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Segmentation of white matter lesions and deep grey matter structures is an important task in the quantification of magnetic resonance imaging in multiple sclerosis. In this paper we explore segmentation solutions based on convolutional neural networks (CNNs) for providing fast, reliable segmentations of lesions and grey-matter structures in multi-modal MR imaging, and the performance of these methods when applied to out-of-centre data. We trained two state-of-the-art fully convolutional CNN architectures on the 2016 MSSEG training dataset, which was annotated by seven independent human raters: a reference implementation of a 3D Unet, and a more recently proposed 3D-to-2D architecture (DeepSCAN). We then retrained those methods on a larger dataset from a single centre, with and without labels for other brain structures. We quantified changes in performance owing to dataset shift, and changes in performance by adding the additional brain-structure labels. We also compared performance with freely available reference methods. Both fully-convolutional CNN methods substantially outperform other approaches in the literature when trained and evaluated in cross-validation on the MSSEG dataset, showing agreement with human raters in the range of human inter-rater variability. Both architectures showed drops in performance when trained on single-centre data and tested on the MSSEG dataset. When trained with the addition of weak anatomical labels derived from Freesurfer, the performance of the 3D Unet degraded, while the performance of the DeepSCAN net improved. Overall, the DeepSCAN network predicting both lesion and anatomical labels was the best-performing network examined.

BackgroundMyelin oligodendrocyte glycoprotein immunoglobulin G associated optic neuritis (MOG-ON) is a recently described entity. Recent studies have shown that MOG-ON has a more severe clinical presentation than classic optic neuritis (ON). ObjectiveThis study aimed to define morphological characteristics of MOG-ON, correlate these with clinical characteristics and compare them with multiple sclerosis associated ON (MS-ON) and healthy controls (CTRL).MethodsIn a retrospective study, we included MOG-ON and MS-ON patients seen between 2011 and 2018 at the University Hospital Bern. Data from clinical examination, perimetry, and optical coherence tomography (OCT) were analyzed.ResultsA total of 66 eyes of 43 patients were included; 22 MS-ON and 33 CTRL eyes were sex- and age-matched to 11 MOG-ON eyes. We found significantly worse visual acuity at nadir, but better recovery and thinner global peripapillary retinal nerve fiber layer thickness in MOG-ON patients compared to MS-ON patients. Both groups exhibited irregular thinning of the macular ganglion cell layer. Furthermore, the visual acuity and visual field parameters correlated to retinal layer thickness only in MOG-ON eyes.ConclusionIn comparison to MS-ON, MOG-ON is associated with more prominent acute vision loss and more pronounced global thinning of the pRNFL. Both entities result in similar final visual acuity and atrophy of the macular ganglion cell layer.

Multiple sclerosis (MS) is a complex chronic neuroinflammatory disease characterized by demyelination leading to neuronal dysfunction and neurodegeneration manifested by various neurological impairments. The endocannabinoid system (ECS) is a lipid signalling network, which plays multiple roles in the central nervous system and the periphery, including synaptic signal transmission and modulation of inflammation. The ECS has been identified as a potential target for the development of novel therapeutic interventions in MS patients. It remains unclear whether ECS-associated metabolites are changed in MS and could serve as biomarkers in blood or cerebrospinal fluid (CSF). In this retrospective study we applied targeted lipidomics to matching CSF and serum samples of 74 MS and 80 non-neuroinflammatory control patients. We found that MS-associated lipidomic changes overall did not coincide between CSF and serum. While glucocorticoids correlated positively, only the endocannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) showed a weak positive correlation ( r  = 0.3, p  < 0.05) between CSF and serum. Peptide endocannabinoids could be quantified for the first time in CSF but did not differ between MS and controls. MS patients showed elevated levels of prostaglandin E2 and steaorylethanolamide in serum, and 2-oleoylglycerol and cortisol in CSF. Sex-specific differences were found in CSF of MS patients showing increased levels of 2-AG and glucocorticoids in males only. Overall, arachidonic acid was elevated in CSF of males. Interestingly, CSF eCBs correlated positively with age only in the control patients due to the increased levels of eCBs in young relapsing-remitting MS patients. Our findings reveal significant discrepancies between CSF and serum, underscoring that measuring eCBs in blood matrices is not optimal for detecting MS-associated changes in the central nervous system. The identified sex and age-specific changes of analytes of the stress axis and ECS specifically in the CSF of MS patients supports the role of the ECS in MS and may be relevant for drug development strategies.

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. Plain language summary 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.

