Different lymphocyte counts of multiple sclerosis patients treated with ofatumumab and ocrelizumab: A retrospective observational study.

Introduction: Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA) show a reduction mainly of B-lymphocytes, but also other lymphocyte subsets can be affected by these treatments. There is limited data on differences between lymphocyte subset counts of pwMS after treatment initiation with OCR or OFA. Objective: To compare lymphocyte subset counts after treatment initiation in pwMS treated with OCR and OFA. Methods: We analyzed 22 pwMS initiated on OFA and 56 sex-, age- and MS course matched pwMS initiated on OCR from 2 prospectively collected observational MS databases (Bern [n: OFA 14, OCR 44] and Vienna [n: OFA 8, OCR 12]) statistically comparing lymphocyte subset counts (Mann Whitney Test). Results: We found that pwMS treated with OCR showed a stronger reduction of CD20 B-lymphocytes (P = .001), and a trend towards lower counts of CD8+ T cells (P = .056) compared to pwMS treated with OFA, whereas reduction of total lymphocyte, CD4+ lymphocyte and NK cell count was equally distributed between both treatments. Conclusion: Different effects on lymphocyte subpopulations appear to be present in pwMS after treatment initiation with different anti-CD20 mAbs. Further studies are needed to determine potential effects on anti-CD20 treatment efficacy as well as treatment associated risks such as failed vaccinations and infections.

Sex differences in multiple sclerosis relapse presentation and outcome: a retrospective, monocentric study of 134 relapse events.

Background: Reporting of sex-specific analyses in multiple sclerosis (MS) is sparse. Disability accrual results from relapses (relapse-associated worsening) and independent thereof (progression independent of relapses). Objectives: A population of MS patients during relapse treated per standard of care was analyzed for sex differences and short-term relapse outcome (3-6 months) as measured by Expanded Disability Status Scale (EDSS) change. Design: Single-center retrospective study. Methods: We analyzed 134 MS relapses between March 2016 and August 2020. All events required relapse treatment (steroids and/or plasma exchange). Demographic, disease, and paraclinical characteristics [cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI)] were displayed separated by sex. Multivariable linear regression was run to identify factors associated with short-term EDSS change. Results: Mean age at relapse was 38.4 years (95% confidence interval: 36.3-40.4) with a proportion of 71.6% women in our cohort. Smoking was more than twice as prevalent in men (65.8%) than women (32.3%). In- and after-relapse EDSSs were higher in men [men: 3.3 (2.8-3.9), women: 2.7 (2.4-3.0); men: 3.0 (1.3-3.6); women: 1.8 (1.5-2.1)] despite similar relapse intervention. Paraclinical parameters revealed no sex differences. Our primary model identified female sex, younger age, and higher EDSS at relapse to be associated with EDSS improvement. A higher immunoglobulin G (IgG) quotient (CSF/serum) was associated with poorer short-term outcome [mean days between first relapse treatment and last EDSS assessment 130.2 (79.3-181.0)]. Conclusion: Sex and gender differences are important in outcome analyses of MS relapses. Effective treatment regimens need to respect putative markers for a worse outcome to modify long-term prognosis such as clinical and demographic variables, complemented by intrathecal IgG synthesis. Prospective trials should be designed to address these differences and confirm our results.

An analysis of 134 acute relapses of multiple sclerosis reveal sex differences influencing recovery from relapse Sex-specific analyses are important in medicine, but more knowledge is still needed. Multiple sclerosis (MS) as an inflammatory disease of the brain and spinal cord mainly affects younger people who are at risk for development of disability. Disability may result from acute relapses of the disease that insufficiently recover. Our analysis aimed to assess sex differences with a special focus on the acute relapse and 3 to 6 months later on average. We collected existing data from our center and identified 134 relapse events with sufficient data for further analysis. All relapses were treated with medical (high-dose steroids) and/or interventional treatment (plasma exchange). We analyzed the influence of sex, age, smoking, relapse severity, relapse treatment and other treatment (immunotherapy) for MS. In a second analysis, cerebrospinal fluid (CSF) and imaging (MRI) parameters were included. Our cohort consisted of 72% women. The mean age was 38 years. Smoking was twice as common in men (66%) than in women (32%). Men also experienced more severe disability in and after the relapse. Several other factors were similar between men and women. Female sex and younger age were associated with lower disability after a relapse. Paradoxically, also higher disability in the relapse was associated with lower disability later on. This might be a statistical phenomenon and partly explained by overall low disability levels in our analysis. It might therefore not be true for more advanced disease stages with higher disability. The presence of a certain CSF marker (intrathecal IgG synthesis) was associated with higher disability after the relapse. Our analysis thus identified markers associated with different relapse recovery, male vs. female sex being one of them.

