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Post-acute COVID-19 vaccination syndrome (PACVS) is a chronic disease triggered by SARS-CoV-2 vaccination (estimated prevalence 0.02%). PACVS is discriminated from the normal post-vaccination state by altered receptor antibodies, most notably angiotensin II type 1 and alpha-2B adrenergic receptor antibodies. Here, we investigate the clinical phenotype using a study registry encompassing 191 PACVS-affected persons (159 females/32 males; median ages: 39/42 years). Unbiased clustering (modified Jaccard index) of reported symptoms revealed a prevalent cross-cohort symptomatology of malaise and chronic fatigue (>80% of cases). Overlapping clusters of (i) peripheral nerve dysfunction, dysesthesia, motor weakness, pain, and vasomotor dysfunction; (ii) cardiovascular impairment; and (iii) cognitive impairment, headache, and visual and acoustic dysfunctions were also frequently represented. Notable abnormalities of standard serum markers encompassing increased interleukins 6 and 8 (>80%), low free tri-iodine thyroxine (>80%), IgG subclass imbalances (>50%), impaired iron storage (>50%), and increased soluble neurofilament light chains (>30%) were not associated with specific symptoms. Based on these data, 131/191 participants fit myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and simultaneously also several other established dysautonomia syndromes. Furthermore, 31/191 participants fit none of these syndromes. In conclusion, PACVS could either be an outlier of ME/CFS or a dysautonomia syndrome sui generis. [ABSTRACT FROM AUTHOR]

Background and purpose: Diagnosing small fiber neuropathies can be challenging. To address this issue, whether serum neurofilament light chain (sNfL) could serve as a potential biomarker of damage to epidermal Aδ‐ and C‐fibers was tested. Methods: Serum NfL levels were assessed in 30 patients diagnosed with small fiber neuropathy and were compared to a control group of 19 healthy individuals. Electrophysiological studies, quantitative sensory testing and quantification of intraepidermal nerve fiber density after skin biopsy were performed in both the proximal and distal leg. Results: Serum NfL levels were not increased in patients with small fiber neuropathy compared to healthy controls (9.1 ± 3.9 and 9.4 ± 3.8, p = 0.83) and did not correlate with intraepidermal nerve fiber density at the lateral calf or lateral thigh or with other parameters of small fiber impairment. Conclusion: Serum NfL levels cannot serve as a biomarker for small fiber damage. [ABSTRACT FROM AUTHOR]

Background: Combination treatment with BRAF/MEK inhibitors favorably impact progression-free survival in malignant melanoma. However, it may cause paradoxical activation of the MAPK/ERK pathway in immune cells without BRAF mutation, which may lead to over activation of the immune system, especially in patients with pre-existing autoimmune conditions. In this case report, treatment of malignant melanoma with BRAF/MEK inhibitors was associated with radiological disease exacerbation of pre-existing multiple sclerosis (MS). Case presentation: A 47-year-old patient with pre-existing MS was diagnosed with malignant melanoma in June 2020. Anti-tumor treatment was initiated with a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. In February 2022, the patient presented at our neurological clinic after routine MRI revealed exacerbation of radiological MS disease activity with ten new and gadolinium-enhancing lesions, and concomitant high levels of neurofilament light chain (NfL) in serum, a marker for axonal damage. In-depth analysis of immune cells in both peripheral blood and cerebrospinal fluid was performed by multi-color flow cytometry. After treatment with the B cell-depleting antibody ocrelizumab, MS disease stability was obtained and anti-tumor medication could be continued. Conclusions: Immunomodulatory treatment in cancer patients is highly effective from an oncological point of view, but may be associated with autoimmune side effects. This is of special importance in patients with pre-existing autoimmune diseases, as reflected by our case of MS disease reactivation under treatment with BRAF/MEK inhibitors. In our case, sequential modulation of immune cell subsets by B cell depletion, associated with marked shifts in B and T cell subsets, allowed for stabilization of disease and continuation of anti-tumor treatment. [ABSTRACT FROM AUTHOR]

Objective: Mechanical thrombectomy (MT) has become standard treatment in acute ischemic stroke due to large vessel occlusion (LVO). However, optimal blood pressure (BP) management following successful recanalization remains unclear. We aim to investigate the association of strictly achieving BP targets of ≤160/90 mmHg with the extent of neuronal loss and functional outcome. Methods: In patients prospectively enrolled in the Gutenberg‐Stroke‐Study (May 2018–November 2019), BP was measured half‐hourly for 24 h following MT. Based on achieving BP target of ≤160/90 mmHg, patients with successful recanalization of LVO were divided into "low‐BP" group (BP ≤ 160/90 mmHg) or "high‐BP" group (BP > 160/90 mmHg). Neuronal loss was quantified by serum‐based measurement of neurofilament light chain (sNfL) after three days. BP groups and association of BP parameters with sNfL were investigated by correlation analyses and multiple regression modeling. Results: Of 253 enrolled patients (mean age 73.1 ± 12.9 years, 53.4% female), 165 met inclusion criteria. 21.2% (n = 35) strictly achieved "low‐BP" target. "low‐BP" was associated with unfavorable functional outcome at 90‐day follow‐up (aOR [95%CI]: 5.88 [1.88–18.32], p = 0.002) and decreased health‐related quality of life (mean EQ‐5D‐index 0.45 ± 0.28 vs 0.63 ± 0.31, p = 0.009). sNfL levels were increased in "low‐BP" patients (median [IQR] 239.7 [168.4–303.4] vs 118.8 [52.5–220.5] pg/mL, p = 0.026). Hypotensive episodes were more frequent in the "low‐BP" group (48.6% vs 29.2%, p = 0.031). sNfL level could identify patients who had experienced hypotensive episodes with high discriminative ability (AUC [95%CI]: 0.68 [0.56–0.78], p = 0.007). Interpretation: Strict BP control (≤160/90 mmHg) within 24 h following successful recanalization of LVO by MT is associated with increased neuronal injury, displayed by higher sNfL levels, and poorer functional outcome, potentially indicating hypotension‐induced neuronal loss during post‐MT phase. [ABSTRACT FROM AUTHOR]

