Therapeutic Advances in Neurological Disorders最新文献

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).

Background: The novel criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) have established imaging with nerve ultrasound (NUS) and magnetic resonance neurography (MRN) as complementary methods for CIDP diagnosis.

Objectives: Our goal was to investigate the role of MRN and NUS for CIDP monitoring.

Methods and design: We longitudinally examined 12 CIDP patients from 2016 to 2022 using NUS, MRN, nerve conduction studies (NCS), and clinical parameters (inflammatory neuropathy cause and treatment (INCAT)/overall disability sum score (ODSS)). NUS evaluated the cross-sectional area (CSA) of the median, ulnar, radial, tibial, fibular, and sural nerve as well as the intranerve CSA variability (INV_csa) of the tibial, fibular, ulnar, and median nerve, whereas MRN evaluated T2-weighted sequences of the fibular and tibial nerve at the popliteal fossa.

Results: Five patients showed clinical improvement/stability with corresponding improved or stable NCS/NUS parameters (number of nerves with increased CSA and INV_CSA). Seven deteriorating patients showed deteriorating NCS and either increasing or decreasing NUS markers possibly indicating inflammatory activity or degenerative CSA reduction. The difference ΔINCAT/ODSS_2022-2016 correlated positively with NUS ΔINV_CSA2022-2016 (p = 0.007, r = 0.731, n = 12) and with NUS ΔCSA_2022-2016 of the tibial nerve (p = 0.0005, r = 0.865, n = 12). Further, NUS-CSA of the tibial nerve in the popliteal fossa in 2016 correlated inversely with the difference of the INCAT/ODSS score (ΔINCAT/ODSS_2022-2016; r = -0.653; p = 0.033; n = 11). Finally, the Bland-Altman analyses for the tibial and fibular nerve showed a bias of -1.903 and 2.195 mm² (bias = NUS-CSA - MRN-CSA) accordingly revealing a difference between MRN and NUS measurements for deeper nerves.

Conclusion: CSA and INV_CSA of the tibial and fibular nerve can be used for monitoring in CIDP, and increased CSA of the tibial nerve is a good prognostic marker. MRN is more reliable for evaluating inflammation in proximal leg nerve segments.

Background: Inflammatory biomarkers, key predictors of ischemic stroke prognosis, may exhibit sex-specific predictive patterns.

Objectives: This study investigates sex-based differences in inflammatory biomarkers as predictors of 90-day clinical outcomes in acute ischemic stroke patients undergoing mechanical thrombectomy (MT).

Design: Multicenter retrospective study.

Methods: This study included 970 patients consecutively treated with MT for anterior circulation large vessel occlusion between 2016 and 2023. Inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), systemic inflammation response index, and systemic immune-inflammation index, were measured on admission and 24-h post-MT. Inverse probability weighting was used to balance baseline characteristics between male and female patients. Least absolute shrinkage and selection operator regression and logistic regression were used to identify independent predictors of 90-day good functional outcomes (modified Rankin scale (mRS) score 0-2) and death, stratified by sex and age groups (<55 and ⩾55 years).

Results: In the male weighted population (516 patients), multivariable analysis showed that MLR (odds ratio (OR): 0.37, 95% confidence interval (CI): 0.13-0.95, p = 0.041), 24-h NLR (OR: 0.88, 95% CI: 0.83-0.94, p < 0.001), and 24-h MLR (OR: 0.33, 95% CI: 0.12-0.94, p < 0.001) were independent predictors of 90-day good functional outcome with age-specific differences noted. Twenty-four-hour MLR (OR: 5.05, 95% CI: 1.36-4.28, p = 0.047) and erythrocyte sedimentation rate (OR: 1.02, 95% CI: 1.01-1.04, p = 0.025) were independent predictors of death, respectively, for men <55 and men ⩾55 years. In the weighted female population (454 patients), 24-h NLR (OR: 0.89, 95% CI: 0.81-0.96, p = 0.007) and 24-h CRP (OR: 0.98, 95% CI: 0.97-0.99, p = 0.029) were independent predictors of good functional outcomes. Twenty-four-hour CRP was also an independent predictor of 90-day death (OR: 1.01, 95% CI: 1.00-1.02, p = 0.017) in women with no age-specific differences noted. Interaction analysis revealed significant sex-specific relationships for MLR and CRP but not for NLR.

Conclusion: This study highlights sex-based differences in the predictive value of widely available inflammatory biomarkers for stroke outcomes. MLR was a distinct predictor in men, while CRP was uniquely associated with outcomes in women. These findings underscore the need for sex-stratified approaches in stroke management and research.

Background: Outcomes after thymectomy differ greatly between non-thymomatous and thymomatous myasthenia gravis (MG), meriting an in-depth exploration.

Objective: To examine the treatment and prognosis of non-thymomatous and thymomatous MG patients after thymectomy.

Design: A multicenter, retrospective, case-control study focused on MG patients following thymectomy from November 2010 to January 2024. After propensity score matching, 284 patients (142 with non-thymomatous MG and 142 with thymomatous MG) were included, with a median follow-up of 2.94 years.

Methods: Four outcomes were examined: minimal manifestations status (MMS) or better at the final visit, sustained clinical response, postoperative myasthenic crisis, and long-term mortality. Kaplan-Meier, logistic regression, cox regression, nomogram, receiver operating characteristic curve, decision curve, and calibration curve analyses were used for assessment.

Results: Non-thymoma patients had a lower proportion of postoperative myasthenic crisis (5.6% vs 13.4%, p = 0.026) and long-term mortality (1.4% vs 9.9%, p = 0.002) but a higher proportion of sustained clinical response (66.2% vs 52.1%, p = 0.016) than thymoma patients. For both non-thymomatous and thymomatous MG, anti-acetylcholine receptor antibody (AChR-Ab) positivity was the independent predictor for MMS or better at the final visit (p = 0.048; p = 0.016) and sustained clinical response (p = 0.035; p = 0.037). Most severe Myasthenia Gravis Foundation of America (MGFA) classification and high-grade Masaoka histopathology were independent predictors for postoperative myasthenic crisis (p < 0.001; p = 0.010) and long-term mortality (p = 0.006; p = 0.014) for thymomatous MG. Postoperative prednisone combined with tacrolimus (Pred + TAC) was associated with achieving sustained clinical response (p = 0.026; p = 0.030) and prednisone tapering for both groups.

Conclusion: Non-thymomatous MG exhibited a more benign course with better outcomes. AChR-Ab positivity indicated a better prognosis for both groups, while thymomatous MG with severe MGFA classification and high-grade histopathology requires close monitoring and follow-up. Postoperative Pred + TAC could be an effective immunotherapy option for beneficial outcomes.