Therapeutic Advances in Neurological Disorders最新文献

In recent decades, neural antibody testing has emerged as a cornerstone of autoimmune encephalitis (AE) diagnosis. Commercially available assays to detect these antibodies are now in widespread use, resulting in dramatically increased test accessibility and reduced turnaround times. However, there remains heterogeneity in testing approach and pitfalls related to test ordering as well as diagnostic test performance, which may vary across laboratories depending on their testing methodologies or algorithms. This creates the potential for both false-negative and false-positive results, which can lead to patient misdiagnosis if clinicians are not familiar with both the strengths and limitations of this testing in practice. In this narrative review, we discuss the approach to patient selection for antibody testing, importance of serum and cerebrospinal fluid testing using appropriately handled specimens, potential limitations of local versus reference laboratory testing, optimal timing of testing, benefit of testing to patient management, and diagnostic performance of different test methodologies and algorithms ( the "who, what, where, when, why, and how" of neural antibody testing in AE), with the aim of providing a practically useful framework for clinicians who order this testing.

Background: Intravenous thrombolysis (IVT) administered as a bridging therapy prior to endovascular thrombectomy (EVT) for acute ischemic stroke may increase the risk of hemorrhagic-transformation (HT). CT-perfusion (CTP) imaging enables quantitative assessment of ischemic core and penumbral tissue and may support individualized hemorrhagic risk stratification.

Objectives: To assess whether baseline CTP-defined ischemic core parameters are associated with parenchymal-hematoma type 2 (PH-2) following bridging IVT before EVT.

Design: Observational-cohort-study.

Data sources and methods: Consecutive patients with large-vessel occlusion treated within 4 h of symptom onset at two tertiary stroke centers between 2017 and 2023 were analyzed. All patients underwent baseline CTP imaging. Outcomes were compared between patients treated with IVT plus EVT and those treated with direct-EVT. HT was assessed on 24-h follow-up noncontrast-CT using ECASS-2 criteria. Multivariable logistic regression was performed to identify independent predictors of PH-2.

Results: Among 398 patients (50.6% male), 180 received IVT + EVT (mean age 70.2 ± 15.0 years) and 218 underwent direct-EVT (69.5 ± 14.5 years). Baseline characteristics, workflow times, thrombectomy passes, and reperfusion rates were comparable. PH-2 was associated with higher mortality (43.8% vs 11.7%, p < 0.001) and worse 90-day functional outcome (median modified Rankin Score 4 (2-6) vs 3 (1-4), p = 0.002). Bridging-IVT was associated with higher PH-2 rates compared with direct EVT (6.1% vs 2.0%, p = 0.036), without increased symptomatic intracranial-hemorrhage. In sensitivity analyses, bridging-IVT was associated with higher PH-2 rates only in patients with any ischemic core (7.8% vs 1.5%, p = 0.014), core volume >10 mL (8.8% vs 0.8%, p = 0.004), and >20 mL (8.7% vs 1.3%, p = 0.03). Penumbral volume was not associated with PH-2. In multivariable analysis, any ischemic core (odds ratio (OR) 12.67, p = 0.02) and core volume >10 mL (OR 11.12, p = 0.034) independently predicted PH-2.

Conclusion: Baseline CTP-defined ischemic core volume is strongly associated with severe HT following bridging intravenous alteplase prior to EVT and may inform individualized risk-benefit assessment of bridging therapy.

Background: Siponimod, a selective sphingosine-1-phosphate receptor modulator was approved for patients with Secondary progressive Multiple Sclerosis (SPMS) with ongoing disease activity. However, its real-world positioning and management after discontinuation remain challenging.

Objectives: To evaluate the real-world use of siponimod in Italian real world setting, focusing on discontinuation rates, possible predictors, and post-treatment management.

Methods: A retrospective, multicenter study on patients treated with siponimod across six Italian MS centers. Demographics, prior disease modifying therapy (DMTs), reasons for discontinuation, adverse events, and subsequent therapies were collected. Statistical analyses included propensity-adjusted Cox model.

