Therapeutic Advances in Neurological Disorders最新文献

Background: Brain atrophy (BA) is a useful predictor of clinical outcomes in people with multiple sclerosis (PwMS). For this reason, MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis), an expert consensus group, recommended that global brain volume loss (BVL) is included as a secondary outcome in therapeutic clinical trials. However, there has not been a recent review of the evidence of the association, or strength of association, between global BA and disability in PwMS.

Objectives: Our aim is to review articles from 2013 onward measuring the associations between percentage of brain volume loss (PBVL), normalized brain volumes (NBV) or normalized brain parenchymal volume (NBPV), and the Expanded Disability Status Scale (EDSS), or disability progression (DP) measured by EDSS in PwMS.

Design: Systematic review.

Methods: We searched Medline, Embase, Cochrane Library, Cochrane Clinical Register of Controlled Trials, Cochrane Database of Systematic Reviews and Cumulative Index to Nursing and Allied Health Literature for observational studies, clinical trials and modelling studies measuring the association between global BVL, PBVL, NBV or NBPV, and EDSS score or DP in PwMS. We included people with clinically isolated syndrome and excluded studies with a population greater than 20% primary progressive multiple sclerosis patients.

Results: We found 58 studies were eligible for the review. Most longitudinal studies (19/23) observed a significant association between global BVL and change in EDSS score or DP. Similarly the majority of cross-sectional studies (26/29) observed an association between baseline BV measures and EDSS. Most studies investigating the association between baseline brain volume (BV) measures and follow-up EDSS, that is, asking if baseline BV is a predictor of DP, or future EDSS score, did not find an association (4/15 observed an association).

Conclusion: Around a 1% (range 0.4%-1.3%) decrease in global BV per year was associated with DP, but caution in comparing studies is recommended due to variations in the definition of DP.

Background: Pediatric headache disorders are a significant public health issue, affecting school performance, social participation, and quality of life.

Objective: Our aim was to explore the age- and gender-related changes in the characteristics and burden of headaches from childhood to adolescence, with a focus on diagnostic shifts, frequency, intensity, and quality-of-life.

Design: We conducted a cross-sectional survey on five primary and secondary schools in the L'Aquila district, Italy.

Methods: Using the translated Italian version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation questionnaire, we collected data on headache frequency, intensity, duration, associated symptoms, and impact. Diagnoses were algorithmically assigned through International Classification of Headache Disorders, 3rd edition criteria. Statistical analyses examined the effects of age, gender, and their interaction on clinical and quality-of-life outcomes.

Results: In total, 431 students were included (mean age: 9.82 ± 2.28 years; range: 6-15; 52.9% female). Findings indicated that as children grow older, headaches become increasingly frequent, longer in duration, and more intensely experienced. The progression from primary to secondary school was accompanied by a transition in diagnosis, with undifferentiated headaches giving way to more specific categories, such as probable or definite migraine and, to a lesser extent, tension-type headache. Age-by-gender interactions revealed that older females experienced greater frequency and a more pronounced impact, while headache frequency affected quality of life with increasing age.

Conclusion: Findings highlight gender-specific developmental trends in headache, characterized by increased frequency, intensity, and diagnostic clarity from childhood to adolescence. The burden of headache, particularly among older students, underscores the need for early recognition and age-appropriate interventions.

Background: Myasthenia gravis (MG) is a rare autoimmune neuromuscular disease characterized by fluctuating muscle weakness and a variable clinical course. While sex differences in MG onset and progression are well documented, the extent to which these disparities affect quality of life (QoL)-particularly through fatigue and psychological burden-remains unexplored.

Objectives: To systematically evaluate gender differences in QoL among MG patients and assess whether psychological factors and fatigue contribute to these disparities.

Design: A systematic review and meta-analysis were conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines.

Data sources and methods: Searches were performed in PubMed, Embase, and PsycINFO from inception through February 2025. Eligible studies included adult MG patients with QoL outcomes stratified by gender. QoL scores were synthesized using a random-effects model. Psychological and fatigue-related variables were examined qualitatively.

Results: Twelve studies (N = 4744; 2889 women, 1855 men) met the criteria for the systematic review, and five studies (N = 3765) were included in the meta-analysis. Women consistently reported lower QoL compared to men. The initial pooled analysis showed a moderate but non-significant effect (Hedges' g = 0.319, p = 0.0812; I² = 94.96%). Sensitivity analysis (excluding an outlier study) reduced heterogeneity (I² = 0%) and revealed a significant gender effect (Hedges' g = 0.440, p < 0.001), with women experiencing significantly poorer QoL. Psychological comorbidities-particularly depression and anxiety-and higher levels of fatigue were more prevalent among female patients and consistently associated with lower QoL.