Background: The presence of contrast enhancement (CE) on magnetic resonance imaging (MRI) is one of the principal criteria for diagnosis and disease activity of multiple sclerosis (MS). Therefore, MS patients are frequently exposed to contrast agents, which may cause deposition in the brain, restricting its use in repeat examinations. Thus, serum biomarkers may be valuable as surrogate parameters to evaluate MS activity. Methods: REDUCE‐GAD was a prospective, multicentric, biobanking study to determine whether established serum markers (neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP], tau protein, ubiquitin‐carboxyl‐terminal‐hydrolase (UCH‐L1), S100B and matrix‐metalloproteinase 9 [MMP9]) are predictive of CE‐positive MRI lesions. Blood samples were obtained from patients undergoing MRI 5 days before or after collection. Results: Patients (N = 102) from four different centers with confirmed MS or related disorders were included; n = 57 (55.9%) showed CE on MRI versus n = 45 (44.1%) without CE. Only higher NfL values indicated CE (odds ratio [OR] 1.05; 95% CI 1.0–1.09) and were correlated with number (ρ = 0.47; p < 0.001) and diameter of CE lesions (ρ = 0.58; p < 0.001). Nfl Z‐scores improved diagnostic accuracy (OR 1.52; 95% CI 1.06–2.18). Receiver operator characteristic analysis revealed a reasonable cut‐off value for NfL at 14.1 pg/mL (sensitivity 49.1%; specificity 82.2%; positive predictive value 77.8%; negative predictive value 56.0%). NfL ≥59.2 pg/mL was exclusively observed in patients with CE. Conclusions: Evaluation of several possible serum biomarkers for CE in MS patients provided the most robust results for NfL, particularly as Z‐scores. Following further evaluation, biomarkers may help stratify the application of contrast agents for brain imaging in MS patients. [ABSTRACT FROM AUTHOR]

Background: For treatment of relapsing-remitting multiple sclerosis (RRMS), a broad range of disease-modifying therapies (DMT) is available. However, few comparative effectiveness studies between different drugs have been performed. Objectives: This study aimed to compare the efficacy and treatment continuation of natalizumab and ocrelizumab in a real-world cohort of patients with relapsing-remitting multiple sclerosis (RRMS) from two German university hospitals. Methods: We performed a retrospective analysis of RRMS patients who initiated treatment with natalizumab or ocrelizumab between January 2016 and April 2019 at the German university hospitals of Mainz and Düsseldorf. Bayesian propensity score matching was conducted to correct for differences in baseline characteristics. Our primary outcome was no evidence of disease activity [NEDA-3: no relapses, no confirmed disability progression, and no magnetic resonance imaging (MRI) activity] and its subcomponents. Secondary outcomes included measurement of neurofilament light chain (NfL) in serum, analysis of premature discontinuation, and evidence of rebound activity in patients switching from natalizumab to ocrelizumab. Results: We identified 63 patients starting treatment with natalizumab and 76 patients starting with ocrelizumab. Binary logistic regression showed that treatment with natalizumab or a higher number of relapses in the previous year were independently associated with a higher risk for relapses. Patients receiving natalizumab had a higher probability of premature discontinuation of therapy (p = 0.002). After propensity score matching of the two treatment arms, 55 patients remained per group. NEDA-3 after 30 months of follow-up was reached by 53.1% in the ocrelizumab group and 36.1% in the natalizumab group (p = 0.177). Ocrelizumab was superior to natalizumab concerning the occurrence of relapses in log-rank test (p = 0.019). NfL levels in serum were low under both treatments. Patients who switched from natalizumab to ocrelizumab showed no increased rebound activity. Discussion: This study provides class IV evidence that treatment of RRMS patients with ocrelizumab and natalizumab show comparable effectiveness in combined endpoints, while ocrelizumab might be more effective in preventing the occurrence of relapses. [ABSTRACT FROM AUTHOR]

Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity. [ABSTRACT FROM AUTHOR]

Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA-synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke. Reducing excitation surrounding stroke: After stroke, excessive glutamate release from damaged cells contributes to secondary injury in the stroke penumbra. Preserving the penumbra is critical for improving stroke outcome; however, current pharmacological approaches have not been successful. Here, Bitar et al. studied the mechanisms mediating excitotoxicity in the penumbra and showed that autotaxin (ATX) was increased in astrocytes after stroke in mice, and ATX increase was also found in the cerebrospinal fluid of patients after stroke. ATX increase mediated lysophosphatidic acid (LPA)–induced hyperexcitability in rodents, and its inhibition ameliorated stroke outcome, suggesting that the ATX-LPA signaling might be a potential target for treating stroke. [ABSTRACT FROM AUTHOR]

