Exploring the relationship between embolic acute stroke distribution and supra-aortic vessel patency: key findings from an in vitro model study.

BACKGROUND: We investigated differences in intracranial embolus distribution through communicating arteries in relation to supra-aortic vessel (SAV) patency. METHODS: For this experimental analysis, we created a silicone model of the extracranial and intracranial circulations using a blood-mimicking fluid under physiological pulsatile flow. We examined the sequence of embolus lodgment on injecting 104 frangible clot analogues (406 emboli) through the right internal carotid artery (CA) as SAV patency changed: (a) all SAV patent (baseline), (b) emboli from a CA occlusion, (c) emboli contralateral to a CA occlusion and (d) occlusion of the posterior circulation. The statistical analysis included a descriptive analysis of thrombi location after occlusion (absolute and relative frequencies). Sequences of occlusions were displayed in Sankey flow charts for the four SAV conditions. Associations between SAV conditions and occlusion location were tested by Fisher's exact test. Two-sided p values were compared with a significance level of 0.05. RESULTS: The total number of emboli was 406 (median fragments/clot: 4 (IQR: 3-5)). Embolus lodgment was dependent on SAV patency (p<0.0001). In all scenarios, embolism lodging in the anterior cerebral artery (ACA) occurred after a previous middle cerebral artery (MCA) embolism (MCA first lodge: 96%, 100/104). The rate of ipsilateral ACA embolism was 28.9% (28/97) at baseline, decreasing significantly when emboli originated from an occluded CA (16%, 14/88). There were more bihemispheric embolisations in cases of contralateral CA occlusion (37%, 45/122), with bilateral ACA embolisms preceding contralateral MCA embolism in 56% of cases (14/25 opposite MCA and ACA embolism). CONCLUSIONS: All emboli in the ACA occurred after a previous ipsilateral MCA embolism. Bihemispheric embolisms were rare, except when there was a coexisting occlusion in either CA, particularly in cases of a contralateral CA occlusion.

Early automated cerebral edema assessment following endovascular therapy: impact on stroke outcome.

BACKGROUND: Cerebral edema (CED) is associated with poorer outcome in patients with acute ischemic stroke (AIS). The aim of the study was to investigate the factors contributing to greater early CED formation in patients with AIS who underwent endovascular therapy (EVT) and its association with functional outcome. METHODS: We conducted a multicenter cohort study of patients with an anterior circulation AIS undergoing EVT. The volume of cerebrospinal fluid (CSF) was extracted from baseline and 24-hour follow-up CT using an automated algorithm. The severity of CED was quantified by the percentage reduction in CSF volume between CT scans (∆CSF). The primary endpoint was a shift towards an unfavorable outcome, assessed by modified Rankin Scale (mRS) score at 3 months. Multivariable ordinal logistic regression analyses were performed. The ∆CSF threshold that predicted unfavorable outcome was selected using receiver operating characteristic curve analysis. RESULTS: We analyzed 201 patients (mean age 72.7 years, 47.8% women) in whom CED was assessable for 85.6%. Higher systolic blood pressure during EVT and failure to achieve modified Thrombolysis In Cerebral Infarction (mTICI) 3 were found to be independent predictors of greater CED. ∆CSF was independently associated with the probability of a one-point worsening in the mRS score (common odds ratio (cOR) 1.05, 95% CI 1.03 to 1.08) after adjusting for age, baseline mRS, National Institutes of Health Stroke Scale (NIHSS), and number of passes. Displacement of more than 25% of CSF was associated with an unfavorable outcome (OR 6.09, 95% CI 3.01 to 12.33) and mortality (OR 6.72, 95% CI 2.94 to 15.32). CONCLUSIONS: Early CED formation in patients undergoing EVT was affected by higher blood pressure and incomplete reperfusion. The extent of early CED, measured by automated ∆CSF, was associated with worse outcomes.

