Therapeutic Advances in Neurological Disorders最新文献

Background: The literature on endovascular treatment (EVT) for large-vessel occlusion (LVO) acute ischaemic stroke (AIS) has been rapidly increasing after the publication of positive randomized-controlled clinical trials (RCTs) and a plethora of systematic reviews (SRs) showing benefit compared to best medical therapy (BMT) for LVO.

Objectives: An overview of SRs (umbrella review) and meta-analysis of primary RCTs were performed to summarize the literature and present efficacy and safety of EVT.

Design and methods: MEDLINE via Pubmed, Embase and Epistemonikos databases were searched from January 2015 until 15 October 2023. All SRs of RCTs comparing EVT to BMT were included. Quality was assessed using Risk of Bias in Systematic Reviews scores and the RoB 2 Cochrane Collaboration tool, as appropriate. GRADE approach was used to evaluate the strength of evidence. Data were presented according to the Preferred Reporting Items for Overviews of Reviews statement. The primary outcome was 3-month good functional outcome [modified Rankin scale (mRS) score 0-2].

Results: Three eligible SRs and 4 additional RCTs were included in the overview, comprising a total of 24 RCTs, corresponding to 5968 AIS patients with LVO (3044 randomized to EVT versus 2924 patients randomized to BMT). High-quality evidence shows that EVT is associated with an increased likelihood of good functional outcome [risk ratio (RR) 1.78 (95% confidence interval (CI): 1.54-2.06); 166 more per 1000 patients], independent ambulation [mRS-scores 0-3; RR 1.50 (95% CI: 1.37-1.64); 174 more per 1000 patients], excellent functional outcome [mRS-scores 0-1; RR 1.90 (95% CI: 1.62-2.22); 118 more per 1000 patients] at 3 months. EVT was associated with reduced 3-month mortality [RR 0.81 (95% CI: 0.74-0.88); 61 less per 1000 patients] despite an increase in symptomatic intracranial haemorrhage [sICH; RR 1.65 (95% CI: 1.23-2.21); 22 more per 1000 patients].

Conclusion: In patients with AIS due to LVO in the anterior or posterior circulation, within 24 h from symptom onset, EVT improves functional outcomes and increases the chance of survival despite increased sICH risk.

Registration: PROSPERO Registration Number CRD42023461138.

Background: Clinically, patients with myasthenia gravis are generally treated with drugs to improve their physical condition, and poor medication adherence can hinder their recovery. Many studies have shown the importance of medication adherence for effective treatment. Various factors may affect a patient's medication adherence; however, studies concerning medication adherence in patients with myasthenia gravis are rare.

Objectives: This study aimed to identify the factors related to medication adherence in patients with myasthenia gravis, and determine the possibility of predicting medication adherence.

Methods: This cross-sectional observational study was conducted among inpatients and outpatients with myasthenia gravis of the First Affiliated Hospital of Guangzhou University of Chinese Medicine in China. Data on patient demographics, disease-related characteristics, and medical treatment were collected. We evaluated medication adherence of the patients using the Morisky Medication Adherence Scale-8, Beliefs about Medicines Questionnaire, and the Self-efficacy for Appropriate Medication Use Scale.

Results: We distributed 200 questionnaires and finally retrieved 198 valid questionnaires. A total of 139 (70.2%) women participated in this study, and 81 (40.9%) among the 198 participants were aged 40-59 years. In total, 103 (52.0%) participants exhibited bad adherence to pharmacological treatment, and factors such as taking medication irregularly [odds ratio (OR) = 0.242, 95% CI = 0.093-0.627], the necessity of taking medicine (OR = 1.286, 95% CI = 1.142-1.449), the concerns of taking medicine (OR = 0.890, 95% CI = 0.801-0.988), and the self-efficacy for taking medications under difficult circumstances (OR = 1.194, 95% CI = 1.026-1.389) had statistically significant impacts on medication adherence.

Conclusion: Our study shows that taking medication irregularly and concerns of taking medicine are the risk factors for medication adherence. Meanwhile, the necessity of talking medicine and self-efficacy for taking medications under difficult circumstances are the protective factors for medication adherence. Our findings can help medical staff to enhance patients' medication adherence by informing patients necessary medical knowledge, emphasizing the necessity for medication, relieving patients' concerns regarding medication, and improving the self-efficacy for taking medications under difficult circumstances.

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments.

Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population.

Design: Ongoing, multicenter, phase III open-label extension (OLE) study.

Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score.

Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints.

Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses.

Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

Background: Post-traumatic acute brain swelling (ABS) is a major cause of elevated intracranial pressure and thus mortality. The current definition of post-traumatic ABS has certain limitations, and there is limited information available regarding ABS associated with traumatic acute subdural hematoma (ASDH).

Objectives: To investigate the incidence, risk factors, and clinical outcomes of ABS associated with traumatic ASDH.

Design: Retrospective study.

Methods: Data for 161 patients diagnosed with traumatic ASDH were retrospectively collected. Novel computed tomography-based criteria were proposed for diagnosing ABS in patients with ASDH and determining its incidence. Univariate and multivariate logistic regression analyses were performed to explore the risk factors of post-traumatic ABS. The Glasgow Outcome Scale (GOS) score, mortality, and functional prognosis of all patients at discharge and the proportion of intraoperative malignant brain bulge in surgical patients were taken as clinical outcome measures.

