It has been 50 years since the first explorations of the physiology of cerebral ischemia by measuring cerebral blood flow (CBF), and 25 years since the approval of tissue plasminogen activator for ...treating acute ischemic stroke. My personal career began and matured during those eras. Here, I provide my perspective on the evolution of acute stroke research and treatment from 1971 to the present, with some in-depth discussion of the National Institutes of Neurologic Disease and Stroke (NINDS) tissue-type plasminogen activator (tPA) stroke trial and development of mobile stroke units.
Studies of CBF and metabolism in acute stroke patients revealed graded tissue injury that was dependent on the duration of ischemia. Subsequent animal research unraveled the biochemical cascade of events occurring at the cellular level after cerebral ischemia. After a decade of failed translation, the development of a relatively safe thrombolytic allowed us to achieve reperfusion and apply the lessons from earlier research to achieve positive clinical results. The successful conduct of the NINDS tPA stroke study coupled with positive outcomes from companion tPA studies around the world created the specialty of vascular neurology. This was followed by an avalanche of research in imaging, a focus on enhancing reperfusion through thrombectomy, and improving delivery of faster treatment culminating in mobile stroke units. Key Messages: The last half century has seen the birth and evolution of successful acute stroke treatment. More research is needed in developing new drugs and catheters to build on the advances we have already made with reperfusion and also in evolving our systems of care to get more patients treated more quickly in the prehospital setting. The history of stroke treatment over the last 50 years exemplifies that medical "science" is an evolving discipline worth an entire career's dedication. What was impossible 50 years ago is today's standard of care, what we claim as dogma today will be laughed at a decade from now, and what appears currently impossible will be tomorrow's realities.
Before December 2014, the only proven effective treatment for acute ischemic stroke was recombinant tissue-type plasminogen activator (r-tPA). This has now changed with the publication of the ...Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE), Extending the Time for Thrombolysis in Emergency Neurological Deficits--Intra-Arterial (EXTEND IA), Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment Trial (SWIFT PRIME), and Randomized Trial of Revascularization With the Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REVASCAT) studies. We review the main results of these studies and how they inform stroke patient management going forward. The main take home points for neurologists are (1) intra-arterial thrombectomy is a potently effective treatment and should be offered to patients who have documented occlusion in the distal internal carotid or the proximal middle cerebral artery, have a relatively normal noncontrast head computed tomographic scan, severe neurological deficit, and can have intra-arterial thrombectomy within 6 hours of last seen normal; (2) benefits are clear in patients receiving r-tPA before intra-arterial thrombectomy; r-tPA should not be withheld if the patient meets criteria, and benefit in patients who do not receive r-tPA or have r-tPA exclusions requires further study; and (3) these favorable results occur when intra-arterial thrombectomy is performed in an endovascular stroke center by a coordinated multidisciplinary team that extends from the prehospital stage to the endovascular suite, minimizes time to recanalization, uses stent-retriever devices, and avoids general anesthesia. In conclusion, stroke teams, including practicing neurologists caring for patients with stroke should now provide the option for intra-arterial thrombectomy for a subset of patients with acute stroke.
Summary Ischaemic stroke is one of the leading causes of death and disability worldwide, and intravenous alteplase is the only proven effective treatment in the acute setting. Hypothermia has been ...shown to improve neurological outcomes after global ischaemia–hypoxia in comatose patients who have had cardiac arrest, and is one of the most extensively studied and powerful therapeutic strategies in acute ischaemic stroke. The protective mechanisms of therapeutic hypothermia affect the ischaemic cascade across several parallel pathways and, when coupled with reperfusion strategies, might yield synergistic benefits for patients who have had a stroke. Technological advances have allowed hypothermia to be induced rapidly, and the treatment has been used safely in acute stroke patients. Conclusive efficacy trials assessing therapeutic hypothermia combined with reperfusion therapies in acute ischaemic stroke are ongoing.
Summary In acute stroke management, time is brain. Bringing swift treatment to the patient, instead of the conventional approach of awaiting the patient's arrival at the hospital for treatment, is a ...potential strategy to improve clinical outcomes after stroke. This strategy is based on the use of an ambulance (mobile stroke unit) equipped with an imaging system, a point-of-care laboratory, a telemedicine connection to the hospital, and appropriate medication. Studies of prehospital stroke treatment consistently report a reduction in delays before thrombolysis and cause-based triage in regard to the appropriate target hospital (eg, primary vs comprehensive stroke centre). Moreover, novel medical options for the treatment of stroke patients are also under investigation, such as prehospital differential blood pressure management, reversal of warfarin effects in haemorrhagic stroke, and management of cerebral emergencies other than stroke. However, crucial concerns regarding safety, clinical efficacy, best setting, and cost-effectiveness remain to be addressed in further studies. In the future, mobile stroke units might allow the investigation of novel diagnostic (eg, biomarkers and automated imaging evaluation) and therapeutic (eg, neuroprotective drugs and treatments for haemorrhagic stroke) options in the prehospital setting, thus functioning as a tool for research on prehospital stroke management.
