Therapeutic Advances in Neurological Disorders最新文献

Background: Previous studies have suggested that the Pro-Kin visual feedback balance system can promote the recovery of balance function in stroke patients.

Objectives: However, this system has not been used effectively in the early stages of stroke rehabilitation. This study aimed to investigate the effect of Pro-Kin system combined with weight loss system for the early recovery of balance and walking ability following a stroke.

Methods: A total of 62 patients who underwent radiological diagnosis of stroke were randomly divided into two groups: a control group (n = 31) and a treatment group (n = 31). Both groups received conventional balance training. The treatment group also received training on the Pro-Kin system in conjunction with a weight loss system. Balance was measured using the Berg Balance Scale (BBS), Timed 'Up & Go' (TUG) test and Pro-Kin system. Walking ability was assessed using the Functional Ambulation Classification (FAC). The tests were performed before the start of treatment and on the 4th week following the training. There was no statistically significant difference between the groups before training.

Results: After 4 weeks of training in both groups, there were significant improvements in balance and walking ability. BBS values and FAC were significantly higher (p < 0.01), TUG times, ellipse area and motion trajectory length were significantly reduced (p < 0.01, p < 0.05) after training. The treatment group outperformed the control group (p < 0.05). In addition, there was a positive correlation between balance function and walking ability (p < 0.01).

Conclusion: The Pro-Kin system combined with weight loss system is a viable method that promotes early reconstruction of balance and walking ability following a stroke.

Trial registration: Clinical trial number ChiCTR1900026370. https://www.chictr.org.cn/showprojEN.html?proj=43736.

Background: Although often asymptomatic, patent foramen ovale (PFO) may cause disabling migraine symptoms. Evidence regarding PFO closure for prevention of migraine is still ambiguous and conflicting.

Objectives: This study aims to analyze the efficacy and safety of PFO closure for mitigating migraine symptoms.

Design: This is a systematic review and meta-analysis of randomized clinical trials (RCTs) and observational studies.

Data sources and methods: A comprehensive search was conducted on the Scopus, Medline, ClinicalTrials.gov, and Cochrane Library databases up until March 12, 2024. This review incorporates literature that examines the comparison between PFO closure and control with outcome data related to migraine. We employed random-effect models to analyze the standardized mean difference (SMD) and odds ratio (OR) for presentation of the outcomes.

Results: A total of five RCTs and six observational studies were incorporated. The results of our meta-analysis showed higher reduction of monthly migraine attacks from baseline (SMD -0.34; 95% CI: -0.51, -0.18, p < 0.0001, I ² = 19%) and monthly migraine days from baseline (SMD -0.30; 95% CI: -0.53, -0.08, p = 0.009, I ² = 0%) among PFO closure than control. However, the complete resolution of migraine (especially based on the evidence from RCTs; p = 0.24), HIT-6 score (p = 0.08), and MIDAS score (p = 0.15) did not differ significantly between two groups of intervention. The majority of adverse events reported were atrial fibrillation and access site infection/bleeding that only occurred in small proportions of patients (⩽5%).

Conclusion: This study suggests better efficacy of PFO closure in reducing monthly migraine attacks and days with similar safety profile when compared to control.

Registration: PROSPERO (CRD42023453635).

Background: Epilepsy is a chronic neurological disorder characterized by recurrent seizures that significantly impact patients' quality of life. Identifying predictors is crucial for early intervention.

Objective: Electroencephalography (EEG) microstates effectively describe the resting state activity of the human brain using multichannel EEG. This study aims to develop a comprehensive prediction model that integrates clinical features with EEG microstates to predict drug-refractory epilepsy (DRE).

Design: Retrospective study.

Methods: This study encompassed 226 patients with epilepsy treated at the epilepsy center of a tertiary hospital between October 2020 and May 2023. Patients were categorized into DRE and non-DRE groups. All patients were randomly divided into training and testing sets. Lasso regression combined with Stepglm [both] algorithms was used to screen independent risk factors for DRE. These risk factors were used to construct models to predict the DRE. Three models were constructed: a clinical feature model, an EEG microstate model, and a comprehensive prediction model (combining clinical-EEG microstates). A series of evaluation methods was used to validate the accuracy and reliability of the prediction models. Finally, these models were visualized for display.

