Neurology and Therapy最新文献

Introduction: Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease. The first approved DMD gene therapy, delandistrogene moxeparvovec, was evaluated in the phase 3, two-part, randomized, placebo-controlled EMBARK trial (NCT05096221), which did not meet statistical significance for its primary endpoint assessed at the end of Part 1 (Week 52). To gather patient experience data possibly not captured by traditional clinical outcome assessments, a qualitative in-trial interview substudy was conducted among caregivers (parents) (≥ 18 years) of male patients (≥ 4 to < 8 years with DMD) who completed Part 1 (Week 52) of EMBARK.

Methods: Semi-structured interviews, conducted with 23 parents within 14 days after the last EMBARK Part 1 visit, assessed DMD-related symptoms and impacts prior to EMBARK, perceptions of meaningful outcomes based on hypothetical examples using DMD-specific Caregiver Global Impression measures for Severity (CaGI-S) and Change (CaGI-C), and observed changes during the trial. Initial analyses were blinded to treatment assignment; follow-up analyses examining changes in physical activities were unblinded.

Results: Debriefing questions demonstrated parents' understanding and correct interpretation of items and response options. Most parents indicated that "no change" or a 1-point improvement on CaGI-S items and "no change" or "minimal" improvement on CaGI-C items would be meaningful. Most (n = 17/23) reported improvements in ≥ 1 CaGI-C item 1 year after treatment; for patients receiving delandistrogene moxeparvovec, most parents (n = 7/10) rated ≥ 1 item as "very much" or "much" improved compared with placebo (n = 5/13). These differences were based on descriptive reporting and were not formally tested for statistical significance. Parents identified improvements in physical abilities (i.e., running, climbing stairs, jumping) as the "most important" types of improvement.

Conclusion: These findings underscore the importance of maintaining stability or achieving minimal improvements in treatment outcomes for patients with DMD. Parental experiences and perceptions provided additional insight beyond clinical outcome assessment measures, offering a complementary subjective perspective on treatment impact.

Trial registration: ClinicalTrials.gov identifier, NCT05096221.

Introduction: Widely used to treat multiple sclerosis, dimethyl fumarate (DMF) is a prodrug metabolized in vivo to monomethyl fumarate (MMF) and methanol; the latter is a gastrointestinal (GI) irritant. GI adverse events (AEs) commonly cause DMF discontinuation. Tegomil fumarate (TMF) comprises two MMF moieties joined by tetraethylene glycol, a low molecular polyethylene glycol (PEG). TMF is cleaved in vivo to MMF and the pharmacologically inactive PEG.

Methods: This randomised, double-blind study compared the GI tolerability of TMF 348 mg and DMF 240 mg, administered twice daily, in healthy adults (3:1 female:male ratio) aged 18-55 years. Participants completed daily questionnaires in an electronic diary, including the Modified Overall Gastrointestinal Symptom Scale (MOGISS), Modified Acute Gastrointestinal Symptom Scale, Flushing Symptom Questionnaire and an ad hoc quality of life assessment. The primary endpoint was the area under the curve (AUC) for each individual MOGISS symptom over 5 weeks of treatment. Between-group treatment differences for each MOGISS symptom AUC were analysed using hierarchical testing in a predefined sequence starting with abdominal pain.

Results: The study enrolled 210 participants; the full analysis set comprised 208 (155 females, 53 males). While AUC values were lower for TMF than DMF for most MOGISS symptoms, the between-group difference for abdominal pain was not statistically different (p = 0.0513) so all subsequent statistical analyses were considered exploratory. MOGISS total and composite score, the number of days with symptoms and number of symptoms were lower with TMF than DMF. Fewer participants receiving TMF (57.7%) versus DMF (73.6%) reported GI AEs or discontinued because of GI AEs (TMF n = 0, DMF n = 2).

Conclusions: The between-group difference for the AUC of MOGISS abdominal pain score was not statistically different. However, compared with DMF, TMF showed improved GI tolerability profile in terms of self-assessed GI events and GI AEs leading to discontinuation.

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disorder of the peripheral nervous system. While some patients with CIDP respond to standard-of-care treatments, a significant proportion remains refractory or has partial response. Evidence on the disease burden of this patient group is limited. This retrospective study aimed to analyze the demographics, clinical characteristics, and healthcare resource use of patients with CIDP in the United States, focusing on those who switched therapies within 2 years of initiating first-line treatment (LOT1).

Methods: Integrated data from the Optum^® de-identified Market Clarity dataset were used to identify adults diagnosed with CIDP from 2008-2020.