Results: A total cohort of 188 patients (63.8% female, median age 52 years) was enrolled, out of them 76(40.4%) discontinued siponimod, with a median treatment duration of 26 months. The main reason for discontinuation was safety concerns (72.4%), particularly persistent lymphopenia (43.6%) and recurrent infections (27.3%). Disease activity accounted for 27.6% of discontinuations. No significant demographic or clinical predictors of discontinuation were identified. After discontinuation, 49 patients (64%) started a new DMT, most commonly ocrelizumab (n = 22) or cladribine (n = 15), while 25 (32.9%) received no further therapy.

Conclusion: High discontinuation rates, mainly due to safety, and frequent post-treatment gaps highlight the need for improved, individualized management strategies for SPMS after siponimod.

Impending and manifest myasthenic crisis (MC) represent life-threatening neurological emergencies that require immediate intervention. Although eculizumab, a terminal complement C5 inhibitor, has established efficacy in generalized myasthenia gravis, most studies have focused on long-term outcomes, and its potential for rapid onset of effect in acute exacerbations has not been well evaluated. We retrospectively analyzed four acetylcholine receptor (AChR) antibody-positive patients (five acute episodes) who received eculizumab as emergency therapy between January 2024 and July 2025. All patients presented with impending or manifest MC; none had received intravenous immunoglobulin, plasma exchange, or neonatal Fc receptor (FcRn) inhibition within the preceding month. According to the Myasthenia Gravis Foundation of America classification, three patients had class IVb and one had class V. Triggers for exacerbation included COVID-19 infection (n = 2), puerperium (n = 1), PD-1 inhibitor exposure (n = 1), and common infection (n = 1). Within 48 h of eculizumab administration, Quantitative Myasthenia Gravis scores improved from 28.2 ± 4.8 to 15.0 ± 4.1, while Myasthenia Gravis Activities of Daily Living scores decreased from 16.8 ± 2.8 to 6.0 ± 4.3. Notable milestones achieved included arterial blood gas improvement within 7.5 h (one patient), nasogastric tube removal within 48 h (three patients), and successful extubation at 17 h (one patient). No treatment-related adverse events were observed. These preliminary findings suggest that eculizumab may be associated with rapid, temporally related clinical improvement within 48 h with a favorable short-term safety profile in AChR antibody-positive patients with impending or manifest MC, particularly those with complement activation triggers. Larger prospective studies with standardized short-term assessment protocols, including frequent neurological evaluations during the first 48 h, are warranted to further validate its efficacy and define its role as an emergency therapy in the acute management of myasthenic exacerbations.

What is this summary about? The purpose of this summary is to explain the results from two studies that looked at the safety and effects of an investigational drug called ecopipam. "Investigational" means that the drug has not been approved by the United States Food and Drug Administration (FDA) yet. The studies tested if ecopipam could safely improve symptoms and quality of life in children and adolescents with Tourette syndrome. Please note that ecopipam is not currently approved to treat Tourette syndrome.

Background: The role of gut-mediated T cell licensing in multiple sclerosis (MS) remains incompletely understood.

Objective: We hypothesized that T cell licensing in the gut contributes to MS pathogenesis and evaluated whether vedolizumab-an anti-α4β7 integrin, gut-selective monoclonal antibody approved for inflammatory bowel disease (IBD)-is associated with MS prevalence.

Design: Retrospective observational study.

Methods: Using Epic Cosmos, a large deidentified U.S. electronic health record platform, we identified individuals with Crohn's disease (CD) or ulcerative colitis (UC) and a concomitant MS diagnosis between August 2010 and August 2025.

Results: Among 1,027,704 CD and 1,294,362 UC patients, 8,098 (0.79%; 95%CI:0.77%-0.81%) and 9,564 (0.74%; 95%CI:0.73%-0.76%) had MS, respectively. In contrast, among vedolizumab-treated patients, only 125 with CD (0.22%; 95%CI:0.18%-0.26%) and 109 with UC (0.17%; 95%CI:0.14%-0.20%) developed MS within five years of treatment.

Conclusion: While causality cannot be inferred, our findings highlight an opportunity to further explore whether vedolizumab-associated differences in MS prevalence may relate to gut-associated immune processes.

Background: Ofatumumab (OFA), a humanized anti-CD20 monoclonal antibody, shows potential in myasthenia gravis (MG) with antibody against acetylcholine receptor (AChR-Ab), but comparative efficacy across AChR and muscle-specific kinase (MuSK) subtypes remains uncharacterized.