Results: In the training and testing sets, the comprehensive prediction model achieved the highest area under the curve values, registering 0.99 and 0.969, respectively. It was significantly superior to other models in terms of the C-index, with scores of 0.990 and 0.969, respectively. Additionally, the model recorded the lowest Brier scores of 0.034 and 0.071, respectively, and the calibration curve demonstrated good consistency between the predicted probabilities and observed outcomes. Decision curve analysis revealed that the model provided significant clinical net benefit across the threshold range, underscoring its strong clinical applicability. We visualized the comprehensive prediction model by developing a nomogram and established a user-friendly website to enable easy application of this model (https://fydxh.shinyapps.io/CE_model_of_DRE/).

Conclusion: A comprehensive prediction model for DRE was developed, showing excellent discrimination and calibration in both the training and testing sets. This model provided an intuitive approach for assessing the risk of developing DRE in patients with epilepsy.

Background: Among the currently approved antiobesity medications, the glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) liraglutide and semaglutide, and the dual glucose-dependent-insulinotropic-polypeptide (GIP)/GLP-1 RA tirzepatide have been suggested to reduce cardiovascular-risk in overweight or obesity without diabetes.

Objectives: The objective of this study was to evaluate the cardio- and neuroprotective potential of these novel agents in the nondiabetic overweight/obese adult population.

Data sources and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate the risk of major adverse cardiovascular events (MACE), all-cause and cardiovascular mortality in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Secondary outcomes included the risk of myocardial infarction (MI) and stroke.

Results: Sixteen RCTs (13 and 3 on GLP-1 RAs and tirzepatide, respectively) comprising 28,168 participants were included. GLP-1 or GIP/GLP-1 RAs reduced MACE (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.71-0.89; p < 0.01; I ² = 0) and all-cause mortality (OR: 0.80; 95% CI: 0.70-0.92; p < 0.01; I ² = 0), while there was a trend toward lower cardiovascular-mortality (OR: 0.84; 95% CI: 0.71-1.01; p = 0.06; I ² = 0%) compared to placebo. Additionally, GLP-1 or GIP/GLP-1 RAs reduced the odds of MI (OR: 0.72; 95% CI: 0.61-0.86; p < 0.01; I ² = 0%) and nonfatal-MI (OR: 0.72; 95% CI: 0.61-0.85; p < 0.01; I ² = 0%); while no associations between antiobesity treatment and fatal-MI, stroke, nonfatal, or fatal stroke were uncovered.

Conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and all-cause mortality in overweight or obese adults without diabetes. Additionally, GLP-1 RAs and GIP/GLP-1 RAs attenuate the risk of MI. Since data on stroke are still limited, future RCTs are warranted to evaluate the neuroprotective potential of these novel antiobesity agents.

Trial registration: PROSPERO CRD42024515966.

Background: Drug-resistant epilepsy (DRE) affects approximately one-third of epilepsy patients who do not achieve adequate seizure control with medication. Vagus nerve stimulation (VNS) is an adjunctive therapy for DRE, but its long-term effects on cortical excitability remain unclear.

Objectives: This study aims to elucidate the long-term effects of VNS on electroencephalography (EEG) aperiodic components in patients with DRE. Our objective is to identify biomarkers that can serve as indicators of therapeutic efficacy and provide mechanistic insights into the underlying neural processes.

Design: This longitudinal observational study focused on patients with DRE undergoing VNS therapy at Sanbo Brain Hospital. The reduction in seizure frequency rates was quantified over short-term (⩽1 year), medium-term (1-3 years), and long-term (⩾3 years) intervals to assess the therapeutic efficacy of VNS. Both the periodic and aperiodic components of EEG data were analyzed.

Methods: Advanced signal processing techniques were utilized to parameterize the periodic and aperiodic components of EEG data, focusing particularly on "offset" and "exponent." These measures were compared before and after VNS therapy. Correlation analyses were conducted to explore the relationship between these EEG parameters and clinical outcomes.

Results: In all, 18 patients with DRE participated in this study. During the long-term follow-up period, the responder rate was 55.56%. Significant decreases were observed in aperiodic offset (p = 0.022) and exponent (p = 0.039) among responders. The impact of age on these results was not significant. Correlation analyses revealed a negative association between therapeutic efficacy and a decrease in offset (R = -0.546, p = 0.019) and exponent (R = -0.636, p = 0.019).

