Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review

Hinchazón celular; Edema; Traumatismo cerebralCellular swelling; Edema; Traumatic brain injuryInflor cel·lular; Edema; Traumatisme cerebralSulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease—providing an overview of the journey from patch-clamp experiments to phase III trials.No funding directly supported the writing of this review. R.M.J. is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (K23NS101036; R01NS115815), and the Barrow Neurological Foundation. J.M.S. is supported by grants from the Department of Veterans Affairs (I01RX003060; 1I01BX004652), the Department of Defense (SC170199), the National Heart, Lung and Blood Institute (R01HL082517) and the NINDS (R01NS102589; R01NS105633)

Thrombectomy for Large‐Vessel Occlusion With Pretreatment Intracranial Hemorrhage

Background Many patients treated with endovascular thrombectomy (EVT) in clinical practice would not have qualified for inclusion in the initial clinical trials demonstrating benefit for EVT, yet likely will benefit from reperfusion. One such subset for which data are sparse is patients with emergent large‐vessel occlusion and concomitant intracranial hemorrhage (ICH). The objective of this report is to document patients who underwent thrombectomy for large‐vessel occlusion in the presence of concomitant ICH and evaluate their clinical characteristics and outcomes. Methods We retrospectively reviewed prospectively collected patient records at 4 comprehensive stroke centers from 2012 to 2019. Patients were identified who had pre‐EVT ICH. Data collected included baseline patient demographics and laboratory values, stroke characteristics, ICH radiographic variables, antiplatelet/anticoagulant/thrombolytic medication use, and procedural factors. The primary safety outcome was any worsening of ICH on neuroimaging obtained 24 hours after EVT. Results Eight patients were identified who underwent thrombectomy with concomitant ICH. The mean age was 71.9 years (range, 37–90). Median National Institutes of Health Stroke Scale score was 25 (interquartile range, 16.5–28.8), and 5 (63%) received tissue plasminogen activator. All patients underwent EVT and had mTICI2B or greater reperfusion. In 7 patients (88%), the initial ICH remained stable on postprocedure imaging. In 1 patient who received intravenous antiplatelet agents during thrombectomy, the hemorrhagic transformation was radiographically increased but without clinical correlate or mass effect. Conclusions In a multi‐institution evaluation of 8 patients with ICH at the time of thrombectomy, 1 patient had radiographic worsening of hemorrhage, and no patient experienced clinical worsening related to hemorrhage progression. These findings suggest that thrombectomy may be safe in this population

Endovascular Therapy vs Medical Management for Patients With Acute Stroke With Medium Vessel Occlusion in the Anterior Circulation

Importance Randomized clinical trials have shown the efficacy of endovascular therapy (EVT) for acute large vessel occlusion strokes. The benefit of EVT in acute stroke with distal, medium vessel occlusion (DMVO) remains unclear. Objective To examine the efficacy and safety outcomes associated with EVT in patients with primary DMVO stroke when compared with a control cohort treated with medical management (MM) alone. Design, Setting, and Participants This multicenter, retrospective cohort study pooled data from patients who had an acute stroke and a primary anterior circulation emergency DMVO, defined as any segment of the anterior cerebral artery (ACA) or distal middle cerebral artery, between January 1, 2015, and December 31, 2019. Those with a concomitant proximal occlusion were excluded. Outcomes were compared between the 2 treatment groups using propensity score methods. Data analysis was performed from March to June 2021. Exposures Patients were divided into EVT and MM groups. Main Outcomes and Measures Main efficacy outcomes included 3-month functional independence (modified Rankin Scale [mRS] scores, 0-2) and 3-month excellent outcome (mRS scores, 0-1). Safety outcomes included 3-month mortality and symptomatic intracranial hemorrhage. Results A total of 286 patients with DMVO were evaluated, including 156 treated with EVT (mean [SD] age, 66.7 [13.7] years; 90 men [57.6%]; median National Institute of Health Stroke Scale [NIHSS] score, 13.5 [IQR, 8.5-18.5]; intravenous tissue plasminogen activator [IV tPA] use, 75 [49.7%]; ACA involvement, 49 [31.4%]) and 130 treated with medical management (mean [SD] age, 69.8 [14.9] years; 62 men [47.7%]; median NIHSS score, 7.0 [IQR, 4.0-14.0], IV tPA use, 58 [44.6%]; ACA involvement, 31 [24.0%]). There was no difference in the unadjusted rate of 3-month functional independence in the EVT vs MM groups (151 [51.7%] vs 124 [50.0%]; P = .78), excellent outcome (151 [38.4%] vs 123 [31.7%]; P = .25), or mortality (139 [18.7%] vs 106 [11.3%]; P = .15). The rate of symptomatic intracranial hemorrhage was similar in the EVT vs MM groups (weighted: 4.0% vs 3.1%; P = .90). In inverse probability of treatment weighting propensity analyses, there was no significant difference between groups for functional independence (adjusted odds ratio [aOR], 1.36; 95% CI, 0.84-2.19; P = .20) or mortality (aOR, 1.24; 95% CI, 0.63-2.43; P = .53), whereas the EVT group had higher odds of an excellent outcome (mRS scores, 0-1) at 3 months (aOR, 1.71; 95% CI, 1.02-2.87; P = .04). Conclusions and Relevance The findings of this multicenter cohort study suggest that EVT may be considered for selected patients with ACA or distal middle cerebral artery strokes. Further larger randomized investigation regarding the risk-benefit ratio for DMVO treatment is indicated