Background: Patients with multiple sclerosis (MS) receiving immunomodulatory drugs were excluded from clinical trials on COVID-19 vaccines. Therefore, data regarding the efficacy of COVID-19 vaccines to induce humoral immunity in MS patients treated with B- and T-cell depleting agents is urgently warranted. Cladribine tablets are a high-efficacy disease-modifying treatment that exerts its therapeutic effect via sustained but transient lymphocyte depletion. Aim: We report humoral responses in a German cohort of MS patients treated with cladribine tablets. Methods: This retrospective analysis included patients ≥18 years who were treated with cladribine tablets for relapsing MS in the first or second year and were fully vaccinated against COVID-19. Two weeks after the second vaccination at the earliest, blood samples were obtained for the assessment of anti-SARS-CoV-2 IgG antibodies, lymphocyte counts, B-cells, CD4+ T-cells, and CD8+ T-cells. Anti-SARS-CoV-2 IgG antibodies were quantified with the LIAISON® SARS-CoV-2 TrimericS IgG assay. Positivity was defined at a cutoff value of 33.8 BAU/mL. Results: In total, 38 patients (73.7% female, aged 23–66 years) were included in the analysis. Ten patients (26.3%) were treatment-naïve before initiating treatment with cladribine tablets. Most patients (84.2%) received mRNA vaccines. The time between the last dose of cladribine tablets and vaccination ranged between 2 and 96 weeks. Six patients (15.8%) were vaccinated within 4 weeks of their last cladribine dose. All patients achieved positive anti-SARS-CoV-2 IgG antibody levels. Humoral immune response was independent of age, time of vaccination in relation to the last cladribine dose, lymphocyte counts as well as B- and T-cell counts. Conclusions: Treatment with cladribine tablets did not impair humoral response to COVID-19 vaccination. Time since last cladribine dose, age, prior therapy, lymphocyte count as well as B- and T-cell counts had no effect on seropositivity of anti-SARS-CoV-2 IgG antibodies. [ABSTRACT FROM AUTHOR]

Background: The aim was to evaluate the diagnostic potential of serum neurofilament light chain (sNfL) measurements in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Methods: sNfL levels were determined by single molecule array assay in a retrospective cross-sectional cohort of 144 patients with systemic lupus erythematosus (SLE). After log-transformation of sNfL levels, mean sNfL levels were compared between NPSLE patients and SLE patients without neuropsychiatric disease using Student's t test. Furthermore, the association of different neuropsychiatric manifestations with sNfL levels was assessed using a one-way analysis of variance (ANOVA) with post hoc analysis. Associations of sNfL with clinical and laboratory parameters were assessed by correlation and multiple linear regression analysis. Results: NPSLE patients (n = 69) had significantly higher sNfL levels than SLE patients without neuropsychiatric disease manifestations (n = 75; mean difference: 0.13, 95% CI: 0.04–0.22, p = 0.006). With regard to the category of NPSLE manifestation, mean sNfL levels were only increased in NPSLE patients with focal central nervous system (CNS) involvement (n = 45; mean difference: 0.16, 95% CI: 0.02–0.30, p = 0.019), whereas mean sNfL levels of NPSLE patients with diffuse CNS and peripheral nervous system involvement did not differ from those of SLE patients without neuropsychiatric manifestations. Age and serum creatinine concentrations were identified as relevant contributors to sNfL levels. Conclusion: sNfL is a promising, easily accessible biomarker for neuropsychiatric involvement in SLE patients and might therefore complement the diagnostic workup of SLE patients with suspected involvement of the nervous system. [ABSTRACT FROM AUTHOR]

Background: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers. Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous history of optic neuritis (HON). In addition, a subgroup of patients (n = 38) was studied longitudinally over 2 years. Support vector machine analysis was applied to test a regression model for significant changes. Results: In our cohort, HON patients had a thinner outer plexiform layer (OPL) volume compared to NHON patients (B = −0.016, SE = 0.006, p = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients (B = −6.734, SE = 2.514, p = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy (B = 5.974, SE = 2.420, p = 0.019). sNfL levels were 75.7% accurate at predicting OPL volume in the supervised machine learning. Conclusions: In summary, sNfL levels were a good predictor of future outer retinal thinning in MS. Changes within the neurofilament-rich OPL could be considered as an additional retinal marker linked to MS neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Serum neurofilament light chain (sNfL) is a promising biomarker to complement the decision-making process in multiple sclerosis (MS) patients. However, although sNfL levels are able to detect disease activity and to predict future disability, the growing evidence has not yet been translated into practicable recommendations for an implementation into clinical routine. Methods: The observation of a patient with extensive inflammatory activity in magnetic resonance imaging (MRI) along with an extremely high sNfL level in the absence of any clinical symptoms prompted us to investigate common characteristics of our MS patients with the highest sNfL levels in a retrospective cohort study. The 97.5th percentile was chosen as a cut-off value because the mean sNfL level of the resulting extreme neurofilament light chain (NfL) cohort corresponded well to the sNfL level of the presented case. Patient characterization included clinical and MRI assessment with a focus on disease activity markers. sNfL levels were determined by single molecule array. Results: The 97.5th percentile of our MS cohort (958 sNfL measurements in 455 patients) corresponded to a threshold value of 46.1 pg/ml. The mean sNfL level of the extreme sNfL cohort (n = 24) was 95.6 pg/ml (standard deviation 68.4). Interestingly, only 15 patients suffered from a relapse at the time point of sample collection, whereas nine patients showed no signs of clinical disease activity. sNfL levels of patients with and without relapse did not differ [median 81.3 pg/ml (interquartile range [IQR] 48.0–128) versus 80.2 pg/ml (IQR 46.4–97.6), p = 0.815]. The proportion of patients with contrast-enhancing lesions was high and also did not differ between patients with and without relapse (92.9% versus 87.5%, p = 0.538); 78.9% of the patients not receiving a high-efficacious therapy had ongoing disease activity during a 2-year follow-up. Conclusion: Extremely high sNfL levels are indicative of subclinical disease activity and might complement treatment decisions in ambiguous cases. [ABSTRACT FROM AUTHOR]