Anti-kelchlike protein 11 antibody-associated encephalitis: Two case reports and review of the literature.

BACKGROUND AND PURPOSE: Kelchlike protein 11 antibodies (KLHL11-IgGs) were first described in 2019 as a marker of paraneoplastic neurological syndromes (PNSs). They have mostly been associated with testicular germ cell tumors (tGCTs). METHODS: Two patients with KLHL11-IgG encephalitis are reported, and the literature is comprehensively reviewed. RESULTS: Patient 1 had been in remission from a tGCT 10 years prior. He developed episodic vertigo and diplopia progressing over a few days. Treatment with corticosteroids (CSs) was started a few days after symptom onset. Patient 2 had transient diplopia, which resolved spontaneously. Visual problems persisted for 7 months, when he additionally developed a progressive cerebellar syndrome. One year after onset, CS treatment was started. Initial magnetic resonance imaging was unremarkable in both patients, but analysis of cerebrospinal fluid (CSF) revealed chronic inflammation. KLHL11-IgG was positive in both patients (Patient 1 only in CSF, Patient 2 in serum). Neoplastic screening has so far not revealed any signs of active underlying malignancy. We found 15 publications of 112 patients in total with KLHL11-IgG encephalitis. Most patients (n = 82) had a cerebellar syndrome with or without signs of rhombencephalitis. The most common symptoms were ataxia (n = 82) and vertigo (n = 47), followed by oculomotor disturbances (n = 35) and hearing disorders (n = 31). Eighty of 84 patients had a GCT as an underlying tumor. CONCLUSIONS: Our cases demonstrate classical symptoms of KLHL11-IgG encephalitis. Early diagnosis and therapy are imperative. As with other PNSs, clinical awareness is needed and further studies are required especially in regard to therapeutic management.

Anti-neurochondrin antibody as a biomarker in primary autoimmune cerebellar ataxia-a case report and review of the literature.

BACKGROUND AND PURPOSE: Neuronal autoantibodies can support the diagnosis of primary autoimmune cerebellar ataxia (PACA). Knowledge of PACA is still sparce. This article aims to highlight the relevance of anti-neurochondrin antibodies and possible therapeutical consequences in people with PACA. METHODS: This is a case presentation and literature review of PACA associated with anti-neurochondrin antibodies. RESULTS: A 33-year-old man noticed reduced control of the right leg in May 2020. During his first clinic appointment at our institution in September 2021, he complained about gait imbalance, fine motor disorders, tremor, intermittent diplopia and slurred speech. He presented a pancerebellar syndrome with stance, gait and limb ataxia, scanning speech and oculomotor dysfunction. Within 3 months the symptoms progressed. An initial cerebral magnetic resonance imaging, June 2020, was normal, but follow-up imaging in October 2021 and July 2022 revealed marked cerebellar atrophy (29% volume loss). Cerebrospinal fluid analysis showed lymphocytic pleocytosis of 11 x 103 /L (normal range 0-4) and oligoclonal bands type II. Anti-neurochondrin antibodies (immunoglobulin G) were detected in serum (1:10,000) and cerebrospinal fluid (1:320, by cell-based indirect immunofluorescence assay and immunoblot, analysed by the EUROIMMUN laboratory). After ruling out alternative causes and neoplasia, diagnosis of PACA was given and immunotherapy (steroids and cyclophosphamide) was started in January 2022. In March 2022 a stabilization of disease was observed. CONCLUSION: Cerebellar ataxia associated with anti-neurochondrin antibodies has only been described in 19 cases; however, the number of unrecognized PACAs may be higher. As anti-neurochondrin antibodies target an intracellular antigen and exhibit a mainly cytotoxic T-cell-mediated pathogenesis, important therapeutic implications may result. Because of the severe and rapid clinical progression, aggressive immunotherapy was warranted. This case highlights the need for rapid diagnosis and therapy in PACA, as stabilization and even improvement of symptoms are attainable.

