Good leptomeningeal collaterals (LMCs) after large vessel occlusion (LVO) extend the time window for endovascular therapy. The mechanisms regulating LMC activation are not fully understood. The aim of this study was to investigate the potential role of two vasoactive molecules endothelin-1 (ET-1)—a vasoconstrictor agent—and nitric oxide (NO)—a vasodilator agent—in the regulation of post-stroke LMCs. Ischemic stroke patients within 6 h of LVO were included. Collateral status was assessed using the Menon scoring system based on computed tomography angiography scans. Patients were accordingly divided into three groups: poor, intermediate, and good LMCs. Recanalization was evaluated using the modified thrombolysis in cerebral infarction (mTICI) score. Serum levels of ET-1 and NO were measured at three time points: T0 (<6 h), T1 (24 h), and T2 (48 h). A total of 105 patients were enrolled (mean age 76 ± 12.8 years): 44 with good (46.2%), 36 with intermediate (37.8%), and 22 with poor LMCs (23.1%). NO values decreased, whereas ET-1 values increased from T0 to T1 in all groups of patients. No significant association was found between serum ET-1 levels and collateral status. Higher ET-1 levels at T1 correlated with poor outcome regardless of the LMC status or the degree of recanalization (p = 0.030). A significant linear positive correlation was revealed at T0 between high levels of ET-1 and the neutrophil count (Spearman’s rho = 0.236, p = 0.035). Subgroup analysis showed a significant inverse correlation at T1 between NO and the collateral score (Spearman’s rho = −0.251, p = 0.021). Although we observed no significant association between LMC score and serum ET-1 concentrations, at 24 h higher ET-1 serum levels were predictive of poor outcome and higher NO levels were correlated with poor collateral status. These findings may indicate an inadequate microvascular reperfusion, possibly due to ET-1-mediated vasoconstriction, neutrophil activation, and NO-mediated oxidative stress, suggesting their potential role in the no-reflow phenomenon.

Perihematomal hypoperfusion may lead to ischemic damage during intraparenchymal cerebral hemorrhage (ICH), resulting in worse prognosis. We aimed to (1) investigate the relationship between serum biomarkers related to oxidative stress and vasoactive substances and the occurrence of hypoperfusion and ischemic perihematomal lesions in ICH and (2) evaluate their correlation with the volumetric evolution of the hematoma and perihematomal edema. We enrolled 28 patients affected by ICH. Blood samples were collected at three different time points from symptom onset: T0, T1, and T2 (admission, 12–24 h, and 48–72 h, respectively), to measure endothelin-1 (ET-1), nitrites/nitrates (NO), soluble nicotinamide adenine dinucleotide 2 (NOX2)-derived peptide (sNOX2-dp), and asymmetric dimethylarginine (ADMA). Patients underwent brain MRI with perfusion study at T1 and MRI without perfusion at T2. 12 patients had ischemic perihematomal lesions at T1. A higher sNOX2-dp concentration at T0 was observed in patients with ischemic perihematomal lesions compared to those without (p = 0.051) and with a more severe perihematomal edema at T2 (p = 0.011). The ischemic perihematomal lesions development was also associated with an increased hematoma volume (p < 0.005), perilesional edema (p = 0.046), and greater midline shift (p = 0.036). ET-1 values at T1 were inversely correlated with hemorrhage volume at T2 (ρ = −0.717, p = 0.030). NOX2 activation may have a role in the development of ischemic perihematomal lesions. The association between higher ET-1 values and a lower hemorrhage volume could be related to the ET-1 vasoconstriction action on the ruptured vessel wall.

Good leptomeningeal collaterals (LMC) after large vessel occlusion (LVO) extend the time window for endovascular therapy. The mechanisms regulating LMC activation are not fully understood. The aim of this study was to investigate the potential role of two vasoactive molecules Endothelin-1 (ET1) – vasoconstrictor agent - and nitric oxide (NO) – vasodilator agent - in the regulation of post-stroke LMC. Ischemic stroke patients within 6 hours of LVO were included. Collateral status was assessed using the Menon scoring system based on Computed Tomography Angiography scans. Patients were accordingly divided into three groups: poor, intermediate, and good LMC. Recanalization was evaluated using the modified Thrombolysis in Cerebral Infarction (mTICI) score. Serum levels of ET1 and NO were measured at three time points: T0 (<6 hours), T1 (24 hours), and T2 (48 hours). A total of 105 patients were enrolled (mean age 76 ± 12.8 years): 44 with good (46.2%), 36 with intermediate (37.8%), and 22 with poor LMCs (23.1%). NO values decreased whereas ET1 values increased from T0 to T1 in all groups of patients. No significant association was found between serum ET-1 levels and collateral status. Higher ET-1 levels at T1 correlated with poor outcome regardless the LMC status and the degree of recanalization (p = 0.030). A significant linear positive correlation was revealed at T0 between high levels of ET-1 and neutrophils count (Spearman’s rho = 0.236; p=0.035). Subgroup analysis showed a significant inverse correlation at T1 between NO and the collateral score (Spearman’s rho= -0.251, p=0.021). Although we observed no significant association between LMC score and serum ET-1 concentrations, at 24 hours higher ET-1 serum levels were predictive of poor outcome and higher NO levels were correlated with poor collateral status. These findings may indicate an inadequate microvascular reperfusion possibly due to ET-1 mediated vasoconstriction, neutrophil activation and NO mediated oxidative stress, suggesting their potential role in no-reflow phenomenon.

