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In network meta-analysis (NMA), we synthesize all relevant evidence about health outcomes with competing treatments. The evidence may come from randomized clinical trials (RCT) or non-randomized studies (NRS) as individual participant data (IPD) or as aggregate data (AD). We present a suite of Bayesian NMA and network meta-regression (NMR) models allowing for cross-design and cross-format synthesis. The models integrate a three-level hierarchical model for synthesizing IPD and AD into four approaches. The four approaches account for differences in the design and risk of bias (RoB) in the RCT and NRS evidence. These four approaches variously ignoring differences in RoB, using NRS to construct penalized treatment effect priors and bias-adjustment models that control the contribution of information from high RoB studies in two different ways. We illustrate the methods in a network of three pharmacological interventions and placebo for patients with relapsing--remitting multiple sclerosis. The estimated relative treatment effects do not change much when we accounted for differences in design and RoB. Conducting network meta-regression showed that intervention efficacy decreases with increasing participant age. We also re-analysed a network of 431 RCT comparing 21 antidepressants, and we did not observe material changes in intervention efficacy when adjusting for studies' high RoB. We re-analysed both case studies accounting for different study RoB. In summary, the described suite of NMA/NMR models enables the inclusion of all relevant evidence while incorporating information on the within-study bias in both observational and experimental data and enabling estimation of individualized treatment effects through the inclusion of participant characteristics.

The detection of contrast-enhancing lesions (CELs) is fundamental for the diagnosis and monitoring of patients with multiple sclerosis (MS). This task is time-consuming and suffers from high intra- and inter-rater variability in clinical practice. However, only a few studies proposed automatic approaches for CEL detection. This study aimed to develop a deep learning model that automatically detects and segments CELs in clinical Magnetic Resonance Imaging (MRI) scans. A 3D UNet-based network was trained with clinical MRI from the Swiss Multiple Sclerosis Cohort. The dataset comprised 372 scans from 280 MS patients: 162 showed at least one CEL, while 118 showed no CELs. The input dataset consisted of T1-weighted before and after gadolinium injection, and FLuid Attenuated Inversion Recovery images. The sampling strategy was based on a white matter lesion mask to confirm the existence of real contrast-enhancing lesions. To overcome the dataset imbalance, a weighted loss function was implemented. The Dice Score Coefficient and True Positive and False Positive Rates were 0.76, 0.93, and 0.02, respectively. Based on these results, the model developed in this study might well be considered for clinical decision support. [ABSTRACT FROM AUTHOR]

Some patients benefit from a treatment while others may do so less or do not benefit at all. We have previously developed a two‐stage network meta‐regression prediction model that synthesized randomized trials and evaluates how treatment effects vary across patient characteristics. In this article, we extended this model to combine different sources of types in different formats: aggregate data (AD) and individual participant data (IPD) from randomized and non‐randomized evidence. In the first stage, a prognostic model is developed to predict the baseline risk of the outcome using a large cohort study. In the second stage, we recalibrated this prognostic model to improve our predictions for patients enrolled in randomized trials. In the third stage, we used the baseline risk as effect modifier in a network meta‐regression model combining AD, IPD randomized clinical trial to estimate heterogeneous treatment effects. We illustrated the approach in the re‐analysis of a network of studies comparing three drugs for relapsing–remitting multiple sclerosis. Several patient characteristics influence the baseline risk of relapse, which in turn modifies the effect of the drugs. The proposed model makes personalized predictions for health outcomes under several treatment options and encompasses all relevant randomized and non‐randomized evidence. [ABSTRACT FROM AUTHOR]