Leptomeningeal enhancement under different MS immunotherapies: A monocentric retrospective cohort study of 214 patients.

BACKGROUND: Leptomeningeal inflammation in patients with multiple sclerosis (MS) mainly affects meningeal B-cell follicle-like structures linked to cortical and subpial lesions and can be visualized as leptomeningeal enhancement (LME). OBJECTIVE: To evaluate the evolution of LME under different MS immunotherapies. METHODS: A total of 214 MS patients treated with anti-CD20 therapies or fingolimod at the university hospital Bern were screened for LME. Magnetic resonance imaging (MRI) and medical records were retrospectively evaluated, and comparative statistics were applied. RESULTS: We compared MS patients treated with anti-CD20 therapies (128 patients (59.8%)) or fingolimod (86 patients (40.2%)). Of 128 anti-CD20-treated patients, 108 (84.4%) had no LME, 11 (8.6%) had persistent LME, and 9 (7.0%) showed resolution of LME. Of 86 fingolimod-treated MS patients, 81 (94.2%) had no LME and 5 (5.8%) persistent LME. Patients with LME persistence were older than those without or resolution of LME (p = 0.039). Resolution of LME was more frequent during anti-CD20 compared with fingolimod treatment (p = 0.019). CONCLUSION: We observed LME resolution under treatment with anti-CD20 therapies. As LME might play an important role in cerebral gray matter pathology in MS, further investigations including extensions to higher field strengths, correlation with clinical phenotypes, and comparison with other immunotherapies are needed.

Reliable brain morphometry from contrast-enhanced T1w-MRI in patients with multiple sclerosis.

Brain morphometry is usually based on non-enhanced (pre-contrast) T1-weighted MRI. However, such dedicated protocols are sometimes missing in clinical examinations. Instead, an image with a contrast agent is often available. Existing tools such as FreeSurfer yield unreliable results when applied to contrast-enhanced (CE) images. Consequently, these acquisitions are excluded from retrospective morphometry studies, which reduces the sample size. We hypothesize that deep learning (DL)-based morphometry methods can extract morphometric measures also from contrast-enhanced MRI. We have extended DL+DiReCT to cope with contrast-enhanced MRI. Training data for our DL-based model were enriched with non-enhanced and CE image pairs from the same session. The segmentations were derived with FreeSurfer from the non-enhanced image and used as ground truth for the coregistered CE image. A longitudinal dataset of patients with multiple sclerosis (MS), comprising relapsing remitting (RRMS) and primary progressive (PPMS) subgroups, was used for the evaluation. Global and regional cortical thickness derived from non-enhanced and CE images were contrasted to results from FreeSurfer. Correlation coefficients of global mean cortical thickness between non-enhanced and CE images were significantly larger with DL+DiReCT (r = 0.92) than with FreeSurfer (r = 0.75). When comparing the longitudinal atrophy rates between the two MS subgroups, the effect sizes between PPMS and RRMS were higher with DL+DiReCT both for non-enhanced (d = -0.304) and CE images (d = -0.169) than for FreeSurfer (non-enhanced d = -0.111, CE d = 0.085). In conclusion, brain morphometry can be derived reliably from contrast-enhanced MRI using DL-based morphometry tools, making additional cases available for analysis and potential future diagnostic morphometry tools.

Multiple sclerosis as a model to investigate SARS-CoV-2 effect on brain atrophy.

