Memory B cell-guided extended interval dosing of ocrelizumab in multiple sclerosis.

BACKGROUND: Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody approved for the treatment of relapsing-remitting and primary-progressive multiple sclerosis (MS). We aimed to evaluate the effectiveness of an individualized OCR extended interval dosing (EID), after switching from standard interval dosing (SID). METHODS: This was a retrospective, observational, single-centre study including MS patients regularly followed at the Neurocenter of Southern Switzerland. After a cumulative OCR dose ⩾1200 mg, stable patients were switched to EID (OCR infusions following CD19+ 27+ memory B cell repopulation). RESULTS: A total of 128 patients were included in the study, and 113 (88.3%) were switched to EID with a median interval of 9.9 (8.8-11.8) months between infusions. No clinical relapses occurred; 2 (1.8%) patients experienced disability worsening. Three (2.7%) and 2 (1.8%) patients experienced new T2 brain and spinal lesions, respectively. There was a mild decrease in IgG and IgM concentrations during both SID and EID OCR regimens (ß = -0.23, p = 0.001 and ß = -0.07, p < 0.001, respectively). CONCLUSION: Switch to personalized dosing of OCR based on CD19+ 27+ memory B cell repopulation led to a great extension of the interval between infusions, with maintained clinical and radiological efficacy. Given the potential advantages in terms of safety and health costs, EID OCR regimens should be further investigated.

Efficacy and safety of the implantable, magnetic resonance imaging-compatible StimRouter neuromodulation system in the treatment of refractory lower urinary tract symptoms in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Lower urinary tract symptoms (LUTS) significantly affect quality of life (QoL) of multiple sclerosis (MS) patients, and pharmacotherapy has limited efficacy. We investigated efficacy and safety of the implantable StimRouter neuromodulation system for treating refractory LUTS in MS. METHODS: This prospective, single-center, clinical trial was conducted at the Multiple Sclerosis Center of Lugano, Switzerland, involving MS patients treated with self-administered percutaneous tibial nerve stimulation delivered by StimRouter over 24 weeks. Changes in video-urodynamic parameters as well as LUTS severity were measured by Overactive Bladder Questionnaire (OAB-q), QoL using the Multiple Sclerosis Quality of Life (MSQoL-54), and treatment satisfaction using a 1-10 visual analogue scale. Adverse events were also recorded. RESULTS: Of 23 MS patients recruited, six had neurogenic detrusor overactivity (NDO), five had detrusor sphincter dyssynergia (DSD), and 12 had both NDO and DSD. Of patients with NDO, median bladder volume at first uninhibited contraction significantly increased from baseline to week 24 (median = 136 mL, interquartile range [IQR] = 101-244 mL vs. 343 mL, IQR = 237-391 mL; ß = 138.2, p = 0.001). No significant changes of urodynamic parameters were found in patients with DSD. OAB-q symptom scores progressively decreased, and OAB-q quality of life scores increased (ß = -0.50, p < 0.001 and ß = 0.47, p < 0.001, respectively), whereas MSQoL-54 scores did not significantly change (ß = 0.24, p = 0.084) in the overall population. Treatment satisfaction was overall high (median = 8, IQR = 6-9). No serious adverse events were recorded. CONCLUSIONS: StimRouter represents a minimally invasive, magnetic resonance imaging-compatible, self-administered neuromodulation device leading to objective and subjective improvements of OAB symptoms and related QoL in MS patients with refractory LUTS.

A Multicenter Longitudinal MRI Study Assessing LeMan-PV Software Accuracy in the Detection of White Matter Lesions in Multiple Sclerosis Patients.

BACKGROUND: Detecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan-PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow-up of MS patients; however, multicenter validation studies are lacking. PURPOSE: To assess the accuracy of LeMan-PV for the longitudinal detection NEL white-matter MS lesions in a multicenter clinical setting. STUDY TYPE: Retrospective, longitudinal. SUBJECTS: A total of 206 patients with a definitive MS diagnosis and at least two follow-up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow-up = 45.2 years (range: 36.9-52.8 years); 70 males. FIELD STRENGTH/SEQUENCE: Fluid attenuated inversion recovery (FLAIR) and T1-weighted magnetization prepared rapid gradient echo (T1-MPRAGE) sequences at 1.5 T and 3 T. ASSESSMENT: The study included 313 MRI pairs of datasets. Data were analyzed with LeMan-PV and compared with a manual "reference standard" provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating-accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1-score, lesion-wise False-Positive-Rate (aFPR), and other measures were used to assess LeMan-PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T. STATISTICAL TESTS: Intraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers. RESULTS: The interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue < 10-20 , CK = 0.82, P value = 0) and good (ICC = 0.75, P value < 10-12 , CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan-PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1-score = 0.44, aFPR = 1.31. When both follow-ups were acquired at 3 T, LeMan-PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1-score = 0.28, aFPR = 3.03). DATA CONCLUSION: In this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan-PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan-PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological-routine flow. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Interplay between age and disease-modifying treatments in influencing infection risk in multiple sclerosis.