Objective: Irisin, released by muscles during exercise, was recently identified as a neuroprotective factor in mouse models of Alzheimer disease (AD). In a cohort of AD patients, we studied cerebrospinal fluid (CSF) and plasma irisin levels, sex interactions, and correlations with disease biomarkers. Methods: Correlations between CSF and plasma irisin levels and AD biomarkers (amyloid β 1‐42, hyperphosphorylated tau, and total tau [t‐tau]) and Clinical Dementia Rating Scale Sum of Boxes (CDR‐SOB) were analyzed in a cohort of patients with Alzheimer dementia (n = 82), mild cognitive impairment (n = 44), and subjective memory complaint (n = 20) biologically characterized according to the recent amyloid/tau/neurodegeneration classification. Results: CSF irisin was reduced in Alzheimer dementia patients (p < 0.0001), with lower levels in female patients. Moreover, CSF irisin correlated positively with Aβ42 in both female (r = 0.379, p < 0.001) and male (r = 0.262, p < 0.05) patients, and negatively with CDR‐SOB (r = −0.234, p < 0.05) only in female patients. A negative trend was also observed between CSF irisin and t‐tau levels in all patients (r = −0.144, p = 0.082) and in the female subgroup (r = −0.189, p = 0.084). Interpretation: The results highlight the relationship between irisin and biomarkers of AD pathology, especially in females. Our findings also offer perspectives toward the use of irisin as a marker of the AD continuum. ANN NEUROL 2024;96:61–73 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (β = −0.23, p = 0.001 and β = −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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Behavioral variant frontotemporal dementia (bvFTD) typically involves subtle changes in personality that can delay a timely diagnosis. Objective: Here, we report the case of a patient diagnosed of GRN-positive bvFTD at the age of 52 presenting with a 7-year history of narcissistic personality disorder, accordingly to DSM-5 criteria. Methods: The patient was referred to neurological and neuropsychological examination. She underwent 3 Tesla magnetic resonance imaging (MRI) and genetic studies. Results: The neuropsychological examination revealed profound deficits in all cognitive domains and 3T brain MRI showed marked fronto-temporal atrophy. A mutation in the GRN gene further confirmed the diagnosis. Conclusions: The present case documents an unusual onset of bvFTD and highlights the problematic nature of the differential diagnosis between prodromal psychiatric features of the disease and primary psychiatric disorders. Early recognition and diagnosis of bvFTD can lead to appropriate management and support for patients and their families. This case highlights the importance of considering neurodegenerative diseases, such as bvFTD, in the differential diagnosis of psychiatric disorders, especially when exacerbations of behavioral traits manifest in adults. [ABSTRACT FROM AUTHOR]

Introduction: Frontotemporal dementia (FTD) is an extremely heterogeneous and complex neurodegenerative disease, exhibiting different phenotypes, genetic backgrounds, and pathological states. Due to these characteristics, and to the fact that clinical symptoms overlap with those of other neurodegenerative diseases or psychiatric disorders, the diagnosis based only on the clinical evaluation is very difficult. The currently used biomarkers help in the clinical diagnosis, but are insufficient and do not cover all the clinical needs. Methods: By the means of a new immunoassay, we have measured and analyzed the proNGF levels in 43 cerebrospinal fluids (CSF) from FTD patients, and compared the results to those obtained in CSF from 84 Alzheimer's disease (AD), 15 subjective memory complaints (SMC) and 13 control subjects. Results: A statistically significant difference between proNGF levels in FTD compared to AD, SMC and controls subjects was found. The statistical models reveal that proNGF determination increases the accuracy of FTD diagnosis, if added to the clinically validated CSF biomarkers. Discussion: These results suggest that proNGF could be included in a panel of biomarkers to improve the FTD diagnosis. [ABSTRACT FROM AUTHOR]

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; β = 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 (β = −0.50, p < 0.001 and β = 0.47, p < 0.001, respectively), whereas MSQoL‐54 scores did not significantly change (β = 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Population-based registries represent a unique sample to estimate survival. The aim of the present study was to assess survival rates and predictors of outcome in incidental frontotemporal lobar degeneration (FTLD). Incident cases with FTLD, included between January 1, 2017 to December 31, 2017, have been followed for five years. Median survival was 8.16 years from disease onset and 5.38 years from diagnosis. Survival rates did not differ between phenotypes. Shorter disease duration from onset to diagnosis was associated with poorer outcome (p = 0.01). FTLD is a relatively homogeneous disease in terms of survival. Future multinational population-based studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]