Narrative Review on the Use of Cladribine Tablets as Exit Therapy for Stable Elderly Patients with Multiple Sclerosis.

The number of ageing people with relapsing multiple sclerosis (RMS) is increasing. The efficacy of disease-modifying therapies (DMTs) for RMS declines with age. Also, older persons with MS may be more susceptible to infections, hospitalisations and malignancy. Aging people with MS have higher rates of comorbidities versus aged-matched controls, increasing the individual risk of disability. We review the therapeutic properties of cladribine tablets (CladT) in ageing people with RMS, with regard to their utility for allowing these individuals to cease continuous administration of a DMT (i.e. to act as an "exit therapy"). CladT is thought to be an immune reconstitution therapy, in that two short courses of oral treatment 1 year apart provide suppression of MS disease activity in responders that far outlasts the duration of treatment and post-treatment reductions in lymphocyte counts. Post hoc analyses, long-term follow-up of populations with RMS in randomised trials, and real-world evidence suggest that the efficacy of CladT is probably independent of age, although more data in the elderly are still needed. No clear adverse signals for lymphopenia or other adverse safety signals have emerged with increasing age, although immunosenescence in the setting of age-related "inflammaging" may predispose elderly patients to a higher risk of infections. Updating vaccination status is recommended, especially against pneumococci and herpes zoster for older patients, to minimise the risk of these infections. CladT may be a useful alternative treatment for ageing people with MS who often bear a burden of multiple comorbidities and polypharmacy and who are more exposed to the adverse effects of continuous immunosuppressive therapy.

Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop).

BACKGROUND AND PURPOSE: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. METHODS: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. RESULTS: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. CONCLUSIONS: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.

Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression. METHODS: CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient. RESULTS: CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001). DISCUSSION: CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

Visual migraine aura iconography: A multicentre, cross-sectional study of individuals with migraine with aura.

INTRODUCTION: Visual disturbances are the most common symptoms of migraine aura. These symptoms can be described systematically by subdividing them into elementary visual symptoms. Since visual symptoms of migraine aura are not easy to describe verbally, we developed a collection of images illustrating previously reported elementary visual symptoms. OBJECTIVES: To test a standardised visual migraine aura iconography in a large population of migraine with aura patients and to improve it based on the participants' feedback. METHODS: We created a set of images representing 25 elementary visual symptoms and a web-based survey where participants could report whether they recognised these images as part of their visual aura. Elementary visual symptoms could also be recognised via a corresponding text description or described in a free text by participants. Individuals with migraine aura recruited from four tertiary headache centres (in Switzerland, Denmark, Norway and Italy) were invited to complete the survey. RESULTS: Two hundred and fifteen participants completed the study (78.9% women, median age 36). They recognised a total of 1645 elementary visual symptoms from our predefined list. Of those, 1291 (78.4%) where recognised via standardised iconography images. A new type of elementary visual symptom was reported by one participant. CONCLUSION: Most elementary visual symptoms experienced by participants were recognised via the standardised iconography. This tool can be useful for clinical as well as research purposes.

Biometry extraction and probabilistic anatomical atlas of the anterior Visual Pathway using dedicated high-resolution 3-D MRI.

Anterior Visual Pathway (aVP) damage may be linked to diverse inflammatory, degenerative and/or vascular conditions. Currently however, a standardized methodological framework for extracting MRI biomarkers of the aVP is not available. We used high-resolution, 3-D MRI data to generate a probabilistic anatomical atlas of the normal aVP and its intraorbital (iOrb), intracanalicular (iCan), intracranial (iCran), optic chiasm (OC), and tract (OT) subdivisions. We acquired 0.6 mm3 steady-state free-precession images from 24 healthy participants using a 3 T scanner. aVP masks were obtained by manual segmentation of each aVP subdivision. Mask straightening and normalization with cross-sectional area (CSA) preservation were obtained using scripts developed in-house. A probabilistic atlas ("aVP-24") was generated by averaging left and right sides of all subjects. Leave-one-out cross-validation with respect to interindividual variability was performed employing the Dice Similarity Index (DSI). Spatially normalized representations of the aVP subdivisions were generated. Overlapping CSA values before and after normalization demonstrate preservation of the aVP cross-section. Volume, length, CSA, and ellipticity index (ε) biometrics were extracted. The aVP-24 morphology followed previous descriptions from the gross anatomy. Atlas spatial validation DSI scores of 0.85 in 50% and 0.77 in 95% of participants indicated good generalizability across the subjects. The proposed MRI standardization framework allows for previously unavailable, geometrically unbiased biometric data of the entire aVP and provides the base for future spatial-resolved, group-level investigations.

