Therapeutic Advances in Neurological Disorders最新文献

Background: Magnetic resonance imaging (MRI) is often used to evaluate disease-related brain changes in patients with aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD).

Objectives: To use a meta-analysis for assessment of quantitative volumetric brain and spinal cord changes in patients with AQP4-IgG+ NMOSD and healthy participants.

Design: We analyzed volume estimates of the brain, gray matter, white matter, thalamus, T2/FLAIR-brain lesions, as well as mean upper cervical cord area (MUCCA). Inclusion criteria included patients with AQP4-IgG+ NMOSD, MRI-based segmentation data, and matched healthy participants. Data from NMOSD patients with mixed/unknown serostatus or significant comorbidities were excluded.

Data sources: We searched MEDLINE through Pubmed for peer-reviewed articles published between 05/2006 (revised NMOSD diagnostic criteria) and 01/2025.

Methods: Standardized mean differences and pooled effect sizes (Hedges' g) were determined with random-effects models, adjusting for duplicate reporting, outliers, and small study effects. Metaregressions were used to determine clinical associations.

Results: Evidence of pooled data showed that whole brain volume (g = -0.61, 95% confidence interval (CI): -0.91 to -0.32, p < 0.001, N _pat/con = 385/325, k = 11) and gray matter volume (g = -0.40, 95% CI: -0.72 to -0.09, p = 0.018, N _pat/con = 259/267, k = 9) were significantly different between patients and healthy participants. Heterogeneity was moderate (τ² = 0.08 and τ² = 0.09, respectively). Moreover, we found a large effect for reduced MUCCA (g = -0.99, 95% CI: -1.59 to -0.39, p = 0.007, N _pat/con = 189/162, k = 7) with moderate heterogeneity (τ² = 0.31). No conclusive evidence emerged for changes in thalamic or white matter volume. Bias analysis did not indicate that smaller studies affected effect sizes. A systematic review of voxel-based morphometry revealed that reduced gray matter volume was most likely in the bilateral thalamus (⩽69%) and occipital (44%), frontal (27%), and temporal cortices (27%).

Conclusion: AQP4-IgG+ NMOSD patients have specific global and local central nervous system volume reductions, potentially induced by astrocytic damage and demyelination. Volumetric outcomes may therefore inform MRI-guided disease monitoring and endpoints in clinical studies.

Trial registration: PROSPERO (CRD42024493121). This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines.

Background: Over recent decades, several high-efficacy disease-modifying therapies (DMTs) have been approved for multiple sclerosis (MS), prompting a shift from an escalation strategy toward early high-efficacy treatment. Yet, DMT initiation patterns and safety profiles remain unexplored in research relying solely on patient self-reports and have not been examined in Switzerland.

Objectives: To investigate (1) time from MS diagnosis to first DMT, (2) temporal trends in initial DMT use, (3) number of suspected adverse drug reactions (sADRs) following the first DMT, and (4) occurrence of any severe sADR.

Design: Retrospective cohort study using longitudinal, patient-reported data from the Swiss MS Registry (SMSR) between 1995 and 2024.

Methods: We analyzed data from SMSR participants with relapsing-remitting MS or clinically isolated syndrome diagnosed after 1995. Time from diagnosis to first DMT was analyzed using Kaplan-Meier analysis. Temporal trends were assessed through annual distributions of first DMTs. sADR burden was modeled with a two-part zero-inflated negative-binomial model, and severe sADRs (⩾1 severe sADR) were assessed with logistic regression. All models were adjusted for sex and age at DMT initiation.

Results: Median time from diagnosis to first DMT decreased from 4.5 months (95% confidence interval (CI): 2-6) in the 1995-2004 diagnosis group to 2 months (95% CI: 1-2) in more recent groups (⩾2010). First DMT use shifted from predominantly low-efficacy to moderate (2013-2020) and, since 2020, to high-efficacy DMTs. Compared to low-efficacy DMTs, moderate (incidence risk ratio (IRR) = 0.63, 95% CI: 0.48-0.84) and high-efficacy DMTs (IRR = 0.55, 95% CI: 0.31-0.98) were associated with fewer sADRs, and high-efficacy DMTs had higher odds of reporting zero sADRs (OR = 8.61, 95% CI: 2.34-31.76). We observed signals of a higher likelihood of severe sADRs in high-efficacy DMTs (OR = 1.41, 95% CI: 0.55-3.24) compared to low-efficacy DMTs, although this was not statistically significant.