Conclusion: Women with MG experience significantly reduced QoL, partially attributable to higher fatigue and psychological burden. These findings underscore the need for gender-sensitive approaches in MG management, including routine psychological screening and fatigue interventions. Future research should adopt standardized assessment tools and explore the impact of hormonal life stages on MG outcomes.

Trial registration: PROSPERO CRD420251011446.

Background: Dual antiplatelet therapy (DAPT) is a cornerstone of secondary prevention in patients with minor ischemic stroke or high-risk transient ischemic attack. The effectiveness and safety of DAPT may differ between patients with posterior (PCI) and anterior circulation infarct (ACI).

Objectives: We aimed to compare short-term outcomes following DAPT between mild-to-moderate stroke patients with PCI versus ACI.

Design: Propensity-matched analysis from a prospective real-world multicentric cohort study (READAPT).

Methods: We included patients with noncardioembolic mild-to-moderate stroke (National Institute of Health Stroke Scale of 0-10) who initiated DAPT within 48 h of symptom onset. Patients were categorized into ACI or PCI based on the infarct(s) location on brain neuroimaging. The primary effectiveness outcome was the 90-day risk of ischemic stroke or other vascular events. The secondary effectiveness outcomes were the 90-day modified Rankin Scale (mRS) score distribution, 24-h early neurological improvement or deterioration, and all-cause mortality. The safety outcomes included the 90-day risk of any bleedings and 24-h hemorrhagic transformation.

Results: We matched 281 PCI patients with 651 ACI patients. The 90-day risk of ischemic stroke or other vascular events was low and similar between PCI and ACI groups (3.1% vs 2.9%, respectively; hazard ratio 0.98, (95% confidence interval (CI) 0.45-2.14); p = 0.845). Patients with PCI had worse 90-day mRS ordinal distribution compared to those with ACI (odds ratio 1.18 (95% CI 1.01-1.39); p = 0.046). There were no differences in other secondary outcomes. Safety outcomes had low incidence and did not differ between groups (any bleedings: 3.2% vs 2.6%; 24-h hemorrhagic transformation: 1.8% vs 1.2%). We found no differences in the risk of ischemic stroke or other vascular events between patients with PCI and ACI across subgroups defined by sex, age, presumed stroke etiology, stroke severity, prestroke mRS, hypertension, diabetes, acute reperfusion therapies, DAPT loading dose, or presence of symptomatic intracranial stenosis.

Conclusion: Our findings suggest that effectiveness and safety outcomes after DAPT in patients with mild-to-moderate noncardioembolic ischemic stroke are consistent regardless of infarct location in the anterior or posterior circulation territory. However, patients with PCI may experience worse short-term functional outcome.

Trial registration: URL: www.clinicaltrials.gov; Unique identifier: NCT05476081.

Introduction: Ozanimod is a new-generation sphingosine-1-phosphate (S1P) modulator, approved for the treatment of multiple sclerosis (MS), offering higher selectivity for S1P receptor 1 and 5 (SPR1-5), minimizing potential safety concerns related to S1P3 receptor activation, compared to fingolimod.

Objectives: We aimed to compare the adherence and persistence on treatment in MS patients switched to ozanimod from fingolimod for safety reasons (mainly lymphopenia or liver enzymes increase).

Methods: We retrospectively recruited patients treated with fingolimod who switched to ozanimod for safety reasons, with at least 12 months of follow-up. We collected demographic, clinical, biochemistry, and safety data during fingolimod and after switching to ozanimod to evaluate (1) lymphocytes and liver enzymes dynamics, (2) persistence on ozanimod over 6 months, (3) proportion of patients with no adverse events (NADE) on ozanimod and no evidence of disease activity (NEDA-3).

Results: We recruited 60 relapsing-remitting MS patients (mean age of 42 ± 7.9 years) who were treated with fingolimod for an average of 5.7 years (61.6% female) and switched to ozanimod due to lymphopenia (70%) or hypertransaminasemia (21.6%). A total of 58/60 (96%) patients persisted on treatment with ozanimod for a mean of 1.50 ± 0.49 years; mean lymphocyte count increased from 0.39 to 0.56 (p = 0.025) in patients who switched due to lymphopenia; hypertransaminasemia decreased from 21.6% in fingolimod to 9.3% in ozanimod. NADE was recorded in 93% patients during ozanimod treatment and NEDA-3 in 88.3% of patients after 1 year. Overall, patients with complete control of disease (NEDA) in the absence of adverse events (NADE) were 83.7% (NEDA3/NADE).

