BACKGROUND: Remote ischemic conditioning (RIC) has shown neuroprotective potential in preclinical stroke models. In patients with acute ischemic stroke, trials report heterogeneous results, supporting ongoing debate about clinical efficacy, especially in those ineligible for recanalization. This trial assessed RIC benefit in this population and evaluated HSP27 (heat shock protein 27) and HIF-1α (hypoxia-inducible factor 1-alpha) as biomarkers of RIC-related biological activity. METHODS: This was a multicenter, phase II, proof-of-concept, block-randomized, controlled, parallel-arm, PROBE (Prospective Randomized Open Blinded End Point)-designed clinical trial. Patients with acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 5–25) who were ineligible for recanalization therapies were randomized 1:1 within 9 hours of symptom onset to RIC (4 5-minute cycles of upper-arm ischemia/reperfusion) plus standard medical therapy or standard therapy alone. The primary outcome was the percentage change in NIHSS score at 72 hours. Secondary outcomes included NIHSS score changes at 24 and 48 hours, 90-day modified Rankin Scale, tolerability, and changes in plasma HSP27 and HIF-1α concentrations from 24 to 72 hours. RESULTS: Eighty patients (40 per group) were enrolled across 4 centers from August 2021 to March 2024. Although slightly in favor of RIC treatment, median NIHSS score percentage change at 72 hours did not differ between the RIC and control groups (23.6% versus 29.9%; adjusted coefficient, −3.8 [95% CI, −19.7 to 12.1]; P =0.635). No significant differences in NIHSS score percentage change were observed at 24 or 48 hours. Ninety-day poor functional outcome (modified Rankin Scale score, 3–6) was similar between groups (57.5% versus 65.0%; adjusted odds ratio, 0.79 [95% CI, 0.21–2.97]; P =0.732). RIC was completed by 97.5% of patients with minimal treatment-related discomfort. No major adverse events occurred. No between-group differences were detected in HIF-1α or HSP27 changes from 24 to 72 hours. CONCLUSIONS: In patients with acute ischemic stroke ineligible for recanalization therapies, early RIC was safe, feasible, and well tolerated but did not improve neurological outcomes or modify HIF-1α and HSP27 levels. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04400981.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle weakness, atrophy, dysarthria, ...

BACKGROUND: Collateral blood flow is a critical determinant of successful recanalization in acute ischemic stroke caused by large vessel occlusion. Head down tilt −15° (HDT15), similar to Trendelenburg positioning, is a simple, low-cost positional therapy that may augment cerebral collateral blood flow and penumbral survival. The aim of the study is to assess the safety, feasibility, and efficacy of HDT15 in improving cerebral collateral circulation and clinical outcomes in patients with large vessel occlusion–acute ischemic stroke treated with mechanical thrombectomy (MT). METHODS: The DOWN-SUITE trial (Head Down Tilt 15° to Increase Collateral Flow in Acute Ischemic Stroke) is a multicenter, randomized, open-label, phase 2a/b clinical trial with blinded outcome assessment, conducted across 7 Italian stroke centers. A total of 118 patients with acute ischemic stroke due to M1 segment middle cerebral artery occlusion will be randomized 1:1 in the emergency department to receive HDT15 or standard positioning (head-of-bed 0° to +30°) before and during MT. RESULTS: The primary end point is good collateral status (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology grade 3–4), assessed on the first angiographic sequence during MT by a blinded imaging core laboratory. Secondary end points include feasibility (proportion maintaining HDT15, admission-to-MT time), safety (symptomatic intracranial hemorrhage, pneumonia, vomiting, neurological deterioration, vital signs), and efficacy (neurological improvement before MT, at 24 hours, and at 7 days or discharge, modified Rankin Scale score at 90 days). CONCLUSIONS: The DOWN-SUITE trial will provide evidence on the acute cerebrovascular effect of HDT15 in large vessel occlusion–acute ischemic stroke, potentially establishing a cost-effective, practice-changing intervention to improve collaterals for global stroke care. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06297863.

Background Since 2005, the European Union of Medical Specialists – Section of Neurology and the European Board of Neurology have outlined a comprehensive curriculum, the European Training Requirements in Neurology (ETRN), which defines the essential clinical knowledge, practical skills, and research competencies that European neurology training programmes should encompass. Despite these standards, notable differences in training quality and resources persist among Italian residency programmes. This survey, conducted by the Italian Section of Young Neurologists, aimed to assess the alignment of Italian neurology residency programmes with ETRN standards and to evaluate residents’ and early-career neurologists’ self-reported knowledge, practical skills, and access to specialised training opportunities. Methods An anonymous, online survey was distributed to neurology residents and recently qualified neurologists across Italy in November 2023. The survey included 39 items across four sections: demographics, residency programme structure, learning objectives, and out-of-network internship opportunities. Responses were evaluated using descriptive statistics and comparative analyses across institution sizes and training years. Results Of 248 respondents (45.2% female, mean age 28.9 years), only 70.5% of ETRN’s basic training objectives were met, with lower compliance observed for advanced competencies. Practical skills like lumbar puncture and history-taking were widely acquired, but advanced diagnostic techniques (e.g., EMG, neuro-sonography) and subspecialty training (e.g., neuro-oncology, palliative care) showed limited availability. Out-of-network internship participation was low (21.7%), mainly due to institutional constraints and lack of financial support, limiting exposure to diverse clinical environments. Conclusions Italian neurology training programmes align reasonably well with ETRN standards at the basic level, though significant gaps remain in advanced training, diagnostic techniques, and interdisciplinary skills. Enhanced standardisation, improved funding for extra-network internships, and focused efforts on advanced training are essential to elevate Italian neurology residency programmes to meet European standards more fully.

Tofersen is a gene-targeted therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS), but neurofilament light chain (NfL) may not fully capture the biological response to treatment. We performed a multicentre retrospective longitudinal study including 24 patients with SOD1-ALS treated with intrathecal tofersen at four Italian referral centres between 2022 and 2025. Cerebrospinal fluid (CSF) and serum biomarkers were assessed at baseline, month 3, month 6, and last available administration using single-molecule array assays to quantify NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL–1), and total Tau. NfL decreased after treatment initiation in both CSF and serum, providing the clearest pharmacodynamic signal. In contrast, CSF GFAP increased progressively over follow-up, while CSF total Tau and UCHL–1 rose mainly at later timepoints; serum GFAP, total Tau, and UCHL–1 also showed increases during follow-up. ALS Functional Rating Scale–Revised trajectories were broadly stable, whereas disease progression rate was lower at last follow-up than at baseline. Greater reductions in CSF NfL were observed in pathogenic versus uncertain SOD1 variants, and early serum NfL and UCHL–1 changes were associated with longer-term changes in disease progression. These findings suggest that longitudinal multi-analyte profiling may refine biological response stratification beyond NfL alone in tofersen-treated SOD1-ALS.