Conclusion: Patient self-reports can reliably capture trends in DMT use. In Switzerland, the first DMT use has evolved, with patients starting DMTs earlier and more frequently with higher-efficacy DMTs. While moderate and high-efficacy DMTs were associated with fewer sADRs, they may also carry a higher risk of severe sADRs, underscoring the need to balance personal preferences, efficacy, and safety in first-line MS treatment.

Background: Drug-resistant epilepsy (DRE) imposes a heavy disease burden and urgently requires new, effective, and safe treatment options.

Objective: To evaluate the efficacy and safety of transcutaneous auricular vagus nerve stimulation (ta-VNS) in patients with DRE.

Design: Ongoing, single-center, prospective real-world study.

Data sources and methods: Patients diagnosed with DRE and undergoing ta-VNS treatment at Beijing Tiantan Hospital, affiliated with Capital Medical University, were prospectively enrolled in this study between January 2023 and December 2024. The follow-up period lasted 1-2 years. The frequency of seizure reduction was assessed using seizure diaries, with a 50% decrease in seizure frequency deemed indicative of efficacy. Adverse reactions and comorbidities were recorded concurrently. All patients were maintained on stable anti-seizure medications during this study.

Results: Ninety-nine patients were enrolled, among whom 16 were lost to follow-up and 18 refused follow-up. Ultimately, 65 patients were successfully followed up for analysis. The overall efficacy rate was 61.54%. Specifically, 15 patients experienced seizure reductions >90%, 8 achieved a reduction between 75% and 90%, 17 demonstrated a reduction ranging from 50% to 75%, and 1 exhibited a reduction of <50%. There were no severe adverse events, although 10 patients reported mild side effects (e.g., ear tingling and tinnitus). The efficacy rate was found to be independent of variables such as age, sex, treatment frequency, and type of epilepsy. However, it demonstrated an association with baseline seizure frequency prior to treatment and the etiology of epilepsy. Patients exhibiting a higher baseline frequency of seizures (>30 episodes per month) demonstrated significantly improved response rates, with an efficacy rate of 90.9%. Etiologies, including posttumor surgery, congenital brain dysplasia, and genetic mutations, demonstrated efficacy rates >90%.

Conclusion: The efficacy of ta-VNS was 61.54% in patients with DRE. Patients with high baseline seizure frequency or identifiable etiologies tended to experience greater therapeutic benefits. Owing to its noninvasive nature and favorable safety profile, it presents a promising alternative for the management of DRE.

[This corrects the article DOI: 10.1177/17562864251313914.].

Background: Higher blood pressure variability (BPV) in patients suffering from acute ischemic stroke were shown to be associated with worse functional outcome and hemorrhagic transformation.

Objectives: To assess the influence of blood pressure variability during endovascular stroke treatment on functional outcome and parenchymal hemorrhage.

Design: We performed a post-hoc exploratory analysis of the individualized blood pressure management during endovascular thrombectomy under procedural sedation in acute ischemic stroke (INDIVIDUATE) study, which was a randomized clinical trial investigating an individualized blood pressure management strategy in comparison to a standardized treatment strategy during endovascular stroke treatment.

Methods: Several BPV parameters, such as procedure time of systolic blood pressure (SBP) in a range of a preprocedural baseline SBP ± 10 mmHg and ±20 mmHg, maximal and minimal SBP, variance and average real variability of intraprocedural SBP values were tested for association with functional outcome and PH1/PH2 hemorrhages in the current post-hoc analysis.

Results: Regression analyses were performed in 250 patients and revealed an association of variance of intraprocedural SBP (aOR, 1.002 (95% CI, 1.0004-1.004); p = 0.016) and average real variability of SBP (aOR, 1.105 (95% CI, 1.019-1.199); p = 0.016) with favorable outcome (modified Rankin Scale 0-2).

Conclusion: In our study, intraprocedural BPV parameters during endovascular stroke treatment were positively associated with favorable clinical outcomes. Potential underlying mechanisms should be further explored to better understand the effects of hemodynamics during the hyperacute time frame of endovascular stroke therapy.

Trial registration: Clinicaltrials.gov; NCT04578288.

Background: The course of relapsing-remitting multiple sclerosis (RRMS), frequently preceded by the clinically isolated syndrome (CIS), is variable and challenging to predict. Given many treatment options available, prognostic algorithms are gaining importance in informing initial treatment decisions. However, to date, only a few externally validated exists. External validation, which involves the application of a model to independent data, is essential. Privacy-preserving federated analyses of individual-level data facilitate external validation using clinical datasets that are typically difficult to access.

