Neurology and Therapy最新文献

Introduction: Oral corticosteroids (OCSs) and nonsteroidal immunosuppressant therapies (NSISTs) remain widely used for the clinical management of patients with generalized myasthenia gravis (gMG), despite well-documented risks. Newer targeted biologic therapies have demonstrated concomitant immunosuppressant therapy reduction; however, long-term comparative real-world evidence remains limited. This retrospective, observational study compared OCS and NSIST use in patients in the USA receiving one of the following US Food and Drug Administration-approved therapies for gMG treatment: ravulizumab or eculizumab (complement protein C5 inhibitor therapies [C5ITs]) or efgartigimod (neonatal Fc receptor antagonist).

Methods: Patients were identified using the IQVIA PharMetrics^® Plus claims database from January 1, 2015 to March 31, 2024. Eligible patients had ≥ 2 MG claims filed ≥ 30 days apart by a nonophthalmologic specialist. Treatment index date was the date of first ravulizumab, eculizumab, or efgartigimod claim. All patients assessed were continuously treated with ravulizumab, eculizumab, or efgartigimod during the 12-month follow-up period. Baseline OCS dose was estimated using claims data 3 months before the index date. Change from baseline in OCS average daily dose (ADD), OCS tapering, and NSIST use were assessed over 3-month intervals during the 12-month post-index follow-up period.

Results: After 12 months of continuous treatment, the C5IT cohort experienced a significantly greater mean reduction from baseline in OCS ADD compared to the efgartigimod cohort (C5IT, - 11.2 mg/day; efgartigimod, - 3.6 mg/day; P = 0.034), and fewer patients were taking OCS ADD > 30 mg/day (C5IT, 7.5%; efgartigimod, 22.2%). The percentage of patients with NSIST claims decreased by 28.3% within the first 12 months in the C5IT cohort (baseline, 55.2%; month 12, 39.6%) and remained stable in the efgartigimod cohort (baseline, 48.9%; month 12, 48.9%).

Conclusion: These results from US clinical practice suggest greater reductions in OCS and NSIST concomitant therapy for patients treated with ravulizumab or eculizumab compared with efgartigimod.

Introduction: Glucose at admission predicted poor outcome for patients with acute large vessel occlusion (LVO) undergoing endovascular therapy (EVT). Prior studies ignored continuous glucose monitoring after EVT. Therefore, we aim to evaluate the association between post-procedural glucose levels and outcomes in real-world settings.

Methods: This study was based on a multicenter cohort. Patients with LVO who underwent EVT within 24 h of symptom onset were enrolled. We analyzed post-procedural blood glucose based on preprandial blood glucose levels within 48 h after EVT recognizing disrupted normal dietary patterns and circadian rhythms due to severe symptoms of LVO. Primary clinical outcome was functional independence (90-day modified Rankin scale score 0-2). We evaluated the association between post-procedural glucose and functional independence using logistic regression and assessed whether stroke severity modified this association.

Results: A total of 693 patients were included. Multivariate logistic regression analysis showed that decreased average post-procedural glucose per unit was significantly related to functional independence (adjusted odds ratio [aOR]: 0.75, 95% confidence interval [CI] 0.68-0.83, P < 0.001). Hyperglycemia was defined as any preprandial blood glucose within 48 h after EVT ≥ 7.6 mmol/L based on the restricted cubic spline regression model. The hyperglycemia group was also significantly associated with functional independence (aOR: 0.54, 95% CI 0.36-0.82, P = 0.003), symptomatic intracranial hemorrhage (aOR: 2.16, 95% CI 1.08-4.34, P < 0.001), and 90-day mortality (aOR: 1.71, 95% CI 1.04-2.79, P = 0.033). Subgroup analysis specifically in individuals with severe stroke (defined as National Institutes of Health Stroke Scale [NIHSS] ≥ 15) showed that hyperglycemia was a risk factor for low functional independence.

Conclusion: Increased post-procedural glucose is associated with poor functional outcome after endovascular treatment and an increased risk of symptomatic intracranial hemorrhage after endovascular treatment, especially for those with more severe strokes.

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: 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.