Discussion and conclusion: Our findings suggest that switching from fingolimod to ozanimod may mitigate lymphopenia or hypertransaminasemia and ameliorate effectiveness on disease activity.

Background: Zilucoplan, a peptide complement component 5 (C5) inhibitor, is self-administered as a subcutaneous (SC) injection, which offers an alternative to intravenous infusion of antibody-based complement C5 inhibitors.

Objective: To evaluate subcutaneous zilucoplan in adults with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG) who switched from intravenous complement C5 inhibitors to zilucoplan.

Design: MG0017 (NCT05514873) was a phase IIIb, open-label, single-arm study.

Methods: Eligible patients had clinically stable gMG on an intravenous complement C5 inhibitor and were willing to switch to zilucoplan. Patients received a 12-week treatment period of daily subcutaneous zilucoplan 0.3 mg/kg. Incidence of treatment-emergent adverse events (TEAEs) was the primary endpoint. Change from baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score at Week 12 was a secondary endpoint. Treatment preference (Week 12) and treatment satisfaction (9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9)) were both exploratory endpoints. Assessments by prior intravenous complement C5 inhibitor were conducted post hoc.

Results: Twenty-six patients enrolled and received zilucoplan; 16 switched from eculizumab and 10 from ravulizumab. TEAEs occurred in 19/26 (73.1%) patients and were mostly mild in severity. At Week 12, least squares (LS) mean (95% confidence interval) MG-ADL scores improved from baseline by -1.15 (-2.11, -0.19), p = 0.0217 and Quantitative MG (QMG) scores by -1.24 (-2.64, 0.16), p = 0.0802. Clinically meaningful improvement from baseline in mean MG-ADL and QMG scores was observed at Week 12 among patients who switched from ravulizumab (-2.41 (-4.52, -0.30; p = 0.0307) and -3.52 (-6.14, -0.90; p = 0.0149), respectively). At Week 12, 76.9% (n = 20) patients preferred subcutaneous injection compared with intravenous infusion. Mean (standard deviation) changes from baseline in the TSQM-9 Global Satisfaction, Effectiveness and Convenience subscores at Week 12 were +19.410 (27.429), +13.889 (21.534) and +21.739 (19.955), respectively. Complement inhibition increased from baseline and was complete (>95%) by Week 2 and maintained to Week 12.

Conclusion: Zilucoplan demonstrated a favourable safety profile. gMG symptoms improved during zilucoplan treatment; this was clinically meaningful for those switching from ravulizumab.

Trial registration: ClinicalTrials.gov (NCT05514873); 22 August 2022. https://clinicaltrials.gov/study/NCT05514873.

Background: Changes in the original protocol of clinical trials should be clearly declared to the readers of journal publications. Otherwise, they can lead to selective outcome reporting bias or distort the appropriate judgement of the study's external validity and statistical power, among other problems.

Objectives: To identify silent protocol modifications in phase III and IV clinical trials examining multiple sclerosis (MS) drugs that have been carried out between 2010 and mid-2023.

Design: Comparative analysis of ClinicalTrials.gov and associated peer-reviewed journal publications.

Methods: An advanced search in ClinicalTrials.gov was performed and consecutive searches in PubMed, EMBASE and Google Scholar were conducted looking for the main journal publication derived from each trial. Information regarding trial design, eligibility criteria, primary outcomes and sample size estimation was simultaneously collected from ClinicalTrials.gov and publications, and subsequently compared.

Results: In total, 112 trials were appraised. Most studies matched between data sources in terms of study arms (96.4%), assignment (99.1%) and randomization (100.0%). Concordance was also high but comparatively lower for masking (82.1%). A total of 3051 eligibility criteria were extracted, 45.5% of which matched, 25.1% were omitted in publications, 2.8% were modified and 26.6% were added. Fifty-eight trials (51.8%) completely matched regarding their published primary outcomes, whereas 20 had major inconsistencies (17.9%) and 34 (30.4%) minor inconsistencies. Fourteen trials were inconsistent in their estimated sample size; among these, the median difference between registry and publications was 36.5 individuals (interquartile range 17-161). The proportion of trials exhibiting silent protocol changes was similar regardless of study phase, industry involvement or type of registration.

Conclusion: Silent protocol changes are common in MS clinical trials and potentially hinder the interpretation and applicability of results. Efforts must be made to promote more transparency in the field of MS clinical research.

