Publications by authors named "Anke Salmen"

55 Publications

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

Ther Adv Neurol Disord 2021 16;14:17562864211030664. Epub 2021 Jul 16.

Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.

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.
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http://dx.doi.org/10.1177/17562864211030664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287642PMC
July 2021

Immunotherapies and COVID-19 mortality: a multidisciplinary open data analysis based on FDA's Adverse Event Reporting System.

Ann Rheum Dis 2021 Jul 20. Epub 2021 Jul 20.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

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http://dx.doi.org/10.1136/annrheumdis-2021-220679DOI Listing
July 2021

An algorithm using clinical data to predict the optimal individual glucocorticoid dosage to treat multiple sclerosis relapses.

Ther Adv Neurol Disord 2021 17;14:17562864211020074. Epub 2021 Jun 17.

Department of Neurology, University Hospital Bern, Inselspital, Bern, Switzerland.

Background: Glucocorticoid (GC) pulse therapy is used for multiple sclerosis (MS) relapse treatment; however, GC resistance is a common problem. Considering that GC dosing is individual with several response-influencing factors, establishing a predictive model, which supports clinicians to estimate the maximum GC dose above which no additional therapeutic value can be expected presents a huge clinical need.

Method: We established two, independent retrospective cohorts of MS patients. The first was an explorative cohort for model generation, while the second was established for its validation. Using the explorative cohort, a multivariate regression analysis with the GC dose used as the dependent variable and serum vitamin D (25D) concentration, sex, age, EDSS, contrast enhancement on cranial magnetic resonance imaging (MRI), immune therapy, and the involvement of the optic nerve as independent variables was established.

Results: In the explorative cohort, 113 MS patients were included. 25-hydroxyvitamin D (25D) serum concentration and the presence of optic neuritis were independent predictors of the GC dose needed to treat MS relapses [(25D): -25.95 (95% confidence interval (CI)): -47.40 to -4.49;  = 0.018; optic neuritis: 2040.51 (95% CI: 584.64-3496.36),  = 0.006]. Validation of the multivariate linear regression model was performed within a second cohort. Here, the predicted GC dose did not differ significantly from the dose administered in clinical routine (mean difference: -843.54; 95% CI: -2078.08-391.00;  = 30,  = 0.173).

Conclusion: Our model could predict the GC dose given in clinical, routine MS relapse care, above which clinicians estimate no further benefit. Further studies should validate and improve our algorithm to help the implementation of predictive models in GC dosing.
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http://dx.doi.org/10.1177/17562864211020074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216377PMC
June 2021

The Effect of Depression on Health-Related Quality of Life Is Mediated by Fatigue in Persons with Multiple Sclerosis.

Brain Sci 2021 Jun 5;11(6). Epub 2021 Jun 5.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich (UZH), 8001 Zurich, Switzerland.

The interrelations between fatigue, depression and health-related quality of life (HRQoL) in persons with multiple sclerosis (PwMS) are complex, and the directionality of the effects is unclear. To address this gap, the current study used a longitudinal design to assess direct and indirect effects of fatigue and depression on HRQoL in a one-year follow-up survey. A sample of 210 PwMS from the nationwide Swiss MS Registry was used. HRQoL was assessed using the European Quality of Life 5-Dimension 5-Level questionnaire. Path analysis on HRQoL, with fatigue and depression as predictors, was applied. Fatigue was measured by the Modified Fatigue Impact Scale (MFIS), including physical, cognitive and psychosocial subscales, and non-somatic depressive symptomatology was examined with the Beck Depression Inventory-Fast Screen (BDI-FS). Fatigue acted as a fully mediating variable (B = -0.718, SE = 0.253) between non-somatic depressive symptomatology and HRQoL. This indirect effect became apparent in the physical (B = -0.624, SE = 0.250), psychosocial (B = -0.538, SE = 0.256) and cognitive subscales (B = -0.485, SE = 0.192) of fatigue. In contrast, non-somatic depressive symptomatology did not act as a mediator. Our findings provide novel and clinically relevant longitudinal evidence showing that the debilitating effect of non-somatic aspects of depression on HRQoL was fully mediated and therefore explainable via fatigue.
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http://dx.doi.org/10.3390/brainsci11060751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227168PMC
June 2021

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

Neurol Neuroimmunol Neuroinflamm 2021 05 2;8(3). Epub 2021 Apr 2.