High-resolution optical coherence tomography (OCT) allows the detection of macular pathology and involvement of the optic nerve in a wide spectrum of diseases. For the differentiation of diseased and healthy status, normal values of retinal layer segmentation are critical. Yet, normative values mostly cover adult populations with only sparse data for paediatric cohorts. We present data of retinal layer characteristics via OCT in a healthy paediatric cohort. This prospective cross-sectional study screened 75 healthy children (male = 42, female = 33, range 4-17 years) without visual problems. OCT was performed with a peripapillary ring and macula scan protocol to determine paediatric normative values for routine parameters (peripapillary retinal nerve fibre layer thickness (pRNFL), total macular volume (TMV), macular retinal thickness (RT)). The macula scan (6mm grid) was segmented using the device-inherent automated segmentation software (Heidelberg Eye Explorer) for retinal layers: RNFL, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL) in 9 segments each and mean of the 9 segments. We obtained OCT data of 72 children with mean age 12.49 years (standard deviation, SD, 2.18; minimum 3.93). Mean global pRNFL was 102.20 [mu]m (SD 8.24), mean TMV 8.81 mm.sup.3 (0.30) and mean RT (all segments) 318.22 [mu]m (10.19). Segmented macular retinal layer thicknesses (mean of all segments) were: RNFL 27.67 [mu]m (2.14), GCL 41.94 [mu]m (2.50), IPL 34.97 [mu]m (2.10), INL 35.18 [mu]m (2.15), OPL 29.06 [mu]m (2.24), ONL 68.35 [mu]m (6.20). The OCT is a useful non-invasive imaging technique for the examination of the retina in children with short duration, high imaging resolution and no known adverse effects. Normative values may serve as a comparator for different neuropaediatric disorders and are first presented with this study using an up-to-date and standardized OCT imaging technique.

Improving health-related quality of life (HRQoL) is an important disease management goal in persons with Multiple Sclerosis (PwMS). HRQoL decreases with increasing age and prolonged disease duration; other factors remain less understood. To identify associations of multiple sclerosis (MS) disease characteristics and symptom burden with low HRQoL. Using the Swiss MS Registry, we applied quantile regression adjusted for age and MS disease duration to determine 25th (low HRQoL) and 75th (high HRQoL) percentiles of the EuroQol-5-Dimension (EQ-5D) distribution for PwMS. We compared PwMS across HRQoL groups by analyzing differences in sociodemographics, symptom burden, MS risk factors, gait impairment, and the MS Severity Score (MSSS), all measured at the same time as HRQoL. The analyses included descriptive methods, multivariable multinomial regression, and simultaneous quantile regression as a sensitivity analysis. We included 1697 PwMS with median age and time-to-diagnosis of 49 and 9 years. Multivariable regression revealed low HRQoL to be associated with receiving invalidity insurance benefits, reporting depression, muscle weakness, memory problems, pain, and severe gait impairment. The analysis for individuals with available MSSS (n = 937) showed an increasing probability of low HRQoL with higher MSSS. Our segmentation method identified symptom burden and MS severity as factors associated with low HRQoL. Pharmacological and non-pharmacological MS symptom management, especially for depression, fatigue, pain, and muscle weakness, may warrant increased attention to preserve or improve HRQoL.

