Therapeutic Advances in Neurological Disorders最新文献

Background: The ADAPT trial demonstrated the benefit of efgartigimod, a neonatal Fc receptor (FcRn) inhibitor, in acetylcholine receptor antibody (AChRAb) positive patients with generalized myasthenia gravis (MG). Information regarding the benefits in those lacking pathogenic antibodies is sparse.

Objectives: We aimed to investigate the safety and efficacy of efgartigimod in patients with double-seronegative (SN) generalized MG.

Design: An open-label 6-month prospective study, conducted at our center.

Methods: Patients aged at least 18 years with clinical and electrodiagnostic features of MG and negative results for AChRAb and muscle-specific tyrosine kinase antibodies were included. Efgartigimod was administered weekly for 4 weeks and then biweekly for 5 months followed by an observation period. The primary endpoint was the change in MG impairment index (MGII) at 6 months compared to baseline. Secondary endpoints include the change in MG activities of daily living (MG-ADL), other MG scores, overall responders, and early responders. The safety analysis included all patients who received at least one dose of efgartigimod.

Results: We enrolled 30 patients with SN MG who were resistant to other treatments and had unacceptable MGII scores. The MGII decreased by 11.92 points (p < 0.01) with efgartigimod treatment. The MG-ADL also improved. Seventy-two percent of patients were responders with 31% being early responders. Adverse events were reported in 83.3% of patients, and in 90.6%, they were mild. Headache was the most common, reported in 26.7%, followed by flu/common cold in 20%, and urinary tract infection in 13.3%.

Conclusion: Efgartigimod was well tolerated and efficacious in patients with SN MG. Future randomized, placebo-controlled studies are needed.

Trial registration: This trial is registered at ClinicalTrials.gov (NCT06587867), accessed via https://clinicaltrials.gov/study/NCT06587867?locStr=Toronto,%20ON,%20Canada&country=Canada&state=Ontario&city=Toronto&cond=Myasthenia%20Gravis&intr=efgartigimod&rank=1.

Background: Stiff person syndrome spectrum disorders (SPSD) are a disabling group of immune-mediated disorders that most commonly cause progressive rigidity and painful spasms. Botulinum neurotoxin (BoNT) has anecdotally improved SPSD symptoms, though evidence regarding treatment strategy and clinical efficacy is scarce.

Objectives: To characterize the location, frequency, dosage, and clinical response to BoNT injections in patients with SPSD.

Design: We conducted a retrospective observational cohort study.

Methods: SPSD patients who received BoNT treatments between August 2018 and February 2024 were included. Detailed information about the injections (formulation, dose, muscle), subjective patient-reported response, and concurrent therapies was recorded and compared between the first, third, and eighth BoNT visits.

Results: Thirty-seven SPSD patients were included. The majority had classic SPS (83.8%), were female (67.7%), white (78.4%), and on immune therapies (70.3%). The paraspinal muscles, hip flexors, distal leg flexors, and shoulder girdle muscles were most frequently injected. Supramaximal total doses up to 980 units of BoNT were used safely. The most common side effect was transient worsening of pain/spasms, which resolved with peak dose effect. Subjective clinical response was positive, with a median patient-reported 5-point Likert rating of 4, 5, and 5 after visits 1, 3, and 8.

Conclusion: BoNT may be an effective and durable adjunctive symptomatic therapy for people with SPSD with targeted muscle selection based on specific symptomatology. Injections into multiple body regions and use of supramaximal dosages may be required for adequate symptom control in this patient population. As our data lacked objective measures and relied on semiqualitative self-reported patient responses, conclusions about the utility of BoNT are limited and randomized placebo-controlled trials are needed to evaluate the impact of BoNT on improving quality of life, mobility, and burden of systemic symptomatic treatment.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy characterized by autoantibodies against aquaporin-4 (AQP) that predominantly affecting women of childbearing potential. Unlike multiple sclerosis, NMOSD poses a higher risk of severe and irreversible postpartum relapse, making pregnancy a significant concern in affected women. Historically, in Japan, immunosuppressive treatments were contraindicated in women who could become pregnant, leading many to discontinue therapy before conception. This often resulted in relapse and sometimes required pregnancy termination or abandonment. At present, immunosuppressants such as azathioprine, tacrolimus, and cyclosporine are considered beneficial during pregnancy. Five monoclonal antibody therapies have now been approved and are covered by national insurance for the treatment of NMOSD. These developments have expanded treatment options, enabling safer pregnancies and allowing more women with NMOSD to consider childbirth. To ensure optimal outcomes, individualized, evidence-based treatment plans are essential. Shared decision-making between patients and healthcare providers is critical, particularly when evaluating the safety of monoclonal antibody therapies during pregnancy and their potential impact on fetal development. This review outlines recent insights into the impact of NMOSD on patients of childbearing age, including family planning, postpartum management, and breastfeeding. It emphasizes the importance of balancing disease control with reproductive goals through informed and collaborative care strategies that also encompass AQP4-antibody-negative NMOSD and myelin oligodendrocyte glycoprotein antibody-associated disease.