From the Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Freiburgstrasse, Bern, Switzerland.

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], = 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%], = 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], = 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.
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http://dx.doi.org/10.1212/NXI.0000000000000991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018793PMC
May 2021

Major depressive disorder subtypes and depression symptoms in multiple sclerosis: What is different compared to the general population?

J Psychosom Res 2021 05 16;144:110402. Epub 2021 Feb 16.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich (UZH), Zurich, Switzerland.

Objective: To compare and characterize major depressive disorder (MDD) subtypes (i.e., pure atypical, pure melancholic and mixed atypical-melancholic) and depression symptoms in persons with multiple sclerosis (PwMS) with persons without MS (Pw/oMS) fulfilling the DSM-5 criteria for a past 12-month MDD.

Methods: MDD in PwMS (n = 92) from the Swiss Multiple Sclerosis Registry was compared with Pw/oMS (n = 277) from a Swiss community-based study. Epidemiological MDD diagnoses were based on the Mini-SPIKE (shortened form of the Structured Psychopathological Interview and Rating of the Social Consequences for Epidemiology). Logistic and multinomial regression analyses (adjusted for sex, age, civil status, depression and severity) were computed for comparisons and characterization. Latent class analysis (LCA) was conducted to empirically identify depression subtypes in PwMS.

Results: PwMS had a higher risk for the mixed atypical-melancholic MDD subtype (OR = 2.22, 95% CI = 1.03-4.80) compared to Pw/oMS. MDD in PwMS was specifically characterized by a higher risk of the two somatic atypical depression symptoms 'weight gain' (OR = 6.91, 95% CI = 2.20-21.70) and 'leaden paralysis' (OR = 3.03, 95% CI = 1.35-6.82) and the symptom 'irritable/angry' (OR = 3.18, 95% CI = 1.08-9.39).

Conclusions: MDD in PwMS was characterized by a higher risk for specific somatic atypical depression symptoms and the mixed atypical-melancholic MDD subtype. The pure atypical MDD subtype, however, did not differentiate between PwMS and Pw/oMS. Given the high phenomenological overlap with MS symptoms, the mixed atypical-melancholic MDD subtype represents a particular diagnostic challenge.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110402DOI Listing
May 2021

Pathological cerebrospinal fluid protein concentration and albumin quotient at relapse predicts short-term disability progression in multiple sclerosis: a retrospective single center observational study.

Ther Adv Neurol Disord 2020 29;13:1756286420975909. Epub 2020 Dec 29.

Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

Background: Blood-brain barrier dysfunction in active multiple sclerosis (MS) lesions leads to pathological changes of cerebrospinal fluid (CSF). Theoretically, CSF analyses could help to predict relapse recovery and the course of disability. In this monocentric study, we investigated the impact of CSF findings assessed during the first relapse of MS on the short-term course of disability.

Methods: We performed a retrospective observational study including MS patients with available CSF data after onset of first MS relapse. Clinical symptoms had to be accompanied by gadolinium-enhanced lesion on magnetic resonance imaging. Expanded Disability Status Scale (EDSS) assessments at timepoint of relapse and after relapse recovery were studied to analyze disability. A two-step multivariate linear regression analysis adjusted for EDSS at spinal tab, duration of symptoms, sex, time until post relapse EDSS assessment, immunotherapy post relapse, and relapse treatment with glucocorticoids/plasma exchange to predict relapse associated disability was run.

Results: In the first step of the regression model, pathological albumin quotient (QAlb) [regression coefficient 0.50, 95% confidence interval (CI) (0.07-0.92),  = 0.02,  = 99] and CSF protein concentration [regression coefficient 0.84, 95% CI (0.33-1.35),  = 0.001,  = 99] predicted EDSS after relapse recovery. In the second step, the sum score of both predictors [range 0-2; per value: 0 ( = 73), 1 ( = 10), 2 ( = 15)] confirmed the negative impact on course of disability after relapse [regression coefficient 0.38, 95% CI (0.13-0.62),  = 0.003,  = 98]. In this final multivariate linear regression model ( < 0.001; 0.34), also EDSS at lumbar puncture [regression coefficient 0.58, 95% CI (0.35-0.81),  < 0.001,  = 98] and time between symptom onset and CSF evaluation [regression coefficient 0.03, 95% CI (0.006-0.048),  = 0.01,  = 98] forecast subsequent disability.

