Real-world treatment outcomes and safety of natalizumab in Finnish multiple sclerosis patients.

Objectives: The primary objective was to evaluate long-term treatment persistence and safety of natalizumab in Finnish multiple sclerosis patients. The secondary objectives were to assess patient characteristics, use of natalizumab-related safety protocol, and treatment persistence in patients with different anti-John Cunningham virus antibody statuses (John Cunningham virus status). Materials & Methods: All adult multiple sclerosis patients in the Finnish multiple sclerosis register who started natalizumab between 1/2006 and 12/2018 were included in this study and followed retrospectively until treatment discontinuation or end of follow-up (12/2019). Results: In total, 850 patients were included. Median duration of natalizumab treatment was 7.8 years in John Cunningham virus negative (n = 229) and 2.1 years in John Cunningham virus positive patients (n = 115; p < 0.001). The most common cause for treatment discontinuation was John Cunningham virus positivity. After natalizumab discontinuation, patients who had a washout duration of less than 6 weeks had fewer relapses during the first 6 months (p = 0.012) and 12 months (p = 0.005) compared with patients who had a washout duration of over 6 weeks. During the median follow-up of 3.6 years, 76% of patients remained stable or improved on their Expanded Disability Status Scale. Conclusions: Treatment persistence was very high among John Cunningham virus negative patients. The study supports long-term effectiveness of natalizumab and a washout duration of less than 6 weeks after discontinuation.

The CLARION study: first report on safety findings in patients newly initiating treatment with cladribine tablets or fingolimod for multiple sclerosis.

OBJECTIVES: As part of the CLARION study: (1) characterize the incidence of severe infections, herpes zoster, and malignancies in patients newly initiating cladribine or fingolimod for relapsing multiple sclerosis (MS); (2) estimate the incidence of severe lymphopenia among cladribine users; and (3) describe prior/subsequent disease-modifying therapy (DMT) in both cohorts. METHODS: Patients were identified from seven participating MS registries/data sources. The incidence rate (IR) of each outcome per 1000 patient-years and its 95% confidence interval (95%CI) were estimated for cohorts using Poisson regression. RESULTS: By cut-off date (01-April-2020), 742 cladribine and 867 fingolimod users were included. Mean follow-up was ∼1 year. The IR for severe infections from all contributing sources (except Denmark) was: cladribine, 7.37 (2.76,19.6); fingolimod, 6.55 (2.46,17.4). The corresponding IR for herpes zoster was 5.51 (1.78,17.1) and 3.27 (0.82,13.1), respectively, while values for opportunistic infections were 0 (0,6.76) and 1.63 (0.23,11.6), respectively. There were no events of progressive multifocal leukoencephalopathy in either cohort. The IR of severe lymphopenia was 63.9 (40.7,100.1) in 349 cladribine users from contributing sources. The IR of malignancies (cut-off date 01-April-2022) was 3.55 (1.59,7.90) for the cladribine cohort (n = 1035) and 3.55 (1.48,8.52) for the fingolimod cohort (n = 843) from three MS registries/data sources. In the combined data sources, 36.8% of cladribine and 27.4% of fingolimod users were DMT-naïve; after initiation of study treatment, 2.5% and 20.2% switched to another DMT, respectively. CONCLUSION: No new safety signal was observed in patients treated with cladribine tablets, although results are limited by a relatively short duration of follow-up.

Exposure to systemic antibiotics in outpatient care and the risk of multiple sclerosis.

BACKGROUND: Infections, early life exposures and the microbiome have been associated with the aetiology of multiple sclerosis (MS). Data on any possible roles of antibiotics is scarce and conflicting. OBJECTIVE: The objective of this study was to investigate associations between outpatient systemic antibiotic exposure and the risk of MS in a nationwide case-control setting. METHODS: Patients with MS were identified from the nation MS registry and their exposure to antibiotics was compared with that of persons without MS, provided by the national census authority. Antibiotic exposure was investigated using the national prescription database and analyzed by Anatomical Therapeutic Chemical (ATC) category. RESULTS: Among the 1830 patients with MS and 12765 control persons, there were no associations between exposure to antibiotics in childhood (5-9 years) or adolescence (10-19 years) and the subsequent risk of MS. There was also no association between antibiotic exposure 1-6 years before disease onset and the risk of MS, save for exposure to fluoroquinolones in women (odds ratio: 1.28; 95% confidence interval: 1.03, 1.60; p = 0.028) which is probably associated with the increased infection burden in the MS prodrome. CONCLUSION: Use of systemic prescription antibiotics was not associated with subsequent MS risk.