Objectives: To evaluate OFA's clinical and immunological effects in AChR-MG versus MuSK-MG, identify predictors of minimal symptom expression (MSE), and explore the dynamics of B-cell repopulation.

Design: A retrospective study in a single center.

Methods: Twenty-one refractory MG patients (13 MuSK+, 8 AChR+) received individualized OFA induction (Regimen 1: two 20 mg doses ⩾2 weeks apart; Regimen 2: single 20 mg dose) and maintenance (20 mg upon CD19 + B counts ⩾5 cells/μL repopulation or clinical exacerbation). Outcomes included time-to-MSE, Quantitative Myasthenia Gravis Score (QMGS) dynamics, prednisone reduction, and serial immunophenotyping (B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), soluble CD40L (sCD40L), microphage migration inhibitory factor (MIF), and immunoglobulin).

Results: MuSK-MG achieved faster MSE (median time: 6 vs 15 months, log-rank p = 0.164, age-adjusted Cox p = 0.027), and a higher 3-month improvement (92.3% vs 50.0%; p = 0.047). Earlier achievement of MSE was associated with shorter disease duration (p = 0.038) and concomitant corticosteroid therapy (p = 0.030). Prednisone doses decreased significantly over 6 months (p = 0.029) without difference between groups (p = 0.109). MuSK-MG showed synchronized BAFF/APRIL declines while AChR-MG presents transient BAFF elevation and sustained APRIL. BAFF levels showed a significant positive correlation with QMGS in MuSK-MG, while IgM/IgG positively correlated with QMGS in both subtypes. Median B cell-repopulation time was 47.7 days.

Conclusion: OFA demonstrates superior efficacy in MuSK-MG with distinct immunological modulation. AChR-MG requires combinatorial strategies targeting compensatory pathways.

Intra- and extracranial tandem occlusions (TOCs) in acute ischaemic stroke (AIS) are defined by the coexistence of an intracranial anterior or posterior circulation large vessel occlusion together with an ipsilateral extracranial occlusion or significant stenosis in the corresponding proximal vascular axis. They represent a distinct subgroup of AIS requiring tailored diagnostic and therapeutic strategies and are commonly divided into anterior (ATOCs) and posterior (PTOCs) forms. This narrative review synthesises the current evidence base regarding diagnosis, management (medical and interventional) and prognosis of TOCs. ATOCs account for around 20% of anterior circulation large-vessel occlusions, while PTOCs appear proportionally more frequent in posterior circulation stroke. Atherosclerosis is the predominant mechanism (around 70%), followed by arterial dissection (around 20%-25%), with cardioembolism and rarer causes playing a smaller role. Diagnosis can be challenging, particularly due to pitfalls such as carotid pseudo-occlusion. Endovascular thrombectomy (EVT) is the cornerstone of treatment for TOCs. In ATOCs, emerging evidence suggests that emergent carotid artery stenting improves outcomes in selected patients, with large observational cohorts such as CERES-TANDEM reporting higher functional independence without increased bleeding risk. In PTOCs, EVT is feasible and technically effective, but evidence remains limited. Vertebral stenting may be beneficial in selected cases, though morbidity and mortality remain high. Periprocedural antithrombotic therapy varies widely between centres, and high-quality data are lacking. Bridging therapy with intravenous thrombolysis appears safe and should be performed in eligible patients with tandem lesions. Prognosis has improved substantially for patients with ATOCs in the EVT era, whereas outcomes in PTOCs are less well defined. Continued efforts to generate higher-quality evidence, particularly for PTOCs, will be essential to guide treatment strategies and improve patient outcomes.

Patients with hypereosinophilic syndrome (HES) suffer from thrombotic events including ischemic stroke. Simultaneous occurrence of stroke and intracerebral hemorrhage (ICH) in such patients have rarely been reported. Here, we describe two patients with HES who suffered from ischemic stroke complicated by ICH. In case 1, we used a recombinant tissue plasminogen activator for acute ischemic stroke without treating hypereosinophilia; consequently, ICH occurred. In case 2, the patient had an ischemic stroke and ICH upon admission. In both cases, we used glucocorticoids to control hypereosinophilia, and no additional ischemic stroke or ICH occurrence was observed. These cases suggest that patients with HES can experience both ischemic and hemorrhagic strokes simultaneously and emphasize the importance of early control of eosinophilia to reduce the risk of cerebrovascular complications.