Therapeutic Advances in Neurological Disorders最新文献

Background: Cladribine tablets are contraindicated during pregnancy; therefore, safety data on pregnancies exposed to this treatment are limited. CLEAR collects and describes pregnancy outcomes in this understudied population.

Objectives: To describe the main features of the CLEAR study design, including the data sources and the methodological approach, and provide a status update.

Design: CLEAR is a non-interventional, multi-database, comparative cohort study. Four cohorts are included: pregnancies of women with multiple sclerosis (MS) exposed to cladribine tablets (maternal cohort exposed); pregnancies of women with MS unexposed to any disease-modifying therapy (DMT; maternal cohort unexposed); pregnancies fathered by men with MS exposed to cladribine tablets; and pregnancies fathered by men with MS unexposed to any DMT.

Methods: A staggered methodological approach, using data from Denmark, Finland, France, Germany, Norway, Scotland, and Sweden, will be applied to analyze the occurrence of major congenital anomalies (primary outcome) and selected pregnancy outcomes. The first interim analysis (performed using German pregnancy cohorts) was conducted when ⩾75 pregnant women (including 25 women from the maternal cohort exposed) were cumulatively reached across all participating countries. The end of the study period will be established once pregnancy counts reach 149 in the maternal cohort exposed and 298 in the maternal cohort unexposed in all countries combined, or 5 years after pregnancy counts are first assessed (whichever occurs first).

Results: As of January 2024, data on pregnancies of women exposed to cladribine tablets (n = 28-36 (numbers are approximate due to masking of some counts)), and pregnancies of women unexposed to cladribine tablets (n = 2834) were available from Denmark, Finland, Germany, Scotland, and Sweden.

Conclusion: The CLEAR study, using a staggered methodological approach, aims to provide further insight into the safety outcome data for cladribine tablets in pregnant women, as a regulatory commitment with the European Medicines Agency.

Trial registration: EU PAS Register number, EUPAS25027.

Background: Complete vaccination coverage is recommended by multiple sclerosis (MS) societies for patients with multiple sclerosis (pwMS) to mitigate infection risks associated with disease-modifying therapies (DMTs).

Objectives: To analyze vaccination coverage and its determinants in pwMS compared to healthy controls, considering vaccination hesitancy, MS-specific vaccination beliefs, trust in information sources, and the role of general practitioners (GPs).

Methods: This cross-sectional multicenter observational study was conducted in six German MS centers. The primary endpoint was a vaccination index (VI) comprising eight standard vaccinations (range 0-1, with higher VI indicating better vaccination coverage). Secondary endpoints included validated measures of general vaccination hesitancy, MS-specific vaccination beliefs, and trust in information sources. Data were collected through questionnaires, vaccination card analysis, and a survey of GPs who vaccinate pwMS.

Results: VI tended to be lower in pwMS (n = 397) compared to healthy controls (n = 300; 0.58 ± 0.30 vs 0.62 ± 0.31, p = 0.057). In pwMS receiving highly effective DMTs, VI did not differ significantly from those on no/platform DMTs. Vaccination hesitancy was comparably low, with no differences between pwMS and controls. Vaccination hesitancy, beliefs, and trust in information sources explained only 10%-16% of the variance in VI. Among 109 GPs, 82% cited reluctance to vaccinate pwMS due to concerns about MS-related side effects or interactions with DMTs.

Conclusion: Despite clear recommendations from MS societies for full vaccination of all pwMS, vaccination coverage remains worryingly low. Approximately half of the patients lack standard vaccination coverage, even those on highly effective DMTs. In fact, vaccination coverage in pwMS tended to be even lower than in healthy controls. Vaccination hesitancy and other intrinsic factors do not sufficiently explain the low vaccination rates. Inconsistent vaccination recommendations from GPs due to uncertainties about vaccine safety and DMT interactions likely contribute.

[This corrects the article DOI: 10.1177/17562864241306684.].

Background: Short-chain fatty acids (SCFAs), including propionic acid (PA), are key in immunological research. Supplementing PA has shown benefits for autoimmune diseases. A comprehensive understanding of the PA pharmacokinetics is essential for the optimal design and execution of studies utilizing orally administered PA.

Objective: We propose two methods of measuring PA in serum, carried out by different laboratories.

Design: Blood samples from 20 volunteers were collected hourly following PA supplementation.

Methods: Serum propionate quantification was performed with two independent mass spectrometry-based (MS) analyses, including liquid-chromatography (LC)-MS and direct-infusion (DI)-MS.

Results: PA levels increased within 1 h of ingestion of 500 mg PA. Serum concentrations ranged from 1.3 to 4.5 µmol/L, rising significantly after 1 h (p < 0.05). Serum levels returned to baseline within 2 h. No significant differences were found regarding sex or diet.

Conclusion: The shown pharmacokinetics can be used in future PA research.