BACKGROUND: Disease-modifying treatments (DMTs) can increase the risk of infections in multiple sclerosis (MS). Aged individuals are usually excluded from clinical trials, and there is uncertainty regarding safety of immunosuppressive DMTs in these patients. OBJECTIVE: To investigate the association of DMTs, ageing and other clinical variables with risk of infections in MS patients. METHODS: Prospective single-centre observational study collecting information on occurrence, type and grade of infections in patients followed at the MS centre, Lugano (Switzerland). Associations with infection risk were tested using multivariable Poisson and Cox regressions. RESULTS: A total of 503 patients were included (injectables/untreated, n = 127; orals, n = 139; monoclonal antibodies (MAB), n = 237) and 326 infections recorded over 12.6 (11.6-14.0) months. As compared to injectable DMTs/no treatment, MAB and oral DMTs were positively associated with infection incidence (IRR = 2.32, 95% confidence interval (CI) = 1.39-3.89, p = 0.001; IRR = 2.04, 95% CI = 1.19-3.49, p = 0.009, respectively). After excluding COVID-19, the effect of MAB was stronger among patients <50 years (IRR = 5.90, 95% CI = 2.80-12.45, p < 0.001) than >50 years (IRR = 1.95, 95% CI = 0.91-4.15, p = 0.084). Higher disability and male sex were the only variables associated with severe infections. CONCLUSION: Treatment with MAB and oral DMTs is associated with higher incidence of infections, with a stronger effect in young MS patients. Disability appears the main predictor of severe infections regardless of treatment.

Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies.

Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear palsy and corticobasal degeneration. However, pathological τ has also been observed in α-synucleinopathies like Parkinson's disease and multiple system atrophy. Based on the involvement of the peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibres in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 kDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both were more expressed in progressive supranuclear palsy/corticobasal degeneration by real-time PCR. Enzyme-linked immunosorbent assay demonstrated significantly higher levels of total τ protein in skin lysates of progressive supranuclear palsy/corticobasal degeneration compared to the other groups. Multivariate regression analysis and receiver operating characteristics curve analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for progressive supranuclear palsy/corticobasal degeneration versus Parkinson's disease (sensitivity 90%, specificity 69%) and progressive supranuclear palsy/corticobasal degeneration versus multiple system atrophy (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in progressive supranuclear palsy/corticobasal degeneration. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiological and pathological conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

OBJECTIVE: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. METHODS: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgGIF and IgMIF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. RESULTS: By categorical analysis, in patients with IgMIF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgMIF < median. Dose-dependent associations were also found for IgMIF but not for IgGIF with magnetic resonance imaging-defined disease activity and sNfL. INTERPRETATION: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.

De-escalating rituximab dose results in stability of clinical, radiological, and serum neurofilament levels in multiple sclerosis.

BACKGROUND: Phase II and observational studies support the use of rituximab in multiple sclerosis. Standard protocols are lacking, but studies suggest comparable efficacy between low- and high-dose regimens. OBJECTIVE: To evaluate effectiveness and safety of de-escalating rituximab dose from 1000 to 500 mg/6 months in multiple sclerosis. METHODS: Patients were switched from rituximab 1000 to 500 mg/6 months and prospectively followed for 12 months. Relapses, disability, occurrence of brain/spinal magnetic resonance imaging (MRI) lesions, serum neurofilament light chain (NfL), CD19+ B cell, and IgG concentrations were analyzed. RESULTS: Fifty-nine patients were included (37 relapsing-remitting, 22 secondary progressive). No relapses occurred, with no difference in expanded disability status scale (EDSS) between baseline (4 (2.5-4.5) and 12 months (3.5 (2.5-5.5) p = 0.284). Overall, three new T2 lesions appeared during follow-up. NfL concentration was stable between baseline (7.9 (5.9-45.2) pg/mL) and 12 months (9.1 (5.9-21.3) pg/mL, p = 0.120). IgG concentrations decreased with greater rituximab load (coefficient = -0.439, p = 0.041). IgG deficient patients had greater risk of infections (OR = 6.27, 95% CI = 1.71-22.9, p = 0.005). CONCLUSION: De-escalating rituximab dose from 1000 to 500 mg/6 months is safe, results in clinical and radiological stability, and does not affect serum NfL over 12 months. Rituximab load negatively influences IgG concentrations, and IgG deficient patients are at higher risk of infections.

