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.

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.

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.

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.

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.

Tolerability and Acceptance of Switching from Brand to Generic Glatiramer Acetate in Multiple Sclerosis.

Background: The costs of disease-modifying therapies (DMTs) for multiple sclerosis (MS) have increased interest in generic alternatives. Methods: This prospective and observational study aims to investigate the safety, tolerability, and acceptance of switching from brand glatiramer acetate (GA) 40 mg/mL three times per week (Copaxone®) to generic GA 40 mg/mL three times per week (Glatiramyl®). Conducted at the Neurocenter of Southern Switzerland from September 2020 to September 2021, the study enrolled 27 patients; 21 completed the study. Participants reported on local and systemic side effects three months before and after the switch, and on switch acceptance by means of visual analogue scales (from 0 to 10). Results: Results indicated that those on generic GA experienced fewer local (81.0% vs. 96.3%) and systemic (33.3% vs. 59.3%) adverse events than with the brand drug. The median intensity of local adverse events was 8 (4-20) on generic GA vs. 16 (9-22) on brand GA, while the median intensity of systemic adverse events was similar between generic and brand GA [0 (0-27) vs. 0 (0-21.5), respectively]. Seventy-one percent of participants rated their acceptance of generic GA as 7/10 or higher. Conclusions: The results suggest that switching from brand to generic GA 40 mg/mL is safe, well-tolerated, and accepted by patients with MS.

Persistent longitudinal T cell responses after SARS-CoV-2 mRNA vaccines in MS patients on different disease modifying treatments.

Few data are available regarding vaccine induced SARS-CoV-2 specific T cell responses over time and after booster doses in multiple sclerosis (MS) patients on different disease modifying treatments. We measured SARS-CoV-2 specific CD4+ T cell responses in 72 samples collected from 36 MS patients. The percentage of CD4+ CTVlow CD25+ ICOS+ T cells after stimulation with Spike Recombinant Protein was 29.9 (17.0-43.6) on teriflunomide, 32.4 (11.9-42.5) on ocrelizumab, but much lower (0.6 [0.3-5.9]) on sphingosine-1-phospate receptor modulators (ß = -26.35, p = 0.003). SARS-CoV-2 specific T cells were mainly of Th1 type and stable over time and after booster vaccine doses. mRNA vaccines elicit strong and persistent CD4+ T cell responses against SARS-CoV-2 in MS patients on anti-CD20 and teriflunomide, but not in those on sphingosine-1-phospate receptor modulators.

Effectiveness, Safety and Patients' Satisfaction of Nabiximols (Sativex®) on Multiple Sclerosis Spasticity and Related Symptoms in a Swiss Multicenter Study.

Background: Cannabinoid oro-mucosal spray nabiximols is approved for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other antispastic medications. Few real-world data are available on the effectiveness, safety and patients' satisfaction in MS patients treated with nabiximols as monotherapy. Methods: To investigate the effectiveness, tolerability and satisfaction of nabiximols in a real-life multicentric Swiss cohort as monotherapy or with stable doses of other antispastic medications, and explore clinical features which may predict treatment response. The following data were collected at treatment start (baseline) and 12 weeks thereafter: Modified Ashworth scale (MAS), scores at numerical rating scales ranging from 0 (absent) to 10 (considerable) for effect on spasticity (sNRS), pain (pNRS), gait (gNRS), urinary symptoms (uNRS), tolerability (tNRS) as assessed by the treating neurologist, and overall treatment satisfaction (TsNRS) and tolerability (tNRS) as assessed by the patient. Results: Ninety-five patients (44 relapsing remitting, 37 secondary progressive and 14 primary progressive MS; median age = 53 (IQR 45-62); female 70%; median EDSS 6 (IQR 4-6), concomitant antispastic treatments in 54% of patients) were included. From baseline to week 12, median MAS score decreased from 3.0 to 2.0 (p < 0.001). Median scores of the each NRS also significantly decreased (p < 0.001 for all comparisons). At week 12, the median TsNRS and tTS scores were 8/10 (IQR: 6-9) and 9/10 (IQR: 7-10), respectively, and 93.7% of patients continued to use nabiximols at the average dose of six sprays/day. No clinical factors, including use of nabiximols as add on vs. monotherapy, were associated with responder status. Conclusions: Our first Swiss, multicentric, observational, real-life study supports and enhances previous finding of nabiximols as monotherapy and as add-on therapy, being an effective, safe and well-tolerated treatment option for resistant MS spasticity and spasticity-related symptoms (pain, bladder dysfunction and gait).