The introduction of numerous therapeutic advancements in the management of myasthenia gravis (MG) may add difficulties in clinical decision-making, especially when no recommendations tailored to the local context are available. For this reason, the Saudi Arabia Neuromuscular and Electrodiagnostic Medicine (SANEM) chapter of the Saudi Neurology Society launched an initiative to discuss and agree on issues related to the management of MG in the Gulf Cooperation Council (GCC) region. An expert panel from all GCC countries (Saudi Arabia, United Arab Emirates, Bahrain, Kuwait, Qatar, and Oman) was formed to develop practical recommendations using the Delphi method to facilitate the management approach of MG and enhance patient outcomes.

Background: Non-ischemic cerebral enhancing (NICE) lesions are a rare complication following endovascular therapy (EVT) for cerebral aneurysms. Although first described in 2008, data on long-term outcome and treatment response remain limited.

Objectives: In this study, we investigated the long-term follow-up of patients with NICE lesions, including magnetic resonance imaging (MRI) findings, clinical course, and treatment.

Design: For this single-center ambispective observational study, we enrolled nine patients with NICE lesions after EVT for cerebral aneurysms.

Methods: We analyzed patients diagnosed with NICE lesions following EVT between 2008 and 2024 at the University Hospital of Augsburg. Data collection included patients' and procedural characteristics, clinical course, MRI findings, and response to immunotherapies.

Results: We present the long-term follow-up of five patients already published and four additional cases. Nine female patients (mean age at diagnosis 50.67 ± 11.82 (± standard deviation, SD) years) were identified and analyzed with a mean follow-up of 1659.44 ± 1426.87 (SD) days, ranging from 328 to 5223 days (cumulative follow-up of 40.92 patient-years). In total, 112 MRIs were available for evaluation. Eight patients developed symptoms at a mean of 11 ± 13.41 (SD) days post-EVT, one patient remained asymptomatic. New NICE lesions during follow-up were detected in six patients, five patients developed new or increasing symptoms. All patients received glucocorticosteroids with variable duration, six patients required additional immunotherapies. At final follow-up, all patients had a favorable outcome (modified Rankin Scale 0-1), though residual symptoms persisted in four of them.

Conclusion: Hitherto, this study presents the longest follow-up period of patients developing NICE lesions after EVT. NICE lesions may have a highly variable course regarding radiological and clinical characteristics, with potential for both clinical and radiological recurrence years after initial presentation. While immunosuppressive therapy appears effective, optimal treatment regimens and duration have yet to be determined. Our findings underline the importance of regular clinical and MRI controls for individual patient care in this rare condition.

Background: Migraine is a disabling neurovascular disorder characterized by recurrent attacks that lead to extracranial and visual involvement. Several studies have investigated the retinal vasculature features in individuals with migraine, but there have been conflicting results.

Objective: To evaluate retinal structure in migraine patients before (T0) and after 6-month therapy (T1) with anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), using optical coherence tomography (OCT) imaging.

Design: A case-control and longitudinal study was conducted between January 2021 and December 2023, including 20 eyes from 10 healthy controls (HCs) and 32 eyes of 16 patients with migraine and treated with anti-CGRP mAbs according to AIFA criteria.

Methods: Patients underwent OCT angiography (OCT-A) to assess retinal vessel density (VD) and spectral-domain OCT (SD-OCT) to evaluate central retinal thickness, macular structure, and peripapillary retinal nerve fiber layer thickness. These parameters were assessed in both groups at T0 and again after 6 months (T1) as part of routine clinical care.

Results: All migraineurs exhibited a significant reduction in disease disability at T1, as assessed by clinical parameters. OCT data analysis revealed that individuals with migraine showed a significant increase in temporal retinal nerve fiber layer (RNFL) thickness and a reduction in nasal RNFL thickness compared to HCs. No differences in retinal circulation were observed between the groups at baseline. At T1, RNFL thickness remained sustained in the superior temporal sector, while the percentage VD of the superficial capillary plexus and radial peripapillary capillary significantly increased in the nasal perifoveal, inferior temporal, and hemi-inferior subregions.

Conclusion: Our study suggests that specific retinal structural changes could precede vascular dysfunction in migraine and can be detected early by combining SD-OCT and OCT-A acquisitions. Short-term treatment with anti-CGRP mAbs may exert neuroprotective effects, potentially preventing permanent ocular damage.

Trial registration: EyeHEAD Study (Trial registration number AIFA July/2024: IT 1735, www.aifa.gov.it/registro-studi-osservazionali).