Results: The CIDP cohort included 1942 treated patients (54% male, 75% aged ≥ 50 years). LOT1 included immunoglobulins (43%), corticosteroids (32%), combination of immunoglobulins and corticosteroids (11%), immunosuppressants (10%), and plasma exchange (5%). Within 2 years, 31% patients switched to second-line treatment (LOT2). The median time to switch from LOT1 to LOT2 was 5.6 months. Within 2 years after initiating LOT1, 92% patients had outpatient visits and 40% were hospitalized. Patients who switched treatments had more healthcare visits than those who did not switch (45.3 vs. 35.3/year).

Conclusion: Approximately one-third of the patients switched to a new treatment within 2 years after starting treatment, which could be partly due to limited efficacy of therapies in LOT1. The decrease in treatment duration after LOT1 may suggest limited utility of subsequent therapies. Frequent treatment changes and increased healthcare encounters in this subgroup highlight significant unmet needs in CIDP.

Introduction: AXIN1 (axis inhibition protein 1), as a rate-limiting component of canonical Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin signaling pathway, may influence midbrain dopaminergic neurons. A recent genome-wide association study identified AXIN1 as a candidate gene for Parkinson's disease (PD). Our study aimed to investigate the potential relevance of AXIN1 single nucleotide polymorphisms (rs13337493 and rs9921222) in the risk, clinical characteristics, and pathology of PD.

Methods: Data were collected from the Northern Han Chinese and Parkinson's Progression Markers Initiative (PPMI) cohorts. Associations between AXIN1 variants, PD-related biomarkers, and clinical manifestations were analyzed.

Results: Both loci were identified as risk factors in the Northern Han Chinese population, and the A allele of rs13337493 [odds ratio (OR) 1.320, 95% confidence interval (CI) 1.052, 1.653, P_c = 0.036] and the T allele of rs9921222 (OR 1.351, 95% CI 1.045, 1.747, P_c = 0.042) showed increased susceptibility to PD. The risk effect of rs9921222 was predominant in the male cohort (OR 1.504, 95% CI 1.058, 2.139, P_c = 0.044). Rs13337493 was related to worse motor function in white individuals, which was represented by the Hoehn & Yahr stage (OR 2.775, 95% CI 1.195, 6.447, P_c = 0.036). It also correlated with compensatory elevation of cerebrospinal fluid (CSF) 3,4-dihydroxyphenylalanine (DOPA, β = 0.040, 95% CI 0.007, 0.073, P_c = 0.038).

Conclusion: Our findings support a gatekeeper role for AXIN1; its polymorphisms contribute to increased PD susceptibility and accelerated motor progression, yet may also trigger a compensatory presynaptic response, as evidenced by elevated CSF DOPA levels, to counteract neurodegeneration. Future studies should include larger sample sizes, more diverse ethnic populations, and protein-level investigations.

Introduction: Calcitonin gene-related peptide (CGRP) pathway-targeted monoclonal antibodies (mAbs) are first-line treatment options for migraine prevention. Data on persistence and patient-reported outcomes including satisfaction are limited. This real-world study aimed to report the experience of patients prescribed ≥ 1 self-injectable anti-CGRP mAb in a large United States healthcare network.

Methods: The Migraine Signature Study, an observational study, conducted at Sutter Health, utilized electronic health records (EHRs) to identify adult patients with migraine who were prescribed ≥ 1 self-injectable anti-CGRP mAb. These patients were invited to participate in a survey (October-December 2020) on sociodemographics, migraine attack characteristics, treatment patterns, and patient-reported outcomes, including the Migraine Disability Assessment Scale (MIDAS) and 4-item Migraine Interictal Burden Scale (MIBS-4). EHRs were used to assess persistence/discontinuation.

Results: Of 4683 eligible patients with migraine, 484 (10.3%) completed the survey. More than half (51%) were 30-54 years old, female (89.1%), and non-Hispanic white (79.1%). Most (53.5%) reported 1-10 headache days in the previous month; 58.2% had moderate or severe migraine-related disability. A total of 430 respondents reported having used ≥ 1 anti-CGRP mAbs, comprising 547 reports of anti-CGRP-mAb experience, 319 (58.3%) current use, and 228 (41.7%) past use. Among participants with prescription-dispensing data (n = 338), ongoing refills were documented for ≥ 2 months in 90.2%, ≥ 6 months in 73.7%, and ≥ 12 months in 54.7%. Greater reduction in number of headache/migraine attacks (62.1% vs. 17.5%), improved ability to function (62.1% vs. 18.0%), and better quality of life (62.4% vs. 17.5%) was reported for current use versus past.