Neurological immune‐mediated side effects are rare but often severe complications of immune checkpoint inhibitor (ICI) treatment. This report describes a severe case of nivolumab/ipilimumab‐associated glutamic acid decarboxylase 65–positive autoimmune encephalitis. It proposes neurofilament light chain levels, a biomarker indicating axonal damage, in the cerebrospinal fluid and serum as a putative novel biomarker for this diagnostically and therapeutically challenging entity with an often unfavorable outcome. Additionally, we provide an overview of previous reports of patients developing autoimmune encephalitis under ICI treatment. [ABSTRACT FROM AUTHOR]

Objective: Adult drug‐resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well‐controlled epilepsy (WCE). Methods: Peripheral blood mononuclear cells and serum from >120 age‐ and sex‐matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array. Results: Using a data‐driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)‐17A, IL‐22, tumor necrosis factor, interferon‐γ, and granulocyte‐macrophage colony–stimulating factor, but not anti‐inflammatory cytokines IL‐10 and IL‐4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17‐related circulating proinflammatory cytokines are elevated, but Th2‐related cytokine IL‐4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals. Significance: Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic might affect health care resources and alter patient admission to hospital in case of stroke or transient ischemic attack (TIA). We aim to determine whether the COVID-19 pandemic is affecting utilization of recanalization procedures and numbers of patients with stroke and TIA admitted to a primary care stroke center. Methods: In this retrospective observational study, we compared patients admitted from January 2019 until February 2020 with patients admitted during the COVID-19 pandemic (March/April 2020) in Germany. We included patients with stroke (hemorrhagic or ischemic) or TIA as classified by International Statistical Classification of Diseases and Related Health Problems version 10 (ICD-10). Results: The number of patients per month with ischemic stroke or TIA was found to have significantly decreased from January 2019 until February 2020 compared to the COVID-19 pandemic (March/April 2020) (ischemic stroke 69.1 ± 4.5 vs. 55 ± 5.7, p < 0.001, TIA 22.1 ± 4.1 vs. 14.5 ± 6.4, p < 0.034). Contrarily, percentages and numbers of recanalization procedures per month were not influenced by the COVID-19 pandemic (intravenous thrombolysis [iv-tPA] 9.4 ± 3.7 vs. 10.5 ± 0.5, p = 0.697, mechanical thrombectomy [MT] 13.1 ± 3.1 vs. 14.5 ± 3.5, p = 0.580, iv-TPA or MT 19.4 ± 4.1 vs. 19.0 ± 0.0, p = 0.889). Conclusions: During the COVID-19 pandemic, resources of the healthcare system in a primary care university hospital in Germany still allowed for unchanged numbers of recanalization procedures due to ischemic stroke. However, the numbers of patients admitted to the hospital specifically due to ischemic stroke or TIA decreased, suggesting that the awareness for non-disabling stroke symptoms has to be increased. [ABSTRACT FROM AUTHOR]

Background: As vitamins and dietary supplements are obtainable without prescription, treating physicians often ignore their intake by patients with multiple sclerosis (MS) and may therefore miss potential adverse effects and interactions. Objective: We aimed to assess the spectrum and intake frequency of supplementary medication in a cohort of MS patients and to analyse the effect of biotin intake on measurement of serum neurofilament light chain (sNfL), an emerging marker of disease activity. Methods: MS patients visiting our neurology outpatient clinic completed a questionnaire on their past or present use of vitamins or dietary supplements. In addition, the impact of two different doses of biotin (10 and 300 mg/day) on sNfL was studied in healthy volunteers. Results: Of 186 patients, 72.6% reported taking over-the-counter vitamins or dietary supplements currently or previously. Most frequently used was vitamin D (60.0%), followed by biotin. Female patients and patients with primary progressive MS tended to use supplements more frequently. Biotin intake did not interfere with sNfL measurement by single molecule array (Simoa). Conclusions: The use of vitamins and dietary supplements is frequent among patients with MS. Thus, treating physicians should be aware of the pitfalls of supplementary treatment and educate their patients accordingly. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) leading to CNS inflammation and neurodegeneration. Current anti-inflammatory drugs have only limited efficacy on progressive neurodegenerative processes underlining the need to understand immune-mediated neuronal injury. Cell adhesion molecules play an important role for immune cell migration over the blood-brain barrier whereas their role in mediating potentially harmful contacts between invading immune cells and neurons is incompletely understood. Here, we assess the role of the CNS-specific neuronal adhesion molecule ICAM-5 using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. ICAM-5 knockout mice show a more severe EAE disease course in the chronic phase indicating a neuroprotective function of ICAM-5 in progressive neurodegeneration. In agreement with the predominant CNS-specific function of ICAM-5, lymphocyte function-associated antigen 1 (LFA-1)/ICAM-1 contact between antigen-presenting cells and T helper (Th)17 cells in EAE is not affected by ICAM-5. Strikingly, intrathecal application of the shed soluble form, sICAM-5, ameliorates EAE disease symptoms and thus might serve locally as an endogenous neuronal defense mechanism which is activated upon neuroinflammation in the CNS. In humans, cerebrospinal fluid from patients suffering from progressive forms of MS shows decreased sICAM-5 levels, suggesting a lack of this endogenous protective pathway in these patient groups. Overall, our study points toward a novel role of ICAM-5 in CNS autoinflammation in progressive EAE/MS. [ABSTRACT FROM AUTHOR]