Discussion: Our study conducted in MS patients during first relapse confirmed that both increased CSF protein concentration and pathological QAlb have a negative impact on EDSS after relapse. As secondary finding, we identified time from symptom onset to lumbar puncture as predictor of disability recovery after relapse.
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http://dx.doi.org/10.1177/1756286420975909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780321PMC
December 2020

Simultaneous lesion and brain segmentation in multiple sclerosis using deep neural networks.

Sci Rep 2021 01 13;11(1):1087. Epub 2021 Jan 13.

Support Center for Advanced Neuroimaging, University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, Bern, Switzerland.

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.
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http://dx.doi.org/10.1038/s41598-020-79925-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806997PMC
January 2021

Immunomodulatory treatment in postural tachycardia syndrome: A case series.

Eur J Neurol 2021 05 19;28(5):1692-1697. Epub 2021 Jan 19.

Department of Neurosurgery, Inselspital, Bern University Hospital, Bern, Switzerland.

Background And Purpose: Postural tachycardia syndrome (POTS) is a form of autonomic dysfunction characterized by symptoms of orthostatic intolerance, often accompanied by sudomotor dysfunction and gastrointestinal dysmotility. Recently, evidence has accumulated that in a subset of patients, the pathogenesis of dysautonomia may be immune-mediated. The aim of the current report was to evaluate the use of intravenous immunoglobulin (IVIG) treatment in patients with progressive and/or refractory immune-mediated POTS.

Methods: We retroactively assessed the effect and tolerance of monthly administered IVIG in six patients using autonomic function testing, standardized symptom questionnaires, and patients' symptom diaries both before and 6 months into IVIG treatment. Objective outcome measures included heart rate increase after 10 min of head-up tilt as well as duration and anhidrotic area in a thermoregulatory sweat test. Subjective outcome measures were patient reports and symptom ratings from the symptom questionnaire.

Results: All patients responded to immunomodulatory treatment, regardless of disease duration. After 6 months of IVIG, symptom severity was reduced by nearly 40%. Autonomic function testing showed improved cardiovascular functioning by 50% and a reduction of anhidrotic areas by one third. Overall, tolerance of IVIG treatment was poor, but could be improved by a reduction in infusion rate, premedication with steroids, and additional intravenous hydration.

Conclusions: Using subjective but also standardized objective measures, the case series describes promising effects of IVIG treatment in POTS patients with immune-mediated dysautonomia. By reducing the infusion rate, pretreatment with steroids, and intravenous hydration, tolerance could be improved, and no patient had to discontinue the treatment.
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http://dx.doi.org/10.1111/ene.14711DOI Listing
May 2021

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Neurology, Neuroimmunological Section, University of Rostock, 18051 Rostock, Germany.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

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

CNS Neurosci Ther 2021 04 13;27(4):426-438. Epub 2020 Oct 13.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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.
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http://dx.doi.org/10.1111/cns.13461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941167PMC
April 2021

c-Jun N-Terminal Kinase as a Therapeutic Target in Experimental Autoimmune Encephalomyelitis.

Cells 2020 09 23;9(10). Epub 2020 Sep 23.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.

c-Jun N-terminal kinase (JNK) is upregulated during multiple sclerosis relapses and at the peak of experimental autoimmune encephalomyelitis (EAE). We aim to investigate the effects of pharmacological pan-JNK inhibition on the course of myelin oligodendrocyte glycoprotein (MOG) EAE disease using in vivo and in vitro experimental models. EAE was induced in female C57BL/6JRj wild type mice using MOG. SP600125 (SP), a reversible adenosine triphosphate competitive pan-JNK inhibitor, was then given orally after disease onset. Positive correlation between SP plasma and brain concentration was observed. Nine, but not three, consecutive days of SP treatment led to a significant dose-dependent decrease of mean cumulative MOG EAE severity that was associated with increased mRNA expression of interferon gamma (INF-γ) and tumor necrosis factor alpha (TNF-α) in the spinal cord. On a histological level, reduced spinal cord immune cell-infiltration predominantly of CD3+ T cells as well as increased activity of Iba1+ cells were observed in treated animals. In addition, in vitro incubation of murine and human CD3+ T cells with SP resulted in reduced T cell apoptosis and proliferation. In conclusion, our study demonstrates that pharmacological pan-JNK inhibition might be a treatment strategy for autoimmune central nervous system demyelination.
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http://dx.doi.org/10.3390/cells9102154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598244PMC
September 2020

Conventional autoantibodies against brain antigens are not routinely detectable in serum and CSF of narcolepsy type 1 and 2 patients.

