AIMS:Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) have been proposed to define "MOG encephalomyelitis" (MOG-EM), with published diagnostic and "red flag" criteria. We aimed to evaluate these criteria in a routine clinical setting.METHODS:We retrospectively analyzed patients with borderline/positive MOG-IgG and applied the diagnostic and red flag criteria to determine likelihood of MOG-EM diagnosis. Para-/clinical parameters were described and analyzed with chi-square test.RESULTS:In total, 37 patients fulfilled MOG-EM diagnostic criteria (female-to-male ratio: 1.6:1, median onset age: 28.0 years [IQR 18.5-40.5], n = 8 with pediatric onset). In 24/37, red flags were present, predominantly MOG-IgG at assay cutoff and/or MRI lesions suggestive of multiple sclerosis (MS). As proposed in the consensus criteria, these patients should rather be described as "possible" MOG-EM. Of these, we classified 13 patients as "unlikely" MOG-EM in the presence of the red flag "borderline MOG-IgG" with negative MOG-IgG retest or coincidence of ≥1 additional red flag. This group mainly consisted of patients diagnosed with MS (n = 11). Frequency of cerebrospinal fluid (CSF-)-specific oligoclonal bands (OCB) is significantly lower in definite vs possible and unlikely MOG-EM (P = .0005).CONCLUSION:Evaluation of diagnostic and red flag criteria, MOG-IgG retesting (incl. change of assay), and CSF-specific OCB are relevant in clinical routine cohorts to differentiate MOG-EM from MS.

Objective Despite frequent use of fingolimod (FTY) and dimethyl fumarate (DMF), studies comparing clinical efficacy and withdrawal rates of DMF and FTY concerning different pretreatment situations are rare. The aim of our study was to compare relapse occurrence and withdrawal rates of DMF and FTY in different pretreatment situations. Methods Patients from 4 European centers were retrospectively identified and followed until the 1st relapse after treatment start or if no relapse occurred for a maximum of 2 years. Cox regression analyses adjusted for relapsing-remitting MS (RRMS) disease duration, sex, and region were performed for the following pretreatment situations: treatment naive or injectables or DMF/FTY or natalizumab. Results Seven hundred thirty-two patients with RRMS (female/male: 2.4:1.0; DMF n = 409, FTY n = 323) were analyzed. Compared with FTY-treated patients, DMF-treated patients discontinued treatment more frequently mainly because of side effects (DMF/FTY: 29.3%/20.7%). Clinical relapses occurred in 24.5% of the patients within 24 months. Survival analysis demonstrated that compared with FTY treatment, DMF treatment was associated with an adjusted hazard ratio (aHR) for occurrence of relapse of 1.9 (95% CI 1.4-2.6, p < 0.001, n = 732). Stratification into pretreatment groups unmasked a higher relapse risk in DMF patients pretreated with natalizumab (aHR [95% CI] 4.5 [1.9-10.8], p = 0.001, n = 122) or to a lesser extend also in treatment-naive patients (aHR [95% CI] 1.9 [1.01-3.6], p = 0.045, n = 230). No differences were observed in patients pretreated with injectables or the respective other oral drug (injectables: p > 0.05, n = 341; other oral: p > 0.05, n = 39). Conclusions DMF treatment was associated with higher clinical disease activity compared with FTY treatment. A subgroup analysis suggested beneficial effects of FTY in treatment-naive and patients pretreated with natalizumab.

Multiple sclerosis (MS) is characterized as an autoimmune disease affecting the central nervous system. It is one of the most common neurological disorders in young adults. Over the past decades, increasing evidence suggested that hypovitaminosis D is a contributing factor to the risk of developing MS. From different risk factors contributing to the development of MS, vitamin D status is of particular interest since it is not only a modifiable risk factor but is also associated with MS disease activity. MS patients with lower serum vitamin D concentrations were shown to have higher disease activity. However, this finding does not demonstrate causality. In this regard, prospective vitamin D supplementation studies missed statistical significance in its primary endpoints but showed promising results in secondary outcome measures or post hoc analyses. An explanation for missed primary endpoints may be underpowered trials. Besides vitamin D supplementation as a potential add-on to long-term immunotherapeutic treatment, a recent laboratory study of our group pointed toward a beneficial effect of vitamin D to improve the efficacy of glucocorticoids in relapse therapy. In the following article, we will briefly review the effects of vitamin D on MS by outlining its effects on the immune and nervous system and by reviewing the association between vitamin D and MS risk as well as MS disease activity. We will also review the effects of vitamin D supplementation on MS risk and MS disease activity.