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.

Assessment of Bone Mineral Density Over 1 Year in a Cross-Sectional Cohort of Migraine Patients Receiving Anti-CGRP Monoclonal Antibodies.

BACKGROUND: Calcitonin gene-related peptide (CGRP), implicated in migraine pain, also possesses bone anabolic properties, which leads to the possibility that monoclonal antibodies targeting CGRP (anti-CGRPs) might increase the risk of bone density abnormalities. OBJECTIVE: The objective of this study was to explore bone mineral density abnormalities in a cohort of migraine patients treated with anti-CGRPs. METHODS: This was a single-center, cross-sectional, cohort study including migraine patients who underwent a densitometry assessment during anti-CGRP treatment. We assessed the frequency of osteopenia or osteoporosis (OSTEO+ status), defined as a bone mineral density T-score of -1 to -2.5, and <-2.5 standard deviations from the young female adult mean, respectively. Additionally, the association of OSTEO+ status with anti-CGRP treatment duration and primary osteoporosis' risk factors was investigated using logistic regression models. RESULTS: Data from 51 patients (43 female, mean age 46 ± 13.9 years) were evaluated. The mean duration of anti-CGRP treatment was 15.7 (±11.8) months. Twenty-seven patients (53%) were OSTEO+ (n = 22 osteopenia; n = 5 osteoporosis). In the final model, menopause [odds ratio 11.641 (95% confidence interval 1.486-91.197), p = 0.019] and anti-seizure drug use [odds ratio 12.825 (95% confidence interval 1.162-141.569), p = 0.037] were associated with OSTEO+ status. CONCLUSIONS: In our cohort of migraine patients, no evidence of an association between anti-CGRP treatment duration and an increasing risk of bone mineral density abnormalities was found. However, these findings are preliminary and necessitate further longitudinal research with larger cohorts and extended follow-up to be validated.

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.

Tau seeding activity in skin biopsy differentiates tauopathies from synucleinopathies.

Most neurodegenerative diseases lack definitive diagnostic tests, and the identification of easily accessible and reliable biomarkers remains a critical unmet need. Since tau protein is highly expressed in skin of tauopathies patients, we aimed to exploit the ultrasensitive seeding activity assay (SAA) to assess tau seeding activity in skin of patients with tauopathies. In this multicentric, case-control study, patients with tauopathies and synucleinopathies were consecutively recruited and sex-matched to healthy controls (HC). Subjects underwent a double 3 mm skin biopsy in cervical area and ankle. Skin tau-SAA, using TauK18 and TauK19 as reaction substrates for 4R and 3R isoforms, seeding score, clinical scales, biochemical and morphological characterization of SAA end-products were evaluated. We analyzed 58 subjects: 24 tauopathies (18 progressive supranuclear palsy, PSP, and 6 corticobasal degeneration, CBD), 20 synucleinopathies (14 Parkinson's disease, PD, and 6 multiple system atrophy, MSA), and 14 HC. PSP and CBD showed higher tau seeding activity at both anatomical sites. A greater sensitivity of 4R-SAA than 3R-SAA was observed. 4R tau-SAA identified tauopathies with 71% sensitivity and 93% specificity. Accuracy was higher for PSP than CBD: PSP vs HC / PD (AUC 0.825), while CBD vs HC / PD (AUC 0.797), and PSP vs MSA (AU 0.778). SAA end-products showed differences in biochemical and morphological characterization according to the anatomical site. Skin tau-SAA identifies tauopathies with good accuracy and can be used to implement the in-vivo clinical diagnosis of patients with neurodegenerative diseases. Further characterization of peripheral tau seed in skin may elucidate the structure of tau deposits in brain.

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.

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.