Therapeutic Advances in Neurological Disorders最新文献

Multiple sclerosis (MS) is an autoimmune condition characterized by inflammatory demyelination that leads to irreversible neurological damage within the central nervous system (CNS). This review examines the therapeutic potential and clinical efficacy of cladribine tablets (CladT) for treating MS, focusing on the immune reconstitution mechanism and CNS effects. CladT represents a notable advance among disease-modifying therapies for MS due to its selective targeting of lymphocytes, resulting in sustained yet reversible immune modulation. This action leads to a substantial reduction in memory B cells while preserving the innate immune system and maintaining immunoglobulin levels, thereby mitigating the risks of secondary autoimmunity and infection. Cladribine appears to penetrate the blood-brain barrier, as indicated by cerebrospinal fluid (CSF) studies from parenteral cladribine use. In MS, CladT is associated with reductions in CSF immunological markers, such as oligoclonal bands and neurofilament light chain levels; it also mitigates acute and chronic inflammation, as evidenced, respectively, by consistent reductions in unique active lesions, and significant decrease in slowly expanding lesions in patients with predominant grey matter damage. These findings underscore the potential of CladT in reducing disability accumulation and improving long-term clinical outcomes in patients with highly active disease. By synthesizing data from clinical trials and real-world studies, this review underscores the effectiveness of CladT in reducing relapse rates, disability progression and magnetic resonance imaging-detected disease activity and emphasizes the importance of early high-efficacy treatment for optimizing long-term outcomes. Furthermore, emerging biomarkers are discussed as potential tools for predicting individual responses to therapy, thereby enabling more personalized treatment strategies. This review also provides valuable insights into the positive impact of CladT on quality of life measures, long-term outcomes and safety profile, all of which support the use of CladT in the evolving landscape of MS management.

Background: There is currently no established standard of care for recurrent glioblastoma (GBM). Re-irradiation (re-RT) and Bevacizumab (BEV) are both used in salvage treatment, but their combined efficacy remains uncertain.

Objectives: To evaluate whether combining re-irradiation with BEV improves survival outcomes compared to BEV alone in patients with recurrent high-grade gliomas (rHGG).

Design: Systematic review and meta-analysis of two-arm clinical trials.

Data sources and methods: A comprehensive literature search was conducted in Scopus, PubMed, Web of Science, and the Cochrane Library up to April 2024. Two independent reviewers assessed studies for eligibility and extracted data. Study quality was evaluated using the ROBINS-I and ROBINS-II tools. The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), toxicity, and prognostic factors.

Results: The meta-analysis demonstrated a significant improvement in OS with combined BEV and re-irradiation compared to BEV alone (hazard ratio (HR) 0.69, 95% confidence interval (CI: 0.56-0.85); p = 0.0005), corresponding to a 31% reduction in the risk of death. PFS also improved significantly (HR 0.64, 95% CI (0.45-0.90); p = 0.01). No significant increase in grade 3 toxicities was observed with the combination therapy. Subgroup analyses indicated that younger age and female gender were statistically associated with better OS, though the effect of age was modest and male gender was linked to poorer survival. Karnofsky performance status significantly influenced survival. Pulsed versus non-pulsed re-irradiation showed no differential effect on outcomes.

Conclusion: The combination of re-irradiation and BEV significantly improves both OS and PFS in patients with rHGG, without increasing severe toxicity. These findings support the safety and efficacy of the combined approach. Prospective trials are warranted to guide standardized treatment protocols.

Trial registration: This review was prospectively registered with PROSPERO (CRD42023463183).

Background: Acute ischemic stroke (AIS) is a leading cause of mortality and disability worldwide. Intravenous thrombolysis (IVT) improves recovery, but predicting outcomes remains challenging. Machine learning (ML) and biomarkers like ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), S100 calcium-binding protein β (S100β), and neuron-specific enolase (NSE) may enhance prognostic accuracy.

Objectives: We aimed to assess the predictive value of serum brain injury biomarkers for 3-month outcomes in AIS patients treated with IVT, using an ML-based model.

Design: A multicenter prospective cohort study was conducted, enrolling AIS patients treated with recombinant tissue plasminogen activator from 16 hospitals.

Methods: Of 1580 patients, 1028 were included and divided into training (n = 571), testing (n = 243), and external validation (n = 214) cohorts. Thirty-three variables, including demographics, clinical data, and biomarkers (UCH-L1, S100β, NSE), were analyzed. Least Absolute Shrinkage and Selection Operator regression was used for feature selection, and six ML algorithms were tested. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), F1-score, calibration curve, and decision curve analysis.

