Background and purpose: The aim was to assess the safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients.Methods: Patients older than 15 years and followed for at least 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM) in five referral centers were included. The clinical and patients' global impression of change (CGI‐C and PGI‐C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS‐R) and the percentage predicted forced vital capacity were collected when available.Results: Seventy‐nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p < 0.001) after 6 months. After a mean follow‐up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (odds ratio [OR] 1.15, p = 0.006), the 6‐min walk test (OR = 1.07, p < 0.001) and the EK2 (OR = 0.81, p = 0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p = 0.033), ALSFRS‐R (p = 0.005) and EK2 (p < 0.001). According to the CGI‐C and PGI‐C, 64.1% and 61.5% of treated patients improved with treatment. Being a non‐sitter was associated with less response to treatment, whilst a longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild.Conclusions: Nusinersen treatment is associated with some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk–benefit ratio.

Immunotherapy with immune checkpoint inhibitors (ICIs) have been reported to induce de novo or exacerbate pre-existing Myasthenia Gravis (MG). We present a single center case series of patients who developed an immune-related myasthenia gravis (irMG) related with ICIs. We performed a retrospective chart review of the electronic medical records between 1 September 2017 and 2022. We report the clinical features, presentation forms, diagnostic workflows, general management and outcomes of six patients who received ICIs for different solid organ malignancies and developed an irMG frequently overlapping with immune-related myocarditis and/or myositis. The aim of the article is to describe the clinical features, treatment and outcomes of this challenging and potentially life-threating syndrome, comparing our data with those described in the literature. Differences between irMG and classic MG are highlighted.

Sporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to identify and validate selected putative biomarkers in the cerebrospinal fluid (CSF) of sALS patients at early disease stages compared with age-matched controls and with other neurodegenerative diseases including Alzheimer disease (AD), spinal muscular atrophy type III (SMA), frontotemporal dementia behavioral variant (FTD), and multiple sclerosis (MS). SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC–MS/MS) for protein quantitation, and ELISA for validation, were used in CSF samples of sALS cases at early stages of the disease. Analysis of mRNA and protein expression was carried out in the anterior horn of the lumbar spinal cord in post-mortem tissue of sALS cases (terminal stage) and controls using RTq-PCR, and Western blotting, and immunohistochemistry, respectively. SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC–MS/MS) revealed 51 differentially expressed proteins in the CSF in sALS. Receiver operating characteristic (ROC) curves showed CXCL12 to be the most valuable candidate biomarker. We validated the values of CXCL12 in CSF with ELISA in two different cohorts. Besides sALS, increased CXCL12 levels were found in MS but were not altered in AD, SMA, and FTD. Therefore, increased CXCL12 levels in the CSF can be useful in the diagnoses of MS and sALS in the context of the clinical settings. CXCL12 immunoreactivity was localized in motor neurons in control and sALS, and in a few glial cells in sALS at the terminal stage; CXCR4 was in a subset of oligodendroglial-like cells and axonal ballooning of motor neurons in sALS; and CXCR7 in motor neurons in control and sALS, and reactive astrocytes in the pyramidal tracts in terminal sALS. CXCL12/CXCR4/CXCR7 axis in the spinal cord probably plays a complex role in inflammation, oligodendroglial and astrocyte signaling, and neuronal and axonal preservation in sALS.

Oxylipins play a critical role in regulating the onset and resolution phase of inflammation. Despite inflammation is a pathological hallmark in amyotrophic lateral sclerosis (ALS), the plasma oxylipin profile of ALS patients has not been assessed yet. Herein, we develop an oxylipin profile-targeted analysis of plasma from 74 ALS patients and controls. We found a significant decrease in linoleic acid-derived oxylipins in ALS patients, including 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE. These derivatives have been reported as important regulators of inflammation on different cell systems. In addition, some 5-lipoxygenase metabolites, such as 5-hydroxy- eicosatetraenoic acid also showed a significant decrease in ALS plasma samples. Isoprostanes of the F2α family were detected only in ALS patients but not in control samples, while the hydroxylated metabolite 11-HETE significantly decreased. Despite our effort to analyze specialized pro-resolving mediators, they were not detected in plasma samples. However, we found the levels of 14-hydroxy-docosahexaenoic acid, a marker pathway of the Maresin biosynthesis, were also reduced in ALS patients, suggesting a defective activation in the resolution programs of inflammation in ALS. We further analyze oxylipin concentration levels in plasma from ALS patients to detect correlations between these metabolites and some clinical parameters. Interestingly, we found that plasmatic levels of 13-HODE and 9-HODE positively correlate with disease duration, expressed as days since onset. In summary, we developed a method to analyze “(oxy)lipidomics” in ALS human plasma and found new profiles of metabolites and novel lipid derivatives with unknown biological activities as potential footprints of disease onset.

Background and purpose: The Frank’s sign is a diagonal earlobe crease running from the tragus to the edge of the auricle at an angle of 45°. Many studies have associated this sign with coronary artery disease and some with cerebrovascular disease. The objective of this study was to analyse the prevalence of the Frank’s sign in patients suffering from acute stroke with a particular focus on its prevalence in each of the five aetiopathogenic stroke subtypes. Special interest is given to embolic stroke of undetermined source (ESUS), correlating the sign with clinical and radiological markers that support an underlying causal profile in this subgroup. Methods: Cross-sectional descriptive study including 124 patients admitted consecutively to a stroke unit after suffering an acute stroke. The Frank’s sign was evaluated by the same blinded member of the research team from photographs taken of the patients. The stroke subtype was classified following SSS-TOAST criteria and the aetiological study was performed following the ESO guidelines. Results: The Frank’s sign was present in 75 patients and was more prevalent in patients with an ischaemic stroke in comparison with haemorrhagic stroke (63.9 vs. 37.5, p<0.05). A similar prevalence was found in the different ischaemic stroke subtypes. The Frank’s sign was significantly associated with age, particularly in patients older than 70 who had vascular risk factors. Atherosclerotic plaques found in carotid ultrasonography were significantly more frequent in patients with the Frank’s sign (63.6%, p<0.05). Analysing the ESUS, we also found an association with age and a higher prevalence of the Frank’s sign in patients with vascular risk factors and a tendency to a high prevalence of atherosclerosis markers. Conclusion: The Frank’s sign is prevalent in all aetiopathogenic ischaemic stroke subtypes, including ESUS, where it could be helpful in suspecting the underlying cardioembolic or atherothrombotic origin and guiding the investigation of atherosclerosis in patients with ESUS and the Frank’s sign.