INTRODUCTION: Data on structural brain changes after infection with SARS-CoV-2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS-CoV-2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates. METHODS: Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre-SARS-CoV-2 images with age as an explanatory variable. The residuals were used to determine whether the post-SARS-CoV-2 volumes differed significantly from the baseline. RESULTS: Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS-CoV-2 for global gray matter volume (p = 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p = 0.0076), suggesting accelerated atrophy during or after infection. CONCLUSIONS: Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS-CoV-2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.

Multidimensional phenotyping of the post-COVID-19 syndrome: A Swiss survey study.

INTRODUCTION: Post-COVID-19 syndrome affects approximately 10-25% of people after a COVID-19 infection, irrespective of initial COVID-19 severity. The aim of this project was to assess the clinical characteristics, course, and prognosis of post-COVID-19 syndrome using a systematic multidimensional approach. PATIENTS AND METHODS: An online survey of people with suspected and confirmed COVID-19 and post-COVID-19 syndrome, distributed via Swiss COVID-19 support groups, social media, and our post-COVID-19 consultation, was performed. A total of 8 post-infectious domains were assessed with 120 questions. Data were collected from October 15 to December 12, 2021, and 309 participants were included. Analysis of clinical phenomenology of post-COVID-19 syndrome was performed using comparative statistics. RESULTS: The three most prevalent post-COVID-19 symptoms in our survey cohort were fatigue (288/309, 93.2%), pain including headache (218/309, 70.6%), and sleep-wake disturbances (mainly insomnia and excessive daytime sleepiness, 145/309, 46.9%). Post-COVID-19 syndrome had an impact on work ability, as more than half of the respondents (168/268, 62.7%) reported an inability to work, which lasted on average 26.6 weeks (95% CI 23.5-29.6, range 1-94, n = 168). Quality of life measured by WHO-5 Well-being Index was overall low in respondents with post-COVID-19 syndrome (mean, 95% CI 9.1 [8.5-9.8], range 1-25, n = 239). CONCLUSION: Fatigue, pain, and sleep-wake disturbances were the main symptoms of the post-COVID-19 syndrome in our cohort and had an impact on the quality of life and ability to work in a majority of patients. However, survey respondents reported a significant reduction in symptoms over 12 months. Post-COVID-19 syndrome remains a significant challenge. Further studies to characterize this syndrome and to explore therapeutic options are therefore urgently needed.

Comparison of mRNA Vaccinations with BNT162b2 or mRNA-1273 in Anti-CD20-Treated Multiple Sclerosis Patients.

Objective: Anti-CD20-treated patients are at risk of a reduced humoral immune response during the SARS-CoV-2 pandemic. Our aim was to compare the antibody response after two vaccinations with the mRNA vaccines BNT162b2 or mRNA-1273 in patients with multiple sclerosis. Methods: Data from the University Hospital of Bern and Cantonal Hospital of Lucerne were retrospectively collected from medical records and then analyzed. Anti-spike IgG serum titers were collected from both centers and were considered to be protective from a value of ≥100 AU/mL. Continuous variables were given as the mean and 95% confidence interval (95% CI); categorical variables were given as frequencies. A Mann-Whitney test and Fisher's exact test as well as a multivariable linear regression analysis with anti-spike IgG (AU/mL) as the dependent variable were run using SPSS Statistic 25 (IBM Corp., Amonk, NY, USA). Results: A total of 74 patients were included; 41/74 (63.51%) were female patients and the mean age was 46.6 years (95% CI 43.4-49.9). Of these patients, 36/74 were vaccinated with BNT162b2 and 38/74 with mRNA-1273, following the national vaccination recommendation. In both vaccine groups, protective anti-spike IgG titers (≥100 AU/mL) were infrequently achieved (5/74: mRNA-1273 3/38; BNT162b2 2/36). Conclusions: In addition to a low rate of protective anti-spike IgG titers in both vaccine groups, we identified a drop in anti-spike IgG serum titers over time. This observation bears therapeutic consequences, as initial positive titers should be checked in case of an infection with the SARS-CoV-2 virus to identify patients who would benefit from an intravenous anti-spike IgG treatment against acute COVID-19.