Conclusion: Among patients who dispensed ≥ 1 anti-CGRP mAb for migraine, rates of sustained treatment over the course of a year were higher than expected; ~ 75% continued their index mAb at 6 months and > 50% at 12 months. Patients using anti-CGRP mAbs at the time of the survey reported higher satisfaction than patients who had discontinued anti-CGRP mAb.

Introduction: Patients with epilepsy (PWE) face an elevated risk of osteoporosis and bone fractures. This study aims to elucidate bone metabolic alterations in PWE and identify early detection biomarkers and contributing factors.

Methods: This cross-sectional study analyzed PWE from the Epilepsy Clinical database stratified by anti seizure medication (ASM) exposure duration. We analyzed bone turnover markers (BTMs), including 25-hydroxy vitamin D, osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), β-crosslaps (β-CTX) and β-CTX/OC ratio. The effects of epilepsy and ASMs on bone metabolism were analyzed by XGBoost model and SHapley Additive exPlanations (SHAP). Finally, we analyzed the mediation analyses assessing inflammatory pathway contributions.

Results: A total of 476 PWE were included in this study. Compared to ASM-naïve PWE, those receiving > 2 years of ASM therapy exhibited a reduced β-CTX/OC ratio (p = 0.002), while P1NP levels declined only after > 10 years of treatment (p < 0.001). Longitudinal data revealed a continued annual decline in the β-CTX/OC ratio during the 2-year follow-up period. After adjusting for confounders, longer ASM exposure duration was significantly correlated with decreased P1NP, β-CTX and β-CTX/OC ratio levels (β = - 1.74, 95% CI - 2.56 to - 0.92; p < 0.001). XGBoost-SHAP analysis identified valproic acid (VPA), oxcarbazepine (OXC) and history of status epilepticus as key contributors to β-CTX/OC ratio variability. Polytherapy had a more pronounced effect than monotherapy, particularly when levetiracetam was combined with VPA or OXC. Mediation analysis demonstrated that platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio mediate epilepsy/ASM-related bone metabolic alterations.

Conclusion: PWE exhibit dynamic bone metabolic alterations. Following > 2 years of ASM therapy, osteoclast inhibition precedes the onset of osteoblast dysfunction. Prolonged ASM exposure eventually reduces bone formation markers, indicating progressive impairment of osteoblastic function and a concomitant decline in bone-forming capacity. Consequently, the β-CTX/OC ratio represents a pivotal early biomarker for monitoring bone health deterioration, demonstrating significant clinical utility.

Introduction: Fingolimod (Gilenya^®), commonly used for relapsing-remitting multiple sclerosis (RRMS), is the first approved oral immunomodulatory agent. While its primary mechanism involves lymphocyte sequestration in lymphoid tissues, emerging studies report a potential link between fingolimod therapy and retinal vascular complications such as central serous chorioretinopathy and macular oedema. This study aims to describe the novel evidence on retinal aneurysmal alterations in patients receiving fingolimod, exploring possible mechanisms and clinical implications.

Methods: Case series of five eyes of five patients with retinal aneurysmal alterations and in therapy with fingolimod for multiple sclerosis. Multimodal imaging scans and medical records of patients on fingolimod therapy were reviewed. Outcome measures included best-corrected visual acuity (BCVA), central subfield thickness (CST) on spectral-domain optical coherence tomography (SD-OCT), presence of retinal aneurysmal alterations and analysis of their change in appearance over time using OCT angiography (OCTA).

Results: Findings indicate a possible association between fingolimod therapy and unilateral retinal aneurysmal changes in certain patients. The proposed mechanisms include endothelial retinal dysfunction, altered retinal vascular permeability and immune modulation effects. The clinical significance of these changes remains uncertain, necessitating further investigation.

Conclusions: Fingolimod may contribute to unilateral retinal aneurysmal vascular changes in a subset of patients. Clinicians should remain vigilant for potential retinal vascular complications, and further research is needed to clarify the underlying mechanisms, the evolution and the long-term risks associated with fingolimod therapy. Notably, in the reported cases, the retinal aneurysmal alterations showed regression following the discontinuation of fingolimod, suggesting a potential reversibility of these changes upon cessation of treatment.

Introduction: The impact of acute alcohol consumption at the onset of spontaneous non-traumatic intracerebral hemorrhage (ICH) remains unclear. We evaluated the association between elevated blood alcohol concentration (BAC) at admission and clinical outcomes in patients with ICH.

Methods: This retrospective single-center cohort study analyzed 1081 patients admitted with ICH between 2000 and 2023. BAC was measured at admission when alcohol use was suspected. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and the Glasgow Coma Scale (GCS). Outcomes-7-day neurological deterioration (ND), mortality, 90-day modified Rankin Scale (mRS) scores-were analyzed using logistic and Cox regression models to assess associations with acute alcohol consumption.