Safety and efficacy of tirofiban in acute ischemic stroke due to tandem lesions undergoing mechanical thrombectomy: A multicenter randomized clinical trial (ATILA) protocol.

Background: In-stent thrombosis after mechanical thrombectomy (MT) worsen outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Although an optimal antiplatelet therapy is needed, the best approach to avoid in-stent thrombosis is yet to be elucidated. Hypothesis: Low-dose intravenous tirofiban is superior to intravenous aspirin in avoiding in-stent thrombosis in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. Methods: The ATILA-trial is a multicenter, prospective, phase IV, randomized, controlled (aspirin group as control), assessor-blinded clinical trial. Patients fulfilling inclusion criteria (AIS due to TL, ASPECTS ⩾ 6, pre-stroke modified Rankin Scale ⩽2 and onset <24 h) will be randomized (1:1) at MT onset to experimental (intravenous tirofiban) or control group (intravenous aspirin). Intravenous aspirin will be administered at a 500 mg single dose and tirofiban at a 500 µg bolus followed by a 200 µg/h infusion during first 22 h. All patients will be followed up to 3 months. Sample size estimated is 240 patients. Outcomes: The primary efficacy outcome is the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. The primary safety outcome is the rate of symptomatic intracranial hemorrhage. Secondary outcomes include functional independence defined as modified Rankin Scale 0-2, proportion of patients undergoing rescue therapy due to in-stent aggregation during MT and carotid reocclusion at 30 days. Discussion: ATILA-trial will be the first clinical trial regarding the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. Trial registration: NCT0522596.

Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial.

BACKGROUND: Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke. METHODS: The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18-80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1-7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6-20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed. FINDINGS: Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9-15), with intra-arterial BMMNC injection done a median of 6 days (4-7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 [95% CI 0·55-7·85]; p=0·28), eight (44%) in the high-dose group (1·89 [0·52-6·96]; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 [0·72-6·85]; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group. INTERPRETATION: Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints. FUNDING: Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia.

Relevance of Carotid Reocclusion in Tandem Lesions.

AIMS: Carotid reocclusion (CRO) after mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to tandem lesion (TL) or isolated internal carotid occlusion (ICO) is associated with worse clinical outcomes. Our aim was to analyze the predictors and clinical impact of CRO. METHODS: A retrospective single-center analysis of all patients with anterior circulation strokes who underwent MT prospectively included in a registry between 2017 and 2020 was performed. ICO and TL as stroke causes were included. Stent deployment was left to the discretion of the interventionist. All patients received at least intravenous aspirin during MT. CRO was assessed using ultrasound within the first 24 h after MT. Efficacy and safety of stenting were assessed. RESULTS: Among 1304 AIS cases, 218 (16.7%) were related to TL or ICO. Of them, 5% (n=11) were associated with internal CRO 24 h after the endovascular procedure. After adjusting per confounders, multivariate analysis showed that the independent variables associated with CRO were the TICI recanalization grade [TICI 2b-3; OR 0.1, 95% confidence interval (CI) 0.01-0.89, p=0.040], pial collateral circulation presence (OR 0.09, 95% CI 0.02-0.45, p=0.03), stent deployment during MT (OR 0.17, 95% CI 0.03-0.84, p=0.030), and general anesthesia use (OR 2.92, 95% CI 1.13-7.90, p=0.034). CRO showed a trend toward worst outcomes (modified Rankin scale 3-6) at 3 months (OR 3.4, 95% CI 0.96-12, p=0.057). After multivariate analysis, variables independently associated with worse outcomes at 90 days were intrastent platelet aggregation phenomena during endovascular therapy, admission National Institute of Health Stroke Scale, and age. Conversely, intravenous thrombolysis and TICI 2b-3 recanalization grade were identified as independent predictors of good outcomes at 90 days. CONCLUSIONS: CRO has a relevant clinical impact in our study, associating lower rates of good functional outcomes at 3 months. Independent factors of CRO were the recanalization degree, presence of pial collateral circulation, use of a stent as a protective factor, and use of general anesthesia during thrombectomy.