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Until 2018, the 2010 McDonald criteria were the most widely used criteria in the diagnosis of multiple sclerosis (MS), defining dissemination in space (DIS) and time (DIT).1 In the evaluation of DIS and DIT, clinical and MRI findings are taken into account.1 Considering new scientific insights and advances in diagnostic techniques, two adaptations of the 2010 McDonald criteria were published in short sequence: (1) the 2017 McDonald criteria and (2) the 2016 MAGNIMS criteria.2,3 In predicting the conversion from clinically isolated syndrome (CIS) to clinically definite MS (CDMS), the 2016 MAGNIMS and 2010 McDonald criteria demonstrated similar sensitivity and specificity.4 In contrast, the 2017 McDonald criteria demonstrated a higher sensitivity but a lower specificity than the 2010 McDonald criteria.5,6 Considering the recency of the publication of the 2017 McDonald criteria, the prediction of conversion to MS and CDMS using this set of criteria has not yet been compared to the 2016 MAGNIMS criteria. Therefore, it is our aim to assess and compare the predictive properties of conversion to MS and CDMS by retrospectively applying the 2017 McDonald and the 2016 MAGNIMS criteria to a single-centre cohort of patients diagnosed with CIS according to the 2010 McDonald criteria. Furthermore, we evaluate the influence of modifications and differences between the 2017 McDonald and the 2016 MAGNIMS criteria on the prediction of conversion to MS and CDMS.

Background: In multiple sclerosis (MS), the frequency of hypogammaglobulinemia is unknown. We aimed to evaluate the frequency of reduced immunoglobulin (Ig) concentrations and its association with immunotherapy and disease course in two independent MS cohorts. Methods: In our retrospective cross-sectional study, MS patients and control patients with head or neck pain from Bern University Hospital (Bern, Switzerland) and Eginition University Hospital (Athens, Greece) were included. The lower limits of normal (LLN) for serum Ig concentration were IgG < 700 mg/dl, IgM < 40 mg/dl, and IgA < 70 mg/dl. Mann–Whitney U test, analysis of variance test, and multiple linear regression analysis were employed. Results: In total, 327 MS patients were retrospectively identified (Bern/Athens: n = 226/101). Serum IgG concentrations were frequently under LLN in both MS cohorts (Bern/Athens: 15.5%/14.9%), even when considering only untreated patients (Bern/Athens: 7.9%/8.6%). MS patients ( n = 327) were significantly more likely to have IgG concentrations below LLN and below 600 mg/dl in comparison with controls ( n = 58) ( p = 0.015 and 0.047, respectively). Between both patient groups, no significant differences were found in frequencies of IgA and IgM concentrations under LLN [ n (MS patients/controls): IgA 203/30, IgM 224/24]. Independently of age, secondary progressive MS patients had lower IgG concentrations than relapsing–remitting and primary progressive patients (both: p ⩽ 0.01). After adjusting for sex, age, and disease course, IgG concentrations were lower in patients treated with rituximab ( p = 0.001; n = 42/327), intravenous corticosteroids ( p < 0.001; n = 16/327), natalizumab ( p < 0.001; n = 48/327), and fingolimod ( p = 0.003; n = 6/327). Conclusion: Our study demonstrated high prevalence rates of reduced serum IgG concentrations in MS patients with and without disease-modifying treatments. The significance of lower IgG concentrations at the levels noted is unclear considering that infections or interference with antibody production generally occur when IgG levels are much lower, at or below 400 mg/dl. However, the information is useful to monitor IgG levels especially with anti-B-cell therapies and consider IgG substitution when levels drop below 400 mg/dl.