[Primary CNS Vasculitis - An Overview]. / Primäre ZNS-Vaskulitis.

Primary CNS Vasculitis - An Overview Abstract. Cerebral vasculitis, especially the primary vasculitis of the central nervous systems (primary CNS vasculitis), are rare inflammatory diseases of the small- and medium-sized vessels of the CNS. The pathogenesis of primary CNS vasculitis is unclear. Infectious triggers are hypothesized to induce an activation of the immune system with resulting inflammation of the blood vessels within the CNS. Clinically, primary CNS vasculitis presents heterogeneously with leading symptoms such as headache, memory impairment and other neurological deficits. A broad diagnostic work-up prior to treatment initiation is crucial. Treatment consists of immunotherapy (pulse and maintenance therapy) and requires long-term neurological treatment and follow-up due to the increased risk of recurrence of the disease.

Fatigue in Post-COVID-19 Syndrome: Clinical Phenomenology, Comorbidities and Association With Initial Course of COVID-19.

Introduction: Post-COVID-19 syndrome affects approximately 10-25% of people suffering from COVID-19 infection, irrespective of initial COVID-19 severity. Fatigue is one of the major symptoms, occurring in 30-90% of people with post-COVID-19 syndrome. This study aims at describing factors associated with fatigue in people with Post-COVID-19 seen in our newly established Post-Covid clinic. Methods: This retrospective single center study included 42 consecutive patients suffering from Post-COVID-19 syndrome treated at the Department of Neurology, University Hospital Bern, between 11/2020 and05/2021. Clinical phenomenology of Post-COVID-19 syndrome with a special focus on fatigue and risk factor identification was performed using Mann-Whitney U Test, Pearson Correlation, and Chi-Quadrat-Test. Results: Fatigue (90.5%) was the most prevalent Post-COVID-19 symptom followed by depressive mood (52.4%) and sleep disturbance (47.6%). Fatigue was in mean severe (Fatigue severity scale (FSS) mean 5.5 points (95% Confidence interval (95CI) 5.1 - 5.9, range .9 - 6.9, n = 40), and it was unrelated to age, COVID-19 severity or sex. The only related factors with fatigue severity were daytime sleepiness and depressed mood. Conclusion: Fatigue is the main symptom of the Post-COVID-19 syndrome in our cohort. Further studies describing this syndrome are needed to prepare the healthcare systems for the challenge of treating patients with Post-COVID-19 syndrome.

Application of the "risk of ambulatory disability" (RoAD) score in a "real-world" single-center multiple sclerosis cohort.

Survival analysis of reaching EDSS ≥4.0 based on RoAD score ≥4 (dashed line) and <4 (solid line) by Cox regression analysis. (A) Unadjusted regression analysis. (B) Regression controlled for sex and immunotherapy groups, and the trajectory of treatment changes during follow-up.

Predicting conversion to multiple sclerosis in patients with radiologically isolated syndrome: a retrospective study.

AIMS: To retrospectively analyse the Bernese radiologically isolated syndrome (RIS) cohort with the goal of developing a prediction score for conversion to multiple sclerosis (MS). METHODS: A total of 31 patients with RIS were identified by screening medical records of neurological patients seen at the University Hospital of Bern between 2004 and 2017 for the diagnoses 'radiologically isolated syndrome' and 'RIS' adhering to 2009 Okuda recommendations. We analysed clinical, paraclinical and magnetic resonance imaging data during a maximum follow-up period of 3 years and identified significant predictors of conversion to MS. RESULTS: Data were available for 31 patients meeting 2009 Okuda RIS criteria. During the 3 years of follow up, 5/31 RIS patients converted to relapsing-remitting (RR) MS. In our univariate analysis, gadolinium (Gd) enhancement, brainstem and cerebellar hemisphere lesions, immune cell count and albumin concentration in cerebrospinal fluid (CSF), and anti-nuclear antibody (ANA) positivity in serum were identified as significant predictors of conversion to MS. Integrating these factors into our 'RIS-MS prediction score' enabled us to calculate a cut-off for prediction of conversion to MS within 3 years with high specificity [1.0, 95% confidence interval (CI) 0.84-1.00) and acceptable sensitivity (0.6, 95% CI 0.17-0.93)]. CONCLUSION: Our RIS-MS prediction score, if validated in an independent cohort, integrating radiological (Gd enhancement, brainstem and cerebellar hemisphere lesions) and paraclinical factors (ANA in serum, cell count and albumin in CSF) could be a useful prognostic tool for early recognition of RIS patients with a high risk of clinical progression to MS.

