Therapeutic Advances in Neurological Disorders最新文献

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.

Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder globally. Deep brain stimulation (DBS) has become a critical therapeutic option for advanced PD. The efficacy of DBS has been well established for up to 1 or 2 years; however, long-term outcome data for Chinese cohorts are limited, and the duration of the "DBS honeymoon" remains underexplored.

Objective: This study aimed to evaluate the long-term efficacy (⩾10 years) of subthalamic nucleus (STN)-DBS in patients with PD in Southern China, and to investigate the duration of "DBS honeymoon."

Design: Retrospective study.

Methods: Thirty-one patients who underwent bilateral STN-DBS between 2010 and 2011 were assessed. Motor symptoms were evaluated using the Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III) in the off- and on-medication states with stimulation. Nonmotor symptoms and the quality of life (QOL) were measured using validated scales. The levodopa equivalent daily dose (LEDD), stimulation parameters, and adverse events were recorded. Genetic testing was performed for seven patients.

Results: Thirteen patients completed the follow-up at 1, 3, and ⩾10 years. The UPDRS-III (off-state) scores improved by 53.02%, 44.79%, and 22.56% at 1, 3, and ⩾10 years, respectively. Tremor and rigidity showed sustained improvement; sleep remained stable postoperatively. In contrast, emotion, cognition, and QOL improved at 3 years; however, they returned to baseline or declined beyond 10 years. The LEDD reductions were 36.29%, 40.40%, and 29.10% at 1, 3, and ⩾10 years, respectively. Stimulation frequency decreased from 141.70 ± 15.72 Hz at 1 year to 110.00 ± 18.22 Hz ⩾10 years. Additionally, genetic testing identified three mutation carriers and rare complications such as DBS withdrawal syndrome appeared beyond 10 years.

Conclusion: STN-DBS provided sustained motor improvement, with tremor and rigidity showing the most significant benefits after 10 years. The initial 3 years likely represented a "DBS honeymoon," with peak improvements in motor and nonmotor symptoms. Genotype may influence the efficacy of DBS, and monitoring rare complications is essential. These findings should be interpreted with caution, given the small sample size and the retrospective design of the study.

Chimeric antigen receptor T-cells (CAR T-cells) have revolutionized the treatment of hematologic malignancies and are now being explored in autoimmune diseases, including neuroimmunological disorders. The first clinical applications of CAR T-cell therapy for autoimmune diseases have demonstrated promising efficacy, particularly in systemic lupus erythematosus and myasthenia gravis. While CAR T-cell therapy can induce profound B-cell depletion, leading to durable remission, concerns remain regarding cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. However, neuroimmunological conditions with lower target cell burdens may carry a reduced risk of these adverse events. Recent evidence suggests CAR T-cells could offer a transformative approach for stiff-person syndrome (SPS), a rare but debilitating autoimmune neurological disorder characterized by muscle rigidity and spasms. The first reported case of anti-CD19 CAR T-cell therapy in a treatment-refractory SPS patient resulted in substantial clinical improvement, including increased mobility and reduced dependence on symptomatic medication. A newly launched phase II clinical trial (NCT06588491) aims to further evaluate the safety and efficacy of anti-CD19 CAR T-cell therapy in SPS. In this review, we examine the current evidence supporting the use of CAR T-cells in neuroimmunological conditions, discuss the clinical picture and pathophysiological processes associated with stiff person spectrum disorders (SPSD), and elaborate on perspectives and limitations of CAR T-cell therapy in SPSD and beyond.

Background: Perampanel (PER) is effective in treating focal and generalised seizures. The PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) Extension study was a large, pooled analysis of PER clinical practice studies that assessed the effectiveness and safety/tolerability of PER in over 6800 people with epilepsy.

Objectives: To determine clinical factors associated with PER retention, response, seizure freedom and tolerability when used in clinical practice.

Design: An exploratory post hoc analysis of data from all individuals included in PERMIT Extension.

Methods: Univariate and multivariable logistic regression analyses were performed to identify baseline factors associated with retention rate, responder rate (⩾50% seizure frequency reduction), seizure freedom rate (no seizures since at least the previous visit) and incidence of adverse events (AEs).

Results: A total of 6822 people with epilepsy treated with PER were included. Baseline factors associated with retention were absence of psychiatric comorbidity (odds ratio [95% confidence interval], 1.99 [1.403-2.825]; p < 0.001), fewer focal seizures (1.01 [1.004-1.014]; p < 0.001) and fewer previous antiseizure medications (ASMs; 1.06 [1.013-1.119]; p = 0.013). Factors associated with response were absence of focal seizures (2.12 [1.532-2.924]; p < 0.001), fewer previous ASMs (1.19 [1.136-1.250]; p < 0.001) and absence of concomitant sodium channel blocker (SCB) ASM(s) (1.96 [1.455-2.628]; p < 0.001). Factors associated with seizure freedom were fewer total seizures (1.04 [1.020-1.061]; p < 0.001), absence of focal seizures (3.45 [2.387-4.979]; p < 0.001), fewer previous ASMs (1.11 [1.028-1.205]; p = 0.008), absence of concomitant SCB ASM(s) (1.46 [1.051-2.028]; p = 0.024) and absence of concomitant gamma-aminobutyric acid (GABA)-ergic ASM(s) (2.08 [1.266-3.412]; p = 0.004). Factors associated with occurrence of AEs were older age (1.01 [1.006-1.015]; p < 0.001), longer epilepsy duration (1.01 [1.010-1.012]; p = 0.044), presence of psychiatric comorbidity (1.74 [1.469-2.062]; p < 0.001) and greater number of previous ASMs (1.09 [1.069-1.119]; p < 0.001).

Conclusion: This study identified clinical factors associated with PER's real-world effectiveness and tolerability, which may help inform treatment decisions in clinical practice.