The advent of antisense oligonucleotide (ASO) therapies in neurodegenerative disorders is associated with enormous hope. Nusinersen treatment was a breakthrough intervention in the recessive disease spinal muscular atrophy, and superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS) seems to be the paradigm disease in dominant degenerative diseases. The results of treatment with the ASO tofersen in SOD1-ALS show that the drug has a convincing beneficial effect on ALS caused by SOD1 mutations, that preclinical studies in rodents predicted the therapeutic effect in the human disease, and that clinical efficacy is associated with a specific sequence of effects of the drug on mechanistic and degenerative biomarkers and, subsequently, functional outcomes such as weight stabilization and ALSFRS-R. Therefore, the enthusiasm seems to be justified; but this should be followed by an attempt to obtain further insights with the goal to improve this therapy. In particular, the following issues are only partially resolved: Which mechanisms are responsible for the clinical effect following the downregulation of SOD1 protein by ASOs? Is long-term downregulation of SOD1 function associated with side effects? Is there an autoimmune response caused by this and other ASO? Is prevention of SOD1-associated ALS possible?

Background: Serum neurofilament light chain (sNfL) is a biomarker for neuro-axonal injury.

Objectives: To assess sNfL's utility as a diagnostic marker for Lyme neuroborreliosis (LNB).

Methods: We compared serum and CSF NfL levels in LNB patients and age-matched controls. Age-adjusted NfL values were used in receiver operating characteristic (ROC) analysis.

Design: Retrospective cohort study.

Results: Eighty-six patients (30 LNB, 29 with-, and 27 without neurological disorders) were included. Compared to individuals without neurological disease, LNB patients showed increased serum (median (interquartile range, IQR): 36.3 pg/ml (19.3-112.0) vs 20 pg/ml (12.9-37.3), p < 0.001) and CSF NfL levels (median (IQR): 1000.0 pg/ml (286.0-6471.0) vs 182 pg/ml (99.3-474.0), p < 0.001). NfL concentrations were similar in LNB and other neurological disorders. ROC analysis of age-adjusted sNfL and CSF NfL levels showed areas under the curve of 0.78 (95% confidence interval (CI): 0.66-0.89) and 0.83 (95% CI: 0.71-0.94), respectively.

Conclusion: sNfL concentrations lack sufficient diagnostic capability for LNB diagnosis.

Background: Dysphagia is a common complication following intracerebral hemorrhage (ICH) and is associated with an increased risk of aspiration pneumonia and poor outcomes.

Objectives: This study aimed to explore associated lesion patterns and contributing factors of post-ICH dysphagia, and predict dysphagia outcomes following ICH.

Design: A multicenter, prospective study.

Methods: Patients with ICH from two stroke centers within 72 h of symptom onset received baseline bedside swallowing evaluations. Dysphagia-related lesion patterns were identified using support-vector regression-based lesion-symptom mapping. Predictors of swallowing impairment on the 7th and 30th day, as well as stroke-associated pneumonia (SAP), were determined through multiple logistic regression analyses, and nomograms were developed.

Results: A total of 153 patients were included in the final analysis. Of those, 28 had dysphagia. Dysphagia-related lesions predominantly affected bilateral subcortical and adjacent cortical regions. Stroke severity, hematoma expansion, and basal ganglia hemorrhage were significantly associated with initial dysphagia. Baseline aspiration risk and age were identified as independent predictors of impaired swallowing function on days 7 and 30, and SAP. Moreover, ICH volume was significantly correlated with swallowing impairment on day 7 and SAP occurrence. Midline shift and basal ganglia hematoma remained independent predictors of impaired swallowing on day 30. Predictive models for swallowing impairment on days 7 and 30, as well as SAP, demonstrated strong calibration and discriminatory ability, with C indices of 0.867, 0.895, and 0.773, respectively.

Conclusion: Post-ICH dysphagia can be predicted based on stroke severity, hematoma expansion, and basal ganglia hemorrhage. Incorporating aspiration risk and imaging evaluation can further improve the identification of patients at high risk for swallowing impairment at both 1 week and 1 month after ICH.

Background: China has a large number of myasthenia gravis (MG) patients, creating an urgent need for rapid and tolerable treatment options. As the first-approved Fc receptor antagonist, efgartigimod has bright prospects for treating MG. However, real-world evidence on its application within the Chinese MG population are limited.

Objective: This study aims to evaluate the rapid efficacy and safety of efgartigimod in Chinese MG population.

Design: This single-center prospective study enrolled Chinese MG patients aged 18 and older who were treated with efgartigimod, classified as Myasthenia Gravis Foundation of America I-IV, with a baseline Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 4.