Collateral Circulation Augmentation and Neuroprotection as Adjuvant to Mechanical Thrombectomy in Acute Ischemic Stroke

PURPOSE OF THE REVIEW: Mechanical thrombectomy (MT)-mediated endovascular recanalization has dramatically transformed treatment and outcomes after acute ischemic stroke caused by a large vessel occlusion (LVO). Current guidelines recommend MT up to 24 hours from stroke onset in carefully selected patients based on favorable clinical and imaging parameters. Despite optimal patient selection and low complication rates with current recanalization technology, approximately 1 in 2 patients with LVO stroke do not achieve functional independence at 3 months. This ceiling effect of MT efficacy may be explained by ischemic core expansion into the ischemic penumbra before recanalization and neuronal loss occurring after recanalization. Factors affecting the efficacy of MT, or the degree of irreversible injury, include time from symptom onset to recanalization, collateral circulation status, and differences in neuronal vulnerability. The purpose of this brief review is to discuss potential targets for neuroprotection, present and future potential pharmacologic and nonpharmacologic agents, and the data available in the literature. RECENT FINDINGS: In experimental ischemia models, several authors reported that pharmacologic and nonpharmacologic agents are able to slow the progression of ischemic core expansion. However, in the era of unsuccessful recanalization of the occluded artery, several neuroprotective agents that were promising in the preclinical stage failed phase II/III clinical trials. SUMMARY: Providing neuroprotection before and after recanalization of an LVO may play an important role in improving outcomes in the era of MT. Neuroprotection is classically defined as a process that results in the salvage, recovery, or regeneration of neuronal (and other supporting CNS cell) structure or function. The advent of successful recanalization of acute LVO by MT in the majority of patients may spur the growth of effective neuroprotection

Utility of tPA administration in acute treatment of internal carotid artery occlusions

Background: Intravenous tissue plasminogen activator (IV-tPA) remains part of the guidelines for acute ischemic stroke treatment, yet internal carotid artery occlusions (ICAO) are known to be poorly responsive to IV-tPA. It is unknown whether bridging thrombolysis (BT) is beneficial in such cases. Purpose: We sought to evaluate whether the use of IV-tPA improved overall clinical outcomes in patients undergoing endovascular thrombectomy (EVT) for ICA occlusions. Methods: Data from 1367 consecutive stroke cases treated with EVT from 2012-2019 were prospectively collected from a single center. Univariate and multivariate logistic regression were used to assess the relationship between IV-tPA administration and clinical outcome. Results: 153 patients were found to have carotid terminus and tandem ICAO who received EVT and presented within 4.5h of last seen well. 50% (n = 82) received IV tPA. There were no differences between the groups with respect to age, NIHSS, time to EVT and ASPECTS score. 53% had tandem ICA-MCA occlusions. Rate of recanalization (≥ TICI 2B) and sICH did not significantly differ between the two groups. Regression analysis demonstrated no effect of IV-tPA on modified Rankin Score (mRS) at 90 days and overall mortality. Factors significantly associated with reduced mortality included lower age, lower NIHSS, and better rate of recanalization. Conclusions: There was no significant difference in clinical outcomes in those receiving BT vs. direct EVT for ICAO. For centers with optimal door-to-puncture times, bypassing IV-tPA may expedite recanalization times and potentially yield more favorable outcomes. Patients with higher NIHSS and tandem lesions may have better outcomes with BT

Abstract Number ‐ 35: Maximum Euclidean Deflection‐A Novel Metric For Safety Of Neurovascular Devices

