Therapeutic Advances in Neurological Disorders最新文献

Background: Cerebral small vessel disease is the most common cause of lacunar strokes (LS). Understanding LS pathogenesis is vital for predicting disease severity, prognosis, and developing therapies.

Objectives: To research molecular profiles that differentiate LS in deep brain structures from those in subcortical white matter.

Design: Prospective case-control study involving 120 patients with imaging-confirmed LS and a 120 control group.

Methods: We examined the relationship between Alzheimer's disease biomarkers [amyloid beta (Aβ_1-40, Aβ_1-42)], serum inflammatory marker (interleukin-6, IL-6), and endothelial dysfunction markers [soluble tumor necrosis factor-like weak inducer of apoptosis, and pentraxin-3 (sTWEAK, PTX3)] with respect to LS occurring in deep brain structures and subcortical white matter. In addition, we investigated links between LS, leukoaraiosis presence (white matter hyperintensities, WMHs), and functional outcomes at 3 months. Poor outcome was defined as a modified Rankin scale >2 at 3 months.

Results: Significant differences were observed in levels of IL-6, PTX3, and sTWEAK between patients with deep lacunar infarcts and those with recent small subcortical infarcts (20.8 versus 15.6 pg/mL, p < 0.001; 7221.3 versus 4624.4 pg/mL, p < 0.0001; 2528.5 versus 1660.5 pg/mL, p = 0.001). Patients with poor outcomes at 3 months displayed notably higher concentrations of these biomarkers compared to those with good outcomes. By contrast, Aβ_1-40 and Aβ_1-42 were significantly lower in patients with deep LS (p < 0.0001). Aβ_1-42 levels were significantly higher in patients with LS in subcortical white matter who had poor outcomes. WMH severity only showed a significant association with deep LS and correlated with sTWEAK (p < 0.0001).

Conclusion: The pathophysiological mechanisms of lacunar infarcts in deep brain structures seem different from those in the subcortical white matter. As a result, specific therapeutic and preventive strategies should be explored.

Myasthenia gravis (MG) is an autoimmune disorder characterized by fluctuating muscle weakness. Severe patients may develop life-threatening respiratory failure and experience crisis. Plasma exchange or intravenous immunoglobulin (IVIg) is the first-line treatment option for myasthenia crisis, but some patients still poorly respond to them. Here, we first reported a generalized MG patient from China who was in a state of impending myasthenic crisis and did not respond effectively to IVIg but was successfully rescued by add-on efgartigimod. Especially, we also detected meaningful changes in T-cell and B-cell subsets after efgartigimod, promoting a potential role of efgartigimod in re-establishing immune homeostasis.

Opportunistic viral infections in individuals with severe immunodeficiency can lead to fatal conditions such as progressive multifocal leukoencephalopathy (PML), for which treatment options are limited. These infections pose significant risks, especially when co-infections with other viruses occur. We describe a combined therapy approach using directly isolated allogeneic Human Polyomavirus 1 (also known as BKV) and Epstein-Barr virus (EBV) specific cytotoxic T-cells for the treatment of PML in conjunction with identified EBV in the cerebrospinal fluid (CSF) of a male patient infected with human immunodeficiency virus (HIV). A 53-year-old HIV-positive male, recently diagnosed with PML, presented with rapidly worsening symptoms, including ataxia, tetraparesis, dysarthria, and dysphagia, leading to respiratory failure. The patient developed PML even after commencing highly active antiretroviral therapy (HAART) 3 months prior. Brain magnetic resonance imaging (MRI) revealed multifocal demyelination lesions involving the posterior fossa and right thalamus suggestive of PML. In addition to the detection of human polyomavirus 2 (also known as JCV), analysis of CSF showed positive results for EBV deoxyribonucleic acid (DNA). His neurological condition markedly deteriorated over the following 2 months. Based on MRI, there was no evidence of Immune Reconstitution Inflammatory Syndrome contributing to this decline. The patient did not have endogenous virus-specific T-cells. We initiated an allogeneic, partially human leukocyte antigen-matched transfer of EBV and utilizing the cross-reactivity between BKV and JCV-BKV specific T-cells. This intervention led to notable neurological improvement and partial resolution of the MRI lesions within 6 weeks. Our case of a patient with acquired immune deficiency syndrome demonstrates that PML and concurrent EBV co-infection can still occur despite undergoing HAART treatment. This innovative experimental therapy, involving a combination of virus-specific T-cells, was demonstrated to be an effective treatment option in this patient.

