Journal of Neurology最新文献

The neuronal ceroid lipofuscinoses (NCLs) are incurable pediatric neurodegenerative diseases characterized by accumulation of lysosomal material and dysregulation of autophagy. Given the promising results of treatment with trehalose, an autophagy inducer, in cell and animal models of NCL, we conducted an open-label, non-placebo-controlled, non-randomized 12-month prospective study in NCL patients receiving oral trehalose (4 g/day). All were treated with a commercially available formulation for 6 months, followed by a 6-month washout. The primary endpoint was the presence of severe adverse reactions during treatment; secondary endpoints were clinical changes documented using the validated Unified Batten Disease Rating Scale and the Hamburg scale. Leveraging on our recent multiomic studies identifying convergent biomarkers in NCLs, fluid biomarker changes were taken as additional secondary endpoints. Of the 17 patients enrolled, 11 completed the study. Oral intake of trehalose in NCL patients with different genetic forms and at different disease stages was found to be well tolerated over 6 months. Oral trehalose is associated with subjective benefits reported by caregivers, but not with improvement or worsening on clinical scales. Analysis of potential biomarkers demonstrated significant differences between patients and controls at baseline, but we observed no modifications over time, or correlations with clinical scales and treatment. In our pilot experience in a heterogeneous disease group of NCL, oral trehalose seemed safe for patients. While subjective improvements were reported by caregivers, larger multicenter randomized placebo-controlled studies, and perhaps additional clinical tools covering multiple functions affected by the disease, will be needed to identify possible improvements in clinical scale scores and biomarkers.

Background: Bilateral deep brain stimulation (DBS) of subthalamic nucleus (STN) has demonstrated efficacy for ameliorating medication-refractory isolated dystonia. Nonetheless, the paucity of evidence regarding its long-term impact on quality-of-life (QoL) necessitates further investigation.

Objectives: This study aimed to elucidate the longitudinal effects of chronic STN stimulation on QoL in patients suffering from isolated dystonia.

Methods: We enrolled 54 subjects diagnosed with isolated dystonia who underwent STN-DBS and maintained post-operative status for over 5 years. The 36-item Short Form General Health Survey (SF-36) assessed QoL, while the Montreal Cognitive Assessment (MoCA) evaluated cognitive functioning.

Results: The average follow-up since implantation extended to 10.9 years. The data analysis revealed a significant enhancement in QoL following STN-DBS treatment, as Physical Component Summary (PCS), Mental Component Summary (MCS), and Global scores demonstrated substantial improvement from pre-DBS to post-DBS (p < 0.0001). The disease classifications yielded differential results; patients with generalized dystonia exhibited superior improvements in PCS (p = 0.0053) and Global scores (p = 0.0120) compared to other types. Patients aged < 36 at the time of implantation experienced greater improvements in PCS (p = 0.0109) and global scores (p = 0.0057) than older counterparts. Cognitive function, as per the MoCA scale, showed no significant difference between pre- and post-operative scores (p = 0.08).

Conclusions: STN-DBS appears to confer enduring improvements to the QoL in dystonia patients, persisting an average of 10 years or more post-surgery. These findings underscore the long-term efficacy of STN-DBS for isolated dystonia and highlight the influence of patient age and disease classification on outcomes.

Background: With the approval of disease-modifying treatments for 5q-spinal muscular atrophy (SMA), there is an increasing need for biomarkers for disease course and therapeutic response monitoring. Radially sampled Averaged Magnetization Inversion Recovery Acquisitions (rAMIRA) MR-imaging enables spinal cord (SC) gray matter (GM) delineation and quantification in vivo. This study aims to assess SC GM atrophy in patients with 5q-SMA and its associations with clinical disability.

Methods: Twenty-one patients with 5q-SMA and twenty-one age- and sex-matched healthy controls (HCs) prospectively underwent 3 T axial 2D-rAMIRA MR-imaging at the intervertebral disc levels C2/C3-C5/C6 and T_max (lumbar enlargement level). Associations between SC GM areas with muscle strength tested by dynamometry, Motor Function Measure (MFM), revised upper limb module (RULM), Revised Hammersmith Scale (RHS), and SMA-Functional Rating Scale (SMA-FRS) were assessed by Spearman Rank correlations and linear regression analysis.

Results: Compared to HCs, patients had significantly reduced SC GM areas at levels C3/C4 (relative reduction (RR) = 13.6%, p < 0.0001); C4/C5 (RR = 16.7%, p < 0.0001), C5/C6 (RR = 17.1%, p < 0.0001), and T_max (RR = 17.4%, p < 0.0001). Significant correlations were found between cervical SC GM areas and muscle strength, RULM, MFM, RHS, and SMA-FRS. In linear regression analysis, GM area C3/C4 explained 33% of RHS variance.