Results: Patients that were BAC positive (alcohol group; n = 31, 2.9%) were younger, predominantly male, had larger hematoma volumes, showed significantly higher rates of 7-day ND (58.1% vs. 27.6%, p < 0.001) and mortality at 7, 30, and 90 days (51.6% vs. 23.7%, 71% vs. 37.6%, 71% vs. 43.3%, all p < 0.001) than patients with no clinical suspicion of alcohol consumption (control group; n = 1050, 97.1%). Multivariable Cox regression identified elevated BAC as an independent predictor of mortality at all time points (HR 2.089, 95% CI 1.091-3.997, p = 0.026 at 7 days; HR 2.133, 95% CI 1.220-3.728, p = 0.008 at 30 days; HR 2.096, 95% CI 1.214-3.622, p = 0.008 at 90 days). Multivariate logistic regression identified elevated BAC as an independent predictor of 7-day ND (OR 4.188, 95% CI 1.163-15.078, p = 0.028) and large ICH volume (≥ 30 cm³) (OR 3.67, 95% CI 1.388-9.704, p = 0.009). In a subgroup analysis of heavy-drinking patients, elevated BAC was associated with early ND, increased mortality, and large ICH volume.

Conclusion: Elevated BAC at ICH onset independently predicts early ND and increased mortality, indicating a potentially modifiable prognostic factor in acute ICH. These results underscore the importance of BAC measurement in patients with suspected alcohol consumption and warrant further research aimed at understanding and mitigating its potential detrimental effects.

Introduction: Cortico-subcortical dysfunction from dopaminergic depletion is a hallmark of Parkinson's disease (PD). Modulating primary motor cortex (M1) excitability with intermittent theta burst stimulation (iTBS) may restore network integrity in PD by targeting neurobiological changes at excitatory, structural, and serological levels. This study aimed to demonstrate the clinical and neurobiological effects of bilateral M1 iTBS in patients with PD.

Methods: Seventeen patients with Hoehn-Yahr stage II-III PD in the on-medication state underwent daily bilateral M1 iTBS sessions for 5 consecutive days in a randomized, double-blind, placebo-controlled, crossover design. The primary clinical outcomes were the relative change from baseline at four follow-up points after the final iTBS session, measured by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II, III, and IV. Changes in corticospinal excitability, structural brain imaging, and serum biomarkers of neurodegeneration, astrocytic activation, and neuroplasticity were also assessed.

Results: Real iTBS induced a significant improvement in MDS-UPDRS Part III scores, yielding more than twice the therapeutic benefit observed with sham stimulation. Responders (> 20% improvement) showed a mean 9-point improvement. Similarly, real iTBS stimulation resulted in an increase in corticospinal excitability of the clinically most affected hemisphere. In responders, serum brain-derived neurotrophic factor levels increased along with an increase in left ventral diencephalon volume, which was the strongest predictor of clinical response.

Conclusion: Bilateral M1 iTBS may represent a valuable adjunctive therapeutic option for pharmacological treatment of motor symptoms in patients with PD by promoting structural brain changes and enhancing synaptic plasticity in intermediate disease stages.

Clinical trial registration: https://clinicaltrials.gov/ : NCT06840145, retrospectively registered on September 9, 2023.

Introduction: Spinal cord injury (SCI), both traumatic and non-traumatic, represents a substantial global health burden, with varying incidence and mortality rates. Despite the availability of multiple data collection tools, there is no standardized, comprehensive instrument addressing the full spectrum of SCI for epidemiologic research. This project introduces a data set for SCI epidemiologic research, developed on the Research Electronic Data Capture (REDCap) platform, to enhance comparability and facilitate data exchange.

Methods: The data set was developed through extensive literature reviews and expert panel consultations. It integrates elements from the National SCI Registry of Iran (NSCIR-IR) for traumatic SCI and the International Spinal Cord Injury Data Sets for non-traumatic SCI. Modifications were made to ensure comprehensive coverage and adaptability for epidemiologic studies. The REDCap platform was utilized for its flow-based data entry design, enhancing usability and relevance.

Results: The finalized instrument contains 78 variables spanning demographics, injury characteristics, hospitalization data, medical history, interventions, and patient outcomes. It incorporates flow-based logic to streamline data entry and accommodate the specific needs of both traumatic and non-traumatic SCI cases. The data set is available for online use in the REDCap Shared Library.

Conclusion: This standardized, modifiable data instrument fills a critical gap in SCI research, enabling consistent data collection for both traumatic and non-traumatic SCI. Its adoption can facilitate comparative analyses and inform healthcare strategies globally.