Background: Teriflunomide is a once-daily oral disease-modifying therapy (DMT) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Only limited information is available about its real-world use and changes over time.

Objectives: To collect real-world data on teriflunomide use in clinical routine (and comparison to the previously conducted study TAURUS-MS).

Design: National, open, non-interventional, prospective, multicenter study.

Methods: TAURUS-MS II was conducted at 220 German sites between July 2017 and March 2022, including RRMS patients treated with teriflunomide. Data on patient demographics, MS history, previous treatment, therapy satisfaction, and safety were collected.

Results: In total, 752 patients were included (65% female) with a mean age (±standard deviation) of 43 ± 11 years. Sixty-six percent had DMT before, and 46% had discontinued their last pretreatment ≤6 months prior to study entry. Among the latter, previous DMTs were interferon (21%), glatiramer acetate (11%), and dimethyl fumarate (9%), and reasons for discontinuation were adverse events (AEs; 55%) and insufficient efficacy (16%). Over 24 months, the mean treatment Satisfaction Questionnaire for Medication scores improved by 6 ± 29 points on effectiveness, 8 ± 20 on convenience, and 12 ± 25 on global satisfaction. The mean number of MS relapses decreased from 0.81 ± 0.81 in the 24 months prior to 0.27 ± 0.57 within 24 months after study entry. Non-serious AEs occurred in 423 patients (56%) and serious AEs in 49 patients (7%). Most reported AEs were alanine aminotransferase increase (11%), hypertension (8%), and alopecia (7%). Compared to TAURUS-MS, patients in TAURUS-MS II were younger, had a higher employment rate, and a higher share of treatment-naïve patients.

Conclusion: Mean number of relapses was significantly reduced. Patient satisfaction was significantly improved compared to previous DMT. Tolerability was comparable to previous trials.

Trial registration: Bundesinstitut für Arzneimittel und Medizinprodukte public database for non-interventional studies, number 7138.

Background: Lacunar ischemic stroke (LIS) and deep intracerebral hemorrhage (dICH) are two stroke phenotypes of deep perforator arteriopathy. It is unclear what factors predispose individuals with deep perforator arteriopathy to either ischemic or hemorrhagic events.

Objectives: We aimed to investigate risk factors and neuroimaging features of small vessel disease (SVD) associated with LIS versus dICH in a cross-sectional study.

Methods: We included patients with clinically presenting, magnetic resonance imaging-confirmed LIS or dICH from two tertiary hospitals between 2010 and 2021. We recorded vascular risk factors and SVD markers, including lacunes, white matter hyperintensities (WMH), perivascular spaces (PVS), and cerebral microbleeds (CMB). Logistic regression modeling was used to determine the association between vascular risk factors, SVD markers, and stroke phenotype. We further created WMH probability maps to compare WMH distribution between LIS and dICH.