Results: The light gradient boosting machines (LightGBM) model achieved the best performance in the training dataset (AUC: 0.846; F1-score: 0.789) and external validation dataset (AUC: 0.714). Eight critical predictors, including age, admission National Institutes of Health Stroke Scale (NIHSS) score, Trial of Org 10172 in Acute Stroke Treatment, white blood cell, finger blood glucose, UCH-L1, S100β, and NSE, were identified and incorporated into an ML model for clinical application. Shapley additive interpretation analysis enhances the interpretability of the model, with NIHSS score and NSE as top contributors. External validation confirmed good calibration and consistent net benefit across threshold probabilities (0.1-0.8).

Conclusion: Integrating serum biomarkers (UCH-L1, S100β, NSE) with ML significantly improves 3-month outcome prediction in AIS patients. The LightGBM model offers robust performance and clinical interpretability for individualized treatment planning.

Background: Migraine inflicts substantial personal, social, and economic tolls on many adults in the United States (US). Acute and preventive medicines can offer some relief, but most patients are untreated or experience treatment failures. How preventive-treatment failures affect outcomes for patients no longer on preventive treatments or for patients with migraine is insufficiently understood.

Objective: To measure the patient-reported health and economic burdens associated with increasing preventive-treatment failures among US adults with diagnosed migraine.

Design: Retrospective, cross-sectional study.

Methods: Data analyzed were from the 2023 US National Health and Wellness Survey. Participants were adults diagnosed with migraine, having ≥4 monthly migraine or headache days, having taken acute or preventive prescription migraine medications or currently taking acute prescription migraine medications, and taking no preventive migraine medications. Participants were categorized as never treated with preventive medicines, having failed 1 preventive medicine, or having failed ≥2 preventive medicines. Health-related quality of life (HRQoL) was assessed with the Migraine Disability Assessment, RAND's 36-Item Short Form Survey Instrument, 5-Level EuroQoL instrument (EQ-5D), Work Productivity and Activity Impairment General Health version, 9-Item Patient Health Questionnaire, and 7-Item Generalized Anxiety Disorder scale. Details about medication use and health care resource use (HCRU) were collected. Data were adjusted by inverse probability of treatment weighting and compared using two-sided two-sample t-tests or Chi-square tests.

Results: Patients who had failed preventive treatments had poorer HRQoL, greater work productivity loss, greater nonwork activity impairment, and greater HCRU than patients who had never taken preventive treatments. The number of preventive-treatment failures scaled with disease burden. Patients with ≥2 treatment failures had significantly lower EQ-5D scores (0.69 vs 0.73) than those for prevention-naïve patients; patients with ≥2 treatment failures had significantly higher overall work productivity loss (45.9% vs 34.9%), activity impairment (46.8% vs 36.7%), and higher rates of emergency room visits (37.0% vs 25.2%), hospitalization (23.5% vs 12.3%), and neurologist visits (17.6 vs 10.9%) than those of prevention-naïve patients. Medication overuse rates were similar among patients with any treatment failures and prevention-naïve patients (migraine-specific: 34.4%-39.3%; overall: 59.2%-62.3%).

Conclusion: US adults with frequent migraines who failed preventive treatments have significantly greater unmet needs and different acute medication use patterns than adults who never took treatments.

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by progressive worsening of motor symptoms. The primary pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are primarily composed of α-synuclein (α-syn) aggregates. Both α-syn and various neurotransmitters, including catecholamines (catechols), play crucial roles in the pathogenesis of PD, although the precise pathogenic mechanisms remain incompletely understood. The crosstalk between neurotransmitters and α-syn is intricate and multifaceted. Pathological α-syn disrupted neurotransmitters' homeostasis by impairing release and reuptake of neurotransmitters, with specific modulation of catecholaminergic and glutamatergic systems. Conversely, neurotransmitters, especially catechols, covalently modify α-syn. Such modifications significantly influence α-syn aggregation dynamics and alter its neurotoxic properties. However, determining whether these interactions induce synergistic toxicity or confer neuroprotection remains controversial. Emerging evidence suggests other neurotransmitters like serotonin and γ-aminobutyric acid may also modulate α-syn aggregation and PD progression, though their roles require further investigation. Understanding these interactions is crucial for developing novel diagnostic and multi-target therapeutic strategies.

Background: Standard management of generalized myasthenia gravis associated with anti-acetylcholine receptor autoantibodies (AChR-gMG) includes corticosteroids and nonsteroidal immunosuppressants. Complement inhibitors (CI) represent a more tailored therapeutic strategy. Real-world data on the steroid-sparing efficacy of CI remain limited.

Objective: To investigate the steroid-sparing efficacy of CI in AChR-gMG.

Design: We identified 69 AChR-gMG patients on corticosteroids treated with azathioprine (AZA), mycophenolate mofetil (MMF), or CI.

Methods: Steroid tapering was assessed by comparing corticosteroid dosage at several time-points to baseline.