Proportion and characteristics of secondary progressive multiple sclerosis in five European registries using objective classifiers.

Background: To assign a course of secondary progressive multiple sclerosis (MS) (SPMS) may be difficult and the proportion of persons with SPMS varies between reports. An objective method for disease course classification may give a better estimation of the relative proportions of relapsing-remitting MS (RRMS) and SPMS and may identify situations where SPMS is under reported. Materials and methods: Data were obtained for 61,900 MS patients from MS registries in the Czech Republic, Denmark, Germany, Sweden, and the United Kingdom (UK), including date of birth, sex, SP conversion year, visits with an Expanded Disability Status Scale (EDSS) score, MS onset and diagnosis date, relapses, and disease-modifying treatment (DMT) use. We included RRMS or SPMS patients with at least one visit between January 2017 and December 2019 if ≥ 18 years of age. We applied three objective methods: A set of SPMS clinical trial inclusion criteria ("EXPAND criteria") modified for a real-world evidence setting, a modified version of the MSBase algorithm, and a decision tree-based algorithm recently published. Results: The clinically assigned proportion of SPMS varied from 8.7% (Czechia) to 34.3% (UK). Objective classifiers estimated the proportion of SPMS from 15.1% (Germany by the EXPAND criteria) to 58.0% (UK by the decision tree method). Due to different requirements of number of EDSS scores, classifiers varied in the proportion they were able to classify; from 18% (UK by the MSBase algorithm) to 100% (the decision tree algorithm for all registries). Objectively classified SPMS patients were older, converted to SPMS later, had higher EDSS at index date and higher EDSS at conversion. More objectively classified SPMS were on DMTs compared to the clinically assigned. Conclusion: SPMS appears to be systematically underdiagnosed in MS registries. Reclassified patients were more commonly on DMTs.

Finnish multiple sclerosis patients treated with cladribine tablets: a nationwide registry study.

BACKGROUND: Cladribine tablets for adult patients with highly active relapsing multiple sclerosis (MS) have been available in Finland since 2018. Real-world data from different genetic and geographical backgrounds are needed to complement data from clinical trials. METHODS: We investigated the use of cladribine tablets in Finland in a non-interventional cohort study, based on real-world data from the nationwide Finnish MS registry. All eligible patients who had initiated treatment with cladribine tablets in 2018-2020 were included. Descriptive analyses for outcomes were conducted using summary statistics. Time-dependent endpoints were analyzed using cumulated events analysis based on 1-Kaplan-Meier estimates and curves. Subgroups were analyzed separately according to the number of previous disease-modifying therapies (DMTs) and the most common last preceding therapies. RESULTS: Data of 179 patients were analyzed. Median follow-up time was 19.0 months (interquartile range [IQR] 12.0-26.2). Of the 134 patients who were followed for at least 12 months, 112 patients (83.6%) remained relapse-free during follow-up. Mean annualized relapse rate (ARR) was 1.0 (standard deviation [SD] 0.89) at baseline, and 0.1 (SD 0.30) at follow-up. Patients with two or more previous DMTs had shorter time to first relapse (median 2.5 months, IQR 0.6-9.3) when compared to patients with 0-1 previous DMTs (median 11.4 months, IQR 8.7-13.1) (p=0.013). After excluding patients switching from fingolimod (n=33), a statistically significant difference in time to first relapse was no longer observed between the two groups (p=0.252). Adverse events (AEs) were reported in 30 patients (16.8%). The most frequent AE was headache (n=14, 7.8%). One patient (0.6%) died of cardiac arrest. Discontinuation of cladribine tablets was reported in nine patients (5.0%). CONCLUSION: The mean ARR observed in this cohort was similar to what has been reported in clinical trials. Approximately half of the patients had used two or more previous DMTs before cladribine tablets. These patients had a shorter time to first relapse when compared to patients with 0-1 previous DMTs, mostly driven by early relapses in patients switching from fingolimod.

Thalamic Atrophy Predicts 5-Year Disability Progression in Multiple Sclerosis.