Introduction Endovascular thrombectomy (EVT) devices are evolving rapidly to improve safety and efficacy of EVT‐mediated recanalization of large vessel occlusion strokes, and to access medium and distal vessel occlusions. To enable effective comparative analyses, there is a need to develop an objective in‐vitro safety metric for new EVT devices. Methods We utilized three FDA‐approved stent‐retrievers (4 mm diameter; variable lengths) currently available in the United States and deployed them in an in‐vitro ischemic stroke bench model (Sim Agility, Mentice Inc., Sweden). The stent‐retrievers were deployed in the M1 segment of the middle cerebral artery of the model using a system comprised of an 0.014 inch guide wire and 0.021 inch microcatheter. After unsheathing in the M1 segment, in the absence of a blood clot, the microcatheter was withdrawn back into the petrous internal carotid artery, and the whole system was withdrawn as a rate of 5 mm per second. Maximum deflection of the terminal internal carotid was measured in 3 axes using a specialized camera set‐up. Results A total of 3 passes were performed for each stent‐retriever (stent A, stent B, and stent C). Maximum deflection of the terminal internal carotid artery (from resting position to largest displacement during stent‐retrieval withdrawal) was measured in 3 planes and the values were as follows (Table).Maximum Euclidean Deflection (MED) ranged from 6.1 to 9.1 mm. Deflection varied based on 3 stent‐retriever designs and the plane of measurement. Figure demonstrates deflections as seen in Stent A. Conclusions Withdrawing an unsheathed stent‐retriever from the middle cerebral artery leads to significant deflection of the internal carotid artery terminus in an in‐vitro stroke model. The degree of deflection is variable in different planes and varies based on stent‐retriever design. Further studies are required to examine the predictors and impact of the deflection

Abstract Number ‐ 205: Impact of Automated Neuroimaging Triage Platform on Time Metrics at a Thrombectomy Capable Stroke Center

Introduction Rapid detection and appropriate triage of large vessel occlusion (LVO) strokes, upon arrival to a hospital system, is key to achieving better outcomes after endovascular thrombectomy (EVT) mediated recanalization of LVO strokes . Automated neuroimaging analyses has the potential to streamline intra‐ hospital workflow. We aim to study the change in vital intra‐hospital time metrics before and after adoption of an automated neuroimaging triage platform (ANTP). Methods We performed a retrospective analysis of prospectively collected data at our EVT capable stroke center between April 2019 and November 2021. IschemaView’s Rapid software was adopted in October 2020 for triage of stroke patients. Patients treated before were our control cohort and patients treated after were our intervention cohort. Confirmed LVO strokes presenting to our center within 24 hours of stroke onset were included. Results A total of 305 patients were included‐ control (n = 150) and intervention cohort (n = 155). Age (70±15 vs 72 ±15,p = .40), NIHSS score (13 ±8 vs 14 ±7, p = .24), and last‐known‐well to arrival (392 ±464 vs 376 ±427 min, p = .38) were comparable between the two groups. Time from arrival to non‐contrast CT head was also comparable between the two groups (150 ±712 vs 161 ±794, p = .89). Time from non‐contrast CT head to decision to EVT (36 ±54 vs 22 ±58, p = .06) and time from non‐contrast CT to groin puncture (41 ±61 vs 61 ±65, p = .01) were shorter in the intervention cohort compared to control cohort. Length of stay and discharge mRS score were similar between the two cohorts. Conclusions Automated neuroimaging triage platform has the potential to improve workflow by decreasing time from non‐contrast CT to EVT decision and groin puncture. Further studies are required to study impact on patient outcomes

Expedited management of low-risk transient ischemic attack patients: The Fast-Track TIA protocol

Objectives: Transient ischemic attack (TIA) serves a precursor for an acute ischemic stroke (AIS); however, not all TIA patients harbor the same risk for subsequent AIS. We aimed to investigate expediting outpatient management of low-risk TIA patients (ABCD: Giles and Rothwell, 2007 score ≤ 3) via our Fast-Track TIA Protocol (FTTP). Materials and methods: A retrospective analysis was performed on patients who presented to our academic network 04/2020 - 2/2021. Patients who presented with ABCD: Giles and Rothwell, 2007 scores ≤ 3 without large vessel occlusion or flow limiting stenosis were eligible for the FTTP. These patients were discharged on dual antiplatelet therapy and statin and received prescriptions for transthoracic echo, holter monitor, LDL, and A1c along with a scheduled follow-up appointment 30 days from presentation. Results: 182 consecutive patients were evaluated during this period, 21 (11%) were excluded from analysis due to NIHSS \u3e 0 and/or infarct present on MRI. 35 (22%) patients qualified for FTTP and were directly discharged from the ED. Median ABCD2 score was 2 for the discharge group and 4 for the admitted group. There was a significant difference with respect to age and hypertension. Additionally, the FTTP patient population were more likely to be smokers than the admitted patient population. 3 FTTP patients re-presented to the ED, but none of them suffered a symptomatic stroke. Conclusions: A FTTP demonstrated feasibility and safety with low rates of re-presentation and ischemic stroke. Further research is warranted to determine an optimal patient population that can be safely managed in an outpatient setting