Methods: Patients received efgartigimod at a dose of 10 mg/kg infused once weekly for 4 weeks. During the treatment, the corticosteroids dosage could be adjusted as appropriate or the non-steroidal immunosuppressive therapies (NSISTs) added. Prior to each infusion, patients' MG-ADL scores, IgG levels, and routine laboratory tests were evaluated, while also recording the prednisone tapering and any adverse events occurring during the treatment.

Results: Twenty five Chinese MG patients were enrolled between November 2023 and June 2024, including 3 with ocular MG (OMG) and 22 with generalized MG (GMG). During the 8-week follow-up, in GMG patients, whether positive for acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) antibodies, the overall efficacy was significant. Within one treatment cycle, 18 (82%) patients showed a reduction of at least 2 points in MG-ADL scores and sustained for at least 4 weeks, and 6 (27%) attained minimal symptom expression (MSE) and sustained for at least 4 weeks. Only 1 patient experienced exacerbation. Among OMG patients, 1 achieved MSE within the treatment cycle, while 2 showed minor improvements. Patients who added tacrolimus concurrently with efgartigimod did not achieve better improvement in MG-ADL scores compared to others. The average reduction in prednisone dosage was 27.4%. Only one patient experienced transient vomiting and diarrhea, with no serious adverse reactions reported.

Conclusion: This study confirmed the short-term efficacy and safety of efgartigimod in Chinese MG patients. However, in clinical practice, careful consideration is needed regarding its application in OMG and whether to add NSISTs regimen during the treatment. Efgartigimod could potentially serve as an alternative to long-term corticosteroids therapy.

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and rare neurodegenerative disease. Therefore, evaluating the risk factors affecting the survival of patients with ALS is crucial. Constipation, a common but overlooked symptom of ALS, can be effectively managed. It is currently unknown whether constipation contributes to the progression and survival of ALS.

Objectives: This study aimed to investigate the association between constipation and ALS development and survival using a novel overlap-weighted (OW) method to enhance the robustness and reliability of results.

Design: This prospective matching nested case-control (NCC) study was conducted within an ongoing ALS cohort at the Second Hospital of Hebei Medical University. Baseline data were collected from patients meeting the inclusion and exclusion criteria, with constipation as the exposure factor. A 9-month follow-up was conducted, with death as the endpoint event.

Methods: We primarily used the OW method in NCC studies to examine the association between constipation and ALS development and survival. Weighted Cox proportional hazards model was used to assess risk factors associated with overall survival. Survival differences between the two groups were analyzed using Kaplan-Meier's plots and log-rank tests. Finally, the bioinformatic analysis explored common pathways between ALS and constipation.

Results: Among the 190 patients included, the prevalence of constipation was 50%. Patients with ALS constipation exhibited faster disease progression (p < 0.001), with a positive correlation between constipation severity and progression rate (r = 0.356, p < 0.001). The constipation group had poorer survival before and after OW (log-rank test, p < 0.0001). In the Cox proportional hazards model of 114 patients, constipation was a risk factor for ALS both before (hazard ratio (HR) = 5.840, 95% confidence interval (CI) = 1.504-22.675, p = 0.011) and after (HR = 5.271, 95% CI = 1.241-22.379, p = 0.024) OW.

Conclusion: Constipation in individuals with ALS is associated with faster disease progression and reduced survival rates, potentially through the peroxisome proliferator-activated receptor pathway.

Background: Characterizing Cladribine tablets prescription pattern in daily clinical practice is crucial for optimizing multiple sclerosis (MS) treatment.

Objectives: To describe efficacy, safety profile and new disease-modifying therapy (DMT) prescriptions following Cladribine treatment.

Design: Independent retrospective cohort study in patients followed at six Italian MS centres.

Methods: Patients diagnosed with relapsing MS (RMS) according to 2017 McDonald criteria, who initiated Cladribine between January 2019 and May 2023, were included. A generalized linear regression model was built for the outcome DMT after Cladribine course. Heatmaps were generated based on weighted pivot tables to visualize the proportion of patients requiring DMT post-Cladribine.

Results: A total cohort of 352 patients was enrolled, 134 naïve to any DMT, 218 switchers from other DMTs. The last DMT was an injectable first-line DMT for 48 (22%) patients, oral first-line DMT for 141 (64.7%) patients, SP1 inhibitor-Fingolimod for 23 (10.6%) patients, and Natalizumab for 6 (2.7%) patients. Overall, Cladribine was efficacious and well tolerated, 12% of patients required a new DMT prescription after a median time of 24 months. The regression model revealed that patients aged >40 years at Cladribine prescription had a 16% decrease in likelihood of receiving a new DMT. Heatmaps showed patients previously on Fingolimod had a lower rate (72.2%) of being free from therapy after Cladribine.

Conclusion: In our multicentric real-world Italian study, Cladribine therapy is generally effective during the investigated follow-up period. Understanding key characteristics of patients responding best to Cladribine can help tailor therapeutic strategies for optimal outcomes.