaths were recorded by the end of 2006. The SMR as compared with the general population among females was 3.4 (95% confidence interval 3.0-3.9) and among males 2.2 (1.9-2.6). In total, 270 patients (58%) died from MS; only one of these deaths occurred during the first 2 years after the MS diagnosis. Mortality was also increased for other natural causes of death (n = 160) in patients followed for more than 10 years (SMR 1.4, 1.2-1.7), with a significant increase in deaths from influenza (29, 6.0-85), pneumonia (4.7, 2.5-8.0) and gastrointestinal causes (4.4, 2.3-7.7). The SMR for violent causes was 1.2 (0.7-1.9) and for alcohol-related deaths 0.2 (0.02-0.7). The SMR for suicides was 1.7 (0.9-2.7)., Conclusions: The MS population has an increased disease mortality, while the increase in the risk of accidents and suicides is not significantly increased among patients with MS in Finland.

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits., (Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Linkage analyses have identified four major MS susceptibility loci in Finns. Here we have fine mapped the region on chromosome 5p in 28 Finnish MS families. Marker D5S416 provided the highest pairwise LOD score, and multipoint and haplotype analyses restrict the critical region to about 5.3 Mb on 5p15 between markers D5S1987 and D5S416. Ascertaining for HLA type and geographical origin indicated that families with and without the HLA DR15 risk haplotype, as well as families within and outside an internal high-risk region, contributed to the linkage to 5p, implying the general significance for this locus in Finnish MS families.

Objective: We estimated the prevalence and incidence of multiple sclerosis (MS) in central Finland up to 2000. Rates were compared with those in other areas in Finland., Material and Method: MS cases were identified in the hospital registry by ICD codes for demyelinating diseases from 1979 to 2000. Cases with definite MS were included. Incidence and prevalence were calculated with 95% CI and standardization was performed using direct method., Results: In 1993 prevalence was 59/10(5) (n = 153). Incidence in 1979-93 was 3.8/10(5) person-years (n = 126). Rates are similar to average in areas with known rates of MS in Finland but substantially less than the over twofold MS risk in the neighbouring district Seinajoki. Extended follow-up to 2000 in central Finland showed increasing prevalence up to 105/10(5) (n = 277) and a significant increase in incidence 1994-98 up to 9.2/10(5) (n = 105). At the same time the diagnostic use of MRI increased up to 97%., Conclusion: Central Finland represents an average risk area of MS when compared with other areas of Finland but still a high risk in global comparison. The recent rapid increase in both prevalence and incidence is largely accounted for by increased use of MRI., (Copyright Blackwell Munksgaard, 2004.)

The risk of cancer among multiple sclerosis (MS) patients was evaluated emphasising cancers with a potentially infectious aetiology. Cancer incidence was estimated among incident MS patients in 1964-1993 (n = 1,597) in Finland. The cohort was followed up for cancer incidence through the Finnish Cancer Registry until 1999. A total of 85 cancer cases were diagnosed showing a standardised incidence ratio (SIR) of 1.0 (95% CI 0.8-1.2) for all cancers. The risk (SIR) of haematological tumours was 1.1 and that of central nervous system (CNS) tumours 1.3. The small excess risk of haematological malignancies is consistent with infectious aetiology, whereas the association between MS and CNS tumours may be due to misclassification.

We have previously demonstrated that there is a high-risk focus for multiple sclerosis (MS) in the southern Ostrobothnian region of western Finland (population 376121 in 1993). Of the two southern Ostrobothnian health-care districts, Vaasa and Seinäjoki, the incidence and prevalence of MS were especially high in the latter. In recent genetic studies, we identified haplotypes of the myelin basic protein (MBP) gene in a group of MS patients originating from southern Ostrobothnia, suggesting a founder effect. This finding led us to explore the population history of the southern Ostrobothnia and correlate it with MS epidemiology. Southern Ostrobothnia can be divided into three distinct regions with respect to its historical settlement: Vaasa, Seinäjoki-south, and Seinäjoki-north. Vaasa, the coastal region was settled by Swedes, who immigrated during the 13th century. In Vaasa, the prevalence of clinically definite MS (CDMS) in 1993 was 107/10(5) (95% CI 90-124). Seinäjoki-south was populated from the 13th century onwards from southwestern Finland, a region which has been recognised as a high-risk focus of MS. In Seinäjoki-south, the prevalence of CDMS in 1993 was 219/10(5) (95% CI 190-247). Seinäjoki-north was inhabited rather late starting in the 16th century from eastern Finland. In Seinäjoki-north the prevalence of CDMS in 1993 was 136/10(5) (95% CI 108-164). The historical settlement pattern of the southern Ostrobothnia indicates that its population is quite heterogeneous. Seinäjoki-south has a very high prevalence of MS, significantly higher than its two neighbouring regions. The distinctive settlement history of Seinäjoki-south, the historical link with the other southwestern high-risk foci and molecular genetic evidence, suggest that a founder effect plays an important role in the high-risk of MS in western Finland.