Myasthenia gravis (MG) is a chronic, autoimmune, neurological condition characterized by fluctuating muscle weakness and fatigue, driven by autoantibodies against the neuromuscular junction (NMJ). Real-world evidence studies of patient registry data show that conventional treatments do not provide sufficient disease control for some patients and that, for them, significant health, quality of life, and economic burdens remain. In recent years, several new, targeted treatments for MG have become available. In light of this evolution of the MG treatment landscape, patients and clinicians have the opportunity to elevate their treatment goals, moving from previously accepted residual symptoms to targeting complete symptom resolution and prioritizing preservation of the NMJ to minimize damage. Patients with MG can now all aim for a fully functional life well into old age, but this requires a concerted and multi-stakeholder approach to disease management. Insights from other neurological diseases in which the availability of new therapies has sparked a shift in patient care could drive faster improvements in MG care. Here, we examine how the multiple sclerosis (MS) community evolved its approach to disease management with the availability of new treatments around a decade ago. In reflecting on the multi-faceted approach taken by the MS community to drive change and improve healthcare outcomes for patients with MS, we ask the questions 'What could constitute best practice care and good outcomes for patients with MG in the future?' and 'How do we, as an MG community, get there?'.

Dravet syndrome (DS) is a rare and severe form of epilepsy, characterised by recurrent seizures that begin during the first year of life, leading to motor, cognitive and behavioural impairments. This article provides the perspectives of a parent of a child with DS ('Ethan') and the treating neuropaediatrician. Ethan's seizures began when he was 9 months old, and were a mixture of focal seizures and status epilepticus. Numerous treatments were tried, including standard anti-seizure medications (such as levetiracetam, clobazam and fenfluramine), other medications (cannabidiol) and nonpharmacological approaches (ketogenic diet), with little success. When Ethan was 3 years old, a prolonged episode of status epilepticus precipitated by coronavirus disease 2019 (COVID-19) led to brain damage. Rehabilitation allowed Ethan to regain some of his previous functioning and, at the age of 38 months, combination therapy with clobazam, sodium valproate and stiripentol was begun and has successfully controlled Ethan's seizures. Ethan's father describes the stress that the diagnosis of DS, interactions with the healthcare system, and the search for effective treatment imposed on the family. Since Ethan's seizures have been better controlled, the family has been able to lead a more normal life, and is now focused on supporting Ethan and looking to the future. Ethan's neuropaediatrician outlines the approach she takes to the diagnosis and management of DS, including the importance of the clinician-parent relationship in imparting the diagnosis and making initial and ongoing treatment decisions. The preferred first-line treatment is sodium valproate, which is followed by sodium valproate-clobazam-stiripentol combination therapy, topiramate or a ketogenic diet as second-line options. In children > 2 years, cannabidiol and fenfluramine can also be considered. The aim of maintenance treatment (which will invariably be polytherapy) is to reduce the number of seizures, particularly status epilepticus, given the significant impact of this seizure type on patients and caregivers.

Introduction: Our preliminary study identified two metabolically distinct thrombus subtypes, demonstrating enhanced lipid metabolic signatures but downregulated folate biosynthesis pathways associated with poor prognosis. This study aimed to assess the prognostic value of routine laboratory parameters involved in lipid and folate metabolism for predicting 90-day futile recanalization (FR) in patients with anterior circulation acute ischemic stroke caused by large vessel occlusion (AIS-LVO) who achieved successful recanalization by endovascular thrombectomy.

Methods: Consecutive patients with anterior circulation AIS-LVO who achieved successful recanalization (modified Thrombolysis in Cerebral Infarction score of 2b-3) were retrospectively screened from April 2019 to February 2024. Admission serum levels of traditional and non-traditional lipid parameters, folate, and homocysteine (Hcy) were measured. FR was defined as a 90-day modified Rankin Scale score of 3-6, despite successful recanalization. Multivariable logistic regression was performed to identify predictors for FR, which were incorporated into a predictive nomogram.

Results: Among 446 enrolled patients [median age 65 (IQR, 56-72.75) years; 32.1% female], 210 (47.1%) experienced 90-day FR. Multivariate logistic regression analysis revealed that lower admission serum folate and higher Hcy levels were independently associated with increased 90-day FR risk. In contrast, neither admission traditional or non-traditional lipid parameters were independent predictors. The addition of folate and Hcy, individually or combined, significantly improved the predictive performance of conventional clinical factor-based model, as reflected by significant increases in net reclassification improvement and integrated discrimination improvement. Finally, a predictive nomogram was developed incorporating age, admission National Institute of Health Stroke Scale, puncture-to-recanalization time, and admission serum glucose, folate, and Hcy levels.

Conclusions: Admission serum folate and Hcy levels are independent predictors of 90-day FR risk and may enhance risk stratification and guide personalized secondary prevention strategies in patients with successfully recanalized AIS-LVO.