Background: With the development of highly effective disease-modifying treatments, vaccinations are becoming increasingly important in people with neurological autoimmune diseases. However, questions regarding the safety and efficacy of vaccinations under immunotherapy remain. Objective: To provide recommendations on types and timing of vaccinations for people with neuroimmunological diseases under different immunotherapies. Design: Our study presents a German evidence-based expert consensus on vaccination under immunotherapies in neurological autoimmune diseases. Methods: Based on literature research, a consortium of experts evaluated the quality of evidence, integrated clinical experience, and responded to a questionnaire determining an agreement (>75%) on statements concerning vaccination upon immune therapies in neuroimmunological diseases. Results: The specific humoral and cellular response to vaccination can be compromised under alemtuzumab, azathioprine, cladribine, cyclophosphamide, CD19/CD20 antibodies (inebilizumab, ocrelizumab, ofatumumab, rituximab, ublituximab), dimethyl fumarate/diroximel fumarate, FcRn inhibitors (efgartigimod, rozanolixizumab), complement C5 inhibitors (eculizumab, ravulizumab, zilucoplan), interleukin-6 receptor antibodies (tocilizumab, satralizumab), intravenous immunoglobulins, long-term steroid administration, methotrexate, mitoxantrone, mycophenolate mofetil, tacrolimus, teriflunomide, tumor necrosis factor-α blockers, and sphingosine-1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, siponimod), as well as after autologous stem cell transplantation. The lymphocyte count can have an influence here. Overall, it is generally advisable to complete vaccination before starting immunotherapy. However, in the case of an active inflammatory disease course with possible irreversible neurological deficits, a delay in therapy initiation until immunization has been completed cannot be justified. The application of live vaccines is contraindicated for most therapies and is only recommended after a strict risk–benefit assessment. Conclusion: Vaccinations are necessary for individuals on immunotherapy to reduce the risk of infections and the associated risk of worsening neurological autoimmune diseases. However, the humoral and cellular vaccination response may be impaired under immunotherapy necessitating close monitoring. Here, we provide applicable recommendations to optimize immunization for individuals receiving immunotherapy due to a neurological autoimmune disease. Plain language summary Cell- and antibody-mediated vaccination response under immunotherapies—German consensus on vaccination strategies in neurological autoimmune diseases Aims and purpose of the research: Based on currently available literature on vaccination in people receiving treatment for a neurological autoimmune disease, a group of experts generated recommendations on how to handle vaccination in people receiving immunotherapy. Background of the research: Medications used in treating autoimmune diseases may create a risk for patients due to reduced immune defence and impact on vaccination success. Protection against the respective pathogen may be reduced under different immunotherapies despite formally completed immunization. This may result in the need for repeated vaccination or special protective measures against infections. Methods and research design: Based on a thorough literature search, a consortium of experts generated applicable recommendations and consented on these via a questionnaire. Results and importance: The vaccination response is evaluated under alemtuzumab, azathioprine, cladribine, cyclophosphamide, CD19/CD20 antibodies (inebilizumab, ocrelizumab, ofatumuab, rituximab, and ublituximab), dimethyl fumarate/diroximel fumarate, FcRn inhibitors (efgartigimod and rozanolixizumab), complement C5 inhibitors (eculizumab, ravulizumab and zilucoplan), interleukin-6 receptor antibodies (tocilizumab, satralizumab), intravenous immunoglobulins, long-term steroid administration, methotrexate, mitoxantrone, mycophenolate mofetil, tacrolimus, teriflunomide, tumor necrosis factor-α blockers and sphingosine-1-phosphate receptor modulators (fingolimod, ozanimod, ponesiomd and siponimod), as well as after autologous stem cell transplantation. The white blood cell count can have an influence on the vaccination response. Overall, it is generally advisable to complete vaccination before starting immunotherapy. However, in the case of an active course of the disease with possible irreversible neurological deficits, a delay in the start of therapy until immunization has been completed cannot be justified. The application of live vaccines is contraindicated for most therapies and is only recommended after a strict risk-benefit assessment. Conclusion:Vaccinations are necessary for individuals receiving immunotherapy to reduce the risk of infections and the associated risk of worsening neurological autoimmune diseases. However, the antibody- and cell-mediated vaccination response may be impaired under immunotherapy, thus necessitating close monitoring.

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.

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.

BackgroundAs the average age of multiple sclerosis (MS) population rises globally, unclear guidelines on disease-modifying therapy (DMT) use in older persons with MS (pwMS) contribute to increased variability in clinical practice. The factors driving DMT utilisation in this population are not well understood. We explored DMT utilisation patterns in pwMS aged 55 and older enrolled in the Swiss MS Registry (SMSR), a nationwide observational study with voluntary participation.MethodsWe conducted an exploratory analysis using data from SMSR participants who had reported DMT status in the most recent follow-up survey and at least once within the previous 3 years. Participants were categorised and compared by current and past DMT use: No DMT (no use), Stopped (prior use), Continued (same DMT), Switcher (changed DMT) and New (initiated DMT). Log-binomial regression identified factors associated with non-use, grouping participants as No DMT (No DMT, Stopped) and DMT (Continued, Switcher, New).ResultsAmong 378 participants (mean age 63.2±6.7 years), 206 (54.5%) reported DMT use: 176 (46.6%) continued the same DMT, 20 (5.3%) switched and 10 (2.6%) newly initiated DMT. Among non-users, 54 (14.3%) had stopped treatment, while the rest did not use DMT during the study period. In participants with regular neurological care, longer MS duration (relative risk (RR)=1.018, 95% CI 1.008 to 1.028) and older age (RR=1.016, 95% CI: 1.001 to 1.032) were associated with higher likelihood of DMT non-use, and participants with primary (RR=1.736, 95% CI: 1.175 to 2.565) and secondary progressive MS (RR=1.423, 95% CI: 1.023 to 1.981) were more likely not to use DMTs compared with relapsing-remitting MS. No significant associations were observed in participants without regular neurological follow-up.ConclusionsDespite unclear efficacy and safety, many older pwMS continue DMT use. Use is primarily associated with relapsing-remitting MS, while age and disease duration show only modest or no association.