Conclusion: EEG aperiodic parameters, including offset and exponent, have the potential to serve as promising biomarkers for evaluating the efficacy of VNS. An understanding of the regulatory influence of VNS on cortical excitability through these aperiodic parameters could provide a basis for the development of more effective stimulation parameters and therapeutic strategies.

Background: The inpatient Parkinson's Disease Multimodal Complex Treatment (PD-MCT) is an important therapeutical approach to improving gait and activities of daily living (ADL) of people with PD (PwP). Wearable device-based parameters (DBP) are new options for specific gait analyses toward individualized treatments.

Objectives: We sought to identify predictors of perceived ADL benefit taking clinical scores and DBP into account. Additionally, we analyzed DBP and clinical scores before and after PD-MCT.

Design: Exploratory observational cohort study.

Methods: Clinical scores and DBP of 56 PwP (mean age: 66.3 years, median Hoehn and Yahr (H&Y) stage: 2.5) were examined at the start and the end of a 14-day inpatient PD-MCT in a German University Medical Center. Participants performed four straight walking tasks under single- and dual-task conditions for gait analyses. Additionally, clinical scores of motor and nonmotor functions and quality of life (QoL) were assessed. Using dichotomized data of change in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part II (MDS-UPDRS II) as a dependent variable and clinical and DBP as independent variables, a binomial logistic regression model was implemented.

Results: Young age, high perceived ADL impairment at baseline, high dexterity skills, and a steady gait were significant predictors of ADL benefit after PD-MCT. DBP like gait speed, number of steps, step time, stance time, and double limb support time were improved after PD-MCT. In addition, motor functions (e.g., MDS-UPDRS III and IV), QoL, perceived ADL (MDS-UPDRS II), and experience of nonmotor functions (MDS-UPDRS I) improved significantly.

Conclusion: The logistic regression model identified a group of PwP who had the most probable perceived ADL benefit after PD-MCT. Additionally, gait improved toward a faster and more dynamic gait. Using wearable technology in context of PD-MCT is promising to offer more personalized therapeutical concepts.

Trial registration: German Clinical Trial Register, https://drks.de; DRKS00020948 number, 30 March 2020, retrospectively registered.

Background: Multiple lines of evidence suggest a role of inflammation in epilepsy. Seizure incidence in patients with multiple sclerosis (MS) is twofold to threefold higher than the age-matched general population.

Objectives: To explore the association of MS disease-modifying therapies (DMTs) and FDA-approved Bruton tyrosine kinase inhibitors (for lymphocytic malignancies) with the occurrence of epilepsy using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Design: Secondary analysis of the FAERS database.

Methods: We conducted a disproportionality analysis of FAERS between 2003-Q4 and 2023-Q3. MS DMTs and the Bruton tyrosine kinase inhibitor, ibrutinib, were included in the analysis. An inverse association was defined by a 95% confidence interval (CI) upper limit of reporting odds ratio (ROR) <1.

Results: We found an inverse association of ibrutinib, ocrelizumab, ofatumumab, rituximab, and teriflunomide with epilepsy. The strongest inverse association was seen with ibrutinib (ROR: 0.338; 95% CI: 0.218-0.524).

Conclusion: Our findings suggest the possibility of considering these medications for repurposing opportunities in epilepsy and support a potential pathogenic role of leukocyte subsets in seizure perpetuation.

Background: Clinical efficacy of zilucoplan has been demonstrated in a 12-week, placebo-controlled, phase III study in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG). However, placebo-controlled zilucoplan data past 12 weeks are not available.

Objectives: Predict the treatment effect of zilucoplan versus control (placebo or standard of care) in patients with gMG up to 24 weeks.

Design: A model-informed analysis (MIA) within a Bayesian framework.

Methods: Part 1 of the MIA comprised a control meta-regression using aggregate data on control response over time from randomised studies and a national myasthenia gravis (MG) registry. In Part 2, a combined Bayesian analysis of individual patient-level data from the phase II (NCT03315130), RAISE (NCT04115293) and RAISE-XT (NCT04225871) studies of zilucoplan was conducted using posterior distributions from Part 1 as informative priors. Population mean treatment effect in the change from baseline (CFB) at week 24 in MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) scores for zilucoplan versus control were assessed.