Results: A total of 45 (28%) patients experienced post-traumatic ABS, exhibiting significantly lower Glasgow Coma Scale scores on admission (p < 0.001). The incidence of hemispheric and whole-brain swelling was 8.1% and 19.9%, respectively. Risk factors independently associated with post-traumatic ABS were: (1) age [odds ratio (OR) = 0.917, p < 0.001]; (2) platelet to white blood cell ratio (PWR) (OR = 0.887, p = 0.012); and (3) traumatic subarachnoid hemorrhage (SAH) (OR = 4.346, p = 0.005). The ABS cohort had a lower GOS score [2 (1-3) versus 4 (3-5); p < 0.001], higher mortality (46.7% versus 6.9%; p < 0.001), and higher proportion of unfavorable functional prognosis (75.6% versus 34.5%; p < 0.001) upon discharge compared to the no ABS cohort, along with higher proportion of intraoperative malignant brain bulge (43.8% versus 0%; p < 0.001).

Conclusion: The incidence of ABS associated with ASDH is significantly high overall. Patients with ASDH who have young age, low PWR, and traumatic SAH are at an increased risk of developing post-traumatic ABS, and therefore of poor clinical outcomes.

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

Background: There are limited data on the real-world healthcare resource use (HCRU) and management costs of myasthenia gravis (MG) in England.

Objective: This study aims to assess the burden of disease for patients with MG in England.

Design: A retrospective, observational cohort study of adult patients diagnosed with MG, using data from the Hospital Episode Statistics data warehouse.

Methods: Patients with a first-ever recorded diagnosis of MG between 30 June 2015 and 30 June 2020 were followed up until 30 June 2021 or death, whichever occurred first. Post-diagnosis patient characteristics, treatment patterns, HCRU, and costs were described. Costs were evaluated using National Health Service reference costs.

Results: A total of 9087 patients with a median follow-up time of 2.9 years (range, 1.7-4.3 years) were included. The mean age at diagnosis was 66.5 years and 53% of the patients were male. A large proportion of patients (72.8%) were admitted as inpatients during follow-up with a mean number of 1.3 admissions. Patients hospitalized for MG-related complications spent a mean of 9.7 days per patient-year in the hospital. During follow-up, 599 (6.6% of the total cohort) and 163 (1.8%) patients had a record of rescue therapy with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX), respectively. Rituximab was administered to 81 (0.9%) patients and 268 (2.9%) patients underwent thymectomy. In those patients receiving rescue therapy or rituximab, >10% received at least three cycles of the same treatment. The average annual cost of hospital admissions across all patients treated with IVIg, PLEX, and rituximab were £907,072, £689,979, and £146,726, respectively.

Conclusion: A majority of MG patients required hospitalization or accident and emergency attendance, resulting in high HCRU and costs. A subset of patients required rescue therapy (including IVIg and PLEX), rituximab administration, ventilation, or thymectomy.

Multiple sclerosis (MS) was defined as a rare disease in China due to its low prevalence. For a long time, interferon β was the only approved disease-modifying therapy (DMT). Since the first oral DMT was approved in 2018, DMT approval accelerated, and seven DMTs were approved within 5 years. With an increasing number of DMTs being prescribed in clinical practice, it is necessary to discuss the standardized MS treatment algorithms depending on the disease activity and DMT availability. In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country.

Background: The consideration of patient preference for a certain drug route of administration (RoA) plays an important role in promoting patient adherence in chronic diseases. Natalizumab is an established treatment for relapsing-remitting multiple sclerosis (RRMS) and can be administered as intravenous (IV) infusion or subcutaneous (SC) injection developed to enable a shorter and easier administration versus IV RoA.

Study objectives: Primary objective is to compare patients' preference for RoA and satisfaction with SC versus IV natalizumab at baseline and subsequent visits up to 12 months. Secondary objectives include drug utilization, clinical outcomes, safety, and treatment satisfaction in a usual care setting.

Design and methods: SISTER (Subcutaneous: Non-Interventional Study for Tysabri Patient Preference - Experience from Real World) is an ongoing, prospective, observational study where natalizumab is utilized according to local label. RRMS patients are included in three natalizumab cohorts: Patients switching from current IV to SC administration (switcher) and patients newly starting natalizumab on either SC or IV route (starter SC/IV). This interim analysis includes 262 patients (184 switchers, 39 SC starters, and 39 IV starters), median observation period was 9 months.

Results: 80.8% IV starters and 93.9% SC starters reported at baseline that they prefer the assigned RoA. Although initial satisfaction with chosen RoA was maintained over time from baseline through Month 12 in all three cohorts, the wish for change of the current RoA after 6 and 12 months was more frequently expressed among IV starters than in either SC cohort. Consistently, six patients (23.1%) starting with IV changed their RoA from IV to SC route.Mean global treatment satisfaction according to TSQM-II score at baseline remained high in the switcher group and increased through Month 12 in both IV and SC starter cohorts.

Conclusion: Based on current data, there is a trend toward patients' preference for the natalizumab SC route over the IV route, which provides valuable insights into patients' preference for natalizumab RoA in routine care and complements available data from clinical studies with real-world data on SC natalizumab.

Trial registration: This observational (non-interventional) study was registered in the local German PEI register for non-interventional studies (NIS-No. 611) and in the international CTgov register (NCT05304520).

Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental.

Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis.

Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm.

Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%.

Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need.

Objectives: To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets.

Design: Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS.

Methods and analysis: Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes.

Discussion: The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.