Economic impact of the first pass effect in mechanical thrombectomy for acute ischaemic stroke treatment in Spain: a cost-effectiveness analysis from the national health system perspective.

OBJECTIVE: The mechanical thrombectomy (MT) benefit is related to the degree of reperfusion achieved. First pass effect (FPE) is defined as complete/near revascularisation of the large-vessel occlusion (modified Thrombolysis in Cerebral Infarction (mTICI) 2c-3) after a single device pass. This study assessed the health benefit and economic impact of achieving FPE for acute ischaemic stroke (AIS) patients from the Spanish National Health System (NHS) perspective. DESIGN: A lifetime Markov model was used to estimate incremental costs and health outcomes (measured in quality-adjusted life-years (QALYs)) of patients that achieve FPE. A subanalysis of the Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischaemic Stroke (STRATIS) registry was performed to obtain clinical outcomes. The base case included all patients that achieved at least a final mTICI ≥2 b, while the alternative scenario included all patients regardless of their final mTICI (0-3). Treatment costs were updated to reflect current practice based on expert panel consensus, while other acute and long-term costs were obtained from a previous cost-effectiveness analysis of MT performed in Spain. Sensitivity analyses were performed to assess the model's robustness. SETTING: Spanish healthcare perspective. PARTICIPANTS: AIS patients in Spain. INTERVENTIONS: FPE following MT. OUTCOME MEASURES: The model estimated QALYs, lifetime costs and net monetary benefit for the FPE and non-FPE group, depending on the inclusion of reperfusion groups and formal care costs. RESULTS: STRATIS subanalysis estimated significantly better clinical outcomes at 90 days for the FPE group in all scenarios. In the base case, the model estimated lifetime cost saving per patient of €16 583 and an incremental QALY gain of 1.2 years of perfect health for the FPE group. Cost savings and QALY gains were greater in the alternative scenario (-€44 289; 1.75). In all scenarios, cost savings were driven by the long-term cost reduction. CONCLUSION: Achieving FPE after MT can lead to better health outcomes per AIS patient and important cost savings for the Spanish NHS.

Arm-only access for combined transarterial and transvenous neurointerventional procedures.

A simultaneous arterial and venous approach has been widely described for the endovascular treatment of dural arteriovenous fistula (DAVFs) and recently for arteriovenous malformation (AVMs). Conventional venous approaches are performed by direct internal jugular puncture or by femoral access. Although complication rates are low, there are potential life-threatening complications that should be avoided. The advantages of radial artery access have been widely proven, nevertheless the use of upper limb veins in neurointervention are rarely reported. We present five cases of the simultaneous arteriovenous approach through the radial artery and superficial veins of the forearm for the treatment of intracranial neurovascular diseases.

Intravenous Thrombolysis Guided by Perfusion CT with Alteplase in >4.5 Hours from Stroke Onset.

INTRODUCTION: The benefit of intravenous thrombolysis (IVT) in wake-up stroke (WUS), stroke of unknown time of onset (SUKO), or when time exceeds 4.5 h from last-seen-normal (LSN) guided by CT perfusion (CTP) or MRI has been recently suggested. However, there is limited information of IVT in those patients in real-world studies. OBJECTIVE: Our aim was to evaluate safety and efficacy of IVT selected by CTP in patients with WUS, SUKO, or stroke of time onset beyond 4.5 h. MATERIAL AND METHODS: We studied a prospective cohort of patients who underwent IVT from January 2010 to December 2017. Two groups were defined: standard of care group (SC) included patients with time onset <4.5 h and CTP group included patients with WUS, SUKO, or onset beyond >4.5 h from LSN with penumbra area in CTP. We evaluated baseline characteristics, functional outcomes according to modified Rankin Scale (mRS) at discharge and at 90 days, and intracranial hemorrhages rates. RESULTS: 657 patients were studied: 604 (92%) were treated in the SC group and 53 (8%) in the CTP group. The mean NIHSS score was 9.8 in the CTP group versus 13 in the SC group (p = 0.001). Seventeen patients in the CTP group (32.1%) received bridging therapy with mechanical thrombectomy (MT). Last time seen well-to-needle time was 538 versus 155 min (p < 0.001). The incidence of symptomatic intracranial hemorrhage was equal in both groups (3.8 vs. 3.8%, p = 1). Good functional outcome (mRS < 2) was achieved in both groups (72 vs. 60.4%, p = 0.107). CONCLUSIONS: IVT in patients with WUS, SUKO, or stroke beyond >4.5 h from LSN, with salvageable brain tissue on CTP, seems to be safe and has similar functional outcomes at 90 days to the standard therapeutic window, even when combined with MT.