Results: At week 24, the predicted mean CFB in MG-ADL score was -4.55 (95% credible interval: -6.04, -3.13) with zilucoplan versus -2.00 (-3.35, -0.64) with control (difference: -2.55 [-3.76, -1.40]). The probability of a favourable treatment effect as measured by MG-ADL score at week 24 with zilucoplan versus control was >99.9%. There was an 82.8% probability that the difference in the predicted mean CFB in MG-ADL score at week 24 was greater than the clinically meaningful threshold (⩾2.0-point improvement). Comparable results were observed with QMG.

Conclusion: This MIA demonstrates the maintenance of efficacy with zilucoplan versus control up to 24 weeks. Through combining real-world evidence with data from randomised studies, this novel method to estimate long-term treatment efficacy facilitated reduced exposure to placebo in the phase III RAISE study. This methodology could be used to reduce the length of future placebo-controlled studies.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting an increasing number of cancer survivors worldwide. However, insights into its pathophysiology and availability of effective therapies remain lacking. Dorsal root ganglia (DRG) have been studied as a key component of chemotherapeutic drug toxicity and a potential therapeutic target for CIPN treatment. This comprehensive review aims to synthesize, summarize, and correlate the results of both preclinical and clinical studies relevant to the pathophysiology and management of CIPN in relation to the DRG. Design: Review. A thorough literature search was conducted using the terms 'dorsal root ganglion' and 'chemotherapy-induced peripheral neuropathy', along with appropriate variations. Searched databases included PubMed, EMBASE, Medline, Cochrane Library, Wiley Library, and Web of Science. Inclusion criteria targeted all English language, peer-reviewed original research from the inception of these databases to the present year. Review articles, book chapters, and other nonoriginal publications were excluded. Of 134 relevant studies identified, the majority were preclinical studies elucidating how various chemotherapeutic agents, especially taxanes, disrupt neurotransmission, inflammatory processes, and apoptotic pathways within sensory neurons of DRG. Not only do these effects correlate with the presentation of CIPN, but their disruption has also been shown to reduce CIPN symptoms in preclinical models. However, clinical studies addressing DRG interventions are very limited in number and scope at this time. These results reveal various pathways within DRG that may be effective targets for CIPN treatment. While limited, clinical studies do offer promise in the utility of DRG neuromodulation in managing painful CIPN. In the future, clinical trials are needed to assess interventions aimed at these neuronal and nonneuronal pathological targets to better treat this complex condition.

Background: The widespread clinical use of lacosamide (LCM) has revealed significant individual differences in clinical response, with various reported influencing factors. However, it remains unclear how genetic factors related to the disposition and clinical response of LCM, as well as drug-drug interactions (DDIs), exert their influence on pediatric patients with epilepsy.

Objectives: To evaluate the impact of genetic variations and DDIs on plasma LCM concentrations and clinical response.

Design: Patients with epilepsy treated with LCM from June 2021 to March 2023 in the Children's Hospital of Nanjing Medical University were included in the analysis.

Methods: The demographic information and laboratory examination data were obtained from the hospital information system. For the pharmacogenetic study, the left-over blood specimens, collected for routine plasma LCM concentration monitoring, were used to perform genotyping analysis for the selected 26 single nucleotide polymorphisms from 14 genes. The trough concentration/daily dose (C ₀/D) ratio and efficacy outcomes were compared.

Results: Patients achieved 90.1% and 68.9% responder rates in LCM mono- and add-on therapy, respectively. The genetic variant in the CYP2C19 *2 (rs4244285) was associated with a better responsive treatment outcome (odds ratio: 1.82; 95% confidence interval: 1.05-3.15; p = 0.031). In monotherapy, 36% of patients were CYP2C19 normal metabolizers (NMs), 49% were intermediate metabolizers (IMs), and 15% were poor metabolizers (PMs) carrying CYP2C19 *2 or *3. Of note, the C ₀/D ratios of IMs and PMs were 9.1% and 39.6% higher than those of NMs, respectively. Similar results were in the add-on therapy group, and we also observed a substantial decrease in the C ₀/D ratio when patients were concomitant with sodium channel blockers (SCBs).

Conclusion: This study was the first to confirm that CYP2C19 *2 or *3 variants impact the disposition and treatment response of LCM in children with epilepsy. Moreover, concomitant with SCBs, particularly oxcarbazepine, also decreased plasma LCM concentration.