Background: Idiopathic intracranial hypertension (IIH) is a condition with elevated intracranial pressure, leading to headaches and vision issues. Current treatments offer limited relief. Glucagon-like peptide-1 (GLP-1) agonists, known for their established metabolic benefits including weight loss and an emerging potential to lower intracranial pressure, may provide a novel approach for managing IIH.

Objectives: This systematic review and meta-analysis aimed to assess the effectiveness of GLP-1 agonists in improving IIH symptoms.

Design: A systematic review and meta-analysis.

Data sources and methods: A systematic search of PubMed, Scopus, Web of Science, and Cochrane was conducted until March 2025. Dichotomous outcomes were pooled using risk ratio (RR), while continuous outcomes were pooled using standardized mean difference. PROSPERO ID: CRD420251008614.

Results: The meta-analysis of four studies assessed the efficacy of GLP-1 agonists across various outcomes. Results showed a significant reduction in Body Mass Index (BMI) over 24 months, with mean differences of -0.36, -1.08, -1.18, and -1.42 at 3, 6, 12, and 24 months, respectively, with 95% CI, and low heterogeneity (I² = 0.0%). GLP-1 agonists also reduced headache risk, with the most significant effect at 3 months (RR: 0.69), remaining statistically significant at 6, 12, and 24 months. The risk of papilledema was reduced across all time points, with the lowest RR at 3 months (RR: 0.69 (95% CI: 0.55, 0.86)), and the effect remained significant through 24 months. Additionally, GLP-1 agonists consistently reduced the risk of visual disturbances and refractory IIH, with statistically significant effects sustained up to 24 months, demonstrating a sustained benefit throughout the treatment period.

Conclusion: This meta-analysis demonstrates that GLP-1 receptor agonists are a promising therapeutic option for patients with IIH, demonstrating significant efficacy in reducing intracranial pressure-related symptoms such as BMI, headache frequency, papilledema, and visual disturbances.

Background: Anti-Yo antibodies, which target the onconeural antigen cerebellar degeneration-related 2-like (CDR2L), have been only sporadically reported in patients with post-immune checkpoint inhibitor (post-ICI) neurological syndromes.

Objectives: To analyze the clinical and tumor features of patients with post-ICI anti-Yo neurological syndromes identified in a national reference center.

Design: Retrospective observational study.

Methods: All patients with post-ICI neurological syndromes and anti-Yo antibody positivity confirmed in a national reference center (2019-2024) were included. Comparative genomic hybridization array, immunohistochemistry against CDR2L, and analysis of Yo immunoreactivity using biotinylated anti-Yo sera were performed on the available tumor samples.

Results: In the five patients (4/5 female, median age 61 years) included, the neurological syndrome occurred after a median of 2 cycles of PD1 inhibitor. Four patients developed a rapidly progressive cerebellar syndrome (RPCS), while one presented with myelitis. All cases were severe (modified Rankin scale score 4-5) and did not improve with treatment. Cancer types were lung adenocarcinoma (2/5), endometrial serous carcinoma (2/5), and ovarian clear cell carcinoma (1/5). Anti-Yo antibodies were retrospectively detected before ICI initiation in one patient with RPCS and an ovarian tumor. This tumor showed a gain in the CDR2L locus, CDR2L overexpression, and Yo immunoreactivity with biotinylated anti-Yo sera, similar to ovarian tumors from patients with spontaneous anti-Yo paraneoplastic neurological syndrome. By contrast, CDR2L was not overexpressed in the lung tumor from one patient with myelitis, which nevertheless had a strong immunoreactivity with anti-Yo sera, absent in the control lung tumor.

Conclusion: Post-ICI anti-Yo neurological syndromes may occur with atypical cancer associations, but mostly manifest with a RCPS indistinguishable from spontaneous anti-Yo paraneoplastic neurological syndromes, suggesting a similar immune-mediated attack on the cerebellum. The CDR2L antigen overexpression and the pre-ICI anti-Yo antibody positivity in the patient with ovarian cancer suggest that the ICI boosted a pre-formed, tumor-driven anti-Yo autoimmunity. Further studies are needed to clarify whether this mechanism applies to all patients and if other types of tumor alterations and/or immune dysfunctions could be involved.