Objectives: Using data from the ProVal-MS study to externally validate the multiple sclerosis treatment decision score (MS-TDS), a predictive algorithm for early RRMS and CIS. The MS-TDS predicts the probability of the occurrence of at least one new or enlarging T2 lesion within 6-24 months following the onset of the disease and supports choosing between initiating platform treatment or a 'wait-and-see' approach. A secondary objective is to demonstrate the feasibility of privacy-preserving federated concepts within the Data Integration for Future Medicine (DIFUTURE) consortium.

Design: Prospective, multicentric, non-interventional cohort study (ProVal-MS) within DIFUTURE.

Methods: The calibrated MS-TDS was evaluated using the area under the receiver operating characteristic curve (AUROC) and the Brier score in both pooled and distributed settings. A decision curve analysis (DCA) was used to evaluate the net benefit of treatment decisions made by the MS-TDS in comparison to those made by treating neurologists.

Results: Of the 271 individuals diagnosed with CIS or early RRMS, 202 (78.2%) received platform treatment, while 59 (21.8%) did not receive treatment. The AUROC was 0.561 (95% CI: 0.492-0.630) in the pooled analysis and 0.567 (95% CI: 0.496-0.634) in the distributed analysis. DCA demonstrated a net benefit that was commensurate with that achieved by decisions made by experienced neurologists.

Conclusion: The external validation of the MS-TDS demonstrated low, non-significant predictive performance; however, it may serve as a useful complement, particularly for less-experienced neurologists. The distributed validation was found to be both feasible and compliant with data protection regulations.

Background: In multiple sclerosis (MS), an increase in whole-brain lesion volume (LV) on MRI can be observed even in the absence of newly demarcated focal lesions or clinical relapses. However, it is unknown whether the presence of increasing LV alone is enough to justify changes in the therapeutic regimen. At this point, blood-based biomarkers may aid to identify patients at risk for progression.

Objective: To determine the prognostic value of blood-based biomarkers (serum neurofilament (sNfL) and serum glial fibrillary acidic protein (sGFAP)) on disability progression in MS patients without newly demarcated lesions or clinical relapses.

Design: Longitudinal cohort study.

Methods: In total, out of 291 MS patients who were retrospectively screened for this study, 171 patients underwent a detailed clinical and MRI assessment and were finally included in the analysis: 100 patients with increasing LV (mean baseline Expanded Disability Status Scale (EDSS) = 1.5) and 71 with stable LV over 2 years (mean baseline EDSS = 1.0). Baseline blood-based measures (sNfL and sGFAP) and MRI metrics (total T2-weighted LV, gray matter (GM) volume) were acquired. EDSS worsening served as a clinical outcome measure and was determined through a 2-year follow-up. Receiver operator characteristic analyses were conducted to determine the predictive discriminative power of both blood-based biomarkers. Multivariate logistic regressions were performed to identify independent risk factors for EDSS progression in both cohorts.

Results: MS patients with increasing LV had lower GM volume (p = 0.0109, q = 0.0490) and worse EDSS scores (p = 0.0065, q = 0.0650) at clinical follow-up compared to patients with stable LV. Patients with increasing LV and EDSS progression had significantly higher sNfL (p = 0.0049, q = 0.0196), but not sGFAP (p = 0.7425, q = 0.9900) levels. In the logistic regression model, sNfL levels remained an independent risk factor for EDSS progression in patients with increasing LV (odds ratio = 1.344, 95% confidence interval: 1.038-1.739, p = 0.025), but not in patients with stable LV. Finally, in patients with increasing LV, sNfL levels, but not sGFAP levels, discriminated progressive from non-progressive MS patients upon clinical follow-up (area under the curve = 0.67, p = 0.004; q = 0.016).

Conclusion: sNfL enhances the prediction of disease progression in MS patients with merely increasing LV on MRI but no new T2 lesions or other signs of inflammatory activity. These findings may support treatment decisions in seemingly stable patients.

Background: Immune checkpoint inhibitors (ICIs) improve cancer survival but can provoke new or worsening autoimmune disease.

Objectives: To explore the association of ICIs with multiple sclerosis (MS) using the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) database, and to compare the disproportionality signal of MS with that of other autoimmune neurological adverse events.

Design: Secondary analysis of the FAERS database.

