Therapeutic Advances in Neurological Disorders最新文献

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.

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.