We have performed a two-stage study to analyse the association of polymorphism on chromosome 2q33 with multiple sclerosis (MS). In all, 17 markers were analysed in stage-1 in 134 Finnish MS families and the observed associations were tested in stage-2 in 186 MS families. We did not find previously reported allelic or haplotype associations with CTLA4. We obtained a weak signal of two distinct predisposing genes, one proximal the other distal of CTLA4. The putative proximal gene was associated with the marker rs3977 in families lacking HLA-DR2 (P=0.02 and 0.02) and the other distal gene was associated with D2S1271 in families from a high-risk region in western Finland (P=0.02 and 0.01). Based on the >3 cM distance and the lack of linkage disequilibrium between these loci, we conclude that the two association signals are independent. Our results provide preliminary evidence for two distinct MS susceptibility genes on 2q33 outside of CTLA4.

We have previously found evidence for linkage as well as allelic and haplotype association between the myelin basic protein (MBP) gene and multiple sclerosis (MS). These findings have, however, not been reproduced in other populations. Here, we have analyzed association between MBP and MS in a new set of 349 Finnish triad families. Families with a parent born in the Southern Ostrobothnian region in western Finland (Bothnia families, n=98) were analyzed as a separate group since our previous studies included a high proportion of patients and families from this high-incidence region. Other families (n=251) were collected at five hospitals in southern, eastern, and northern Finland. The MBP short tandem repeat was genotyped, and haplotype patterns were verified by sequencing. In the Bothnia families, the previously detected associations with the 1.27 kb allele and haplotype 1.27-B10 were confirmed (P=0.01 and 0.02, respectively), whereas in the other families there was not even a trend toward association. These results demonstrate a geographic/genealogical restriction in the association between MS and the MBP short tandem repeat, highlight the importance of genealogical information in genetic studies of complex traits, and may provide an explanation why the association has not been found in many other populations.

Objective: To compare the secular trends and geographical differences in the incidence of relapsing-remitting (RRMS) and primary progressive multiple sclerosis (PPMS) in Finland, and to draw inferences about aetiological differences between the two forms of the disease., Methods: New multiple sclerosis cases in southern Uusimaa and the western districts Vaasa and Seinäjoki of Finland in 1979-1993 were verified from hospital records and classified into RRMS and PPMS. Patients met the Poser criteria for definite multiple sclerosis or otherwise satisfied the criteria for PPMS. Disease course was categorised by the same neurologist. Crude and age adjusted incidence in 1979-1993 was estimated., Results: During 1979-1993 the age adjusted incidence was 5.1 per 100 000 person-years in Uusimaa, 5.2 in Vaasa, and 11.6 in Seinäjoki. The rates in Uusimaa remained stable, while a decrease occurred in Vaasa and an increase in Seinäjoki. Between 1979-86 and 1987-93 the incidence of PPMS increased in Seinäjoki from 2.6 to 3.7 per 10(5) and decreased in Vaasa from 1.9 to 0.2 per 10(5); the trends were similar for RRMS., Conclusions: There are significant differences in secular trends for multiple sclerosis incidence in Finland by geographical area, but these are similar for PPMS and RRMS. The recent changes point to locally acting environmental factors. The parallel incidence trends for RRMS and PPMS suggest similar environmental triggers for the two clinical presentations of multiple sclerosis.