Vaccine Hesitancy in Patients With Multiple Sclerosis: Preparing for the SARS-CoV-2 Vaccination Challenge.

OBJECTIVE: Vaccine hesitancy is a complex public health issue referring to concerns about safety, efficacy, or need for vaccination. Using pneumococcal vaccination, which is recommend in anti-CD20-treated multiple sclerosis (MS) patients, as a model, we assessed vaccination behavior in patients with MS to prepare for the upcoming SARS-CoV-2 vaccination challenge. METHODS: By a medical chart review, we retrospectively identified patients with MS treated with ocrelizumab at the University Hospital Bern in 2018-2020. Pneumococcal vaccination was discussed with the patients during clinical visits and highlighted in the after-visit summary addressed to the general practitioner before ocrelizumab initiation as part of our clinical standard of care. RESULTS: Pneumococcal vaccination was performed in 71/121 (58.7%) of patients, and 50/121 (41.3%) patients were not vaccinated. Patients who did not get a pneumococcal vaccination were younger (no vaccination vs vaccination; mean [95% CI] 40.1 [36.1-44.1] vs 45.4 [41.9-48.8], p = 0.028) and had more frequently a relapsing remitting disease course (no vaccination vs vaccination, n [%]; 43/50 [86.0%] vs 49/71 [69.0%], p = 0.031). Furthermore, patients who did not get vaccination had more frequently a history of comorbid psychiatric disorder (no vaccination vs vaccination, n (%); 12/50 [24.0] vs 7/71 [9.8], p = 0.035). CONCLUSION: Our study demonstrated that in our single-center cohort, 41.3% of patients with MS do not get the recommended pneumococcal vaccination. Future research should focus on vaccine hesitancy in the vulnerable cohort of patients with MS to improve the safety of MS immunotherapies.

Evaluation of diagnostic criteria and red flags of myelin oligodendrocyte glycoprotein encephalomyelitis in a clinical routine cohort.

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.

Automatic detection of lesion load change in Multiple Sclerosis using convolutional neural networks with segmentation confidence.

The detection of new or enlarged white-matter lesions is a vital task in the monitoring of patients undergoing disease-modifying treatment for multiple sclerosis. However, the definition of 'new or enlarged' is not fixed, and it is known that lesion-counting is highly subjective, with high degree of inter- and intra-rater variability. Automated methods for lesion quantification, if accurate enough, hold the potential to make the detection of new and enlarged lesions consistent and repeatable. However, the majority of lesion segmentation algorithms are not evaluated for their ability to separate radiologically progressive from radiologically stable patients, despite this being a pressing clinical use-case. In this paper, we explore the ability of a deep learning segmentation classifier to separate stable from progressive patients by lesion volume and lesion count, and find that neither measure provides a good separation. Instead, we propose a method for identifying lesion changes of high certainty, and establish on an internal dataset of longitudinal multiple sclerosis cases that this method is able to separate progressive from stable time-points with a very high level of discrimination (AUC = 0.999), while changes in lesion volume are much less able to perform this separation (AUC = 0.71). Validation of the method on two external datasets confirms that the method is able to generalize beyond the setting in which it was trained, achieving an accuracies of 75 % and 85 % in separating stable and progressive time-points.

Reduced serum immunoglobulin G concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course.

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.

Time course of lymphocyte repopulation after dimethyl fumarate-induced grade 3 lymphopenia: contribution of patient age.

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.