Results: A total of 834 patients with LIS (mean age 61.7 ± 12.1 years) and 405 with dICH (57.7 ± 13.2 years) were included. Hypertension was equally frequent between LIS and dICH (72.3% versus 74.8%, p = 0.349). Diabetes mellitus, hyperlipidemia, smoking, and prior ischemic stroke were more associated with LIS [odds ratio (OR) (95% confidence interval (CI)), 0.35 (0.25-0.48), 0.32 (0.22-0.44), 0.31 (0.22-0.44), and 0.38 (0.18-0.75)]. Alcohol intake and prior ICH were more associated with dICH [OR (95% CI), 2.34 (1.68-3.28), 2.53 (1.31-4.92)]. Lacunes were more prevalent in LIS [OR (95% CI) 0.23 (0.11-0.43)], while moderate-to-severe basal-ganglia PVS and CMB were more prevalent in dICH [OR (95% CI) 2.63 (1.35-5.27), 4.95 (2.71-9.42)]. WMH burden and spatial distribution did not differ between groups.

Conclusion: The microangiopathy underlying LIS and dICH reflects distinct risk profiles and SVD features, hence possibly SVD subtype susceptibility. Prospective studies with careful phenotyping and genetics are needed to clarify the mechanisms underlying this difference.

Background: The calcium channel has been considered to have great potential as a drug target for neuroprotective therapy in Parkinson's disease (PD), but previous studies yielded inconsistent results.

Objectives: This study aimed to conduct a systematic review and meta-analysis to assess the relationship between using calcium channel blockers (CCBs) and the risk and progression of PD.

Data sources and methods: The terms such as 'Parkinson's disease', 'PD', 'calcium channel blockers', and 'CCB' were used to search the literature published before 1 May 2023 in English databases, including PubMed, Embase, and Cochrane Library, for studies on CCB and PD. Data analysis was performed using Review Manager 5.3 software.

Results: A total of 190 works of literature were preliminarily retrieved, and 177 works of literature were excluded by eliminating duplicates, reading abstracts, and reading full texts. A total of nine studies were finally included in the meta-analysis of the CCB and the risk of PD, and five studies were included in the systematic review of the CCB and the progression of PD. A total of 2,961,695 participants were included in the meta-analysis. The random-effects model was used for analysis due to significant heterogeneity. The main results of the meta-analysis showed that the use of CCB could reduce the risk of PD (relative risk 0.78, 95% confidence interval 0.62-0.99).

Conclusion: CCB use was associated with a significantly reduced risk of PD. Whether CCB use has a disease-modifying effect on PD needs further study.

Registration: PROSPERO: CRD42024508242.

Background: Refractory generalized myasthenia gravis (GMG) remains a substantial therapeutic challenge. Telitacicept, a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein, holds promise for interrupting the immunopathology of this condition.

Objectives: This study retrospectively assessed the effectiveness and safety of telitacicept in patients with refractory GMG.

Design: A single-center retrospective study.

Methods: Patients with refractory GMG receiving telitacicept (160 mg/week or biweekly) from January to September in 2023 were included. We assessed effectiveness using Myasthenia Gravis Foundation of America post-intervention status (MGFA-PIS), myasthenia gravis treatment status and intensity (MGSTI), quantitative myasthenia gravis (QMG), and MG-activity of daily living (ADL) scores, alongside reductions in prednisone dosage at 3- and 6-month intervals. Safety profiles were also evaluated.

Results: Sixteen patients with MGFA class II-V refractory GMG were included, with eight females and eight males. All patients were followed up for at least 3 months, and 11 patients reached 6 months follow-up. At the 3-month evaluation, 75% (12/16) demonstrated clinical improvement with MGFA-PIS. One patient achieved pharmacological remission, two attained minimal manifestation status, and nine showed functional improvement; three remained unchanged, and one deteriorated. By the 6-month visit, 90.1% (10/11) sustained significant symptomatic improvement. MGSTI scores and prednisone dosages significantly reduced at both follow-ups (p < 0.05). MG-ADL and QMG scores showed marked improvement at 6 months (p < 0.05). The treatment was well tolerated, with no severe adverse events such as allergy or infection reported.

Conclusion: Our exploratory investigation suggests that telitacicept is a feasible and well-tolerated add-on therapy for refractory GMG, offering valuable clinical evidence for this novel treatment option.

[This corrects the article DOI: 10.1177/17562864231213240.].