Therapeutic Advances in Neurological Disorders最新文献

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.

Background: Very-late-onset myasthenia gravis (VLOMG) refers to myasthenia gravis (MG) with onset at age 65 or older. Current research on VLOMG prognosis remains limited, especially regarding factors influencing outcomes.

Objectives: To identify the clinical factors that affect the short- and long-term prognosis of MG patients with an onset age ⩾65 years.

Design: This was a single-center, retrospective cohort study of AChR-ab positive VLOMG patients, classified into two subgroups based on age of onset: sub-very-late-onset MG (S-VLOMG, onset age ⩾65 and <75 years), and super-late-onset MG (SLOMG, onset age ⩾75 years).

Methods: A total of 93 patients were included, including 75 in the S-VLOMG group and 18 in the SLOMG group. Clinical, therapeutic, and prognosis data were reviewed, and the Cox regression model was used to identify factors influencing short- and long-term prognosis.

Results: Patient characteristics were well balanced between the groups. Overall, 49.5% of patients achieved minimal symptom expression (MSE) within 6 months and 86% within 24 months. There was no significant difference between the groups in the proportion achieving MSE at 6 months (p = 0.635) or 24 months (p = 0.714). The median time to achieve MSE was also comparable between the S-VLOMG and SLOMG groups (199.0 days vs 280.5 days, p = 0.463). Low baseline MG-ADL score and steroid therapy were associated with better short-term prognosis (p = 0.007 and p = 0.002, respectively). For long-term prognosis, baseline bulbar and limb involvement, time to treatment initiation, and use of immunosuppressants were significant factors (p = 0.025, p = 0.004, p = 0.025, and p < 0.0001, respectively). There were no significant differences in side effects or drug withdrawal rates between two groups.

Conclusion: This study demonstrated that AChR-ab positive VLOMG patients have a favorable prognosis and responded well to medication, with age and comorbidities showing no significant impact.

Background: Thymoma-associated myasthenia gravis (TAMG) is a subtype of myasthenia gravis (MG) that is associated with more severe symptoms and a relatively poor prognosis. Eculizumab, an inhibitor to target human C5 component of the complement cascade, is considered a treatment option for refractory generalized MG (gMG).

Objectives: To explore the safety and efficacy of eculizumab in patients with TAMG.

Design: This is an observational multicenter real-world cohort study to assess TAMG who were treated with eculizumab from June 2023 to June 2024.

Data sources and methods: Clinical features associated with thymoma-associated multi-organ autoimmunity (TAMA), Myasthenia Gravis Activities of Daily Living (MG-ADL) score, and the incidence of treatment-emergent adverse events (TEAEs) were prospectively collected.

Results: Overall, 42 patients with gMG were treated with eculizumab at 5 research centers, of whom 22 patients with TAMG were finally included. This cohort had a mean age of 51.5 ± 12.1 years and an average disease duration of 4.0 ± 4.3 years. Regarding thymomas, the World Health Organization (WHO) histological classification was primarily B2 and B3 (63.7%), and Masaoka staging was predominantly IV (45.5%). Nine participants (40.9%) switched from efgartigimod to eculizumab aiming at a better clinical improvement and reducing steroid use. By week 12, the MG-ADL score decreased to 4.8 ± 4.7 (baseline: 11.7 ± 6.0), and the corticosteroid dose reduced to 23.2 ± 26.5 mg (baseline: 41.8 ± 63.9 mg). Two patients with TAMA showed significant improvement in skin lesions and thrombocytopenia. Two TEAEs were recorded including COVID-19 and herpes labialis infection. Four patients (18.2%) died of respiratory or circulatory failure owing to thymoma metastasis.

Conclusion: This real-world study demonstrates the efficacy of eculizumab in achieving symptom control and corticosteroid reduction for TAMG. It may also be a therapeutic option for refractory TAMG and TAMA.

Trial registration: NCT04535843.

In seropositive myasthenia gravis (MG), complement inhibition has been shown to be an effective and a fast-acting therapeutic option. Myasthenic crisis (MC), usually preceded by impending MC, is a life-threatening complication requiring highly effective treatments with rapid onset of action. Currently used treatment options of MC are limited, consisting mainly of symptomatic and immune therapies, that is, intravenous immunoglobulins and plasma exchange/immunoadsorption. So far, there is only very limited data on complement inhibitors in impending or manifest MC or termination of frequently recurring impending crises. Here, we report three cases of acetylcholine receptor antibody positive MG, two with impending and one case suffering from high-frequency impending MC, where complement inhibition with eculizumab or ravulizumab resulted in a rapid and sustained remission. Meningococcal vaccination, mandatory when using complement inhibitors, did not result in symptom-worsening or manifest MC.

Background: Drug-resistant epilepsy (DRE) patients exhibit aberrant large-scale brain networks.

Objective: The purpose of investigation is to explore the differences in resting-state electroencephalogram (EEG) microstates between patients with DRE and well-controlled (W-C) epilepsy.

Design: Retrospective study.