• Even among MS patients considered mildly affected, most showed disease activity • Driven by MRI activity, loss of NEDA-3 was the most frequent marker of disease activity • PIRA occurred in 50% of patients and was often not accompanied by loss of NEDA-3 • MRI and clinical measurements often did not show disease activity simultaneously • Measuring different disease activity outcome measures could improve monitoring The current range of disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has placed more importance on the accurate monitoring of disease progression for timely and appropriate treatment decisions. With a rising number of measurements for disease progression, it is currently unclear how well these measurements or combinations of them can monitor more mildly affected RRMS patients. To investigate several composite measures for monitoring disease activity and their potential relation to the biomarker neurofilament light chain (NfL) in a clearly defined early RRMS patient cohort with a milder disease course. From a total of 301 RRMS patients, a subset of 46 patients being treated with a continuous first-line therapy was analyzed for loss of no evidence of disease activity (lo-NEDA-3) status, relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA), up to seven years after treatment initialization. Kaplan-Meier estimates were used for time-to-event analysis. Additionally, a Cox regression model was used to analyze the effect of NfL levels on outcome measures in this cohort. In this mildly affected cohort, both lo-NEDA-3 and PIRA frequently occurred over a median observational period of 67.2 months and were observed in 39 (84.8%) and 23 (50.0%) patients, respectively. Additionally, 12 out of 26 PIRA manifestations (46.2%) were observed without a corresponding lo-NEDA-3 status. Jointly, either PIRA or lo-NEDA-3 showed disease activity in all patients followed-up for at least the median duration (67.2 months). NfL values demonstrated an association with the occurrence of relapses and RAW. The complementary use of different disease progression measures helps mirror ongoing disease activity in mildly affected early RRMS patients being treated with continuous first-line therapy. [ABSTRACT FROM AUTHOR]

• BDNF and NfL levels in CSF correlate inversely with cognition in newly diagnosed MS. • More severely impaired patients have higher BDNF/NfL CSF levels. • Combining BDNF and NfL measures results in higher correlations with cognition. • NfL and BDNF in CSF might reflect early levels of neural damage. • BDNF might be triggered as a compensatory mechanism in parallel to neural damage. Cognitive performance may be impaired in MS even at the earliest stages of disease. We tested whether brain-derived neurotrophic factor and neurofilament light chain levels in serum and cerebrospinal fluid (CSF) samples (sNfL/cNfL/sBDNF/cBDNF) collected at the time of diagnosis are associated with cognitive performance. We measured sNfL/cNfL/sBDNF/cBDNF using single-molecule array (Simoa) in 47 newly diagnosed patients (32 relapsing-remitting MS/6 primary progressive MS/9 clinically isolated syndrome). Partial correlations between average z-score on neuropsychological tests and sNfL/sBDNF/cNfL/cBDNF were computed after adjusting for covariates. Multivariate analysis of covariance determined the effect of cognitive status on biomarker levels. A composite measure of NfL and BDNF was submitted to similar exploratory analysis. Cognitive performance correlated inversely with cNfL (r=-0.451/q=0.032) and cBDNF (r=-0.406/q=0.034). Impairment in at least two different tests was linked to higher cNfL (p=0.011) and cBDNF (p=0.035) levels compared to impairment in only one test and for cNfL also compared to no impairment at all (p=0.01). Composite CSF biomarker measure accounting for both cNfL and cBDNF correlated more strongly with tests of information processing (p=0.048) and verbal learning/memory consolidation (p = 0.02) as compared to the single CSF biomarkers. CSF BDNF and NfL levels measured at the time of diagnosis are inversely associated with cognitive performance in MS. Our findings suggest that CSF biomarkers linked to different pathophysiological processes reflect neuropsychological impairment in the earliest stages of the disease. Combining different CSF measures might facilitate the developing of a better biomarker of cognition in MS. [ABSTRACT FROM AUTHOR]