Purpose: Thalamus is among the first brain regions to become atrophic in multiple sclerosis (MS). We studied whether thalamic atrophy predicts disability progression at 5 years in a cohort of Finnish MS patients. Methods: Global and regional brain volumes were measured from 24 newly diagnosed relapsing MS (RMS) patients 6 months after initiation of therapy and from 36 secondary progressive MS (SPMS) patients. The patients were divided into groups based on baseline whole brain parenchymal (BP) and thalamic atrophy. Standard scores (z scores) were computed by comparing individual brain volumes with healthy controls. A z score cutoff of -1.96 was applied to separate atrophic from normal brain volumes. The Expanded Disability Status Scale (EDSS), brain magnetic resonance imaging (MRI) findings, and relapses were assessed at baseline and at 2 years and EDSS progression at 5 years. Results: Baseline thalamus volume predicted disability in 5 years in a logistic regression model (p = 0.031). At 5 years, EDSS was same or better in 12 of 18 patients with no brain atrophy at baseline but only in 5 of 18 patients with isolated thalamic atrophy [odds ratio (OR) (95% CI) = 5.2 (1.25, 21.57)]. The patients with isolated thalamic atrophy had more escalations of disease-modifying therapies during follow-up. Conclusion: Patients with thalamic atrophy at baseline were at a higher risk for 5-year EDSS increase than patients with no identified brain atrophy. Brain volume measurement at a single time point could help predict disability progression in MS and complement clinical and routine MRI evaluation in therapeutic decision-making.

Lipid Profile Alterations during Fingolimod Treatment in Multiple Sclerosis Patients.

Fingolimod reduces inflammatory activity in multiple sclerosis (MS) by acting as a functional antagonist of sphingosine 1-phosphate (S1P) receptors. It has been suggested that S1P might also contribute to the antiatherogenic effect of high-density lipoprotein (HDL). We conducted a retrospective observational study using data of 72 MS patients from two Finnish hospital districts to find out whether lipid profiles change during treatment with fingolimod. A mixed-effects model with patient as a random effect was used to analyze lipid profile alterations. We found a statistically significant elevation in both total cholesterol (0.12 mmol/L per year) and HDL (0.04 mmol/L per year) during a median follow-up of 12 months, while low-density lipoprotein (LDL) and triglycerides remained unchanged. Since the mean elevation observed in both lipid values seems to be modest, we suggest that routine lipid profile monitoring is unnecessary during fingolimod treatment in MS patients without pre-existing cardiovascular comorbidities. Graphical abstract.

Vitamin D supplementation and serum neurofilament light chain in interferon-beta-1b-treated MS patients.

OBJECTIVES: Serum neurofilament light chain (sNfL) is a promising biomarker of MS activity, progression, and treatment response. The aim of the present study was to address whether sNfL concentrations are affected by supplementation of vitamin D and correlate with disease activity in interferon-beta-1b (IFNb-1b)-treated Finnish MS. MATERIALS AND METHODS: Serum samples were available of 32 participants of the Finnish vitamin D randomized controlled trial (17 vitamin D/15 placebo). Serum 25 hydroxyvitamin D was measured using radioimmunoassay and sNfL using single-molecule array (Simoa). Correlation of sNfL with brain magnetic resonance imaging (MRI) activity, burden of disease (BOD, mm3 ), and disability was assessed at the study baseline and at 52 weeks. RESULTS: Serum NfL concentrations were similar in the patients randomized to high-dose vitamin D and placebo at the study baseline and at month 12 follow-up (p-value). Concentrations of sNfL were higher in patients with Gadolinium-enhancing lesions in brain MRI: median (95% CI) sNfL was 14.84 (9.9-42.5) pg/ml and 11.39 (8.9-13.2) pg/ml in patients without Gd+ lesions (p = .0144) and correlated with enhancing lesion volume (Pearson r = .36, p = .037) at the study baseline but not at week 52. Serum NfL did not correlate with the MRI BOD or disability measured by expanded disability status scale and 25-foot walk test. CONCLUSION: In this small cohort of clinically stable IFN-treated Finnish MS patients, sNfL levels were similarly low in patients supplemented with high-dose vitamin D or placebo. Subclinical disease activity in MRI was associated with higher sNfL levels.

Trends and characteristics of infection-related hospital admissions in multiple sclerosis patients in Southwest Finland in 2009-2018.