Sleep Med 2020 11 7;75:188-191. Epub 2020 Aug 7.

Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland; Neurology Department, Sechenov First Moscow State Medical University, Moscow, Russia.

Narcolepsy with cataplexy (NT1) is a chronic hypothalamic disorder with a presumed immune-mediated etiology leading to a loss of hypocretin neurons. Previous studies reported conflicting results in terms of presence of auto-antibodies involved in narcolepsy pathophysiology. A total of 86 patients with primary/idiopathic narcolepsy (74 NT1, 12 NT2) and 23 control patients with excessive daytime sleepiness due to other causes were tested for the presence of a wide range of anti-neuronal antibodies in both serum and cerebrospinal fluid (CSF). Anti-neuronal antibodies were rarely found in patients with narcolepsy (n = 2) and in controls (n = 1). Our results are in line with previous reports. We can therefore support the current evidence, that conventional anti-neuronal antibodies are not routinely detected during the workup of NT1 and other CDH patients.
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http://dx.doi.org/10.1016/j.sleep.2020.08.001DOI Listing
November 2020

Differences in morphology and visual function of myelin oligodendrocyte glycoprotein antibody and multiple sclerosis associated optic neuritis.

J Neurol 2021 Jan 12;268(1):276-284. Epub 2020 Aug 12.

Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland.

Background: Myelin 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).

Objective: This 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).

Methods: In 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.

Results: A 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.

Conclusion: In 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.
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http://dx.doi.org/10.1007/s00415-020-10097-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815569PMC
January 2021

Factors associated with employment and expected work retention among persons with multiple sclerosis: findings of a cross-sectional citizen science study.

J Neurol 2020 Oct 11;267(10):3069-3082. Epub 2020 Jun 11.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, 8001, Zurich, Switzerland.

Background: Multiple sclerosis (MS) notably affects adults of working age. For persons with MS (PwMS), being employed enhances their quality of life and it may be regarded as an indicator of overall functioning. Thus, ensuring work participation in PwMS is of general public health interest.

Objective: To examine relevant socio-demographic, MS-, health- and work-related factors, including psychosocial working conditions, associated with currently working PwMS in Switzerland and their expected work retention.

Methods: Using cross-sectional data of PwMS in the Swiss MS Registry (n = 541, median age = 48 [IQR 40;55]), multivariable logistic regression models were computed. First, currently working PwMS were characterised in comparison with those not currently working. Second, expected work retention, operationalized as subjective judgement "likely to work in the same job in 2 years", was examined within the group of currently working PwMS.

Results: The factors age (OR 0.96, 95% CI 0.92-0.99), sex (OR 0.28, 95% CI 0.13-0.60), highest achieved job position (OR 1.21, 95% CI 1.01-1.46), health-related quality of life (HRQoL) (OR 1.02, 95% CI 1.01-1.04) and the number of MS symptoms (OR 0.90, 95% CI 0.82-0.98) were associated with currently working PwMS. Moreover, HRQoL (OR 1.07, 95% CI 1.04-1.10) and psychosocial working conditions, such as job resources (e.g. autonomy, control or social support) (OR 2.83, 95% CI 1.50-5.33) and job demands (e.g. workload, time pressure) (OR 0.41, 95% CI 0.18-0.90) were important factors for expected work retention among this group.

Conclusions: Resourceful psychosocial working conditions are crucial for PwMS to maintain employment. Employers could contribute to work retention among PwMS by creating a work environment with resourceful psychosocial working conditions and providing, for instance, social support.
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http://dx.doi.org/10.1007/s00415-020-09973-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501110PMC
October 2020

Clinical implications of serum neurofilament in newly diagnosed MS patients: A longitudinal multicentre cohort study.

EBioMedicine 2020 Jun 24;56:102807. Epub 2020 May 24.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Background: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients.

Methods: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up.

Findings: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels.

Interpretation: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions.

Funding: Supported the German Federal Ministry for Education and Research, the German Research Council, and Hertie-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2020.102807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251380PMC
June 2020

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.

J Neurol Neurosurg Psychiatry 2020 07 5;91(7):681-686. Epub 2020 May 5.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Objective: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).