Background: As B cell-depleting therapies in multiple sclerosis (MS) have gained significant importance in the last several years, their long-term safety profile is of considerable clinical interest. Late-onset neutropenia (LON) is a rare, but potentially severe, adverse event that was first described in patients with rheumatic disorders under therapy with rituximab. Ofatumumab was approved in 2021 for the treatment of relapsing-remitting multiple sclerosis (RRMS). Neutropenia occurred in 0.2% of patients in clinical phase 3 trials, and to date, no cases of LON have been reported under ofatumumab treatment., Methods: Here, we report a case of repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment. Additionally, we review the literature on rare occurrences of LON in patients with MS, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) undergoing B cell-depleting therapies, including rituximab, ocrelizumab, ofatumumab, inebilizumab, and ublituximab., Findings: In our case, the patient presented with repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment leading to febrile infections, subsequent use of antibiotics, and application of granulocyte-colony-stimulating factor. After repetitive episodes of LON under both B cell-depleting strategies, cladribine was subsequently initiated. A nine-month follow-up showed a normal neutrophil count and no evidence of disease activity., Conclusions: This case highlights the significance of symptomatic late-onset blood count changes under both ocrelizumab and ofatumumab and emphasizes the importance of continuous monitoring of the differential blood count under B cell-depleting treatment., Funding: This study was supported by the Deutsche Forschungsgemeinschaft (DFG; SFB CRC-TR-128 to F.Z., V.F., and S.B..; SFB 1080 and SFB CRC-1292 to F.Z..; and SFB/TRR 355 to S.B.) and the Hermann and Lilly Schilling Foundation (to S.B.)., Competing Interests: Declaration of interests S.B. has received honoraria and compensation for travel from Biogen Idec, Bristol Myers Squibb, Merck Serono, Novartis, Sanofi-Genzyme, Roche, and Teva. F.Z. has received research grants and/or consultation funds from Biogen, Ministry of Education and Research (BMBF), Bristol Myers Squibb, Celgene, German Research Foundation (DFG), Janssen, Max Planck Society (MPG), Merck Serono, Novartis, Progressive MS Alliance, Roche, Sanofi-Genzyme, and Sandoz., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible. Using two independent multicentric longitudinal cohorts of patients with early multiple sclerosis ( n = 309 discovery and n = 232 validation), we were able to identify three distinct peripheral blood immunological endophenotypes by a combination of high-dimensional flow cytometry and serum proteomics, followed by unsupervised clustering. Longitudinal clinical and paraclinical follow-up data collected for the cohorts revealed that these endophenotypes were associated with disease trajectories of inflammation versus early structural damage. Investigating the capacity of immunotherapies to normalize endophenotype-specific immune signatures revealed discrete effect sizes as illustrated by the limited effect of interferon-β on endophenotype 3-related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-β exhibited higher disease progression and MRI activity over a 4-year follow-up compared with treatment with other therapies. We therefore propose that ascertaining a patient's blood immune signature before immunomodulatory treatment initiation may facilitate prediction of clinical disease trajectories and enable personalized treatment decisions based on pathobiological principles.

