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This review provides an updated analysis of the main aspects involving the diagnosis and the management of children with acute ischemic stroke. Acute ischemic stroke is an emergency of rare occurrence in children (rate of incidence of 1/3500 live birth in newborns and 1–2/100,000 per year during childhood with peaks of incidence during the perinatal period, under the age of 5 and in adolescence). The management of ischemic stroke in the paediatric age is often challenging because of pleomorphic age-dependent risk factors and aetiologies, high frequency of subtle or atypical clinical presentation, and lacking evidence-based data about acute recanalization therapies. Each pediatric tertiary centre should activate adequate institutional protocols for the optimization of diagnostic work-up and treatments.Conclusion: The implementation of institutional standard operating procedures, summarizing the steps for the selection of candidate for neuroimaging among the ones presenting with acute neurological symptoms, may contribute to shorten the times for thrombolysis and/or endovascular treatments and to improve the long-term outcome. What is Known:•Acute ischemic stroke has a higher incidence in newborns than in older children (1/3500 live birth versus 1–2/100,000 per year).•Randomized clinical trial assessing safety and efficacy of thrombolysis and/or endovascular treatment were never performed in childrenWhat is New:•Recent studies evidenced a low risk (2.1% of the cases) of intracranial haemorrhages in children treated with thrombolysis.•A faster access to neuroimaging and hyper-acute therapies was associated with the implementation of institutional protocols for the emergency management of pediatric stroke.

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 (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.

Leptomeningeal collateral (LMC) circulation helps preserve brain tissue during acute ischemic stroke (AIS), with poor collateral status predicting worse outcomes. This study assessed the association between asymmetric dimethylarginine (ADMA), LMCs, infarct volume, and oxidative stress in 101 AIS patients with large vessel occlusion within 6 h or wake-up stroke. LMC status was graded using the Menon score (poor, intermediate, or good) on CT angiography, and recanalization was assessed by the modified Thrombolysis in Cerebral Infarction score. Serum ADMA, NADPH oxidase 2 (NOX2), and nitric oxide (NO) levels were measured at admission (< 6 h, T0), 24 h (T1), and 48 h (T2). Among patients, 43.1% had good, 35.3% intermediate, 21.6% poor LMC status. Higher admission ADMA levels were significantly associated with poor LMC at T0 (p = 0.028) and more severe neurological deficits at T1 and T2 (p = 0.005, p = 0.008). ADMA levels increased over time (p = 0.046), and correlated with NOX2 at T1 (p < 0.001). Rising NOX2 was associated with increased neutrophils (p = 0.013) and decreased lymphocytes (p = 0.006). ADMA may impair endothelial function by reducing NO availability and enhancing NOX2-driven oxidative stress. These findings support a role for the ADMA-NO-NOX2 axis in limiting collateral circulation. Targeting this axis may represent a therapeutic strategy to improve outcomes in AIS.

ObjectiveAntiphospholipid syndrome (APS) is an autoimmune condition characterized by recurrent thrombosis, pregnancy-related complications and circulating antiphospholipid antibodies, including anti-β2-glycoprotein I (β2-GPI). Platelet factor 4 (PF4) is a pro-coagulant protein expressed by activated platelets. It is considered a potential platelet ligand for oxidized β2-GPI, and this interaction may play a role in the thrombotic manifestations of APS. This study aims to assess β2-GPI/PF4 complex autoantibodies in sera of thrombotic patients with APS and their potential functional role in platelet activation.MethodsWe analysed sera from 73 patients with thrombotic APS, 20 with obstetric APS, 20 with systemic lupus erythematosus (SLE), 20 with non-APS thrombosis, 3 with vaccine-induced immune thrombotic thrombocytopenia (VITT), 20 with COVID-19 and 45 healthy donors (HDs). These samples were tested by ELISA for antibodies to the β2-GPI/PF4 complex after in vitro induction of spontaneous β2-GPI protein oxidation.ResultsAnti-β2-GPI/PF4 were detected in 34.24% of thrombotic APS patients and 20% of obstetric APS. All VITT and none of the SLE, non-APS thrombosis, COVID-19 patients and HDs were positive for anti-β2-GPI/PF4. In thrombotic APS, a significant association was found between anti-β2-GPI/PF4 positivity and antibody titer with venous thrombotic complications (p = 0.032, p = 0.01) as well as between anti-β2-GPI/PF4 and triple positivity to conventional aPLs (p = 0.028). Notably, antibody titer correlated with the young age both at diagnosis (p<0.001) and at the current evaluation (p=0.001). Moreover, HDs’ platelets, in vitro treated with Ig fractions from APS patients, exhibited a significant increase in phospho-ERK and phospho-p38 expression, leading to NF-κB activation and TF expression.ConclusionThis study demonstrated the presence of anti-β2-GPI/PF4 in patients with APS, where it may be involved in the mechanism underlying the hypercoagulable state and correlated with a greater risk of developing thrombosis, especially in the young population.

The pathophysiology of COVID-19-associated coagulopathy is complex and not fully understood. SARS-CoV-2 spike protein (SP) may activate platelets and interact with fibrin(ogen). We aimed to investigate whether isolated SP can be present in clots retrieved in COVID-19 patients with acute ischemic stroke (by mechanical thrombectomy) and myocardial infarction. In this pilot study, we could detect SP, but not nucleocapsid protein, on platelets of COVID-19 patients’ thrombi. In addition, in all three COVID-19 thrombi analyzed for molecular biology, no SARS-CoV-2 RNA could be detected by real-time polymerase chain reaction. These data could support the hypothesis that free SP, besides the whole virus, may be the trigger of platelet activation and clot formation in COVID-19.