BACKGROUND: Multiple sclerosis (MS) patients are at increased risk for infections. The aim of this study was to investigate the trends in hospital admissions of patients with MS and to identify the factors predisposing to infection-related admissions. METHODS: Hospital admissions with MS as a primary or an auxiliary diagnosis in the hospital district of Southwest Finland in 2009-2018 were searched and MS patients with infection admissions compared with other MS patients in the hospital district. Data were derived from hospital registries, patient charts and the Finnish MS register. Group comparisons were performed using Pearson´s chi-squared test, Fisher´s exact test or Wilcoxon rank sum test. Overdispersion-adjusted Poisson regression was used to analyze the annual admission numbers and multivariable logistic regression to examine the predictors of infection-related admissions. RESULTS: 1380 hospital admissions for 532 patients were identified. The annual number of admissions decreased by 8.9% annually (p<0.001). Proportion of infection-related admissions declined from 26.5% to 19.5% (p = 0.049). The patients with infection admissions were on average 8.2 years older (p<0.001), more often male (p<0.001), had on average 5.3 years longer disease duration (p<0.001), more disability (median EDSS 5.0 vs. 2.0; p<0.001), more often progressive disease (p<0.001) and more comorbidities (p = 0.006) than other MS patients. Disease modifying therapies (DMTs) were used less often by patients with infection admissions (p<0.001). Infection admissions were not associated with the number of recent relapses. In-hospital mortality was higher in the infection-related admissions (3.57% vs 0.29%; p<0.001). Only 14.3% of patients with over two infection admissions had a DMT during the study period. CONCLUSION: Hospital admissions, with or without an infection, have become more infrequent in MS patients of Southwest Finland over the decade from 2009 to 2018. Infection-related admissions were associated with lesser use of DMTs, older age, male gender and disability.

Medication adherence/persistence among patients with active multiple sclerosis in Finland.

OBJECTIVES: To explore adherence, persistence, and treatment patterns in patients with multiple sclerosis (MS) in Finland treated with disease-modifying therapies (DMTs) for active MS in 2005-2018. MATERIALS AND METHODS: The study cohort was identified using the Drug Prescription Register of Social Insurance Institute, Finland. All patients had at least one prescription of glatiramer acetate (GA), beta-interferons, teriflunomide, or delayed-release dimethyl fumarate (DMF). Adherence was calculated using proportion of days covered (PDC) (cutoff ≥0.8). Time to non-persistence was calculated by the number of days on index DMT treatment before the first treatment gap (≥90 days) or switch and analyzed with time-to-event methodology. RESULTS: The cohort included 7474 MS patients (72.2% female; mean age 38.9 years). Treatment switches were steady over 2005-2012, peaked in 2015. PDC means (standard deviations) were GA, 0.87 (0.17); beta-interferons, 0.88 (0.15); DMF, 0.89 (0.14); teriflunomide, 0.93 (0.10). Adherence frequencies were GA, 78.4%; beta-interferons, 81.3%; DMF, 86.9%; teriflunomide, 91.7%. Logistic regression showed that age group, DMT and the starting year, sex, and hospital district independently affected adherence. Patients receiving teriflunomide and DMF, males, and older patients were more likely to persist on treatment. There was no difference in persistence between patients prescribed teriflunomide and DMF, or between GA and beta-interferons. CONCLUSIONS: Oral DMTs had greater adherence and persistence than injectable DMTs.

Changes in multiple sclerosis epidemiology in Finland over five decades.

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.

Hospital admission and prevalence trends of adult myasthenia gravis in Finland in 2004-2014: A retrospective national registry study.

Hospital admission trends in Myasthenia Gravis are largely unknown, so they were here investigated in Finland between 2004 and 2014 using national mandatory registry data. There were 2989 hospital admissions (59.7% for women) for 861 individuals (median 2 admissions/individual) The annual number of admissions (p = .56), the age of admitted patients (p = .24) or length of stay (p = .20) showed no change during the study period. The proportion of infections as the primary diagnosis increased from 4.5% to 10.4% (p = .0056). These admissions lasted longer than admissions with a non-infectious primary diagnosis (median 6 vs. 4 days, p < .0001). In-hospital mortality rate was 1.0%, predicted by age over 65 (HR 8.8; p = .0034) and infection as the primary diagnosis (HR 6.9; p < .0001). Annual frequencies of thymectomies (p = .66) or plasmaphereses (p = .12) remained unchanged. Myasthenia drug reimbursement data suggested increasing MG prevalence during the study period (p < .00001). Considering that the annual hospitalisation frequency remained stable, this would suggest decreased need of hospitalisations per patient. The importance of infections as causes of myasthenia hospitalisations merits further study.

Progressive dopaminergic defect in a patient with primary progressive multiple sclerosis.