Background and Objectives: Immunomodulatory therapies reduce the relapse rate but only marginally control disability progression in patients with MS. Although serum neurofilament light chain (sNfL) levels correlate best with acute signs of inflammation (e.g., relapses and gadolinium-enhancing [Gd+] lesions), their role in predicting progressive biology and irreversible axonal damage is less clear. We aimed to determine the ability of sNfL to dissect distinct measures of disease severity and predict future (no) evidence of disease activity (EDA/no evidence of disease activity [NEDA])., Methods: One hundred fifty-three of 221 patients with relapsing-remitting MS initially enrolled in the Neurofilament and longterm outcome in MS cohort at the MS outpatient clinic of the University Medical Center Mainz (Germany) met the inclusion criteria for this prospective observational cohort study with a median follow-up of 6 years (interquartile range 4-7 years). Progressive disease forms were excluded. Inclusion criteria consisted of Expanded Disability Status Scale (EDSS) assessment within 3 months and MRI within 12 months around blood sampling at baseline (y0) and follow-up (y6). EDSS progression at y6 had to be confirmed 12 weeks later. sNfL was measured by single-molecule array, and the following additional variables were recorded: therapy, medical history, and detailed MRI parameters (T2 hyperintense lesions, Gd+ lesions, and new persistent T1 hypointense lesions)., Results: Patients experiencing EDSS progression or new persistent T1 lesions at y6 showed increased sNfL levels at y0 compared with stable patients or patients with inflammatory activity only. As a potential readily accessible marker of neurodegeneration, we incorporated the absence of persistent T1 lesions to the NEDA-3 concept (NEDA-3 T1 : n = 54, 35.3%; EDA T1 : n = 99, 64.7%) and then evaluated a risk score with factors that distinguish patients with and without NEDA-3 T1 status. Adding sNfL to this risk score significantly improved NEDA-3 T1 prediction (0.697 95% CI 0.616-0.770 vs 0.819 95% CI 0.747-0.878, p < 0.001). Patients with sNfL values ≤8.6 pg/mL showed a 76% risk reduction for EDA T1 at y6 (hazard ratio 0.244, 95% CI 0.142-0.419, p < 0.001)., Discussion: sNfL levels associate with severe focal axonal damage as reflected by development of persistent T1 lesions. Baseline sNfL values predicted NEDA-3 T1 status at 6-year follow-up., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: To increase the validity of biomarker measures in multiple sclerosis (MS), factors affecting their concentration need to be identified. Here, we test whether the volume of distribution approximated by the patients' estimated blood volume (BV) and body mass index (BMI) affect the serum concentrations of glial fibrillary acidic protein (GFAP). As a control, we also determine the relationship between BV/BMI and GFAP concentrations in CSF. To confirm earlier findings, we test the same hypotheses for neurofilament light chain (NfL)., Methods: NfL and GFAP concentrations were measured in serum and CSF (sNFL/sGFAP and cNFL/cGFAP) in 157 patients (n = 106 with MS phenotype and n = 51 with other neurologic/somatoform diseases). Using multivariate linear regressions, BV was tested in the MS cohort as a predictor for each of the biomarkers while controlling for age, sex, MS phenotype, Expanded Disability Status Scale score, gadolinium-enhancing lesions, and acute relapse. In addition, overweight/obese patients (BMI ≥25 kg/m 2 ) were compared with patients with BMI <25 kg/m 2 using the general linear model. The analyses were repeated including the neurologic/somatoform controls., Results: In the MS cohort, BV predicted sGFAP (ß = -0.301, p = 0.014). Overweight/obese patients with MS had lower sGFAP concentrations compared with patients with MS and BMI <25 kg/m 2 (F = 4.732, p = 0.032). Repeating the analysis after adding patients with other neurologic/somatoform diseases did not change these findings (ß = -0.276, p = 0.009; F = 7.631, p = 0.006). Although sNfL was inversely correlated with BV (r = -0.275, p = 0.006) and body weight (r = -0.258, p = 0.010), those results did not remain significant after adjusting for covariates. BV and BMI were not associated with cGFAP or cNfL concentrations., Discussion: These findings support the notion that the volume of distribution of sGFAP approximated by BV and BMI is a relevant variable and should therefore be controlled for when measuring sGFAP in MS, while this might not be necessary when measuring cGFAP concentrations., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Adapted ketogenic diet (AKD) and caloric restriction (CR) have been suggested as alternative therapeutic strategies for multiple sclerosis (MS), but information on their impact on neuroaxonal damage is lacking. Thus, we explored the impact of diets on serum neurofilament light chain (sNfL) levels in patients with relapsing-remitting MS., Methods: We retrospectively evaluated a prospective randomized controlled trial of 60 patients with MS who were on a common diet or ketogenic diet or fasting. We examined sNfL levels of 40 participants at baseline and at the end of the study after 6 months using single molecule array assay., Results: sNfL levels were investigated in 9 controls, 14 participants on CR, and 17 participants on AKD. Correlation analysis showed an association of sNfL with age and disease duration; an association was also found between sNfL and the Multiple Sclerosis Functional Composite. AKD significantly reduced sNfL levels at 6 months compared with the common diet group ( p = 0.001)., Discussion: For clinical or study use, consider that AKD may incline sNfL levels independent of relapse activity up to 3 months after initiation. At 6 months, AKD, which complements current therapies, reduced sNfL levels, therefore suggesting potential neuroprotective effects in MS. A single cycle of seven-day fasting did not affect sNfL. AKD may be an addition to the armamentarium to help clinicians support patients with MS in a personalized manner with tailored diet strategies., Trial Registration Information: Clinical trial registration number NCT01538355., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilamentandlongtermoutcome inMS (NaloMS) cohort., Methods: The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome) and validated with an external independent cohort (Düsseldorf, Essen, n=204). Both relapse-free EDSS-progression (RFP: inflammatory-independent EDSS-increase 12 months prior to FU) and SPMS-transition (minimum EDSS-score of 3.0) were investigated., Findings: During the study period, 17% (n=34) of NaloMS patients suffered from RFP and 14% (n=27) converted to SPMS at FU (validation cohort RFP n=42, SPMS-conversion n=24). sNfL at BL was increased in patients with RFP (10.8 pg/ml (interquartile range (IQR) 7.7-15.0) vs. 7.2 pg/ml (4.5-12.5), p<0.017). In a multivariable logistic regression model, increased sNfL levels at BL (Odds Ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04, p=0.012) remained an independent risk factor for RFP and predicted individual RFP risk with an accuracy of 82% (NaloMS) and 83% (validation cohort) as revealed by support vector machine. In addition, the sNfL FU/BL ratio was increased in SPMS-converters (1.16 (0.89-1.70) vs. 0.96 (0.75-1.23), p=0.011). This was confirmed by a multivariable logistic regression model, as sNfL FU/BL ratio remained in the model (OR 1.476, 95%CI 1.078-2,019, p=0.015) and individual sNfL FU/BL ratios showed a predictive accuracy of 72% in NaloMS (63% in the validation cohort) as revealed by machine learning., Interpretation: sNfL levels at baseline predict relapse-free disability progression in a prospective longitudinal cohort study 6 years later. While prediction was confirmed in an independent cohort, sNfL further discriminates patients with SPMS at follow-up and supports early identification of patients at risk for later SPMS