Introduction: The concurrent use of direct oral anticoagulants (DOACs) and antiseizure medications (ASMs) is increasingly common, particularly among patients with atrial fibrillation, stroke, and epilepsy. Certain ASMs may affect the pharmacokinetics of DOACs through enzyme induction or modulation of P-glycoprotein, potentially altering their effectiveness and safety. However, evidence regarding these interactions and their impact on clinical outcomes remains limited, heterogeneous, and inconsistently reported. The objective of this systematic review is to synthesize current evidence on cerebrovascular outcomes, bleeding risk, and pharmacokinetic effects in patients treated concurrently with DOACs and ASMs.

Methods: This protocol outlines a systematic review and meta-analysis of randomized controlled trials, observational studies, case-control studies, and pharmacokinetic investigations involving patients aged 8 years or older treated with DOACs in combination with ASMs. Databases including MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and clinical trial registries (ClinicalTrials.gov, WHO ICTRP) will be searched without language restrictions. Additional studies will be identified via reference screening, expert contact, and AI-assisted evidence discovery (Elicit). Dual independent review will be applied for study selection, data extraction, and risk of bias assessment using validated tools (Newcastle-Ottawa Scale (NOS), the Quality In Prognosis Studies (QUIPS) tool, and the Cochrane Risk of Bias 2.0 tool). Where appropriate, meta-analysis will be performed using random-effects models; otherwise, results will be synthesized narratively in accordance with SWiM (Synthesis Without Meta-analysis) guidelines.

Planned outcomes: Primary effectiveness outcome: composite of ischemic stroke and systemic embolism (IS/SE).

Secondary outcomes: ischemic stroke alone, systemic embolism alone, transient ischemic attack (TIA), major bleeding, intracranial hemorrhage, pharmacokinetic measures, and seizure occurrence. Subgroup analyses will stratify by ASM type, pharmacokinetic interaction potential, age groups (8-17, ≥ 18 years), and DOAC indications (e.g., non-valvular atrial fibrillation, venous thromboembolism, left ventricular thrombus). An individual participant data (IPD) meta-analysis is planned if sufficient eligible data are available. A summary table of outcomes and definitions (Table 1) and an overview flow diagram of the planned process (Fig. 1) are provided.

Systematic review registration: PROSPERO CRD4201050986.

Introduction: People with advanced Parkinson's disease (aPD) frequently experience unpredictable "Off" time and debilitating motor fluctuations. Foslevodopa/foscarbidopa (LDp/CDp), a levodopa/carbidopa (LD/CD) prodrug, is delivered as a 24-h continuous subcutaneous infusion. This post hoc analysis evaluated the efficacy of LDp/CDp in achieving consistent motor symptom control and stable motor states in people with aPD.

Methods: Diaries of people with aPD treated with LDp/CDp participating in a 12-week, phase 3, randomized controlled trial (RCT) were evaluated versus oral LD/CD, and in a 52-week open-label, single-arm trial (OLT) with LDp/CDp alone. Motor symptom control was assessed by frequency (30-min intervals) and duration (4-h blocks) of motor states (good "On" time [without dyskinesia or troublesome dyskinesia] or "Off" time) over a 16-h waking day. Motor state stability was evaluated by changes in daily motor fluctuations and extreme fluctuations (defined as transition from "Off" to "On" with troublesome dyskinesia, or vice versa). Outcomes were analyzed using adjusted regression models.

Results: Analysis included 47 (RCT) and 55 (OLT) people with aPD on LDp/CDp. In the RCT, LDp/CDp had an approximately 1-h gain in good "On" time in the mornings versus a quarter-hour gain for those on LD/CD (P = 0.001), with > 80% of participants on LDp/CDp waking up in good "On." At week 12, fewer motor fluctuations/day occurred with LDp/CDp versus LD/CD (3.2 vs 5.3; nominal P = 0.001), and twice as many participants on LDp/CDp had ≤ 3 fluctuations/day (53.2% vs 25.8%). In the OLT, the results seen at 12 weeks were sustained through week 52, with fewer mean fluctuations/day (3.1) than baseline (7.4) and more participants reporting ≤ 3 fluctuations/day at 52 weeks (66.6%) versus baseline (12.9%).

Conclusion: LDp/CDp provided consistent motor symptom control throughout the day, enhanced motor state stability, and reduced motor fluctuation, highlighting LDp/CDp's potential to significantly improve the management of unpredictable motor states and overall quality of life for people with aPD.

Trial information: Clinicaltrials.gov ID: NCT04380142, NCT03781167.