Intravenous thrombolysis or endovascular therapy for acute ischemic stroke associated with cervical internal carotid artery occlusion: the ICARO-3 study.

74sinonenonePaciaroni M; Inzitari D; Agnelli G; Caso V; Balucani C; Grotta JC; Sarraj A; Sung-Il S; Chamorro A; Urra X; Leys D; Henon H; Cordonnier C; Dequatre N; Aguettaz P; Alberti A; Venti M; Acciarresi M; D'Amore C; Zini A; Vallone S; Dell'Acqua ML; Menetti F; Nencini P; Mangiafico S; Barlinn K; Kepplinger J; Bodechtel U; Gerber J; Bovi P; Cappellari M; Linfante I; Dabus G; Marcheselli S; Pezzini A; Padovani A; Alexandrov AV; Shahripour RB; Sessa M; Giacalone G; Silvestrelli G; Lanari A; Ciccone A; De Vito A; Azzini C; Saletti A; Fainardi E; Orlandi G; Chiti A; Gialdini G; Silvestrini M; Ferrarese C; Beretta S; Tassi R; Martini G; Tsivgoulis G; Vasdekis SN; Consoli D; Baldi A; D'Anna S; Luda E; Varbella F; Galletti G; Invernizzi P; Donati E; De Lodovici ML; Bono G; Corea F; Sette MD; Monaco S; Riva M; Tassinari T; Scoditti U; Toni D.Paciaroni, M; Inzitari, D; Agnelli, G; Caso, V; Balucani, C; Grotta, Jc; Sarraj, A; Sung Il, S; Chamorro, A; Urra, X; Leys, D; Henon, H; Cordonnier, C; Dequatre, N; Aguettaz, P; Alberti, A; Venti, M; Acciarresi, M; D'Amore, C; Zini, A; Vallone, S; Dell'Acqua, Ml; Menetti, F; Nencini, P; Mangiafico, S; Barlinn, K; Kepplinger, J; Bodechtel, U; Gerber, J; Bovi, P; Cappellari, M; Linfante, I; Dabus, G; Marcheselli, S; Pezzini, Alessandro; Padovani, Alessandro; Alexandrov, Av; Shahripour, Rb; Sessa, M; Giacalone, G; Silvestrelli, G; Lanari, A; Ciccone, A; De Vito, A; Azzini, C; Saletti, A; Fainardi, E; Orlandi, G; Chiti, A; Gialdini, G; Silvestrini, M; Ferrarese, C; Beretta, S; Tassi, R; Martini, G; Tsivgoulis, G; Vasdekis, Sn; Consoli, D; Baldi, A; D'Anna, S; Luda, E; Varbella, F; Galletti, G; Invernizzi, P; Donati, E; De Lodovici, Ml; Bono, G; Corea, F; Sette, Md; Monaco, S; Riva, M; Tassinari, T; Scoditti, U; Toni, D

Call to Action: SARS-CoV-2 and CerebrovAscular DisordErs (CASCADE)

BACKGROUND AND PURPOSE: The novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic. METHODS: This is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center. CONCLUSION: The proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities

Intravenous thrombolysis or endovascular therapy for acute ischemic stroke associated with cervical internal carotid artery occlusion: the ICARO-3 study.

The aim of the ICARO-3 study was to evaluate whether intra-arterial treatment, compared to intravenous thrombolysis, increases the rate of favourable functional outcome at 3 months in acute ischemic stroke and extracranial ICA occlusion. ICARO-3 was a non-randomized therapeutic trial that performed a non-blind assessment of outcomes using retrospective data collected prospectively from 37 centres in 7 countries. Patients treated with endovascular treatment within 6 h from stroke onset (cases) were matched with patients treated with intravenous thrombolysis within 4.5 h from symptom onset (controls). Patients receiving either intravenous or endovascular therapy were included among the cases. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale (mRS), dichotomized as favourable (score of 0-2) or unfavourable (score of 3-6). Safety outcomes were death and any intracranial bleeding. Included in the analysis were 324 cases and 324 controls: 105 cases (32.4 %) had a favourable outcome as compared with 89 controls (27.4 %) [adjusted odds ratio (OR) 1.25, 95 % confidence interval (CI) 0.88-1.79, p = 0.1]. In the adjusted analysis, treatment with intra-arterial procedures was significantly associated with a reduction of mortality (OR 0.61, 95 % CI 0.40-0.93, p = 0.022). The rates of patients with severe disability or death (mRS 5-6) were similar in cases and controls (30.5 versus 32.4 %, p = 0.67). For the ordinal analysis, adjusted for age, sex, NIHSS, presence of diabetes mellitus and atrial fibrillation, the common odds ratio was 1.15 (95 % IC 0.86-1.54), p = 0.33. There were more cases of intracranial bleeding (37.0 versus 17.3 %, p = 0.0001) in the intra-arterial procedure group than in the intravenous group. After the exclusion of the 135 cases treated with the combination of I.V. thrombolysis and I.A. procedures, 67/189 of those treated with I.A. procedures (35.3 %) had a favourable outcome, compared to 89/324 of those treated with I.V. thrombolysis (27.4 %) (adjusted OR 1.75, 95 % CI 1.00-3.03, p = 0.05). Endovascular treatment of patients with acute ICA occlusion did not result in a better functional outcome than treatment with intravenous thrombolysis, but was associated with a higher rate of intracranial bleeding. Overall mortality was significantly reduced in patients treated with endovascular treatment but the rates of patients with severe disability or death were similar. When excluding all patients treated with the combination of I.V. thrombolysis and I.A. procedures, a potential benefit of I.A. treatment alone compared to I.V. thrombolysis was observed

Contribution of Zinc-Dependent Delayed Calcium Influx via TRPC5 in Oxidative Neuronal Death and its Prevention by Novel TRPC Antagonist

Oxidative stress is a key mediator of neuronal death in acute brain injuries, such as epilepsy, trauma, and stroke. Although it is accompanied by diverse cellular changes, increases in levels of intracellular zinc ion (Zn2+) and calcium ion (Ca2+) may play a critical causative role in oxidative neuronal death. However, the mechanistic link between Zn2+ and Ca2+ dyshomeostasis in neurons during oxidative stress is not well-understood. Here, we show that the exposure of cortical neurons to H2O2 led to a zinc-triggered calcium influx, which resulted in neuronal death. The cyclin-dependent kinase inhibitor, NU6027, inhibited H2O2-induced Ca2+ increases and subsequent cell death in cortical neurons, without affecting the early increase in Zn2+. Therefore, we attempted to identify the zinc-regulated Ca2+ pathway that was inhibited by NU6027. The expression profile in cortical neurons identified transient receptor potential cation channel 5 (TRPC5) as a candidate that is known to involve in the generation of epileptiform burst firing and epileptic neuronal death (Phelan KD et al. 2012a; Phelan KD et al. 2013b). NU6027 inhibited basal and zinc-augmented TRPC5 currents in TRPC5-overexpressing HEK293 cells. Consistently, cortical neurons from TRPC5 knockout mice were highly resistant to H2O2-induced death. Moreover, NU6027 is neuroprotective in kainate-treated epileptic rats. Our results demonstrate that TRPC5 is a novel therapeutic target against oxidative neuronal injury in prolonged seizures and that NU6027 is a potent inhibitor of TRPC5