conversion., Funding: This work was supported by the German Research Council (CRC-TR-128), Else Kröner Fresenius Foundation and Hertie-Stiftung., Competing Interests: Declaration of Competing Interest Timo Uphaus has received honoraria from Merck Serono. Tobias Ruck has received travel grants and financial research support from Genzyme and Novartis and received honoraria for lecturing from Roche, Merck, Genzyme, Biogen, and Teva. Sven G. Meuth has received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. Frauke Zipp has recently received research grants and/or consultation funds from DFG, BMBF, PMSA, Genzyme, Janssen, Merck Serono, Roche, Novartis, Celgene, and Sanofi-Aventis. Stefan Bittner has received honoraria and compensation for travel from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Roche. The other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Falk Steffen, Vinzenz Fleischer, Muthuraman Muthuraman, Sergiu Groppa, and Mark Mühlau declare no competing interests. Stefan Bittner has received honoria and compensation for travel from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Roche. Timo Uphaus received honoria from Merck Serono. Carsten Lukas received consulting and speaker's honoraria from BiogenIdec, Bayer Schering, Novartis, Sanofi, Genzyme, and TEVA; has received research scientific grant support from Bayer Schering, TEVA, and Merck Serono; holds an endowed professorship supported by the Novartis Foundation. Anke Salmen received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme and research support by the Swiss MS Society, none related to this work. Felix Luessi received consultancy fees from Roche and support with travel cost from Teva Pharma. Achim Berthele reports personal fees from Bayer Healthcare, Biogen, Merck Serono, Mylan, Roche, and Sanofi Genzyme, and his institution received compensations for clinical trials from Alexion Pharmaceuticals, Biogen, Chugai, Novartis, Roche, Sanofi Genzyme, and Teva - all outside the submitted work. Luisa Klotz received honoraria for lecturing and serving on advisory boards, as well as travel expenses for attending meetings and financial research support from Immunic AG, Biogen, Janssen, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva, Grifols, Alexion, Santhera, Bayer Healthcare, the Deutsche Forschungsgemeinschaft (DFG; German Research Society), the German Ministry for Education and Research (BMBF), the Interdisciplinary Center for Clinical Studies (IZKF) Muenster and the program Innovative Medical Research (IMF) Muenster. Sven G. Meuth receives honoraria for lecturing, and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. Antonios Bayas received personal compensation from Merck, Biogen, Bayer Vital, Novartis, TEVA, Roche and Sanofi-Aventis/Genzyme and grants for congress trips and participation from Biogen, TEVA, Novartis, Sanofi-Aventis/Genzyme, and Merck. Friedemann Paul receives honoraria for lecturing, and travel expenses for attending meetings from Guthy Jackson Foundation, Sanofi Genzyme, Novartis, Alexion, Viela Bio, Roche, UCB, Mitsubishi Tanabe and Celgene. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Teva, Alexion, Roche, Parexel and Almirall. Hans-Peter Hartung has received fees for consulting, serving on steering committees and data monitoring committees from Bayer Healthcare, Biogen, GeNeuro, Medimmune, Merck, Novartis, Roche, Sanofi Genzyme, Teva and TG Therapeutics with approval by the Rector of Heinrich-Heine-University. Ralf Linker received Research Support and/or personal compensation for activities with Bayer Health Care, Biogen, Genzyme/Sanofi, Merck, Novartis Pharma, Roche, and TEVA Pharma; none related to this work. Christoph Heesen received research grants and speaker honoraria from Biogen, Genzyme, Roche, and Merck; none related to this work. Martin Stangel received honoraria for scientific lectures or consultancy from Alexion, Bayer Healthcare, Biogen, CSL Behring, Grifols, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Takeda, and Teva. His institution received research support from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva; none related to this work. Brigitte Wildemann received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck Serono, Sanofi Genzyme, Novartis pharmaceuticals, and personal fees from Bayer Healthcare, Biogenm, Teva Pharma; none related to this work. Florian Then Bergh received travel support to attend scientific meetings, personal speaker honoraria, and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. He received, through his institution, unrestricted research grants from Novartis, TEVA, Bayer Healthcare, and Actelion; none related to this work. He received funding from the DFG and, through TRM Leipzig, from the BMBF. Björn Tackenberg received personal speaker honoraria and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, CSL Behring, GRIFOLS, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, TEVA und UCB Pharma. His University received unrestricted research grants from Biogen-idec, Novartis, TEVA, Bayer Healthcare, CSL-Behring, GRIFOLS, Octapharma, Sanofi Genzyme und UCB Pharma; none related to this work. He is currently an employee of Roche. The data collection, evaluation and drafting of the manuscript was performed before beginning employment at Roche. Tania Kuempfel has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis, Sanofi-Aventis/Genzyme, Roche and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma. Frank Weber received honoraria from Genzyme, Novartis TEVA and Biogen for speaking or for serving on a scientific advisory board, a travel grant for the attention of a scientific meeting from Merck-Serono and Novartis and grant support from Merck-Serono, Novartis and from the Federal Ministry of Education and Research (BMBF, Projects Biobanking and Omics in ControlMS as part of the Competence Network Multiple Sclerosis). Uwe K. Zettl received speaker fees, travel compensation and/or his section received research support from Alexion, Almirall, Bayer Health Care, Biogen, Celgene, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, Teva and grants from German Ministry for Education and Research (BMBF), German Ministry for Economy (BMWi), Deutsche Forschungsgemeinschaft (DFG), European Union (EU), outside the submitted work. Ulf Ziemann received speaker honoraria and/or travel compensation from Biogen Idec GmbH, Bayer Vital GmbH, Bristol Myers Squibb GmbH, CorTec GmbH, Medtronic GmbH, and grants from Biogen Idec GmbH, Servier, and Janssen Pharmaceuticals NV; none related to this work. Hayrettin Tumani received speaker honoraria from Bayer, Biogen, Fresenius, Genzyme, Merck, Novartis, Roche, Siemens, Teva; serves as section editor for the Journal of Neurology, Psychiatry, and Brain Research; and his institution receives research support from Fresenius, Genzyme, Merck, and Novartis; none related to this work. Bernhard Hemmer served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Polpharma, and TG therapeutics; he or his institution have received speaker honoraria from Desitin; his institution has received research support from Regeneron; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralising antibodies to interferon β during the last 3 years. Heinz Wiendl receives honoraria for acting as a member of Scientific Advisory Boards and as a consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Global. Prof. Wiendl is acting as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. His research is funded by the BMBF, DFG, Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen GmbH, GlaxoSmithKline GmbH, and Roche Pharma AG, Sanofi-Genzyme. Ralf Gold serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis; none related to this work. Frauke Zipp has recently received research grants and/or consultation funds from the DFG, BMBF, PMSA, Novartis, Octapharma, Merck Serono, ONO Pharma, Biogen, Genzyme, Celgene and Roche., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)