Methods: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.

Results: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.

Conclusion: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
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http://dx.doi.org/10.1136/jnnp-2020-322941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361012PMC
July 2020

Development and validation of the self-reported disability status scale (SRDSS) to estimate EDSS-categories.

Mult Scler Relat Disord 2020 Jul 28;42:102148. Epub 2020 Apr 28.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland. Electronic address:

Background: Clinician-assessed Expanded Disease Status Scale (EDSS) is gold standard in clinical investigations but normally unavailable in population-based, patient-centred MS-studies. Our objective was to develop a self-reported gait measure reflecting EDSS-categories.

Methods: We developed the self-reported disability status scale (SRDSS) with three categories (≤3.5, 4-6.5, ≥7) based on three mobility-related questions. The SRDSS was determined for 173 persons with MS and validated against clinical EDSS to calculate sensitivity and specificity.

Results: Accuracy was 88.4% (153 correctly classified) and weighted kappa 0.73 (0.62-0.84). Sensitivity/specificity-pairs were 94.5%/77.8%, 69.0%/94.7% and 100%/98.2% for SRDSS ≤3.5, 4-6.5 and ≥7, respectively.

Conclusions: Self-reported SRDSS approximates EDSS-categories well and fosters comparability between clinical and population-based studies.
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http://dx.doi.org/10.1016/j.msard.2020.102148DOI Listing
July 2020

Is ε4 associated with cognitive performance in early MS?

Neurol Neuroimmunol Neuroinflamm 2020 07 1;7(4). Epub 2020 May 1.

From the Department of Neurology and Focus Program Translational Neuroscience (FTN) (S.E., C.G., M.M., S.B., S.G., F.Z., C.M.L., F.L.), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Neurology (A.S.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology (A.S., B.A., R.G.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biostatistics (G.T.), Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology (A. Bayas), Klinikum Augsburg; Department of Neurology (A. Berthele, B.H.), Klinikum rechts der Isar, Technical University of Munich; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Clinic of Neurology (L.K., S.G.M., H.W.), University Hospital Münster, Westphalian-Wilhelms-University Münster; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (R.A.L.), University Hospital Erlangen; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité - Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (M.S.), Hannover Medical School; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), Sana Kliniken des Landkreises Cham; Department of Neurology (B.W.), University of Heidelberg; Department. of Neurology (U.K.Z.), University of Rostock; Central Information Office (CIO) (G.A.), Philipps-University Marburg; and Genetic and Molecular Epidemiology Group (C.M.L.), Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Germany.

Objective: To assess the impact of polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).

Methods: This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the haplotype were assessed by allelic discrimination assays Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors.

Results: ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for ε4 heterozygosity or ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for carrier status.

Conclusion: Along with parameters of a higher disease burden, ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217661PMC
July 2020

60/30: 60% of the Morbidity-Associated Multiple Sclerosis Disease Burden Comes From the 30% of Persons With Higher Impairments.

Front Neurol 2020 6;11:156. Epub 2020 Mar 6.

Department of Epidemiology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Multiple sclerosis (MS) is the most common chronic, non-traumatic, neurologic disease in young adults. While approximate values of the disease burden of MS are known, individual drivers are unknown. To estimate the age-, sex-, and disease severity-specific contributions to the disease burden of MS. We estimated the disease burden of MS using disability-adjusted life years (DALYs) following the Global Burden of Disease study (GBD) methodology. The data sources consisted of the Swiss MS Registry, a recent prevalence estimation, and the Swiss mortality registry. The disease burden of MS in Switzerland in 2016 was 6,938 DALYs (95%-interval: 6,018-7,955), which corresponds to 97 DALYs per 100,000 adult inhabitants. Morbidity contributed 59% of the disease burden. While persons in an asymptomatic (EDSS-proxy 0) and mild (EDSS-proxy >0-3.5) disease stage represent 68.4% of the population, they make up 39.8% of the MS-specific morbidity. The remaining 60.2% of the MS-specific morbidity stems from the 31.6% of persons in a moderate (EDSS-proxy 4-6.5) or severe (EDSS-proxy ≥7) disease stage. Morbidity has a larger influence on the disease burden of MS than mortality and is shared in a ratio of 2:3 between persons in an asymptomatic/mild and moderate/severe disease stage in Switzerland. Interventions to reduce severity worsening in combination with tailored, symptomatic treatments are important future paths to lower the disease burden of MS.
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http://dx.doi.org/10.3389/fneur.2020.00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068809PMC
March 2020

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.