Calcitonin gene-related peptide antagonists in pregnancy: a disproportionality analysis in VigiBase®.

BACKGROUND: Current evidence on the safety of calcitonin gene-related peptide antagonists (CGRP-A) in pregnancy for the treatment of both episodic and chronic migraine is scarce and does not yet provide definitive information. By querying VigiBase®, the World Health Organization global pharmacovigilance database, this study aimed to detect differences in the reporting frequency between CGRP-A and triptans in relation to pregnancy. METHODS: Disproportionality analyses on de-duplicated safety reports collected in VigiBase® as of 31.05.2023 reporting exposure to CGRP-A in pregnancy with or without pregnancy outcomes. A Reporting Odds Ratio (ROR) with a 95% confidence interval (CI) was used as a measure of disproportionality and the threshold for the detection of a signal of disproportionate reporting was set with a 95% CI lower limit > 1. FINDINGS: Four hundred sixty-seven safety reports reported exposure to CGRP-A in pregnancy, mostly originating from the United States of America (360/467, 77%), more frequently reported by patients (225/467, 48%), who were mainly females (431/467, 92%), and more frequently reported exposure to CGRP-A during pregnancy (400/467, 86%). Compared to triptans, no signals of disproportionate reporting were detected with CGRP-A either for the overall reporting of pregnancy-related safety reports (ROR 0.91, 95% CI 0.78-1.06), for the reporting of pregnancy outcomes (maternal and/or foetal/neonatal, ROR 0.54, 95% CI 0.45-0.66), or for the reporting of foetal/neonatal outcomes (ROR 0.53, 95% CI 0.41-0.68). CONCLUSIONS: This study showed that, to date, there are no signals of increased reporting with CGRP-A compared to triptans in relation to pregnancy in VigiBase®. Future pharmacovigilance studies are needed to confirm these findings.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. METHODS: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. RESULTS: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). DISCUSSION: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

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.

Neuropathies related to hepatitis E virus infection: A prospective, matched case-control study.

BACKGROUND: Acute hepatitis E virus (HEV) infection has recently emerged as a potential trigger for acute dysimmune neuropathies, but prospective controlled studies are lacking. AIMS: To compare the frequency of concomitant acute HEV infection in patients with neuralgic amyotrophy (NA), Guillain-Barré syndrome (GBS), and Bell's palsy with a matched control population. METHODS: Swiss multicenter, prospective, observational, matched case-control study over 3 years (September 2019-October 2022). Neurological cases with NA, GBS, or Bell's palsy were recruited within 1 month of disease onset. Healthy controls were matched for age, sex, geographical location, and timing of blood collection. Diagnostic criteria for acute hepatitis E were reactive serum anti-HEV IgM and IgG assays (ELISA test) and/or HEV RNA detection in serum by real-time polymerase chain reaction (RT-PCR). RT-PCR was performed on sera to confirm IgM positivity. RESULTS: We included 180 patients (59 GBS, 51 NA, 70 Bell's palsy cases) and corresponding matched controls (blood donors) with median age 51 years for both groups and equal gender distribution. Six IgM+ cases were detected in the NA, two in the GBS, and none in the Bell's palsy group. Two controls were anti-HEV IgM-positive. At disease onset, most cases with acute HEV infection had increased liver enzymes. A moderate association (p = 0.027, Fisher's exact test; Cramér's V = -0.25) was observed only between acute HEV infection and NA. CONCLUSION: This prospective observational study suggests an association between concomitant acute HEV infection and NA, but not with GBS or Bell's palsy.

Phase I clinical trial of intracerebroventricular transplantation of allogeneic neural stem cells in people with progressive multiple sclerosis.

We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines.

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis.