Background: Subcutaneous natalizumab (scN) was recently approved in Argentina for people with multiple sclerosis (pwMS). The impact of this change in this population is unknown.

Objectives: To evaluate the use, access and satisfaction of scN and correlate it with clinical and demographic variables. Desing: cross-sectional study was conducted, surveying pwMS who received scN and ivN from public and private MS Centres since its approval.

Methods: Treatment adherence was assessed using the MS Treatment Adherence Questionnaire (MS-TAQ) and satisfaction using Treatment Satisfaction of Questionnaire for Medication (TSQM). Clinical and demographic variables were also recorded. Results: 84 pwMS were included, 58.3% female, mean EDSS: 2.4 ± 1.2, mean age: 34.8 ± 10.8 years, mean disease duration: 7.8 ± 4.5 years, mean time under N: 43.7 ± 28.7 months, 45.2% naïve of prior disease modifying treatments, 77.4% (n = 65) under scN (60.7%, n = 51 are switchers from ivN, 49% due to difficult access to an infusion centre); and 22.6% 8 (n = 19) under ivN. The main barrier for change from iv to sc was the refusal from health insurance. Of the total of pwMS, 42% (n = 36) had a delay or lack of at least one dose from their social insurance, all from public hospitals. We found an association between scN use and high scores on the convenience items of TSQM (p < 0.0001, X ² = 74), unlike ivN. Regardless of route of administration, most of pwMS showed high percentages of satisfaction in the effectiveness and global satisfaction items, without differences between ivN and scM.

Conclusion: We found a high rate of change to scN from ivN, associated with a higher score in the comfort and convenience items in people receiving scN, compared to ivN. Access barriers should be addressed in order to improve treatment comfort.

Pediatric-onset multiple sclerosis (POMS), accounting for ~5% of all MS cases, is a chronic immune-mediated demyelinating disorder of the central nervous system. Relapse prevention remains a challenge, and B cells play a central role in the pathogenesis. Ofatumumab (OFA), a fully human anti-CD20 monoclonal antibody, is approved for adult MS. To assess the safety and efficacy of off-label OFA use in pediatric MS patients. We retrospectively analyzed clinical data from four pediatric patients with MS who received OFA. Retrospective case series. Four pediatric MS patients received OFA as disease-modifying treatment at ages ranging from 9.7 to 12.8 years for durations between 6 and 20 months. Three patients received OFA treatment for uncontrolled relapses, while one switched from rituximab. After the initial treatment phase of OFA, B-cell depletion was achieved in three patients, and this depletion was not consistently maintained throughout the maintenance phase. All patients remained relapse-free, with no new or enlarging T2 lesions or contrast-enhancing lesions observed on MRI or EDSS progression. The annual relapse rate after OFA treatment decreased compared with that before OFA treatment. One patient reported mild adverse events, including transient fever and atopic dermatitis, all of which were manageable. Ofatumumab showed favorable tolerability and potential benefit in this small pediatric MS cohort. Its subcutaneous administration offers practical advantages. While these findings suggest feasibility, the limited evidence precludes clinical recommendation at this stage. Larger prospective studies are warranted.

Background: Detection of atrial fibrillation (AF) after ischemic stroke (IS) is crucial for starting anticoagulant therapy to prevent IS recurrence. Strategies to identify patients who might benefit the most from extended electrocardiography (ECG) monitoring would be highly desirable.

Objectives: We aimed to investigate the role of brain natriuretic peptide (BNP) and echocardiographic parameters as biomarkers for predicting new AF detection in a large cohort of patients with acute IS.

Design: We retrospectively analyzed data of 2411 consecutive patients admitted for IS to a single Stroke Center from January 1, 2018, to May 31, 2023.

Methods: BNP levels were measured within 48 h of onset. Clinical and echocardiographic variables were evaluated. Single or multiple 12-lead ECG and continuous monitoring with external or implantable devices were used to detect new AF. The outcome measure was new AF detection at 3 months.