Conclusion: SC GM atrophy is detectable in patients with 5q-SMA and is consistently associated with clinical measures of upper limb function, physiotherapeutic assessments, and SMA-FRS indicating the clinical relevance of the observed atrophy. Further longitudinal investigations are necessary next steps to evaluate this novel and easily applicable imaging marker as a potential disease course and therapeutic response marker.

Objective: In Italy, around 137,000 people live with multiple sclerosis, facing organizational complexities due to the current model's limited focus on proximity care. This project aims to define a proximity model, in accordance with recent developments in the Italian healthcare landscape, engaging over 150 healthcare stakeholders and potentially impacting approximately 14,000 patients.

Methods: An analysis was pursued to map the multiple sclerosis pathway, followed by interviews to capture the actual implementation in Italian Multiple Sclerosis Centers. Through the experts' insights, an optimal proximity care pathway and a Maturity Model framework were defined. This model was piloted in 14 centers, and a preliminary pre-post analysis was performed to evaluate initial improvements. Finally, a two-round Delphi method validated the Maturity Model dimensions and a set of key performance indicators. A scientific board including neurologists, patient associations and scientific associations, supervised project progresses and methodologies.

Results: The Pilot study results show an overall increase in the centers' positioning within the Maturity Model levels after adopting center-specific action plans. To generalize the model, the Delphi panel validated a subset of process, volume, outcome and patient experience indicators (9 of 26 proposed) along with qualitative dimensions defining the Maturity Model (13 of 20 proposed), therefore, outlining a comprehensive monitoring framework for the multiple sclerosis patient pathway.

Conclusion: This study shows, for the first time in Italy, the efficacy of a bottom-up approach in addressing organizational challenges within the current multiple sclerosis scenario. This integrated model offers future opportunity for replication across various care pathways and settings.

PROPEL (ATB200-03; NCT03729362) compared the efficacy and safety of cipaglucosidase alfa plus miglustat (cipa + mig), a two-component therapy for late-onset Pompe disease (LOPD), versus alglucosidase alfa plus placebo (alg + pbo). The primary endpoint was change in 6-min walk distance (6MWD) from baseline to week 52. During PROPEL, COVID-19 interrupted some planned study visits and assessment windows, leading to delayed visits, make-up assessments for patients who missed ≥ 3 successive infusions before planned assessments at weeks 38 and 52, and some advanced visits (end-of-study/early-termination visits). These were remapped to the respective planned visits. To evaluate if remapping may have overestimated treatment effects, we conducted post hoc analyses using a mixed-effect model for repeated measures based on actual time points of assessments. In this post hoc analysis, estimated mean treatment difference between cipa + mig and alg + pbo for change from baseline to week 52 in 6MWD was 11.7 m (95% confidence interval [CI] - 1.0 to 24.4; p = 0.072). In the original published analyses, between-group difference using last observation carried forward was 13.6 m (95% CI - 2.8 to 29.9; p = 0.071 [p value from separate non-parametric analysis of covariance]). Both statistical analysis approaches led to similar results and consistent conclusions, confirming the efficacy of cipa + mig for adults with LOPD. NCT03729362; trial start date: December 4, 2018.Trial registration number.

Background: Randomized controlled trials have demonstrated the efficacy and safety of endovascular thrombectomy (EVT) in patients with acute large vessel occlusion stroke. However, its long-term benefits remain uncertain. Therefore, this study aimed to investigate the long-term clinical outcomes of EVT.

Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science databases to identify relevant literature pertaining to patients with acute ischemic stroke who were treated with EVT plus medical management (MM) compared with MM alone, until August, 31, 2024. The primary outcome was functional independence (defined as a score of 0 to 2 on the modified Rankin scale [mRS]) at 12 months or beyond, while the safety outcome was mortality at 12 months or longer. Effect sizes were computed as risk ratio (RR) with random-effect or fixed-effect models. This study was registered on the International Prospective Register of Systematic Reviews on June 15, 2024 (PROSPERO, CRD42024554043).

Results: A total of 4546 articles were obtained through the search. After excluding those that did not meet the inclusion criteria, 9 randomized controlled trials with 3358 patients (1821 and 1537 assigned to EVT + MM and MM alone group, respectively) were included in this analysis. The EVT + MM group had a higher proportion of functional independence (32.9% vs 18.2%, risk ratio 2.07, 95% confidence interval 1.50-2.87, P < 0.001) and lower mortality (34.1% vs 39.7%, risk ratio 0.86, 95% confidence interval 0.78-0.94, P = 0.001) compared to the MM group.

Conclusion: Endovascular thrombectomy was associated with improved functional outcomes and reduced mortality in acute large vessel occlusion stroke patients and presented a long-term favorable effect.