Introduction: In acute inflammatory optic neuritis (ON) as a typical onset of multiple sclerosis (MS), only few studies have investigated plasma exchange (PLEX) as a sequential treatment after insufficient response to high-dose intravenous glucocorticosteroids. Therefore, we aimed to investigate treatment outcome on visual acuity (VA) with PLEX in patients with steroid-refractory ON. Methods: In our retrospective monocentric study, medical records were screened for patients with acute ON as their first relapse with sequential MS diagnosis or with an established MS diagnosis from the Bern University Hospital (Switzerland) that were treated with PLEX between 2016 and 2018 due to lacking steroid response. VA prior to steroid administration, and before and after PLEX were assessed and compared using the Friedman multiple comparison test. Results: In total, 18 patients were included in the analysis. Interval from symptom onset to PLEX was 20.3 days (mean, 95% CI 14.8-25.9). Relevant functional improvement (VA of >= 0.5, after a mean of 15.9 (13.3-18.5) days after start of PLEX) was detected in 16/18 (88.9%) with a significant amelioration as compared to VA before glucocorticosteroids and before PLEX (p < 0.0001). VA improvement at a later time point (38.1 weeks, 25.2-51.0) was present in 15/16 (93.8%) patients. No serious adverse events were detected. PLEX could be performed via peripheral access in 13/18 patients (72.2%). Conclusion: Our study demonstrates significant improvements of VA with PLEX in a cohort of MS patients with steroid-refractory ON. High response rates may be due to the timely treatment initiation. Despite the small sample size, our data support the early use of PLEX in steroid-refractory ON with a favorable safety profile.

Background: Dimethyl fumarate (DMF) is licensed for treatment of relapsing–remitting multiple sclerosis (RRMS). DMF can induce lymphopenia, which is assumed to increase the risk for opportunistic infections like progressive multifocal leukoencephalopathy. Our goal for this work was to estimate the frequency of grade 3 lymphopenia in DMF-treated patients with RRMS and to characterize patient-sided factors influencing the time course of lymphocyte repopulation after DMF withdrawal. Material and methods: A single-center retrospective data analysis was performed at University Hospital Bern, Switzerland. Patients with DMF treatment were analyzed for lymphocyte counts. Demographic factors were statistically analyzed in grade 3 lymphopenic patients. Results: We estimated a grade 3 lymphopenia frequency of 11/246 (4.5%), corroborating previous studies. In all patients, lymphocytes recovered to values ⩾800/µl within 0.5 years. Multivariate linear regression analysis unmasked older age as being associated with a longer duration of repopulation. Conclusion: Considering the aging population, our findings warrant further investigations of DMF-induced lymphopenia.

Background: Anti-CD20 therapies are an emerging treatment strategy in multiple sclerosis (MS). Objective: Retrospective analysis of efficacy and safety in an MS cohort treated with rituximab (RTX) with identification of potential treatment response predictors. Methods: This retrospective study describes a monocentric cohort of 30 MS patients treated with RTX in a routine clinical setting. Patient characteristics, disease course, clinical and magnetic resonance imaging (MRI) treatment response markers, and laboratory assessments were analyzed. Logistic regression analysis corrected for demographic characteristics was used to identify treatment response predictors. Results: The RTX-treated cohort (mean age at RTX initiation 48 years (SD 14)) comprised patients with relapsing-remitting MS (n = 9), primary progressive MS (n = 11), and secondary progressive MS (n = 10). Two-thirds of patients had at least one MS medication prior to RTX; 27.6% of patients improved on the Expanded Disability Status Scale during RTX, whereas 72.4% of patients were stable or worsened. Based on this classification, we identified the presence of gadolinium enhancement in MRI before RTX as a predictor of response (odds ratio (OR) 12.2, confidence interval (CI) 1.02–144.55). After receiver operating characteristic curve definition of immunoglobulin (Ig) class cutoffs and creation of a sum score, the latter also predicted RTX response (OR 5.15, CI 1.21–21.88). Infectious complications were seen in three patients under RTX treatment. Conclusion: With the limitation of the retrospective approach and small sample size, this study confirms gadolinium enhancement before treatment initiation as a predictor of anti-CD20 response in MS. Lower Ig levels were associated with RTX response; however, these will have to be further investigated for a potential role for infectious complications.