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. Exposure: Association between NfL z scores and CDW. Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Amyloid detection and typing yield of skin biopsy in systemic amyloidosis and polyneuropathy.

OBJECTIVE: Disease-modifying therapies are available for amyloidosis but are ineffective if end-organ damage is severe. As small fiber neuropathy is an early and common feature of amyloidosis, we assessed detection and typing yield of skin biopsy for amyloid in patients with confirmed systemic amyloidosis and neuropathic symptoms. METHODS: In this case-control study, patients with transthyretin and light chain amyloidosis (ATTRv, ATTRwt, and AL) were consecutively recruited. They were sex and age-matched to three control groups (1) non-neuropathic controls (NNC), (2) monoclonal gammopathy of undetermined significance (MGUS), and (3) other neuropathic disease controls (ONC). Patients underwent a double 3 mm skin biopsy in proximal and distal leg. Amyloid index and burden, protein typing by immuno-electron microscopy, intraepidermal nerve fiber density, electroneuromyography, and clinical characteristics were analyzed. RESULTS: We studied 15 subjects with confirmed systemic amyloidosis, 20 NNC, 18 MGUS, and 20 ONC. Amyloid was detected in 100% of patients with amyloidosis (87% in ankle and 73% in thigh). It was not detected in any of the control groups. A small fiber neuropathy was encountered in 100% of amyloidosis patients, in 80% of MGUS, and in 78% of ONC. Amyloid burden was higher in ATTRv, followed by AL and ATTRwt. The ultrastructural examination allowed the identification of the precursor protein by immunotyping in most of the cases. INTERPRETATION: Skin biopsy is a minimally invasive test with optimal sensitivity for amyloid. It allows amyloid typing by electron microscope to identify the precursor protein. The diagnostic work up of systemic amyloidosis should include a skin biopsy.

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.

Influence of Disease Modifying Treatment, Severe Acute Respiratory Syndrome Coronavirus 2 Variants and Vaccination on Coronavirus Disease 2019 Risk and Outcome in Multiple Sclerosis and Neuromyelitis Optica.

Patients suffering from neuro-inflammatory diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) remain vulnerable to COVID-19. We investigated the risk of COVID-19 in MS and NMOSD patients over time, considering the impact of disease-modifying treatments (DMTs), vaccinations, and the spread of new SARS-CoV-2 variants. We retrospectively collected clinical information regarding all MS and NMOSD consecutive patients seen at the Neurocenter of Southern Switzerland. Logistic regression was used to test variables (age, sex, vaccination status, DMT at vaccination, DMT at infection, disease course, disability scores, prevalent SARS-CoV-2 variant) for association with COVID-19 risk and severe outcome (hospitalization or death). We included 352 individuals in this study; 315 (89.5%) received ≥1 dose of SARS-CoV-2 mRNA-vaccine, and 134 (38.1%) experienced COVID-19 between March 2020 and August 2022. COVID-19 risk decreased in vaccinated patients (OR = 0.10, 95% CI = 0.05-0.20, p < 0.001) and increased in anti-CD20 therapies (OR = 2.26, 95% CI = 1.28-4.00, p = 0.005). Anti-CD20 treatment was associated with severe COVID-19 (OR = 27.41, 95% CI = 3.68-204.25, p = 0.001), whereas Omicron infections were milder compared to Alpha infections (OR = 0.03, 95% CI = 0.01-0.35, p = 0.006). We confirmed a protective effect of mRNA vaccines on COVID-19 risk, which is impaired by anti-CD20 treatment. We provided evidence for milder COVID-19 with the Omicron SARS-CoV-2 variant, which should not, however, discourage vaccinations.

Longitudinal serum neurofilament light kinetics in post-anoxic encephalopathy.

Serum neurofilament light (sNfL) is a promising marker of outcome after cardiac arrest, but its kinetics are unclear. We prospectively measured sNfL concentrations in 62 patients at 0, 1, 3, 5, 7 and 10 days after cardiac arrest. Survivors and non-survivors had similar sNfL at admission (14.2 [8.6-21.9] vs. 22.5 [14.2-46.9] pg/mL) but largely different at 24 h (16.4 [10.2-293] vs. 464.3 [151.8-1658.2], respectively). The AUC for sNfL concentrations predicting death was above 0.95 from Day 1 to 10 (highest on Day 3). Late sNfL measurements may exert prognostic value, especially when early samples are unavailable or prognosis remains unclear.

Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study.

BACKGROUND: Neurological conditions represent an important driver of paediatric disability burden worldwide. Measurement of serum neurofilament light chain (sNfL) concentrations, a specific marker of neuroaxonal injury, has the potential to contribute to the management of children with such conditions. In this context, the European Medicines Agency recently declared age-adjusted reference values for sNfL a top research priority. We aimed to establish an age-adjusted sNfL reference range database in a population of healthy children and adolescents, and to validate this database in paediatric patients with neurological conditions to affirm its clinical applicability. METHODS: To generate a paediatric sNfL reference dataset, sNfL values were measured in a population of healthy children and adolescents (aged 0-22 years) from two large cohorts in Europe (the Coronavirus Antibodies in Kids from Bavaria study, Germany) and North America (a US Network of Paediatric Multiple Sclerosis Centers paediatric case-control cohort). Children with active or previous COVID-19 infection or SARS-CoV-2 antibody positivity at the time of sampling, or a history of primary systemic or neurological conditions were excluded. Linear models were used to restrospectively study the effect of age and weight on sNfL concentrations. We modelled the distribution of sNfL concentrations as a function of age-related physiological changes to derive reference percentile and Z score values via a generalised additive model for location, scale, and shape. The clinical utility of the new reference dataset was assessed in children and adolescents (aged 1-19 years) with neurological diseases (epilepsy, traumatic brain injury, bacterial CNS infections, paediatric-onset multiple sclerosis, and myelin oligodendrocyte glycoprotein antibody-associated disease) from the paediatric neuroimmunology clinic at the University of California San Francisco (San Francisco, CA, USA) and the Children's Hospital of the University of Regensburg (Regensburg, Germany). FINDINGS: Samples from 2667 healthy children and adolescents (1336 [50·1%] girls and 1331 [49·9%] boys; median age 8·0 years [IQR 4·0-12·0]) were used to generate the reference database covering neonatal age to adolescence (target age range 0-20 years). In the healthy population, sNfL concentrations decreased with age by an estimated 6·8% per year until age 10·3 years (estimated multiplicative effect per 1 year increase 0·93 [95% CI 0·93-0·94], p<0·0001) and was mostly stable thereafter up to age 22 years (1·00 [0·52-1·94], p>0·99). Independent of age, the magnitude of the effect of weight on sNfL concentrations was marginal. Samples from 220 children with neurological conditions (134 [60·9%] girls and 86 [39·1%] boys; median age 14·7 years [IQR 10·8-16·5]) were used to validate the clinical utility of the reference Z scores. In this population, age-adjusted sNfL Z scores were higher than in the reference population of healthy children and adolescents (p<0·0001) with higher effect size metrics (Cohen's d=1·56) compared with the application of raw sNfL concentrations (d=1·28). INTERPRETATION: The established normative sNfL values in children and adolescents provide a foundation for the clinical application of sNfL in the paediatric population. Compared with absolute sNfL values, the use of sNfL Z score was associated with higher effect size metrics and allowed for more accurate estimation of the extent of ongoing neuroaxonal damage in individual patients. FUNDING: Swiss National Science Foundation, US National Institutes of Health, and the National Multiple Sclerosis Society.

Prevalence of amyloid in ligamentum flavum of patients with lumbar spinal stenosis.

BACKGROUND: Transthyretin (ATTR) amyloidosis is often diagnosed in an advanced stage, when irreversible cardiac damage has occurred. Lumbar spinal stenosis (LSS) may precede cardiac ATTR amyloidosis by many years, offering the opportunity to detect ATTR already at the time of LSS surgery. We prospectively assessed the prevalence of ATTR in the ligamentum flavum by tissue biopsy in patients aged >50 years undergoing surgery for LSS. METHODS: Ligamentum flavum thickness was assessed pre-operatively on axial T2 magnetic resonance imaging (MRI) slices. Tissue samples from ligamentum flavum were screened centrally by Congo red staining and immunohistochemistry (IHC). RESULTS: Amyloid in the ligamentum flavum was detected in 74/94 patients (78.7%). IHC revealed ATTR in 61 (64.9%), whereas amyloid subtyping was inconclusive in 13 (13.8%). Mean thickness of ligamentum flavum was significantly higher at all levels in patients with amyloid (p < .05). Patients with amyloid deposits were older (73.1 ± 9.2 vs. 64.6 ± 10.1 years, p = .01). No differences in sex, comorbidities, previous surgery for carpal tunnel syndrome or LSS were observed. CONCLUSIONS: Amyloid, mostly of the ATTR subtype, was found in four out of five patients with LSS and is associated with age and ligamentum flavum thickness. Histopathological work-up of ligamentum flavum might inform future decision making.

Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study.

Introduction: SOD1 was the first gene associated with both familial and sporadic forms of amyotrophic lateral sclerosis (ALS) and is the second most mutated gene in Caucasian ALS patients. Given their high clinical and molecular heterogeneity, a detailed characterization of SOD1-ALS patients could improve knowledge about the natural history of this disease. Here, the authors aimed to provide a clinical and molecular description of a monocentric cohort of SOD1-ALS patients. Methods: Amyotrophic lateral sclerosis (ALS) patients referring to the neurology unit of our center between 2008 and 2021 were clinically assessed and underwent molecular testing for SOD1. Segregation studies in available family members and in silico analysis were performed to sustain the pathogenicity of the identified SOD1 variants. Results: Among the 576 patients in our cohort, we identified 19 individuals harboring a mutation in SOD1 (3.3%), including 15 (78.9%) with a familial and four (21.1%) with a sporadic form. The spinal onset of the disease was observed in all patients, and survival was extremely variable, ranging from 8 months to over 30 years. Twelve different SOD1 missense variants were identified in our cohort, including one novel mutation (p.Pro67Leu). Discussion: In the present series, we provided the first description of an Italian monocentric cohort of SOD1-ALS patients, and we expanded the repertoire of SOD1 mutations. Our cohort presents several remarkable features, including variable expressivity in the same family, atypical presentation (ataxia, cognitive impairment, and other extra-motor symptoms), and different modes of inheritance of a given mutation in the same family. Given the recent authorization of SOD1-directed antisense oligonucleotide for use in SOD1-ALS patients, we recommend prompt screening for SOD1 mutations in novel ALS patients with familiar or sporadic presentations.

Experiences of persons with multiple sclerosis with the Covid-19 vaccination: A cross-sectional study of the Swiss Multiple Sclerosis Registry.

BACKGROUND: Despite strong recommendations for coronavirus disease 2019 (Covid-19) vaccination by multiple sclerosis (MS) organizations, some persons with MS (pwMS) remain vaccine hesitant. The Swiss MS Registry conducted a survey to explore Covid-19 vaccine hesitancy, self-reported side effects and changes in MS symptoms following vaccination in adult pwMS. METHODS: Self-reported data were analyzed cross-sectionally. Multivariable logistic regression was used to explore participant characteristics associated with Covid-19 vaccine hesitancy. RESULTS: Of 849 respondents, 73 (8.6%) were unvaccinated. Hesitation to vaccinate was most often a personal preference (N = 42, 57.53%). Factors negatively associated with vaccine hesitancy included older age (OR = 0.97 per year, 95% CI [0.94, 0.99]) and regularly seeing healthcare professionals (OR = 0.25, 95% CI [0.07, 0.85]). A history of confirmed Covid-19 infection (OR = 3.38, 95% CI [1.69, 6.77]) and being underweight (OR = 4.50, 95% CI [1.52, 13.36]) were positively associated with vaccine hesitancy. Of 768 participants who provided information, 320 (41.2%) and 351 (45.2%) reported vaccination side effects after the first and second vaccinations, respectively. Changes in MS symptoms were reported by 49 (6.3%) participants after the first and 67 (9.0%) participants after the second vaccination, and were most often described as increased or new-onset fatigue (N = 17/49 (34.7%) after the first and N = 21/67 (31.3%) after the second dose). CONCLUSIONS: Covid-19 vaccine hesitancy was low among surveyed pwMS. The risk of vaccine hesitancy was higher among younger pwMS, those with a history of Covid-19 infection, and those without regular contact with healthcare professionals.