Several viral and bacterial infections, including COVID-19, may lead to both thrombotic and hemorrhagic complications. Previously, it has been demonstrated an \" \" pathogenic effect of \"antiphospholipid\" antibodies (aPLs), which are able to activate a proinflammatory and procoagulant phenotype in monocytes, endothelial cells and platelets. This study analyzed the occurrence of aPL IgG in patients with acute ischemic stroke (AIS) during COVID-19, evaluating the effect of Ig fractions from these patients on signaling and functional activation of platelets. Sera from 10 patients with AIS during COVID-19, 10 non-COVID-19 stroke patients, 20 COVID-19 and 30 healthy donors (HD) were analyzed for anti-cardiolipin, anti-β2-GPI, anti-phosphatidylserine/prothrombin and anti-vimentin/CL antibodies by ELISA. Platelets from healthy donors were incubated with Ig fractions from these patients or with polyclonal anti-β2-GPI IgG and analyzed for phospho-ERK and phospho-p38 by western blot. Platelet secretion by ATP release dosage was also evaluated. We demonstrated the presence of aPLs IgG in sera of patients with AIS during COVID-19. Treatment with the Ig fractions from these patients or with polyclonal anti-β2-GPI IgG induced a significant increase of phospho-ERK and phospho-p38 expression. In the same vein, platelet activation was supported by the increase of adenyl nucleotides release induced by Ig fractions. This study demonstrates the presence of aPLs in a subgroup of COVID-19 patients who presented AIS, suggesting a role in the mechanisms contributing to hypercoagulable state in these patients. Detecting these antibodies as a serological marker to check and monitor COVID-19 may contribute to improve the risk stratification of thromboembolic manifestations in these patients.

Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood–brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) as well as neuro-axonal damage in COVID-19 patients without severe neurological symptoms according to disease severity and after recovery, comparing the obtained findings with healthy donors (HD). Overall, COVID-19 patients (n = 55) showed higher plasma NfL levels compared to HD (n = 31) (p < 0.0001), especially those who developed ARDS (n = 28) (p = 0.0005). After recovery, plasma NfL levels were still higher in ARDS patients compared to HD (p = 0.0037). In neuro-COVID patients (n = 12), higher CSF and plasma NfL, and CSF MMP-2 levels in ARDS than non-ARDS group were observed (p = 0.0357, p = 0.0346 and p = 0.0303, respectively). SARS-CoV-2 RNA was detected in four CSF and two plasma samples. SARS-CoV-2 RNA detection was not associated to increased CSF NfL and MMP levels. During COVID-19, ARDS could be associated to CNS damage and alteration of BBB integrity in the absence of SARS-CoV-2 RNA detection in CSF or blood. CNS damage was still detectable after discharge in blood of COVID-19 patients who developed ARDS during hospitalization.

Background: Ischemic stroke may trigger neuroplastic changes via proliferation, migration towards the lesion, and differentiation of neuroprogenitor cells into mature neurons. Repetitive Transcranial Magnetic Stimulation (rTMS) may promote brain plasticity. This study aimed to assess rTMS’s effect on post-stroke endogenous neuroplasticity by dosing plasma miRs 17~92, Netrin-1, Sema3A, and BDNF. Methods: In this case-controlled study, we randomized 19 ischemic stroke patients within five days from symptoms onset (T0) to neuronavigated-rTMS or sham stimulation. Stimulation was applied on the stroke hemisphere daily between the 7th and 14th day from stroke onset. Blood samples were collected at T0, before the first rTMS section (T7), and at the end of the last rTMS session (T14). Five healthy controls were also enrolled in this study. Results: Of 19 patients, 10 received rTMS and 9 sham stimulation. Compared with the sham group, in the rTMS group, plasma levels of miRs17~92 and Ntn-1 significantly increased whereas Sema3A levels tended to decrease. In multivariate linear regression analyses, rTMS was independently related to Ntn-1 and miR-25 levels at T14. Conclusions: We found an association between rTMS and neurogenesis/axonogenesis biomarker enhancement. Our preliminary data suggest that rTMS may positively interfere with natural endogenous plasticity phenomena of the post-ischemic human brain.

BackgroundFutile recanalization (FR) is de fined as a poor 90-day outcome or lack of neurological improvement at 24 h despite successful recanalization in acute ischemic stroke (AIS) with large vessel occlusion (LVO) treated by mechanical throbectomy (MT).The No-reflow phenomenon (NRP) could be a possible cause of FR, but its evidence in AIS patients is scarce.MethodsWe retrospectively analyzed 185 digital subtraction angiographies (DSA) of AIS patients with anterior circulation LVO after endovascular treatment. To better define NRP, we designed a score called the modified capillary index score (mCIS). The score is obtained by dividing the middle cerebral artery territory in three segments. For each segment, we gave 2 points if the capillary blush was present without any delay, 1 if delayed, and 0 if absent. The primary endpoint was to use mCIS to identify NRP on post-interventional DSA and to test whether this marker may predict FR and failure of early neurological improvement (fENI). The secondary endpoint was to search for a correlation between NRP, lesion volume, and hemorrhagic transformation. We used the ROC curve to define mCIS ≤ 3 as the cut-off and marker of NRP.ResultsNRP was present in 35.1% of patients. NRP predicted fENI at 24 h (aOR 2.825, 95% CI 1.265–6.308, P = 0.011) and at 7 days (aOR 2.191, 95% CI 1.008–4.762, P = 0.048), but not 90-day FR. Moreover, NRP predicted hemorrhagic transformation (aOR 2.444, 95% CI 1.266–4.717, P = 0.008).ConclusionsThe modified capillary index score (mCIS) seems useful in identifying NRP in AIS. In addition, mCIS was able to predict NRP that correlated with early clinical outcome and hemorrhagic transformation of the ischemic lesion. An external validation of the score is warranted.