SummaryIntroductionMultiple sclerosis (MS) is an autoimmune disease of the CNS, which predominantly affects women. Studies investigating the sex distribution in MS are sparse. We aim to analyze the female‐to‐male ratio (F/M ratio) in different MS phenotypes in association with age at diagnosis and year of birth.MethodsWe performed a retrospective cross‐sectional analysis by cumulating data (sex, year of birth, age at diagnosis, and MS phenotypes) from unpublished and published studies of the participating centers.ResultsDatasets of 945 patients were collected. The overall F/M ratio was 1.9:1.0 and female preponderance was present in all phenotypes except for primary progressive MS (PPMS), in which men were predominantly affected (F/M ratio: 0.5:1.0). Female preponderance declined with increasing age at diagnosis and was no longer present in relapsing‐remitting MS (RRMS) patients > 58 years of age.ConclusionOur data demonstrate an age dependency of female preponderance in MS except for PPMS. This could be influenced by the lifecycle of sex hormone secretion in women. In PPMS, a male preponderance was observed in all age‐groups, which might point to pathophysiological mechanisms being less influenced by sex hormones.

Introduction Substantial evidence has indicated an association between hypogonadism and depressive symptoms, which led to the conduction of studies that found an ameliorating effect of testosterone (T) supplementation (S) upon depression in men. Methods Retrospective analysis of medical records identified 16 depressed, hypogonadal men who have not responded adequately to initial antidepressant therapy and subsequently received intramuscular T injections. Following the proposal of Button et al., a minimal clinically important difference was defined as an 18% reduction of the Beck Depression Inventory-II (BDI-II) score. Results After TS, the BDI-II score decreased by approximately 31% (p<0.01), from 27.2 (mean; standard deviation [SD] 11.8) to 18.8 (mean; SD 11.3). Patients with baseline BDI-II scores ranging from 29 to 63 (severe depression) showed a significantly higher absolute and relative reduction through TS. Also, men with a shorter depression duration (<2 years) demonstrated a greater benefit. Conclusions The depressed, hypogonadal men generally benefited from TS given that the BDI-II score reduction was almost twice as much as needed for a minimal clinically important difference.