Results: Steroids reductions were statistically significant for all therapies at every time point compared to baseline (all p < 0.001). Pairwise comparisons using the Mann-Whitney U test revealed significant differences between CI and MMF at 3 months (p = 0.0372), 6 months (p = 0.0193), and 9 months (p = 0.0321) and between CI and AZA at 6 months (p = 0.0415).

Conclusion: CI rapidly and effectively reduced corticosteroid dosage in most AChR-gMG patients, suggesting their potential role as steroid-sparing therapeutic options.

Neuropsychiatric symptoms in Parkinson's disease (PD) are highly prevalent and profoundly disabling, often emerging even before the onset of motor symptoms. As the disease progresses, these symptoms usually become increasingly impairing and are now recognized as having the greatest impact on quality of life not only for patients but also for caregivers. In recent years, there have been significant advances in the diagnosis and management of neuropsychiatric symptoms. However, there are still substantial gaps in therapeutic approaches and algorithms, with limited pharmacological and nonpharmacological treatment options currently available. One of the main reasons for this is the complex molecular and neural bases of these symptoms, which involve both dopaminergic and nondopaminergic neurotransmission systems and extend far beyond the nigrostriatal pathway. As a result, the drugs currently recommended for treating neuropsychiatric symptoms in PD are few and supported by limited evidence. In this context, the experience of the treating neurologist remains critical in selecting the most appropriate individualized therapy. The aim of this paper is to review the available therapeutic options and provide an overview of current research efforts, particularly those focusing on pharmacological treatments.

Background: Epidemiological research indicates a heightened incidence of cerebrovascular disorders among patients with multiple sclerosis (MS).

Objectives: The aim of the present systematic review was to investigate the potential association between disease modifying therapies (DMTs) and the risk of stroke in MS patient populations.

Data sources and methods: A systematic literature search was performed in MEDLINE and SCOPUS databases up to April 6, 2024, to identify randomized-controlled clinical trials (RCT), registry-based and cohort-studies, case-series, and case-reports reporting on acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) in MS patients under different DMTs.

Results: Twenty-one studies were included: 1 RCT, 6 registry-based or cohort studies, 2 case-series and 11 case-reports. Overall, DMTs appear to reduce the risk of stroke in MS patients, with DMT exposure linked to a 50% reduction of the risk of stroke compared to no DMT exposure. Although glatiramer acetate and dimethyl fumarate appear to lower the risk of stroke, concerns about fingolimod exists due to an observed elevated risk for ischemic heart disease and hypertension. Despite the absence of detected safety concerns with alemtuzumab at the MS population level, alemtuzumab-related complications, although rare, signal the need for heightened clinical vigilance. Similarly, β-interferons have been linked to life-threatening adverse events, comprising thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). No associations between the risk of stroke and other DMTs, comprising natalizumab and teriflunomide, were detected; yet, newly approved DMTs were underrepresented.

Conclusion: These findings highlight the importance of personalizing DMT selection and monitoring cardiovascular risk factors to reduce stroke risk in patients with MS.

Trial registration: PROSPERO CRD42024534470.

Background: The Migraine in Poland study is a cross-sectional survey that assesses symptomatology, consulting, diagnosis, treatment and impact of migraine in Poland.

Objectives: The purpose of this article is to define patterns of care for migraine in Polish patients.

Methods: The survey was conducted from August 2021 to June 2022. Participants were recruited through various channels, targeting mostly persons suffering from headaches. The web survey included questions allowing for diagnosis according to the International Classification of Headache Disorders. A detailed questionnaire evaluated healthcare system utilization, history of diagnosis, as well as the use of acute or preventive treatment, including non-pharmacological methods.

Results: In total, 3225 individuals aged 13-80 (mean age 38.9) responded to the questionnaire (87.1% were women). Migraine without aura (MwoA) diagnosis was confirmed in 1679 (52.7%) of subjects, and 1571 (93.6%) of them consulted a medical professional for their headaches in the past. Among those who consulted for headache, 91% reported having received a medical diagnosis of migraine. 92.5% of MwoA participants declared the current use of some form of treatment. Non-steroidal anti-inflammatory drugs and acetaminophen were the most frequently used acute medications (n = 1318, 78.5%) followed by combination analgesics, especially those containing codeine (n = 991, 59%). Triptans/ergots were used by 57.1%. A total of 22.8% of subjects used acute treatment with a frequency indicating medication-overuse. Prophylactic treatment was at some point used by 35.68%, while 11.49% were currently on preventive medications. The most frequently prescribed preventives were iprazochrome (8.99%), followed by flunarizine (8.10%) and topiramate (5.90%). A total of 23.28% subjects used nutraceuticals for migraine prevention (most frequently magnesium).

Conclusion: Despite high consultation and diagnosis rates among Polish patients with migraine, there is a need for improving standards of care, especially in regard to choice of treatment. There is also a need to raise public awareness of the dangers of codeine-based medications (available over-the-counter in Poland).