Pain 2020 04;161(4):787-796

Department of Neurology, Technical University of Munich (TUM), School of Medicine, Munich, Germany.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.
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http://dx.doi.org/10.1097/j.pain.0000000000001767DOI Listing
April 2020

Pneumococcal serotype determines growth and capsule size in human cerebrospinal fluid.

BMC Microbiol 2020 01 20;20(1):16. Epub 2020 Jan 20.

Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Friedbühlstrasse 51, CH-3001, Bern, Switzerland.

Background: The polysaccharide capsule is a major virulence factor of S. pneumoniae in diseases such as meningitis. While some capsular serotypes are more often found in invasive disease, high case fatality rates are associated with those serotypes more commonly found in asymptomatic colonization. We tested whether growth patterns and capsule size in human cerebrospinal fluid depends on serotype using a clinical isolate of S. pneumoniae and its capsule switch mutants.

Results: We found that the growth pattern differed markedly from that in culture medium by lacking the exponential and lysis phases. Growth in human cerebrospinal fluid was reduced when strains lost their capsules. When a capsule was present, growth was serotype-specific: high carriage serotypes (6B, 9 V, 19F and 23F) grew better than low carriage serotypes (7F, 14, 15B/C and 18C). Growth correlated with the case-fatality rates of serotypes reported in the literature. Capsule size in human cerebrospinal fluid also depended on serotype.

Conclusions: We propose that serotype-specific differences in disease severity observed in meningitis patients may, at least in part, be explained by differences in growth and capsule size in human cerebrospinal fluid. This information could be useful to guide future vaccine design.
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http://dx.doi.org/10.1186/s12866-020-1700-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971925PMC
January 2020

Dimethyl fumarate vs fingolimod following different pretreatments: A retrospective study.

Neurol Neuroimmunol Neuroinflamm 2020 03 14;7(2). Epub 2020 Jan 14.

From the Department of Neurology (L.D., A.M., M.B., A.S., A.C., M.E.E., R.H.), Inselspital, Bern University Hospital and University of Bern, Freiburgstrasse, Bern, Switzerland; Department of Neurology (A.D., C.K., M.E.E.), Eginition University Hospital, National and Kapodistrian University of Athens, Greece; Department of Neurology (O.F.), Cantonal Hospital Aarau, Tellstrasse, Aarau, Switzerland; Department of Neurology (O.F.), Karl Landsteiner University of Health Sciences, Site Tulln, Austria; and Department of Neurology (R.G.), St. Josef Hospital Ruhr University Bochum, Germany.

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, < 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], = 0.001, n = 122) or to a lesser extend also in treatment-naive patients (aHR [95% CI] 1.9 [1.01-3.6], = 0.045, n = 230). No differences were observed in patients pretreated with injectables or the respective other oral drug (injectables: > 0.05, n = 341; other oral: > 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.
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http://dx.doi.org/10.1212/NXI.0000000000000660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984136PMC
March 2020

Visual Outcomes of Plasma Exchange Treatment of Steroid-Refractory Optic Neuritis: A Retrospective Monocentric Analysis.

Transfus Med Hemother 2019 Dec 14;46(6):417-422. Epub 2019 Nov 14.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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 ( < 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.
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http://dx.doi.org/10.1159/000504027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944937PMC
December 2019

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

Neuroimage Clin 2020 9;25:102104. Epub 2019 Dec 9.

Support Center for Advanced Neuroimaging, University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Switzerland.

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.
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http://dx.doi.org/10.1016/j.nicl.2019.102104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953959PMC
January 2021

Functional relevance of the multi-drug transporter abcg2 on teriflunomide therapy in an animal model of multiple sclerosis.

J Neuroinflammation 2020 Jan 8;17(1). Epub 2020 Jan 8.

Department of Neurology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Freiburgstrasse, 3010, Bern, Switzerland.

Background: The multi-drug resistance transporter ABCG2, a member of the ATP-binding cassette (ABC) transporter family, mediates the efflux of different immunotherapeutics used in multiple sclerosis (MS), e.g., teriflunomide (teri), cladribine, and mitoxantrone, across cell membranes and organelles. Hence, the modulation of ABCG2 activity could have potential therapeutic implications in MS. In this study, we aimed at investigating the functional impact of abcg2 modulation on teri-induced effects in vitro and in vivo.