Fingolimod (FTY) is approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Two case series1, 2 have reported that FTY cessation can cause rebound of MS disease activity. The underlying mechanism is elusive but may include a prompt repopulation of immune cells, which is also supported by preclinical studies.3, 4 Magnitude and phenotype of the rebound phenomenon are still under investigation. We therefore aimed to evaluate the frequency and clinical characteristics of rebounds in an independent cohort of patients with MS. The retrospective analysis was approved by the Cantonal Ethics Committee (KEK 2017-01369). Patients with RRMS who discontinued FTY between 01/2013 and 06/2017 were identified by retrospective chart analysis (Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland). The assessment of MS rebound followed previous definitions (combination of new neurological symptoms after cessation of FTY treatment and the development of multiple new or enhancing lesions exceeding baseline activity).1 Data from our patient group were also pooled with those from all other published cohort studies.1, 2 Articles, which only include patients with FTY rebound in terms of case reports or case series, were excluded to not overestimate rebound frequency. Data are presented as mean (95% confidence interval (95% CI)). Of 91 patients with RRMS, 29 stopped FTY treatment between 01/2013 and 06/2017. From the 29 patients who discontinued FTY, 10 of 29 patients stopped treatment due to disease activity and 2 of 10 had a disease rebound. From the 19 of 29 patients discontinuing for other reasons such as cardiac side effects (2/29), unspecific side effects (5/29), neoplasia (2/29), planned pregnancy (3/29), lymphopenia (3/29), increased liver enzymes (2/29), patients' preference (2/29), only one patient presented with a rebound. This single patient had stopped FTY because of patients' preference to switch to another treatment. In general, a rebound occurred in 3 of these 29 patients (Table 1). Data were then pooled with two other cohort studies (San Francisco: 5/46 (1), Istanbul: 4/28 (2); Table 1). This resulted in an overall MS rebound frequency of 11.7% (95% CI: 5.4-18.0, 12/103). In our cohort, rebounds were polysymptomatic with 2.4 (mean, 95% CI: 1.8-2.9; n = 12) new symptoms. Motor weakness was the most frequent deficit (6/12), followed by sensory deficits (5/12) and encephalopathy/fatigue (4/12). On average, 13 (95% CI: 4-20, n = 9; information missing in 3 cases in2) new gadolinium (Gd)-positive lesions were present on cranial MRI. Rebounds occurred 7.8 weeks (mean, 95% CI: 5.7-10.0, n = 12) after stop of FTY (Bern: 8 (0.6-16.6); Istanbul 8 (2.8-13.2); San Francisco 7.6 (2.5-12.7) (1, 2)). Breast cancer Brainstem relapse In our MS cohort, FTY rebounds occurred in approximately 10% of the patients, which is in line with previously published studies, also mirrored in the pooled data.1, 2 Rebounds occurred earlier than described for natalizumab (8-24 weeks),1 which may at least in part be associated with shorter half-life of FTY (6-9 days) vs natalizumab (12-20 days).5, 6 Different studies argue for a true rebound rather than a reoccurrence of MS relapse. Thus, phenotype of FTY relapse appears to be more aggressive with polysymptomatic presentation, whereas literature data suggests that the majority of MS relapses are monosymptomatic.7 Also, encephalopathy is not frequently encountered as MS relapse. This clinical severity was paralleled by a high number of Gd-enhancing lesions. Limitations of our study are the retrospective design, the different data presentation of MS patients with rebound and the missing clinical data of the patients without rebounds presented in,1, 2 which prohibits further detailed analysis. In conclusion, our retrospective study points to the risk of a disease rebound after cessation of FTY, which appears to be relatively frequent and possibly severe. Further research is warranted on underlying mechanisms as well as potential epidemiological characteristics or biomarkers of this phenomenon that could guide safe discontinuation. Furthermore, given that several S1P modulators with different pharmacological properties (eg, half-life, lymphocyte recovery and S1P receptor specificity) are under development, such data may aid in benefit risk assessment. Evangelopoulos ME has received travel grants and consulting fees from Biogen, Novartis, Teva, Genzyme and Merk. Miclea A reports no disclosures. Schrewe L received travel grants from Genzyme Sanofi. Briner M received travel grants from Merck. Salmen A received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche and Sanofi Genzyme, none related to this work. Engelhardt B reports no disclosures. Huwiler A reports no disclosures. She receives research support from the Swiss National Science Foundation (no. 310030_175561/1). Chan A has received personal compensation for activities with Bayer, Biogen, Genzyme, Merck, Novartis, Roche, Teva. He receives research support from the Swiss National Fonds (SNF, No. 310030_172952), Genzyme, and UCB. He serves in the editorial board for Clinical and Translational Neuroscience and the Journal of International Medical Research. Hoepner R received research and travel grants from Novartis and Biogen Idec. He also received speaker's honoraria from Biogen, Novartis, Merk, and Almirall.

In acute lymphoblastic leukemia (ALL), steroid resistance and hypovitaminosis D are both associated with a poor prognosis. We show that methylprednisolone, calcitriol and the AKT-inhibitor MK-2206 have a synergistic effect on the apoptosis of steroid resistant T-ALL cells. Compared to methylprednisolone monotherapy, calcitriol increases methylprednisolone induced apoptosis dose-dependently (1.37–1.92-fold; p < 0.05). Pre-incubation with calcitriol increases the apoptotic effect of MK-2206 even further (3.6-fold; p < 0.05). It also potentiates synergism between MK-2206 and methylprednisolone (vehicle control 38% vs. calcitriol 58%, p < 0.01). The combination of calcitriol and AKT inhibition should be investigated further as treatment options for steroid resistance in T-ALL.

Low ultraviolet‐B (UVB) radiation causes hypovitaminosis D, which is a known risk factor for multiple sclerosis (MS) and associated with MS disease activity. Our objective is to test whether vitamin D supplementation is most effective in lowering disease activity during the period of the year with low UVB radiation and consequently low serum 25‐hydroxyvitamin D3 (25(OH)D3) concentration.