Background and Purpose- The availability of and expertise to interpret advanced neuroimaging recommended in the guideline-based endovascular stroke therapy (EST) evaluation are limited. Here, we ...develop and validate an automated machine learning-based method that evaluates for large vessel occlusion (LVO) and ischemic core volume in patients using a widely available modality, computed tomography angiogram (CTA). Methods- From our prospectively maintained stroke registry and electronic medical record, we identified patients with acute ischemic stroke and stroke mimics with contemporaneous CTA and computed tomography perfusion (CTP) with RAPID (IschemaView) post-processing as a part of the emergent stroke workup. A novel convolutional neural network named DeepSymNet was created and trained to identify LVO as well as infarct core from CTA source images, against CTP-RAPID definitions. Model performance was measured using 10-fold cross validation and receiver-operative curve area under the curve (AUC) statistics. Results- Among the 297 included patients, 224 (75%) had acute ischemic stroke of which 179 (60%) had LVO. Mean CTP-RAPID ischemic core volume was 23±42 mL. LVO locations included internal carotid artery (13%), M1 (44%), and M2 (21%). The DeepSymNet algorithm autonomously learned to identify the intracerebral vasculature on CTA and detected LVO with AUC 0.88. The method was also able to determine infarct core as defined by CTP-RAPID from the CTA source images with AUC 0.88 and 0.90 (ischemic core ≤30 mL and ≤50 mL). These findings were maintained in patients presenting in early (0-6 hours) and late (6-24 hours) time windows (AUCs 0.90 and 0.91, ischemic core ≤50 mL). DeepSymNet probabilities from CTA images corresponded with CTP-RAPID ischemic core volumes as a continuous variable with
=0.7 (Pearson correlation,
<0.001). Conclusions- These results demonstrate that the information needed to perform the neuroimaging evaluation for endovascular therapy with comparable accuracy to advanced imaging modalities may be present in CTA, and the ability of machine learning to automate the analysis.
We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant ...tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients.
Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 μg/kg bolus) followed by infusion of either 1 (low dose) or 3 μg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0).
Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively.
In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated.
URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.
Acute stroke management has been revolutionised by evidence of the effectiveness of thrombectomy. Because time is brain in stroke care, the speed with which a patient with large vessel occlusion is ...transferred to a thrombectomy-capable centre determines outcome. Therefore, each link in the stroke rescue chain, starting with symptom onset and ending with recanalisation, should be streamlined. However, in contrast to inhospital delays, prehospital delays are unchanged despite substantial efforts in quality improvement. Furthermore, thrombectomy is offered by only a few, usually distant, specialised centres and not by the many other, usually nearer, hospitals. To take maximum advantage of the first so-called golden hours after stroke, and because of the difficulty of on-scene triage decision making with respect to the target hospital offering the required level of care, the focus of stroke research has shifted to the prehospital setting. Current research focuses on the effects of public education, implementation of protocols for emergency medical services for streamlining clinical investigations and accurate triage, use of preclinical scales for stroke recognition, and deployment of novel technical solutions such as smartphone applications, telemedicine, and mobile stroke units.
Background and Purpose- Recent landmark trials provided overwhelming evidence for effectiveness of endovascular stroke therapy (EST). Yet, the impact of these trials on clinical practice and ...effectiveness of EST among lower volume centers remains poorly characterized. Here, we determine population-level patterns in EST performance in US hospitals and compare EST outcomes from higher versus lower volume centers. Methods- Using validated diagnosis codes from data on all discharges from hospitals and Emergency Rooms in Florida (2006-2016) and the National Inpatient Sample (2012-2016) we identified patients with acute ischemic stroke treated with EST. The primary end point was good discharge outcome defined as discharge to home or acute rehabilitation facility. Multivariate regressions adjusted for medical comorbidities, intravenous tPA (tissue-type plasminogen activator) usage and annual hospital stroke volume were used to evaluate the likelihood of good outcome over time and by annual hospital EST volume. Results- A total of 3890 patients (median age, 73 61-82 years, 51% female) with EST were identified in the Florida cohort and 42 505 (median age, 69 58-79, 50% female) in the National Inpatient Sample. In both Florida and the National Inpatient Sample, the number of hospitals performing EST increased continuously. Increasing numbers of EST procedures were performed at lower annual EST volume hospitals over the studied time period. In adjusted multivariate regression, there was a continuous increase in the likelihood of good outcomes among patients treated in hospitals with increasing annual EST procedures per year (odds ratio, 1.1; 95% CI, 1.1-1.2 in Florida and odds ratio, 1.3; 95% CI, 1.2-1.4 in National Inpatient Sample). Conclusions- Analysis of population-level datasets of patients treated with EST from 2006 to 2016 demonstrated an increase in the number of centers performing EST, resulting in a greater number of procedures performed at lower volume centers. There was a positive association between EST volume and favorable discharge outcomes in EST-performing hospitals.
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