Dose adjustment of clopidogrel in hyper-responder patients with unruptured intracranial aneurysms treated with stents.

BACKGROUND: The management of clopidogrel in hyper-responders has not been well described. We report the treatment and dose adjustment individualization with clopidogrel oral solution (COS) in hyper-responder patients with an unruptured intracranial aneurysm treated with a stent. METHODS: A prospective study (2015-2018) in patients receiving clopidogrel prior to endovascular treatment was performed. Platelet reactivity after clopidogrel therapy was evaluated with the VerifyNow PRU test. Initial values ≤80 PRU (P2Y12 reactivity units) were classified as a hyper-response according to prior evidence. Patients were treated with clopidogrel for 7-10 days before stent treatment. Seven days post-procedure the dose of COS was gradually reduced (30 mg-20 mg-10 mg-5 mg) every 5 days to 5 mg (1 mL)/day. RESULTS: Twenty patients with 24 aneurysms were classified as having a hyper-response to clopidogrel. Mean age was 55.2 years (range 42-64) and 80% were women. Mean baseline PRU value and the percentage of platelet inhibition were 16.4±11.5 PRU and 92.05±7.5%, respectively. The mean time used to decrease the dose of clopidogrel to 5 mg/day was 27±4.3 days. Modified dosing strategies were shown to increase the final PRU values and to decrease the percentage of platelet inhibition (137.42±27.4 and 41.5±14.8%, respectively). Two of the 20 patients with dose adjustment of oral solution of clopidogrel (5 mg/day) in our cohort exhibited a delayed conversion to hypo-response. No patients suffered thromboembolic events related to the dose adjustment of clopidogrel with 5 mg/day during the follow-up. CONCLUSION: Reduction of the daily maintenance dose of clopidogrel in hyper-responder patients could provide a similar antiplatelet effect to the standard dose of clopidogrel, allowing a PRU value in the optimal range.

Circulating microRNA after autologous bone marrow mononuclear cell (BM-MNC) injection in patients with ischemic stroke.

Previous studies have shown the potential of microRNAs (miRNA) in the pathological process of stroke and functional recovery. Bone marrow mononuclear cell (BM-MNC) transplantation improves recovery in experimental models of ischemic stroke that might be related with miRNA modifications. However, its effect on circulating miRNA has not been described in patients with stroke. We aimed to evaluate the circulating levels of miRNAs after autologous BM-MNC transplantation in patients with stroke. We investigate the pattern of miRNA-133b and miRNA-34a expression in patients with ischemic stroke included in a multicenter randomized controlled phase IIb trial (http://www.clinicaltrials.gov; unique identifier: NCT02178657). Patients were randomized to 2 different doses of autologous intra-arterial BM-MNC injection (2×106/kg or 5×106/kg) or control group within the first 7 days after stroke onset. We evaluate plasma concentration of miRNA-113b and miRNA-34a at inclusion and 4, 7, and 90 days after treatment. Thirteen cases (8 with 2×106/kg BM-MNC dose and 5 with 5×106/kg dose) and 11 controls (BM-MNC non-treated) were consecutively included. Mean age was 64.1±12.3 with a mean National Institutes of Health Stroke Scale score at inclusion of 14.5. Basal levels of miRNA were similar in both groups. miR-34a-5p and miR-133b showed different expression patterns. There was a significant dose-dependent increase of miRNA-34a levels 4 days after BM-MNC injection (fold change 3.7, p<0.001), whereas miRNA-133b showed a significant increase in the low-dose BM-MNC group at 90 days. Intra-arterial BM-MNC transplantation in patients with ischemic stroke seems to modulate early circulating miRNA-34a levels, which have been related to precursor cell migration in stroke and smaller infarct volumes.