The association between ischemic stroke (IS) and malignancy is well established. Cancer-related strokes are predominantly embolic and classified as embolic strokes of undetermined source (ESUS). While malignancy-associated coagulopathy represents the primary pathogenic mechanism, neoplastic embolization of circulating tumor cells is another potential etiology, particularly in cases of cardiac and pulmonary malignancies. We report the case of a 58-year-old man who presented with ESUS and concurrent multiple pulmonary nodules. Despite a comprehensive oncologic evaluation, including an ultrasound-guided bronchoscopic biopsy of the suspected lesion, no malignancy was detected. Several months later, the patient developed focal seizures, and brain magnetic resonance imaging (MRI) revealed multiple left frontoparietal space-occupying lesions with imaging features suggestive of brain metastases (BMs). A follow-up whole-body computed tomography (CT) scan confirmed a right upper lobe lung mass, which was diagnosed as pulmonary adenocarcinoma on subsequent mediastinal lymph node biopsy. The ischemic event may have contributed to the subsequent development of BMs through neoplastic embolization, allowing malignant cells to proliferate within the ischemic brain parenchyma. Alternatively, the stroke may have resulted from cancer-associated coagulopathy. In this context, post-stroke pathophysiological changes—including blood–brain barrier (BBB) disruption, neuroinflammation, hypoxia-induced angiogenesis, and extracellular matrix (ECM) remodeling—may have created a permissive microenvironment for tumor cell seeding and colonization, definable as a “pre-metastatic niche”. ESUS can be the initial clinical manifestation of an undiagnosed malignancy, and IS itself may facilitate tumor dissemination, ultimately leading to BMs. This case underscores the importance not only of a thorough oncologic workup in patients with ESUS, but also of a strict neuroradiological follow-up, as a delayed diagnosis of cancer-related stroke may allow malignancy progression, significantly worsening the prognosis and limiting therapeutic options.

Background and aims Perihematomal hypoperfusion may lead to ischemic damage during intraparenchymal cerebral hemorrhage (ICH), resulting in worse prognosis. We aimed to (1) investigate the relationship between serum biomarkers related to oxidative stress and vasoactive substances and the occurrence of hypoperfusion and ischemic perihematomal lesions in ICH, (2) to evaluate their correlation with the volumetric evolution of the hematoma and perihematomal edema. Methods We enrolled 28 patients affected by ICH. Blood samples were collected at timepoint T0 (admission to Emergency-Room), T1 (12-24hs from symptoms onset), T2 (48- 72hs from onset), to measure Endothelin-1 (ET-1), nitrites/nitrates (NO), NADPH oxidase-2 (NOX-2), metalloproteinase-12 (MMP12) and asymmetric dimethylarginine (ADMA). Patients underwent brain MRI with perfusion study at T1 and MRI without perfusion at T2. Results 12 patients had ischemic perihematomal lesions at T1. A higher NOX-2 concentration at T0 was observed in patients with ischemic perihematomal lesions compared to those without, (34.9 pg/ml vs 22.4 pg/ml, p=0.051) and with a more severe perihematomal edema at T2 (37.99 pg/ml vs. 19.17 pg/ml, p=0.011). The ischemic perihematomal lesions development was also associated with an increased hematoma volume (p<0.005), perilesional edema (p=0.046), greater midline shift (p=0.036). ET-1 values at T1 inversely correlated with hemorrhage volume at T2 (ρ=-0.717, p=0.030). Conclusions NOX-2 seems to have a role in the development of ischemic perihematomal lesions. The association between higher ET-1 values and a lower hemorrhage volume could be related to the ET-1 vasoconstriction action on the ruptured vessel wall.

Ischemic stroke is one of the leading causes of mortality and long-term disability worldwide, emphasizing the need for rapid and effective acute management. Revascularization therapies are critical to this strategy, demanding swift intervention. Intravenous thrombolysis (IVT) with alteplase (ALT) was traditionally recommended within 4.5 h from symptom onset for acute ischemic stroke (AIS) patients. However, landmark studies, such as ECASS IV, EXTEND, and EPITHET have demonstrated that IVT may be extended up to 9 h in select patients, identified through perfusion imaging with computed tomography or magnetic resonance imaging, enabling differentiation of viable, at-risk brain tissue in the ischemic penumbra from the infarct core. This allows treatment in cases with favorable “mismatch” profiles, Similarly, endovascular procedures for large vessel occlusions (LVOs) were initially recommended within 6 h, but trials, such as DEFUSE-3 and DAWN have established efficacy for thrombectomy up to 16 – 24 h from the last known well time, using perfusion imaging to guide patient selection. These advancements prioritize tissue viability over rigid temporal thresholds. Despite significant progress, optimal revascularization strategies for AIS remain uncertain in complex clinical contexts, such as posterior circulation strokes, large infarct core AIS, distal vascular occlusions, and mild clinical deficit LVO-related AIS. Recent research aims to address these gaps, expanding reperfusion criteria and exploring new thrombolytic agents with potential benefits over ALT. Collectively, these studies aim to refine and broaden therapeutic criteria, improving outcomes for a wider AIS patient population.