Background: Diagnosing chronic inflammatory demyelinating polyneuropathy (CIDP) can be challenging, leading to delays in initiating therapy. As disability in CIDP is mainly dependent on axonal damage, the impact of delayed immunotherapy remains unclear. We multimodally investigated the clinical outcomes of patients with early CIDP regarding different treatment strategies and time points.

Methods: Patients with CIDP diagnosis within 1 year before study inclusion were systematically selected from the prospective Immune-mediated Neuropathies Biobank (INHIBIT) registry. Clinical and therapeutic data, and findings from nerve conduction study (NCS), and nerve and muscle ultrasound were correlated at inclusion and 12 months later. The patient outcomes were compared between immunotherapies. The effect of timing immunotherapy on clinical outcomes was determined using regression analysis.

Results: In total, 30 patients were included (time from diagnosis to inclusion 22 ± 19 weeks). Low amplitudes of compound muscle potential were significantly associated with pathological spontaneous activity (PSA, r = 0.467) and correlated with the Heckmatt scale (r_Sp = 0.391). All three parameters were significantly associated with higher overall disability sum scores (NCS score r_Sp = 0.581, PSA r = 0.385, Heckmatt scale r_Sp = 0.472). The delays in initiating therapy resulted in progression of axonal damage (r_Sp = 0.467) and disability (R² = 0.200). The combination of first-line therapies led to reduced disability progression (r = 0.773), while second-line therapies resulted in improved overall axonal damage (r = 0.467).

Conclusions: Axonal damage occurs early and is the main cause of clinical disabilities. Prompt initiation of therapy is crucial to prevent axonal damage and thereby disability progression. A comprehensive therapeutic approach, including a combination of first- or second-line therapies, may improve long-term outcomes.

Background: Seizures, including status epilepticus (SE), are common in anti-NMDA receptor encephalitis (NMDARE). We aimed to describe clinical and electrographic features of patients with seizures with NMDARE, determine factors associated with SE, and describe long-term seizure outcomes.

Methods: We retrospectively identified patients with seizures in the setting of NMDARE treated at inpatient Mayo Clinic sites during the acute phase of encephalitis between October 2008 and March 2023. Seizure semiology, clinical symptoms, electrographic features, neuroimaging, treatment course, complications, and outcome were abstracted. We compared clinical features between patients with and without SE.

Results: We identified 29 patients with seizures during acute NMDARE. Temporal onset was the most common EEG localization (n = 14, 48.3%). Subclinical seizures were recorded in 15 (51.7%). Twelve (41.4%) patients had SE, which was associated with temporal T2-signal hyperintensity, seizures with unilateral clonic and/or tonic movements, multiple seizure foci on EEG, temporal and midline/central onset seizures, higher acute CASE scores, intensive care unit (ICU) admission, longer length of hospitalization, and need for post-hospitalization rehabilitation. One patient (3.4%) died during the acute encephalitis. One patient (3.4%) developed chronic epilepsy. The remaining patients were seizure-free at the last follow-up (median 23 months, range 2-163 months). SE was not associated with differences in outcome at last follow-up.

Discussion: Seizures in NMDARE are frequently temporal onset. SE is common and associated with higher likelihood of ICU level care, longer hospitalization, and higher need for post-hospital rehabilitation. Despite the significant short-term impact of SE, long-term outcome was not affected, and seizure prognosis was favorable.

Background: Distal myopathies (MPDs) are heterogeneous diseases of complex diagnosis whose prevalence and distribution in specific populations are unknown.

Methods: Demographic, clinical, genetic, neurophysiological, histopathological and muscle imaging characteristics of a MPDs cohort from a neuromuscular reference center were analyzed to study their epidemiology, features, genetic distribution and factors related to diagnosis.

Results: The series included 219 patients (61% were men, 94% Spanish and 41% sporadic cases). Mean age at onset and years of follow-up were 29 and 12.4, respectively. Patients commonly presented with gait disturbances in adulthood and did not usually exhibit a purely distal involvement, but disto-proximal involvement. HyperCKemia was detected in 56.6%, leading to consultation in 11.7%. Myopathic electromyography patterns and spontaneous activity were common; however, neurogenic features were also observed. Muscle imaging was useful for diagnosis as were certain histological features. Suspected pathogenic variants were identified in 68.7% of patients across 19 genes, but 85% concentrated in 8: MYH7, ANO5, DYSF, TTN, MYOT, HSPB1, GNE and HNRNPDL. Founder/cluster variants were found as well as overlap between myopathic and neurogenic processes. Onset before 60 years old, familial cases, very high CK levels and myopathic histopathological features were associated with a higher probability of molecular diagnosis. We found a minimum prevalence of MPDs of 3.9 per 100,000 individuals in the Valencian Community.

Conclusions: This series being the largest cohort of patients with MPDs presents their frequency and behavior. This study identifies new genes presenting as MPDs, provides data to guide diagnosis and lays the groundwork for cooperative studies.