Results: Of 2337 included patients, 1907 (81.6%) had not previously known AF, and new AF was detected in 422 (22%) patients. In the multivariate analysis, older age (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.02-1.05, p < 0.001), higher National Institutes of Health Stroke Scale score (OR 1.05, 95% CI 1.03-1.07, p < 0.001), BNP ⩾150 pg/ml (OR 4.10, 95% CI 2.95-5.69, p < 0.001), and left atrium (LA) enlargement (OR 2.88, 95% CI 1.99-4.18, p < 0.001) were independently associated with new AF detection. The combination of both BNP ⩾150 pg/ml and LA enlargement showed a strong association (adjusted OR 4.74, 95% CI 3.47-6.48, p < 0.001) and a good discriminative performance for predicting new AF detection at 3 months (area under the receiver operating characteristic curve 0.74, 95% CI 0.71-0.77, sensitivity 0.70 (95% CI 0.65-0.74), specificity 0.78 (95% CI 0.76-0.80)).

Conclusion: BNP ⩾150 pg/ml within 48 h of IS onset and LA enlargement, especially if combined, may be valuable biomarkers for predicting new AF detection and identifying patients who might benefit the most from extended ECG monitoring.

Background: Timely treatment of ischaemic stroke with intravenous thrombolysis (IVT) and endovascular treatment (EVT) depends on efficient communication within a multiprofessional team. Mobile applications can streamline communication and documentation processes in acute stroke care.

Objective: This study aims to implement a mobile app to facilitate digital documentation and communication in acute stroke care and evaluate its impact on documentation rates and treatment times. Furthermore, a user experience survey was performed to gather information about the app usage in an acute medical process.

Design: The study is designed as an observational post-market clinical follow-up cohort study.

Methods: The mobile app 'Join' was implemented in a tertiary stroke care centre. Feasibility was assessed by monitoring documentation rates and process times, that is, 'door-to-needle time' (DNT) and 'door-to-groin time' (DGT). All patients treated for suspected stroke or transitory ischaemic attack were included in a 6-month period prior to (T1) and a 3-month period after (T2) implementation of the Join app. User experience was evaluated through a standardized survey including technical features.

Results: The interface between the mobile application, hospital information, picture archiving and communication, and quality assurance system as well as various magnetic resonance imaging/computer tomography scanners was implemented for acute stroke care. A total of 504 stroke patients was treated, 334 in T1 and 170 in T2. Of these, 65 received IVT and 87 received endovascular treatment (EVT). DNT (T1 vs T2, 27.5 vs 32 min, p = 0.987) and DGT (T1 vs T2, 50 vs 61.5 min, p = 0.481) were numerically longer during T2. Documentation rates increased threefold for all patients and 1.5 times for those receiving recanalization therapy. The survey revealed that documentation (76%) and case information retrieval (52%) were the most used app features, while other functionalities were less frequently utilized.

Conclusion: Implementing a mobile app facilitated real-time digital documentation accessible to the entire stroke care team. The introduction of the app did not improve treatment times for patients receiving acute recanalizing therapies. We recommend systematic training programmes to promote user acceptance and effective use.

Background: Migraine is a highly prevalent neurological disorder and a leading cause of disability worldwide. Although triptans and non-steroidal anti-inflammatory drugs are widely used, a substantial proportion of patients show inadequate responses. Lasmiditan, a selective 5-HT1_F receptor agonist introduced in Japan in January 2022, represents a novel acute treatment option that lacks vasoconstrictive activity and can be prescribed even in patients with cardiovascular risk. However, little is known about the trend of its long-term real-world use.

Objectives: To characterize 2-year lasmiditan prescription patterns using time-series clustering.

Design: A retrospective observational study using nationwide health insurance claims data in Japan.

Methods: Data were extracted from the REZULT database for patients aged ⩾15 years diagnosed with migraine (ICD-10 code G43) between January 2022 and December 2024. Prescription claims were analyzed in 90-day intervals for up to 24 months after the initial lasmiditan prescription. Time-series clustering was applied to identify subgroups with distinct trajectories of lasmiditan use.

Results: Lasmiditan was prescribed to 21,199 of 167,461 (12.7%) migraine patients (mean age 33.8 ± 10.3 years; 76.6% female). In the first 3 months, 86.2% received 50 mg, 12.8% received 100 mg, and 1.0% received both doses. About half were also prescribed analgesics, 66.7% triptans, and 33.9% prophylactic drugs. Lasmiditan prescriptions were gradually tapered over 2 years, with the most common long-term pattern being combination therapy with analgesics and triptans. Clustering identified three groups: Cluster 1 (massively continuous use), Cluster 2 (gradual tapering), and Cluster 3 (early discontinuation).

Conclusion: This nationwide claims-based study provides the first real-world evidence of long-term lasmiditan prescribing patterns. The identification of three distinct trajectories highlights the heterogeneity of clinical practice. It underscores the need for further research on lasmiditan's optimal use, particularly regarding combination therapy and potential medication overuse.