Methods: T cells from C57BL/6 J wild-type (wt) and abcg2-knockout (KO) mice were treated with teri at different concentrations with/without specific abcg2-inhibitors (Ko143; Fumitremorgin C) and analyzed for intracellular teri concentration (HPLC; LS-MS/MS), T cell apoptosis (annexin V/PI), and proliferation (CSFE). Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6J by active immunization with MOG/CFA. Teri (10 mg/kg body weight) was given orally once daily after individual disease onset. abcg2-mRNA expression (spinal cord, splenic T cells) was analyzed using qRT-PCR.

Results: In vitro, intracellular teri concentration in T cells was 2.5-fold higher in abcg2-KO mice than in wt mice. Teri-induced inhibition of T cell proliferation was two fold increased in abcg2-KO cells compared to wt cells. T cell apoptosis demonstrated analogous results with 3.1-fold increased apoptosis after pharmacological abcg2-inhibition in wt cells. abcg2-mRNA was differentially regulated during different phases of EAE within the central nervous system and peripheral organs. In vivo, at a dosage not efficacious in wt animals, teri treatment ameliorated clinical EAE in abcg2-KO mice which was accompanied by higher spinal cord tissue concentrations of teri.

Conclusion: Functional relevance of abcg2 modulation on teri effects in vitro and in vivo warrants further investigation as a potential determinant of interindividual treatment response in MS, with potential implications for other immunotherapies.
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http://dx.doi.org/10.1186/s12974-019-1677-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951012PMC
January 2020

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

Ther Adv Neurol Disord 2019 27;12:1756286419878340. Epub 2019 Sep 27.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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 test, analysis of variance test, and multiple linear regression analysis were employed.

Results: In total, 327 MS patients were retrospectively identified (Bern/Athens:  = 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 ( = 327) were significantly more likely to have IgG concentrations below LLN and below 600 mg/dl in comparison with controls ( = 58) ( = 0.015 and 0.047, respectively). Between both patient groups, no significant differences were found in frequencies of IgA and IgM concentrations under LLN [ (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:  ⩽ 0.01). After adjusting for sex, age, and disease course, IgG concentrations were lower in patients treated with rituximab ( = 0.001;  = 42/327), intravenous corticosteroids ( < 0.001;  = 16/327), natalizumab ( < 0.001;  = 48/327), and fingolimod ( = 0.003;  = 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.
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http://dx.doi.org/10.1177/1756286419878340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767745PMC
September 2019

How do patients enter the healthcare system after the first onset of multiple sclerosis symptoms? The influence of setting and physician specialty on speed of diagnosis.

Mult Scler 2020 04 18;26(4):489-500. Epub 2019 Jan 18.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Background: Diagnosing multiple sclerosis (MS) early is crucial to avoid future disability. However, potentially preventable delays in the diagnostic cascade from contact with a physician to definite diagnosis still occur and their causes are still unclear.

Objective: To identify the possible causes of delays in the diagnostic process.

Methods: We analyzed the data of the Swiss MS Registry. With logistic regression, we modeled the time from the first contact to the first consultation (contact-to-evaluation time, ⩽1 month/>1 month) and the evaluation-to-diagnosis time (⩽6 months/>6 months). Potential factors were health system characteristics, sociodemographic variables, first symptoms, and MS type.

Results: We included 522 participants. Mostly, general practitioners (67%) were contacted first, without delaying the diagnosis. In contrast, first symptoms and MS type were the major contributors to delays: gait problems were associated with longer contact-to-evaluation times, depression as a concomitant symptom with longer evaluation-to-diagnosis times, and having primary progressive MS prolonged both phases. In addition, living in mountainous areas was associated with longer contact-to-evaluation times, whereas diagnosis after 2000 was associated with faster diagnoses.

Conclusion: For a quicker diagnosis, awareness of MS as a differential diagnosis of gait disorders and the co-occurrence of depression at onset should be raised, and these symptoms should be attentively followed.
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http://dx.doi.org/10.1177/1352458518823955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140343PMC
April 2020

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

Ther Adv Neurol Disord 2019 8;12:1756286419843450. Epub 2019 May 8.

Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

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.
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http://dx.doi.org/10.1177/1756286419843450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506915PMC
May 2019
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