Safety of Early Carotid Artery Stenting for Symptomatic Stenosis in Daily Practice.

OBJECTIVE/BACKGROUND: In 2006, the American Heart Association recommended that for preference carotid endarterectomy (CEA) or, alternatively, carotid angioplasty and stenting (CAS) for symptomatic carotid artery stenosis should ideally occur within 14 days of an ischaemic event. The aim was to determine the safety of CAS according to those recommendations in daily practice. METHODS: A retrospective analysis was performed of all consecutive patients (2000-16), with ipsilateral carotid symptoms who underwent CAS for extracranial carotid stenosis ≥70%, who were previously included in a prospective database. Thirty day morbidity was assessed (any stroke without transient ischaemic attack [TIA]/amaurosis fugax), along with mortality of the procedure in the early (≤14 days after stroke onset) and delayed phases (15-180 days after stroke onset). Patients who received CAS and/or mechanical thrombectomy for acute ischaemic stroke treatment were not included. RESULTS: In total, 1227 patients with symptomatic carotid stenosis who underwent CAS were identified. Early and delayed CAS was performed in 291 and 936 patients, respectively. Morbidity (any stroke) and mortality was 2.2% (n = 27) in the whole cohort (n = 8 [2.7%] in early vs. n = 19 [2%] in delayed CAS; p = .47). There were no differences in morbidity between early and delayed CAS regarding TIA (n = 15 vs. 36 [5.2% vs. 3.9%]; p = .33), minor stroke (n = 4 vs. 5 [1.4% vs. 0.5%]; p = .14), or major stroke (n = 2 vs. 6 [0.7% vs. 0.6%]; p = .59). Two patients (0.7%) died after early CAS and eight (0.9%) after delayed CAS (p = .56). CONCLUSION: CAS may be safely performed in the early phase after an ischaemic stroke with low clinical complication rates. Further studies are needed to validate CAS safety conducted even earlier in the acute phase of ischaemic stroke.

Novel balloon application for rescue and realignment of a proximal end migrated pipeline flex embolization device into the aneurysmal sac: complication management.

The pipeline embolization device (PED) has become a routine firstline option for the treatment of an increasing population of intracranial aneurysms at many neurovascular centers. Intraprocedural complications during PED deployment, or complications associated with migration of the device, are rarely reported problems. Significant mismatch in luminal diameter between the inflow vessel and the outflow vessel or excessive dragging-stretching of the PED have been related to 'watermelon seed' or 'accordion' effects, respectively, resulting in stent migration. Here we present a novel balloon technique that was successfully used to realign an in situ flow diverting stent that had prolapsed into a large aneurysm. This represents a useful salvage technique and should be considered when encountering this potential complication.

Novel balloon application for rescue and realignment of a proximal end migrated pipeline flex embolization device into the aneurysmal sac: complication management.

The pipeline embolization device (PED) has become a routine firstline option for the treatment of an increasing population of intracranial aneurysms at many neurovascular centers. Intraprocedural complications during PED deployment, or complications associated with migration of the device, are rarely reported problems. Significant mismatch in luminal diameter between the inflow vessel and the outflow vessel or excessive dragging-stretching of the PED have been related to 'watermelon seed' or 'accordion' effects, respectively, resulting in stent migration. Here we present a novel balloon technique that was successfully used to realign an in situ flow diverting stent that had prolapsed into a large aneurysm. This represents a useful salvage technique and should be considered when encountering this potential complication.