Duration of Ischemia Impacts Postreperfusion Clinical Outcomes Independent of Follow‐Up Infarct Volume

Background Time to reperfusion is believed to influence clinical outcomes following thrombectomy mainly through reduction of infarct growth. In this study, we aim to understand whether clinical outcomes can be influenced by ischemia duration (penumbral time) independent of postintervention infarct volume by comparing outcomes following thrombectomy in patients with similar (and small) follow‐up infarct volumes. Methods We performed a retrospective analysis of a prospectively maintained large‐vessel occlusion stroke thrombectomy database across 3 US centers. Demographic, clinical, radiological, and outcomes data of patients with anterior circulation large‐vessel occlusion (internal carotid or middle cerebral artery M1) stroke who had a witnessed‐onset stroke, had substantial penumbral volumes, achieved successful reperfusion (modified thrombolysis in cerebral infarction 2b‐3), and had a follow‐up infarct volume of <20 mL were analyzed. Results A total of 233 patients (center A, 25; center B, 33; center C, 175) were included. Mean age was 71±16 years, and median National Institutes of Health Stroke Scale was 15 (10–20). Median penumbral time was 4.7 (2.9–10) hours, and median follow‐up infarct volume was 4.7 (0.2–9.4) mL. Despite comparable baseline characteristics and 24‐hour infarct volumes, patients reperfused in the 0‐ to 6‐hour time window had significantly higher rates of modified Rankin scale 0 to 2 (61% versus 40%; P=0.002) and numerically lower rates of mortality (11% versus 17%; P=0.16) at 90 days when compared with patients reperfused in the 6‐ to 24‐hour time window. Duration of ischemia is an independent predictor of modified Rankin scale 0 to 2 (odds ratio, 0.91 [0.80–0.99]; P=0.012). In multivariable analysis accounting for age and baseline National Institutes of Health Stroke Scale score, the association between penumbral time and modified Rankin scale 0 to 2 remained significant (absolute risk difference, −1.2% [(95% CI, −1.9 to −0.4)]/h delay). Conclusion Longer penumbral duration is associated with a lower likelihood of functional independence among large‐vessel occlusion strokes with small and comparable 24‐hour follow‐up infarct volume. Our findings indicate that delays in time to reperfusion affect clinical outcomes through mechanisms mediated by factors not solely limited to infarct reduction

Thrombectomy for Large‐Vessel Occlusion With Pretreatment Intracranial Hemorrhage

Background Many patients treated with endovascular thrombectomy (EVT) in clinical practice would not have qualified for inclusion in the initial clinical trials demonstrating benefit for EVT, yet likely will benefit from reperfusion. One such subset for which data are sparse is patients with emergent large‐vessel occlusion and concomitant intracranial hemorrhage (ICH). The objective of this report is to document patients who underwent thrombectomy for large‐vessel occlusion in the presence of concomitant ICH and evaluate their clinical characteristics and outcomes. Methods We retrospectively reviewed prospectively collected patient records at 4 comprehensive stroke centers from 2012 to 2019. Patients were identified who had pre‐EVT ICH. Data collected included baseline patient demographics and laboratory values, stroke characteristics, ICH radiographic variables, antiplatelet/anticoagulant/thrombolytic medication use, and procedural factors. The primary safety outcome was any worsening of ICH on neuroimaging obtained 24 hours after EVT. Results Eight patients were identified who underwent thrombectomy with concomitant ICH. The mean age was 71.9 years (range, 37–90). Median National Institutes of Health Stroke Scale score was 25 (interquartile range, 16.5–28.8), and 5 (63%) received tissue plasminogen activator. All patients underwent EVT and had mTICI2B or greater reperfusion. In 7 patients (88%), the initial ICH remained stable on postprocedure imaging. In 1 patient who received intravenous antiplatelet agents during thrombectomy, the hemorrhagic transformation was radiographically increased but without clinical correlate or mass effect. Conclusions In a multi‐institution evaluation of 8 patients with ICH at the time of thrombectomy, 1 patient had radiographic worsening of hemorrhage, and no patient experienced clinical worsening related to hemorrhage progression. These findings suggest that thrombectomy may be safe in this population