Dopamine has a modulatory role in a number of autoimmune diseases, but there are no published cases of longitudinal dopaminergic imaging in multiple sclerosis (MS). Here we report a patient with primary progressive multiple sclerosis (PPMS) who was scanned twice with brain dopamine transporter single photon emission computed tomography (SPECT) with an interval of four years. The results showed a loss of tracer binding that corresponded to a 4-7 fold steeper decline than in normal ageing. The finding points to a relevant role of nigrostriatal dopaminergic degeneration in the pathological process of PPMS.

Risk of cancer among Finnish multiple sclerosis patients.

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.

Multiple sclerosis in Finland 2018-Data from the national register.

OBJECTIVES: Finland is a high-risk multiple sclerosis (MS) region, but a national MS register has not existed until 2014. In this paper, we present the Finnish MS register variables and data collected by 31 December 2018. MATERIALS AND METHODS: Numbers and data counts of MS patients in the register (ICD-10 code G35) are presented. The disease types and proportion of patients receiving disease-modifying treatments (DMTs) were analysed in five hospital districts with most complete data sets. MS prevalence in Finland was estimated using administrative hospital discharge data as an additional resource. RESULTS: There were a total of 8722 MS patients in the Finnish MS register by 31 December 2018 (71.5% females). Mean age at MS diagnosis was 38.7 years and peak prevalence was at age 50-54 years. Disease course was relapsing remitting (RRMS) in 66.7%, secondary progressive (SPMS) in 13.5%, and primary progressive (PPMS) in 7.9% of the 5365 MS patients in the selected districts with most complete data. A total of 66.0% of RRMS patients, 19.6% of SPMS patients and 9.9% of PPMS patients were receiving DMTs. By combining MS register data with databases of those hospitals that had not joined the register, the nationwide prevalence estimate was between 10 and 11 thousand patients (corresponding to crude prevalence 180-200/100 000). CONCLUSIONS: The Finnish MS register is currently used in 15/21 Finnish hospital districts. By register integration into the electronic patient files, the coverage of the register has increased to approximately 80% of the estimated Finnish MS population.

Epstein-barr virus and multiple sclerosis risk in the finnish maternity cohort.

OBJECTIVE: To determine whether maternal Epstein-Barr virus (EBV) IgG antibody levels are associated with risk of multiple sclerosis (MS) in the offspring. METHODS: We conducted a prospective nested case-control study in the Finnish Maternity Cohort (FMC) with serum samples from >800,000 women collected during pregnancy since 1983. Cases of MS among offspring born between 1983 and 1991 were identified via hospital and prescription registries; 176 cases were matched to up to 3 controls (n = 326) on region and dates of birth, sample collection, and mother's birth. We used conditional logistic regression to estimate relative risks (RRs) and adjusted models for sex of the child, gestational age at sample collection, and maternal serum 25-hydroxyvitamin D and cotinine levels. Similar analyses were conducted among 1,049 women with MS and 1,867 matched controls in the FMC. RESULTS: Maternal viral capsid antigen IgG levels during pregnancy were associated with an increased MS risk among offspring (RRtop vs bottom quintile = 2.44, 95% confidence interval [CI] = 1.20-5.00, p trend = 0.004); no associations were found between maternal EBV nuclear antigen 1 (EBNA-1), diffuse early antigen, or cytomegalovirus IgG levels and offspring MS risk. Among women in the FMC, those in the highest versus lowest quintile of EBNA-1 IgG levels had a 3-fold higher risk of MS (RR = 3.21, 95% CI = 2.37-4.35, p trend <1.11e-16). These associations were not confounded or modified by 25-hydroxyvitamin D. INTERPRETATION: Offspring of mothers with high viral capsid antigen IgG during pregnancy appear to have an increased risk of MS. The increase in MS risk among women with elevated prediagnostic EBNA-1 IgG levels is consistent with previous results. ANN NEUROL 2019;86:436-442.

Thalamic Atrophy Without Whole Brain Atrophy Is Associated With Absence of 2-Year NEDA in Multiple Sclerosis.