Methods: We performed a disproportionality analysis of FAERS between 2003-Q4 and 2024-Q2. Outcomes were MS, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), and autoimmune encephalitis (AIE). A signal required ⩾3 reports, proportional reporting ratio ⩾2, and χ² ⩾ 4.

Results: There were 48 reports of MS or MS relapse associated with ICIs. The reporting odds ratio (ROR) for MS or MS relapse was 0.09 (95% confidence interval (CI): 0.068-0.12). In comparison, RORs were 21.05 (95% CI: 19.287-22.974) for MG, 8.075 (95% CI: 6.677-9.766) for GBS, and 29.03 (95% CI: 23.564-35.764) for AIE.

Conclusion: We found no significant safety signal for MS with ICIs, in contrast to MG, GBS, and AIE. This heterogeneity underscores the need for continued pharmacovigilance and mechanistic research.

Background: Tobacco smoking is an established risk factor for accelerated multiple sclerosis (MS) progression and worse MS symptoms. Generic smoking cessation programs might not fully meet the needs of people with MS (pwMS), as they don't address MS-specific barriers influencing smoking behavior (e.g., worries about relapses when quitting). Yet, no MS-specific smoking cessation interventions have been evaluated.

Objective: This study aimed to develop an MS-specific smoking cessation intervention.

Design: This is an intervention development and initial feasibility study, informed by the Behavior Change Wheel and the design and evaluation framework for digital health interventions, which have been successfully utilized before, including in MS contexts.

Method: Between January and December 2024, we developed MS-specific information videos to supplement an existing smoking cessation intervention. We used identified intervention functions and results from preceding studies to identify the most effective way to change smoking behavior in pwMS. For the evaluation of the videos, we developed a theory-based questionnaire, and recruited pwMS and MS experts via our MS day clinic for assessment. The evaluation informed final revised videos for integration into the existing program to form a MS-tailored smoking cessation intervention.

Results: We identified five out of nine intervention functions from the behavior change wheel to be relevant and created six videos based on these functions. The content of the videos includes, among other things, education about the connection of smoking and MS, and persuasion and incentivization about the positive effects of quitting. Eleven pwMS and five MS experts assessed the material. Overall, the videos were perceived as understandable and appropriate in length in both groups. The modified smoking cessation intervention includes all videos, integrating them into a structure of five online-meetings across 3 weeks.

Conclusion: The successful development of education videos using the Behavior Change Wheel, as well as the positive findings from our feasibility testing underline the potential of our video-based approach in the context of smoking cessation for pwMS. Next, the modified smoking cessation intervention should be tested for feasibility, acceptability, and efficacy. If successful, this approach could be implemented widely for people with MS.

Background: Two principal methods for detecting anti-John Cunningham virus (JCV) antibodies are currently utilized in clinical practice: STRATIFY JCV™, an ELISA developed by Biogen, and IMMUNOWELL™, a solid-phase ELISA assay by Polpharma Biologics/GenBio.

Objective: We aimed to evaluate the concordance between STRATIFY and IMMUNOWELL in detecting anti-JCV antibodies in a real-world population of patients with relapsing-remitting multiple sclerosis (RRMS) undergoing natalizumab therapy.

Design: This monocentric observational study screened all patients treated with natalizumab for at least 6 months, referring to the MS Center of the University Hospital of Catania.

Methods: Each patient's serum was tested simultaneously using STRATIFY-2 (STRATIFY JCV DxSelect) and IMMUNOWELL assays. The qualitative results (positive/negative) were compared, and the index values were analyzed using Pearson's correlation and Bland-Altman plots. Inter-method agreement was calculated using Cohen's kappa coefficient.

Results: Among the 120 patients tested, 82 were positive and 31 negative with both STRATIFY and IMMUNOWELL. Four cases were STRATIFY-negative but IMMUNOWELL-positive, and three were the opposite. Overall concordance was 94.2%, with a Cohen's Kappa of 0.86, indicating strong agreement. The index values showed strong correlation (Pearson r = 0.79, p < 0.001) and the coefficient of determination (r ²) was 0.62.

Conclusion: STRATIFY and IMMUNOWELL demonstrate a high level of agreement in the detection of anti-JCV antibodies in patients with RRMS receiving natalizumab. IMMUNOWELL may serve as a reliable complementary method, especially in cases where borderline serostatus could influence therapeutic strategy. Regular and accurate monitoring of JCV status remains essential for guiding long-term treatment safety and optimizing individual patient outcomes.