Effectiveness of percutaneous posterior tibial nerve stimulation for the management of bowel dysfunction in multiple sclerosis patients.

BACKGROUND: Neurogenic bowel dysfunctions (NBDs) in the form of both fecal incontinence (FI) and functional constipation (FC) are frequent in multiple sclerosis (MS) patients and significantly affect their quality of life. Therapeutic options are limited. OBJECTIVE: To investigate effectiveness of percutaneous posterior tibial nerve stimulation (PTNS) in MS patients suffering from FI and FC. METHODS: Prevalence and severity of FI and FC were prospectively collected among MS patients undergoing 12 weeks of PTNS for neurogenic bladder. The Cleveland Clinic Fecal Incontinence Score (CCFIS) and the Rome III criteria were used to define FI and FC, respectively. Subjective treatment satisfaction was estimated using the Benefit Satisfaction and Willingness to Continue (BSWC) questionnaire. RESULTS: A total of 60 patients undergoing PTNS suffered from NBDs (25 FI+/FC+, 5 FI+/FC-, 30 FI-/FC+). Median CCFIS decreased after PTNS from 12.0 (11.0-13.0) to 8.5 (7.0-11.0, p < 0.001), with particular improvements in liquid and flatal incontinence, pads' need, and lifestyle restrictions. Seven patients became FC free after PTNS and no patients developed FC during the study (p = 0.023). More than 50% of the patients were satisfied and willing to continue PTNS at study end. CONCLUSION: PTNS represents a valid minimally invasive alternative treatment for MS patients suffering from NBDs.

Contribution of sleep disturbances to fatigue in multiple sclerosis: a prospective study using clinical and polysomnographic parameters.

BACKGROUND AND PURPOSE: Fatigue is amongst the most frequent and disabling symptoms of multiple sclerosis and a close relation between fatigue and sleep quality has been hypothesized. In this study the contribution of sleep disturbances measured by clinical and polysomnographic parameters to fatigue in multiple sclerosis was investigated. METHODS: This was a prospective instrumental study performed at the Neurocenter of Southern Switzerland. Demographic data and clinical characteristics including fatigue (as measured by the modified fatigue impact scale [MFIS]), neurological disability, psychiatric symptoms, medications and sleep-related variables were collected at baseline visit and by a home full-night polysomnography. The associations between sleep-related variables and the MFIS were tested using partial correlations adjusted by demographic and sleep-unrelated clinical factors. RESULTS: Seventy-six patients were included in the study, of whom 53 (69.7%) had an MFIS ≥38 points (median 49.5, interquartile range 31.0-62.0). MFIS scores were positively associated with age, neurological disability, symptoms of depression and anxiety, and use of benzodiazepines and selective serotonin reuptake inhibitors. When adjusting for these variables, the presence of restless legs syndrome (RLS) (r = 0.37, p = 0.005) and periodic leg movements index (r = -0.33, p = 0.014) were associated with MFIS. Excessive daytime sleepiness, total sleep time, sleep efficiency, respiratory disturbances, and percentage of time spent in the different sleep stages (N1, N2, N3 and rapid eye movement) were not associated with fatigue. CONCLUSIONS: Multiple sclerosis patients with a diagnosis of RLS had significantly higher global fatigue scores compared to those without RLS. Future studies should investigate whether medical treatment of RLS can ameliorate fatigue.

Serum neurofilament measurement improves clinical risk scores for outcome prediction after cardiac arrest: results of a prospective study.

BACKGROUND: A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. METHODS: This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. RESULTS: Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p < 0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p < 0.001) and CAHP score (from AUC 0.89 to 0.92, p < 0.05). Adding NfL to both scores also resulted in significant improvement in reclassification statistics with a Net Reclassification Index (NRI) of 0.58 (p < 0.001) for OHCA and 0.83 (p < 0.001) for CAHP. CONCLUSIONS: Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

Neurofilament light levels are associated with long-term outcomes in multiple sclerosis.