Purpose: To study which brain volume measures best differentiate early relapsing MS (RMS) and secondary progressive MS (SPMS) patients and correlate with disability and cognition. To test whether isolated thalamic atrophy at study baseline correlates with NEDA (no evidence of disease activity) at 2 years. Methods: Total and regional brain volumes were measured from 24 newly diagnosed RMS patients 6 months after initiation of therapy and 2 years thereafter, and in 36 SPMS patients. Volumes were measured by SIENAX and cNeuro. The patients were divided into subgroups based on whole brain parenchyma (BP) and thalamic atrophy at baseline. Standard scores (z-scores) were computed by comparing individual brain volumes against healthy controls. A z-score cut-off of -1.96 was applied to separate atrophic from normal brain volumes. The Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) were assessed at baseline and at 2 years. Differences in achieving NEDA-3, NEDA-4, EDSS progression, and SDMT change were analyzed between patients with no thalamic or BP atrophy and in patients with isolated thalamic atrophy at baseline. Results: At baseline, 7 SPMS and 12 RMS patients had no brain atrophy, 8 SPMS and 10 RMS patients had isolated thalamic atrophy and 2 RMS and 20 SPMS patients had both BP and thalamic atrophy. NEDA-3 was reached in 11/19 patients with no brain atrophy but only in 2/16 patients with isolated thalamic atrophy (p = 0.012). NEDA-4 was reached in 7/19 patients with no brain atrophy and in 1/16 of the patients with isolated thalamic atrophy (p = 0.047). At 2 years, EDSS was same or better in 16/19 patients with no brain atrophy but only in 5/17 patients with isolated thalamic atrophy (p = 0.002). There was no significant difference in the EDSS, relapses or SDMT between patients with isolated thalamic atrophy and no atrophy at baseline. Conclusion: Patients with isolated thalamic atrophy were at a higher risk for not reaching 2-year NEDA-3 and for EDSS increase than patients with no identified brain atrophy. The groups were clinically indistinguishable. A single measurement of thalamic and whole brain atrophy could help identify patients needing most effective therapies from early on.

Progressive multifocal leukoencephalopathy in Finland: a cross-sectional registry study.

OBJECTIVE: To investigate if progressive multifocal leucoencephalopathy (PML) incidence has increased in Finland like in the neighbouring Sweden. METHODS: National administrative registries were searched for all PML admissions aged 16 years or more in 2004-2014 on all neurological and internal medicine wards in Finland. The mortality data of the patients was extracted from the national causes of death registry. National level data on annual predisposing drug use was obtained from the national pharmaceutical authority. RESULTS: We identified 35 PML cases (57% male) with a peak in 2010-2011 that amounted to 49% of all cases. The annual incidence for the entire study period was 0.072/100,000 person-years (95% CI 0.050-0.10) with no temporal trend (p = 0.18). Mean age was 57 years (22-88 years) with no sex difference (p = 0.42). Neoplasms (60%), HIV infection (17%) and systemic connective tissue disorders (CTD, 14%) were the most common predisposing conditions. MS was recorded in three cases (9%). The national level use of drugs that predispose to PML increased during the study period, with the exceptions of alemtuzumab and fludarabine. Overall survival was 85% at 90 days, 79% at 1 year, and 66% at 5 years. Survival was worst in patients with malignancy and best in patients with CTD. CONCLUSIONS: PML most often occurs in patients with malignancies and patients with HIV or CTD cover a third. PML incidence in Finland is lower than in Sweden and shows no temporal trend despite increasing use of predisposing drugs. Mortality after PML varies according to the predisposing condition.

Multiple sclerosis epidemiology in Finland: Regional differences and high incidence.

OBJECTIVES: Studies on the east-west gradient of multiple sclerosis (MS) are scarce. In Finland, epidemiological differences have been only partially elucidated, but the MS risk is high, and it has been claimed that the occurrence follows a longitudinal gradient. In this register-based study, we updated the MS epidemiology in southwest Finland (SwF) and compared it to the easternmost hospital district, North Karelia (NK), for which no previous data exist. MATERIALS AND METHODS: Patients with ICD-10 code G35 were identified from hospital district administrative data. Patient records were reviewed to include only cases with a definitive diagnosis. Incidence period covered 5 years (2012-2016), and the prevalence date was December 31, 2016. Results were standardized using the direct method. RESULTS: A total of 1184 persons had MS in SwF and 253 persons in NK at the end of 2016. The prevalence was 280/100 000 (95% CI 264-296) in SwF and 168/100 000 (95% CI 148-190) in NK (age-standardized for the European standard population 2013). During the incidence period, 211 new MS diagnoses were made in SwF and 49 in NK. The annual age-standardized (ESP 2013) incidence was 12.1/100 000 person-years (95% CI 10.5-13.8) in SwF and 8.6/100 000 person-years (95% CI 6.4-11.2) in NK in the age-group 10-69 years. CONCLUSIONS: There are regional differences in MS epidemiology in Finland, possibly related to demographic, social, and genetic circumstances, but the retrospective nature and limited sample size of this study might introduce some uncertainty to the calculations. SwF is a region with a globally very high risk for MS.