Methods: Clinical data of epilepsy patients treated at the Epilepsy Center of Fujian Medical University Union Hospital from January 2020 to May 2023 were collected for a minimum follow-up period of 2 years. Participants meeting inclusion and exclusion criteria were categorized into two groups based on follow-up records: W-C group and DRE group. To ensure that the recorded EEG data were not influenced by medication, all EEG recordings were collected before patients commenced any antiepileptic drug treatment. Resting-state EEG datasets of all participants underwent microstate analysis. This study comprehensively compared the average duration, frequency per second, coverage, and transition probabilities (TPs) of each microstate between the two groups.

Results: A total of 289 individuals who met the criteria were included, categorized into the W-C group (n = 112) and the DRE group (n = 177). EEG microstate analysis revealed substantial variances between the two groups. The analysis highlights differences in three of four microstate classifications. Microstate transition analysis demonstrated altered probabilities in DRE patients. Increased probabilities were observed in TP_AB, TP_BA, TP_BC, TP_CB, TP_BD, and TP_DB. Decreased probabilities included TP_CA, TP_DA, TP_AC, TP_AD, TP_CD, and TP_DC.

Conclusion: This study highlights distinctive EEG microstate parameters and TPs in DRE patients compared to those with W-C epilepsy. The results may potentially advance the clinical application of EEG microstates.

In acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG), neonatal Fc-receptor (FcRn) inhibition has broadened the therapeutic spectrum. Myasthenic crisis (MC), heralded by an impending myasthenic crisis (iMC), is a critical condition requiring treatments with rapid onset and sustained efficacy. Currently treatments used for iMC, including intravenous immunoglobulins and plasma exchange/immunoadsorption, have limitations, such as delayed onset of action and potential side effects. So far, there is limited data on the use of FcRn inhibitors in the management of impending or manifest MC (mMC). Here, we present a case of AChR antibody-positive gMG with iMC, where subcutaneous administration of the FcRn inhibitor efgartigimod resulted in rapid clinical remission. Within 24 h of administration, the patient exhibited significant improvement in respiratory and bulbar muscle function, preventing progression to manifest MC and the need for mechanical ventilation. This rapid response was accompanied by a marked reduction in AChR antibody level by 89.8% within 4 weeks. This case supports the potential of efgartigimod as a fast-acting and effective treatment option for managing iMC, offering an alternative to existing therapies.

In multiple sclerosis (MS), increasing disability is considered to occur due to persistent, chronic inflammation trapped within the central nervous system (CNS). This condition, known as smoldering neuroinflammation, is present across the clinical spectrum of MS and is currently understood to be relatively resistant to treatment with existing disease-modifying therapies. Chronic active white matter lesions represent a key component of smoldering neuroinflammation. Initially characterized in autopsy specimens, multiple approaches to visualize chronic active lesions (CALs) in vivo using advanced neuroimaging techniques and postprocessing methods are rapidly emerging. Among these in vivo imaging correlates of CALs, paramagnetic rim lesions (PRLs) are defined by the presence of a perilesional rim formed by iron-laden microglia and macrophages, whereas slowly expanding lesions are identified based on linear, concentric lesion expansion over time. In recent years, several longitudinal studies have linked the occurrence of in vivo detected CALs to a more aggressive disease course. PRLs are highly specific to MS and therefore have recently been incorporated into the MS diagnostic criteria. They also have prognostic potential as biomarkers to identify patients at risk of early and severe disease progression. These developments could significantly affect MS care and the evaluation of new treatments. This review describes the latest knowledge on CAL biology and imaging and the relevance of CALs to the natural history of MS. In addition, we outline considerations for current and future in vivo biomarkers of CALs, emphasizing the need for validation, standardization, and automation in their assessment.

Background: Time elapsed from stroke onset and baseline infarct volume is influential on endovascular thrombectomy (EVT) outcomes.

Objectives: This study aimed to explore the utility of early infarct growth rate (EIGR) measured by apparent diffusion coefficient (ADC) in predicting symptomatic intracranial hemorrhage (sICH) of ischemic stroke patients after EVT.

Methods: We retrospectively analyzed patients from the prospectively maintained stroke registry admitted between January 2019 and March 2023, presenting with large vessel occlusive stroke in the anterior circulation. EIGR was defined as ischemic core volume on magnetic resonance perfusion imaging (ADC ⩽620 × 10^-6 mm²/s) divided by the time from stroke onset to imaging. sICH was diagnosed according to the Heidelberg Bleeding Classification within 72 h after the procedure.

Results: A total of 315 patients met the inclusion criteria. We observed sICH in 36 (11.4%) patients. After adjusting for the potential confounders, increased EIGR was confirmed to be independently associated with a higher risk of sICH (adjusted odds ratio, 1.033; 95% confidence interval (CI), 1.018-1.048; p = 0.001). Similar results were also confirmed when EIGR was analyzed as a categorical variable. Using a logistic regression model with restricted cubic splines, we found a linear correlation between EIGR and sICH risk (p = 0.001 for linearity). Furthermore, adding EIGR to a model containing conventional risk factors significantly improved risk reclassification for sICH (category-free net reclassification index, 0.393; 95% CI, 0.227-0.560; p = 0.001; integrated discrimination improvement, 0.245; 95% CI, 0.146-0.343; p = 0.001).

Conclusion: Increased EIGR may predict the sICH in ischemic stroke patients who receiving EVT.