BACKGROUND: Neurofilament light chain (NfL) is a promising marker of disease activity/treatment response in multiple sclerosis (MS), although its predictive value for long-term clinical outcomes remains unclear. OBJECTIVE: We measured NfL from a phase 3 trial in relapsing-remitting MS and investigated its association with outcomes after 8 and 15 years. METHODS: NfL concentrations were measured by single molecule array assay in cerebrospinal fluid (CSF) from MS patients (n = 235) in a 2-year randomized clinical trial (RCT) of intramuscular interferon ß-1a, and in serum (n = 164) from the extension study. RESULTS: Year 2 CSF and Year 3 serum NfL were associated with brain parenchymal fraction (BPF) change over 8 years (p < 0.0001, r = -0.46; p < 0.05. r = -0.36, respectively) and were predictive of reaching Expanded Disability Status Scale (EDSS) ⩾ 6.0 at Year 8 (odds ratio (OR) (upper vs lower tertile) = 3.4; 95% confidence interval (CI) = 1.2-9.9, p < 0.05; OR = 11.0, 95% CI = 2.0-114.6; p < 0.01, respectively). Serum NfL concentration (Year 4) was predictive of reaching EDSS score ⩾6.0 at 15 years (OR (upper vs lower tertile) = 4.9; 95% CI = 1.4-20.4; p < 0.05). NfL concentrations were complementary to 2-year BPF change in predicting long-term outcomes. CONCLUSION: Serum and CSF NfL concentrations were associated with long-term clinical outcomes in MS patients and are promising biomarkers for disease severity stratification supporting treatment decisions.

Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease.

Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR), whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects the binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (>2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. The approach's validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels.

Prodromal symptoms of multiple sclerosis in primary care.

OBJECTIVE: Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings. METHODS: This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p < 0.001; 2-5 years: OR = 1.29, 95% CI = 1.25-1.33, p < 0.001; 5-10 years: OR = 1.20, 95% CI = 1.15-1.26, p < 0.001). Sensitivity analyses in patients with age at index < 40 years and no neurological disturbances prior to symptoms of interest showed consistent results. INTERPRETATION: Various clinical disturbances precede MS diagnosis by several years, supporting a prodromal phase to the disease and improving our clinical knowledge of early MS. Integrating these symptoms in the diagnostic procedure may help earlier disease identification. Ann Neurol 2018.

Use of glatiramer acetate between 2010-2015: effectiveness, safety and reasons to start GA as first or second line treatment in Swiss multiple sclerosis patients.

BACKGROUND: Glatiramer acetate (GA) is one of the first therapies approved for multiple sclerosis (MS). We prospectively included and monitored drug-naïve and pre-treated MS patients who had been prescribed GA for 1 year, to investigate reasons for GA prescription, its effectiveness and safety in real life clinical practice. METHODS: One year, prospective, multicentre, observational study performed between 2010 and 2015 in consecutive MS and clinically isolated syndrome patients starting GA as a first ("naïve") or second ("switcher") line therapy. Primary endpoint was the annualized relapse rate (ARR) over 1 year of GA treatment (from baseline, V1, to 12 months, V2) in naïve and switchers compared to previous 24 months. Secondary endpoints were: EDSS changes between V1 and V2, frequency of adverse events, and reasons for prescribing and discontinuing GA. Baseline demographics and clinical characteristics were retrieved from medical records, and outcome measures were documented at V1 and V2, and in case of clinical worsening. RESULTS: One hundred ninety-four consecutive patients were monitored over 12 months (N = 64 naïve, N = 130 switchers). Side effect profile (naïve = 36%, switchers = 28%) and comorbidities (naïve = 31%, switchers = 15%) were the most frequent reasons to start GA. The ARR was reduced in both naïve and switchers during V1-2 as compared to the 24 months preceding V1 [naïve: 0.0 (0.0-0.0) vs 0.5 (0.5-1.0, p = 2.9e-10); switchers: 0.0 (0.0-0.0) vs 0.5 (0.0-0.5, p = 0.022)]. EDSS at V2 was significantly reduced only in naïve [(1.5 (1.0-2.5) vs 2.0 (1.5-2.5), p = 0.003)]. Naïve status and EDSS at V1 were negatively associated with EDSS change between V1-V2 in multivariable analysis (regression coefficient = - 0.436, p = 0.008, and regression coefficient = - 0.263, p = 6.18e-05, respectively). No new unexpected AE was reported. CONCLUSION: In our Swiss cohort, GA was prescribed mainly to naïve or switcher MS patients fearing interferon related side effects, with various comorbidities or considering pregnancy, and showed effectiveness and safety comparable with data of previous GA studies.

Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis.

Neuro-axonal injury is a key factor in the development of permanent disability in multiple sclerosis. Neurofilament light chain in peripheral blood has recently emerged as a biofluid marker reflecting neuro-axonal damage in this disease. We aimed at comparing serum neurofilament light chain levels in multiple sclerosis and healthy controls, to determine their association with measures of disease activity and their ability to predict future clinical worsening as well as brain and spinal cord volume loss. Neurofilament light chain was measured by single molecule array assay in 2183 serum samples collected as part of an ongoing cohort study from 259 patients with multiple sclerosis (189 relapsing and 70 progressive) and 259 healthy control subjects. Clinical assessment, serum sampling and MRI were done annually; median follow-up time was 6.5 years. Brain volumes were quantified by structural image evaluation using normalization of atrophy, and structural image evaluation using normalization of atrophy, cross-sectional, cervical spinal cord volumes using spinal cord image analyser (cordial). Results were analysed using ordinary linear regression models and generalized estimating equation modelling. Serum neurofilament light chain was higher in patients with a clinically isolated syndrome or relapsing remitting multiple sclerosis as well as in patients with secondary or primary progressive multiple sclerosis than in healthy controls (age adjusted P < 0.001 for both). Serum neurofilament light chain above the 90th percentile of healthy controls values was an independent predictor of Expanded Disability Status Scale worsening in the subsequent year (P < 0.001). The probability of Expanded Disability Status Scale worsening gradually increased by higher serum neurofilament light chain percentile category. Contrast enhancing and new/enlarging lesions were independently associated with increased serum neurofilament light chain (17.8% and 4.9% increase per lesion respectively; P < 0.001). The higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss: serum neurofilament light chain above the 97.5th percentile was associated with an additional average loss in brain volume of 1.5% (P < 0.001) and spinal cord volume of 2.5% over 5 years (P = 0.009). Serum neurofilament light chain correlated with concurrent and future clinical and MRI measures of disease activity and severity. High serum neurofilament light chain levels were associated with both brain and spinal cord volume loss. Neurofilament light chain levels are a real-time, easy to measure marker of neuro-axonal injury that is conceptually more comprehensive than brain MRI.

Serum neurofilament light chain as a prognostic marker in postanoxic encephalopathy.

Functional outcome in patients with postanoxic encephalopathy after cardiac arrest (CA) often remains unclear, and there is a strong need of new prognostication measures. We aimed at investigating serum neurofilament light (NfL) chain concentration in patients with a postanoxic encephalopathy after CA and its prognostic potential. Serum samples were prospectively collected at different time points after CA in consecutive patients admitted to the intensive care unit (ICU) of Ticino Cardiocentre (Lugano, Switzerland) between June 2017 and March 2018. Serum NfL concentration was measured using a single molecule array (SIMOA) assay. The association of NfL levels with time to return of spontaneous circulation (ROSC), serum neuronal specific enolase (NSE) concentration, time between CA and sample collection, electroencephalogram (EEG) pattern and clinical outcome (death status at one month) were explored. Fourteen patients experiencing 15 CAs were included in the study (median age = 58 (57-68) years, 8 males). Median serum NfL concentration was 1027.0 (25.5-6033.7) pg/ml. There were positive associations between serum NfL and time to ROSC (rho = 0.60, p < 0.0001), NSE concentration (rho = 0.76, p < 0.0001), and severity of brain damage as estimated by EEG, with the highest concentrations measured in patients with suppressed electrical activity (14,954.0 [9006.0-25,364.0] pg/ml). Neurofilament light concentration remained high in samples collected up to 17 days after CA. Median NfL levels were higher among dead than alive patients at one month (6401.7 [3768.5-15,573.3] vs 25.5 [25.2-75.4] pg/ml). High NfL levels performed better than NSE in predicting death status at one month (NfL area under the curve (AUC) = 0.98, 95% confidence interval (CI) = 0.94-1.00; NSE AUC = 0.80, 95% CI = 0.67-0.94). These results support the potential inclusion of serum NfL in the battery of prognostication measures to be used in patients with postanoxic encephalopathy in ICU settings. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis.

OBJECTIVE: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS). METHODS: sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross-sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow-up = 3.1 years, interquartile range [IQR] = 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes. RESULTS: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (ß = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR = 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9-41.8; ß = 1.461, p = 0.005 and ß = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (ß = 1.105, p < 0.001) and presence of relapses (ß = 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (ß = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21-3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07-5.42, p = 0.034). INTERPRETATION: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017;81:857-870.

Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis.

BACKGROUND: Epstein-Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis (MS). OBJECTIVES: To investigate the effect of high-dose vitamin D3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti-EBNA-1 antibody levels. METHODS: This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D3 (14,000 IU/day; n = 30) or placebo ( n = 23) over 48 weeks. Circulating levels of 25-hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti-cytomegalovirus (CMV) antibodies were measured. EBV load in leukocytes, EBV-specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored. RESULTS: The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D3 group (526 (368-1683) to 455 (380-1148) U/mL) compared to the placebo group (432 (351-1280) to 429 (297-1290) U/mL; p = 0.023). EBV load and cytotoxic T-cell responses were unaffected. Anti-EBNA-1 antibody levels remained below detection limits in B-cell cultures. CONCLUSION: High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.

Half-dose fingolimod for treating relapsing-remitting multiple sclerosis: Observational study.

OBJECTIVES: To investigate the efficacy and safety of fingolimod (FTY) 0.5 mg administered every other day (FTY-EOD) compared to every day (FTY-ED) in multiple sclerosis patients. METHODS: Multicentre retrospective observational study. Clinical, laboratory and neuroimaging data were consecutively collected from 60 FTY-EOD and 63 FTY-ED patients. Baseline characteristics were compared using logistic regression. Efficacy in preventing occurrence of relapses and demyelinating lesions was tested using propensity score-adjusted Cox and linear regressions. RESULTS: Weight was inversely associated with risk of switch to FTY-EOD because of any reason (odds ratio (OR) = 0.94, 95% confidence interval (95% CI) = 0.89-0.99, p = 0.026), and female sex and lower baseline lymphocyte count were positively associated with switch because of lymphopenia. Compared to FTY-ED patients, FTY-EOD patients were at higher risk of developing relapses (hazard ratio (HR) = 2.98, 95% CI = 1.07-8.27, p = 0.036) and either relapses or new magnetic resonance imaging (MRI) demyelinating lesions (combined outcome, HR = 2.07, 95% CI = 1.06-4.08, p = 0.034). Within FTY-EOD, treatment with natalizumab before FTY and lower age were positively associated with risk of developing relapses and combined outcome, respectively (HR = 25.71, 95% CI = 3.03-217.57, p = 0.002 and HR = 0.85, 95% CI = 0.77-0.96, p = 0.005). FTY-EOD was overall well tolerated. CONCLUSION: Disease reactivation was observed in a significant proportion of patients treated with FTY-EOD. Neurologists should be cautious when reducing FTY administration to every other day, especially in younger patients and those previously treated with natalizumab.

The Swiss Multiple Sclerosis Registry (SMSR): study protocol of a participatory, nationwide registry to promote epidemiological and patient-centered MS research.

BACKGROUND: Multiple sclerosis (MS) is one of the most frequently observed neurological conditions in Switzerland, but data sources for country-wide epidemiological trend monitoring are lacking. Moreover, while clinical and laboratory MS research are generally well established, there is a gap in patient-centered MS research to inform care management, or treatment decisions and policy making not only in Switzerland but worldwide. METHODS: In light of these research gaps, the Swiss Multiple Sclerosis Society initiated and funded the Swiss Multiple Sclerosis Registry (SMSR) an open-ended, longitudinal and prospective, nationwide, patient-centered study. The SMSR recruits adult persons with a suspected or confirmed MS diagnosis who reside or receive care in Switzerland. The SMSR has established a governance structure with clear rules and guidelines. It follows a citizen-science approach with direct involvement of persons with MS (PwMS), who contribute actively to registry development, operations, and research. Main scientific goals entail the study of MS epidemiology in Switzerland, health care access and provision, as well as life circumstances and wellbeing of persons with MS. The innovative study design ("layer model") offers several participation options with different time commitments. Data collection is by means of regular surveys and medical record abstraction. Survey participation is offered in different modes (web, paper & pencil) and in the three main national languages (German, French, Italian). Participants also receive regular data feedbacks for personal use and self-monitoring, contextualized in the whole population of study participants. Data feedbacks are also used to solicit data corrections of key variables from participants. DISCUSSION: The SMSR combines the advantages of traditional and novel research methods in medical research and has recruited over 1600 PwMS in its first year. The future-oriented design and technology will enable a response not only to future technological innovations and research trends, but also to challenges in health care provision for MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT02980640 ; December 6, 2016; retrospectively registered.